Nelson Textbook of Pediatrics, 2-Volume Set [21 ed.] 032352950X, 9780323529501

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Nelson Textbook of Pediatrics 21 EDITION

ROBERT M. KLIEGMAN, MD Professor and Chair Emeritus Department of Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin

JOSEPH W. ST GEME III, MD Professor of Pediatrics and Microbiology and Chair of the Department of Pediatrics University of Pennsylvania Perelman School of Medicine Chair of the Department of Pediatrics and Physician-in-Chief Leonard and Madlyn Abramson Endowed Chair in Pediatrics Children's Hospital of Philadelphia Philadelphia, Pennsylvania

NATHAN J. BLUM, MD William H. Bennett Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Chief, Division of Developmental and Behavioral Pediatrics

Children's Hospital of Philadelphia Philadelphia, Pennsylvania

SAMIR S. SHAH, MD, MSCE Professor of Pediatrics University of Cincinnati College of Medicine Director, Division of Hospital Medicine Chief Metrics Officer James M. Ewell Endowed Chair Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

ROBERT C. TASKER, MBBS, MD Professor of Neurology Professor of Anesthesia Harvard Medical School Senior Associate, Critical Care Medicine Director, Pediatric NeuroCritical Care Program Boston Children's Hospital Boston, Massachusetts

KAREN M. WILSON, MD, MPH Professor of Pediatrics Debra and Leon Black Division Chief of General Pediatrics Vice-Chair for Clinical and Translational Research Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York Editor Emeritus

RICHARD E. BEHRMAN, MD Nonprofit Healthcare and Educational Consultants to Medical Institutions Santa Barbara, California

Table of Contents Instructions for online access Cover image Title Page Copyright Dedication Contributors Preface Videos

Volume 1 Part I The Field of Pediatrics Chapter 1 Overview of Pediatrics Vital Statistics About Children's Health Globally The Changing Pediatric World

The New Morbidities Chronic Illness and Children With Special Health Care Needs Systems of Care Bibliography Chapter 2 Child Health Disparities Determinants of Health and Health Disparities Disparities in Child Health and Healthcare: Approaches to Eradicating Disparities: Interventions Keywords Racism as Social Determinant Explaining Racial Disparities: A Taxonomy of Racism Opportunities to Address Racism Bibliography Bibliography Chapter 3 Global Child Health Global Burden and Trends in Child Health Social Determinants of Child Health Evidence-Based Interventions and Innovations to Address Child Health Inequities Challenges in Global Health

Bibliography Chapter 4 Quality and Value in Healthcare for Children The Need for Improvement in Quality and Value What Is Quality? Framework for Quality Developing Guidelines to Establish the Standard for Quality Improving Quality Measuring Quality Analyzing Quality Data Comparing and Reporting Quality Implications of the U.S. Healthcare Reform for Quality Information Technology and Quality Improvement Expanding Individual Quality Improvement Initiatives to Scale Bibliography Chapter 5 Safety in Healthcare for Children Error vs Harm Safety Frameworks Identifying and Analyzing Harm, Errors, and Latent Threats Safety Culture Reliability Science and High-Reliability Organizations

Serious Harm Events and Healthcare-Associated Conditions Safety Opportunities and Gaps Emerging Areas of Safety Research and Improvement Bibliography Chapter 6 Ethics in Pediatric Care Assent and Parental Permission Treatment of Critically Ill Children Neonatal Ethics Declaring Death and Organ Donation Religious or Cultural Objections to Treatment Pediatric Ethics Committees and Ethics Consultation Newborn Screening Genetics, Genomics, and Precision Medicine Adolescent Healthcare Research Balancing Maternal and Fetal Interests Justice and Pediatric Ethics Emerging Issues Bibliography Chapter 7 Pediatric Palliative Care

Care Settings Communication, Advance Care Planning, and Anticipatory Guidance Bibliography Chapter 8 Domestic and International Adoption Domestic Adoption Intercountry Adoption Role of Pediatricians Bibliography Chapter 9 Foster and Kinship Care Epidemiology Legislation in the United States Early Childhood Trauma Leads to Poor Health Outcomes Health Issues Healthcare for Children and Adolescents in Foster Care Bibliography Chapter 10 Medical Evaluation of the Foreign-Born Child Commonly Encountered Infections Immunizations Bibliography

Chapter 11 Cultural Issues in Pediatric Care What Is Culture? Culturally Informed Care Bibliography Chapter 12 Maximizing Children's Health Periodicity Schedule and Guidelines Tasks of Well-Child Care Infancy and Early Childhood Middle Childhood and Adolescence Office Intervention for Behavioral and Mental Health Issues Evidence Caring for the Child and Youth in the Context of the Family and Community Bibliography Chapter 13 Injury Control Scope of the Problem Principles of Injury Control Risk Factors for Childhood Injuries Mechanisms of Injury Psychosocial Consequences of Injuries

Bibliography Chapter 14 Impact of Violence on Children Impacts of Violence Keywords Bullying and Cyberbullying School Violence Treatment and Prevention of Bullying and School Violence Bibliography Resources Keywords Screening Recommendations (see Table 14.1) Bibliography Resources Keywords Susceptibility of Children in Times of War Psychological Impact of War Efforts to Protect Children From the Effects of War Role of Pediatricians and Allied Health Professionals Bibliography

Bibliography Chapter 15 Child Trafficking for Sex and Labor Clinical Presentation Approach to the Potentially Trafficked Child Examination and Diagnostic Testing Referrals and Resources Bibliography Chapter 16 Abused and Neglected Children Definitions Incidence and Prevalence Etiology Clinical Manifestations General Principles for Assessing Possible Abuse and Neglect General Principles for Addressing Child Maltreatment Outcomes of Child Maltreatment Prevention of Child Abuse and Neglect Advocacy Keywords Definition Presentation of Sexual Abuse

Role of General Pediatrician in Assessment and Management of Possible Sexual Abuse Physical Examination of the Child With Suspected Sexual Abuse Additional Management Sexual Abuse Prevention Bibliography Keywords Clinical Manifestations Diagnosis Treatment Bibliography Bibliography Chapter 17 Strategies for Health Behavior Change Unified Theory of Behavior Change Transtheoretical Model of Health Behavior Change Common Factors Approach Motivational Interviewing Shared Decision-Making Bibliography

Part II Growth, Development, and Behavior

Chapter 18 Developmental and Behavioral Theories Biopsychosocial Model and Ecobiodevelopmental Framework: Models of Development Bibliography Chapter 19 Positive Parenting and Support The Importance of Parenting The Role of the Family Parenting Styles Child Temperament Child Behavioral Problems Defining Positive Parenting Parenting as an Intervention The Role of the Pediatrician Bibliography Chapter 20 Assessment of Fetal Growth and Development Somatic Development Neurologic Development Behavioral Development Psychologic Changes in Parents Threats to Fetal Development

Bibliography Chapter 21 The Newborn Parental Role in Mother–Infant Attachment The Infant's Role in Mother–Infant Attachment Implications for the Pediatrician Bibliography Chapter 22 The First Year Age 0-2 Months Age 2-6 Months Age 6-12 Months Bibliography Chapter 23 The Second Year Age 12-18 Months Age 18-24 Months Bibliography Chapter 24 The Preschool Years Structural Development of the Brain Physical Development Language, Cognition, and Play

Bibliography Chapter 25 Middle Childhood Physical Development Cognitive Development Social, Emotional, and Moral Development Bibliography Chapter 26 Adolescence Chapter 27 Assessment of Growth Techniques to Measure Growth Growth Curves Other Growth Considerations Bibliography Chapter 28 Developmental and Behavioral Surveillance and Screening Developmental and Behavioral Surveillance Developmental and Behavioral Screening Beyond Surveillance and Screening Bibliography Chapter 29 Childcare

Provision, Regulation, and Use of Childcare in America Childcare's Role in Child Health and Development Role of Pediatric Providers in Childcare Bibliography Chapter 30 Loss, Separation, and Bereavement Separation and Loss Divorce Move/Family Relocation Separation Because of Hospitalization Military Families Parental/Sibling Death Grief and Bereavement Developmental Perspective Role of the Pediatrician in Grief Treatment Spiritual Issues Bibliography Chapter 31 Sleep Medicine Basics of Sleep and Chronobiology Developmental Changes in Sleep

Common Sleep Disorders Health Supervision Evaluation of Pediatric Sleep Problems Bibliography

Part III Behavioral and Psychiatric Disorders Chapter 32 Psychosocial Assessment and Interviewing Aims of Assessment Presenting Problems General Principles of the Psychosocial Interview Indications for Referral Psychiatric Diagnostic Evaluation Special Considerations in the Diagnostic Evaluation of Infants and Young Children Bibliography Chapter 33 Psychopharmacology Stimulants and Other ADHD Medications Antidepressants Antipsychotics Mood Stabilizers Medication Use in Physical Illness

Bibliography Chapter 34 Psychotherapy and Psychiatric Hospitalization Psychotherapy Psychiatric Hospitalization Bibliography Chapter 35 Somatic Symptom and Related Disorders Epidemiology Risk Factors Assessment Management Bibliography Chapter 36 Rumination and Pica Epidemiology Etiology and Differential Diagnosis Treatment Bibliography Epidemiology Etiology and Differential Diagnosis Treatment

Bibliography Chapter 37 Motor Disorders and Habits Description Clinical Course Epidemiology Differential Diagnosis Comorbidities Etiology Sequelae Screening Assessment Treatment Description Clinical Course Epidemiology Comorbidity Differential Diagnosis Etiology Treatment Habits

Bibliography Chapter 38 Anxiety Disorders Anxiety Associated With Medical Conditions Safety and Efficacy Concerns About SSRIs Bibliography Chapter 39 Mood Disorders Description Epidemiology Clinical Course Differential Diagnosis Comorbidity Sequelae Etiology and Risk Factors Prevention Screening/Case Finding Early Intervention Treatment Level of Care Bibliography Description

Epidemiology Clinical Course Differential Diagnosis Comorbidity Sequelae Etiology and Risk Factors Prevention Case Finding Treatment Level of Care Bibliography Chapter 40 Suicide and Attempted Suicide Epidemiology Risk Factors Assessment and Intervention Prevention Bibliography Chapter 41 Eating Disorders Definitions Epidemiology

Pathology and Pathogenesis Clinical Manifestations Differential Diagnosis Laboratory Findings Complications Treatment Prognosis Prevention Bibliography Chapter 42 Disruptive, Impulse-Control, and Conduct Disorders Description Epidemiology Clinical Course Differential Diagnosis Comorbidity Sequelae Etiology and Risk Factors Prevention Screening/Case Finding Early Intervention

Treatment Level of Care Bibliography Chapter 43 Tantrums and Breath-Holding Spells Bibliography Chapter 44 Lying, Stealing, and Truancy Lying Stealing Truancy Bibliography Chapter 45 Aggression Bibliography Chapter 46 Self-Injurious Behavior Bibliography Chapter 47 Childhood Psychoses Description Epidemiology Clinical Course

Differential Diagnosis Comorbidity Sequelae Etiology and Risk Factors Neuroanatomic Abnormalities Prevention Screening/Case Finding Assessment Treatment Bibliography Bibliography Diagnosis and Treatment Bibliography Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Bibliography

Part IV Learning and Developmental Disorders Chapter 48 Neurodevelopmental and Executive Function and Dysfunction Terminology and Epidemiology

Etiology and Pathogenesis Core Neurodevelopmental Functions Clinical Manifestations Assessment and Diagnosis Treatment Bibliography Chapter 49 Attention-Deficit/Hyperactivity Disorder Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Prognosis Prevention Bibliography Chapter 50 Dyslexia Etiology Epidemiology Pathogenesis

Clinical Manifestations Diagnosis Management Prognosis Bibliography Chapter 51 Math and Writing Disabilities Keywords Math Learning Disability Defined Epidemiology Causes of Math Learning Disability Treatment and Interventions Bibliography Keywords Epidemiology Skill Deficits Associated With Impaired Writing Treatment Bibliography Chapter 52 Language Development and Communication Disorders Normal Language Development Language and Communication Disorders

Motor Speech Disorders Hearing Impairment Hydrocephalus Rare Causes of Language Impairment Noncauses of Language Delay Treatment Prognosis Comorbid Disorders Keywords Epidemiology Genetics Etiology Comorbidities Developmental Progression Treatment Bibliography Bibliography Chapter 53 Developmental Delay and Intellectual Disability Definition Etiology

Epidemiology Pathology and Pathogenesis Clinical Manifestations Diagnostic Evaluation Differential Diagnosis Diagnostic Psychologic Testing Complications Prevention Treatment Supportive Care and Management Prognosis Bibliography Chapter 54 Autism Spectrum Disorder Definition Diagnostic Criteria and Symptoms Epidemiology Etiology Differential Diagnosis Comorbid Conditions Screening

Assessment Treatment and Management Outcome Bibliography

Part V Nutrition Chapter 55 Nutritional Requirements Dietary Reference Intakes Energy Fat Protein Carbohydrates Fiber Micronutrients Water Measuring Nutritional Adequacy Bibliography Chapter 56 Feeding Healthy Infants, Children, and Adolescents Feeding During the First Year of Life Cow's Milk Protein–Based Formulas

Soy Formulas Protein Hydrolysate Formulas Amino Acid Formulas Milk and Other Fluids in Infants and Toddlers Complementary Feeding Feeding Toddlers and Preschool-Age Children Feeding School-Age Children and Adolescents Nutrition Issues of Importance Across Pediatric Ages Bibliography Chapter 57 Nutrition, Food Security, and Health Malnutrition as the Intersection of Food Insecurity and Health Insecurity Food Security Undernutrition Severe Acute Malnutrition Bibliography Chapter 58 Refeeding Syndrome Bibliography Chapter 59 Malnutrition Clinical Manifestations

Etiology and Diagnosis Treatment Prognosis Bibliography Chapter 60 Overweight and Obesity Epidemiology Body Mass Index Etiology Comorbidities Identification Evaluation Intervention Prevention Keywords Clinical Manifestations Diagnosis Management Etiology: Studies and Hypotheses Differential Diagnosis Bibliography

Bibliography Chapter 61 Vitamin A Deficiencies and Excess Overview of Vitamin A Metabolism of Vitamin A Functions of Vitamin A and Mechanisms of Action Vitamin A Deficiency Hypervitaminosis A Bibliography Chapter 62 Vitamin B Complex Deficiencies and Excess Keywords Thiamine Deficiency Thiamine Toxicity Bibliography Keywords Riboflavin Deficiency Riboflavin Toxicity Bibliography Keywords Niacin Deficiency Niacin Toxicity

Bibliography Keywords Vitamin B6 Deficiency Vitamin B6 Toxicity Bibliography Keywords Bibliography Keywords Folate Deficiency Folate Toxicity Bibliography Keywords Vitamin B12 Deficiency Bibliography Chapter 63 Vitamin C (Ascorbic Acid) Deficiency and Excess Dietary Needs and Sources of Vitamin C Vitamin C Deficiency Vitamin C Toxicity Bibliography

Chapter 64 Vitamin D Deficiency (Rickets) and Excess Rickets Vitamin D Disorders Calcium Deficiency Phosphorus Deficiency Rickets of Prematurity Distal Renal Tubular Acidosis Hypervitaminosis D Bibliography Chapter 65 Vitamin E Deficiency Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Treatment Prognosis Prevention Bibliography Chapter 66 Vitamin K Deficiency Pathogenesis

Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Prevention Bibliography Chapter 67 Micronutrient Mineral Deficiencies Bibliography

Part VI Fluid and Electrolyte Disorders Chapter 68 Electrolyte and Acid-Base Disorders Keywords Total Body Water Fluid Compartments Electrolyte Composition Osmolality Point-of-Care Testing Bibliography Keywords Regulation of Osmolality Regulation of Volume

Bibliography Keywords Sodium Metabolism Hypernatremia Hyponatremia Bibliography Keywords Potassium Metabolism Hyperkalemia Hypokalemia Bibliography Keywords Magnesium Metabolism Hypomagnesemia Hypermagnesemia Bibliography Keywords Phosphorus Metabolism Hypophosphatemia Hyperphosphatemia

Bibliography Keywords Acid-Base Physiology Normal Acid-Base Balance Clinical Assessment of Acid-Base Disorders Metabolic Acidosis Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis Bibliography Chapter 69 Maintenance and Replacement Therapy Maintenance Therapy Maintenance Water Intravenous Solutions Glucose Selection of Maintenance Fluids Variations in Maintenance Water and Electrolytes Replacement Fluids Bibliography Chapter 70 Deficit Therapy

Clinical Manifestations Laboratory Findings Calculation of the Fluid Deficit Approach to Severe Dehydration Monitoring and Adjusting Therapy Hyponatremic Dehydration Hypernatremic Dehydration Bibliography Chapter 71 Fluid and Electrolyte Treatment of Specific Disorders Acute Diarrhea Pyloric Stenosis Perioperative Fluids

Part VII Pediatric Drug Therapy Chapter 72 Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics Definition of Terms Developmental or Pediatric Pharmacogenetics and Pharmacogenomics Drug Biotransformation: Applications to Pediatric Therapy Pharmacogenetics of Drug Transporters

Polymorphisms in Drug Receptors Current and Future Applications in Pediatrics Bibliography Chapter 73 Principles of Drug Therapy General Pharmacokinetic and Pharmacodynamic Principles Impact of Ontogeny on Drug Disposition Impact of Ontogeny on Pharmacodynamics Additional Considerations in Pediatric Therapeutics Drug Formulation and Administration Adherence and Compliance Drug-Drug Interactions Adverse Drug Reactions Personalized Medicine Bibliography Chapter 74 Anesthesia and Perioperative Care Preanesthetic Evaluation Preoperative Preparation General Anesthesia Induction of General Anesthesia Maintenance of Anesthesia

Postanesthesia Care Unit Postoperative Pain Management Keywords Bibliography Bibliography Chapter 75 Procedural Sedation Bibliography Chapter 76 Pediatric Pain Management Definition and Categories of Pain Assessment and Measurement of Pain in Children Conceptual Framework for Treatment of Pediatric Pain Unconventional Medications in Pediatric Pain Nonpharmacologic Treatment of Pain Invasive Interventions for Treating Pain Intrathecal Analgesia Nerve Ablation and Destruction Considerations for Special Pediatric Populations Chronic and Recurrent Pain Syndromes Managing Complex Chronic Pain Problems Bibliography

Chapter 77 Poisoning Prevention Approach to the Poisoned Patient Principles of Management Select Compounds in Pediatric Poisoning Bibliography Chapter 78 Complementary Therapies and Integrative Medicine Dietary Supplements Dietary Supplement Safety Dietary Supplement Efficacy Massage and Chiropractic Mind-Body Therapies Acupuncture Cannabis Bibliography

Part VIII Emergency Medicine and Critical Care Chapter 79 Emergency Medical Services for Children Primary Care Physician and Office Preparedness Pediatric Prehospital Care

The Emergency Department Keywords Communications and Dispatch Center Medical Control Physician Transport Team Ground vs Air Ambulance Transport Physiology Safety Family-Centered Care Referring Hospital Responsibilities Educational Outreach Bibliography Keywords Outcome Measures in Emergency Medical Services for Children Risk Adjustment Bibliography Keywords Continuum-of-Care Model Humanitarian Disasters Bibliography

Bibliography Chapter 80 Triage of the Acutely Ill Child Assessment of Vital Signs History Physical Examination Management Disposition Bibliography Chapter 81 Pediatric Emergencies and Resuscitation Approach to the Emergency Evaluation of a Child Recognition and Treatment of Respiratory Distress and Failure Recognition and Management of Shock Recognition of Bradyarrhythmias and Tachyarrhythmias Recognition and Management of Cardiac Arrest Vascular Access Nonvascular Emergency Procedures Postresuscitation Care Bibliography Chapter 82 Acute Care of Multiple Trauma

Epidemiology Regionalization and Trauma Teams Primary Survey Secondary Survey Psychological and Social Support Bibliography Chapter 83 Spinal Cord Injuries in Children Clinical Manifestations Clearing the Cervical Spine in Children Treatment Prevention Bibliography Chapter 84 Care of Abrasions and Minor Lacerations Lacerations and Cuts Abrasions Bibliography Chapter 85 Neurologic Emergencies and Stabilization Neurocritical Care Principles Traumatic Brain Injury

Bibliography Chapter 86 Brain Death Epidemiology Clinical Manifestations and Diagnosis Observation Periods Ancillary Studies Documentation Supportive Care Objections to the Idea of Brain Death Bibliography Chapter 87 Syncope Mechanisms Evaluation Treatment Keywords Clinical Presentation Diagnosis Management Bibliography Bibliography

Chapter 88 Shock Epidemiology Types of Shock Pathophysiology Clinical Manifestations Diagnosis Laboratory Findings Treatment Prognosis Bibliography Chapter 89 Respiratory Distress and Failure Respiratory Distress Respiratory Failure Monitoring a Child in Respiratory Distress and Respiratory Failure Management Keywords Basic Concepts of Ventilator Management Noninvasive Mechanical Ventilation Invasive Mechanical Ventilation Additional Ventilatory Modalities

Conventional Ventilator Settings Patient-Ventilator Asynchrony Monitoring Respiratory Mechanics Ventilator-Induced Lung Injury Bibliography Bibliography Chapter 90 Altitude-Associated Illness in Children (Acute Mountain Sickness) Etiology General Effects of Hypobaric Hypoxia Acute Mountain Sickness High-Altitude Cerebral Edema High-Altitude Pulmonary Edema Special Considerations Bibliography Chapter 91 Drowning and Submersion Injury Etiology Epidemiology Pathophysiology Management Prognosis

Prevention Bibliography Chapter 92 Burn Injuries Epidemiology Prevention Acute Care, Resuscitation, and Assessment Treatment Electrical Burns Bibliography Chapter 93 Cold Injuries Pathophysiology Etiology Clinical Manifestations Cold-Induced Fat Necrosis (Panniculitis) Bibliography

Part IX Human Genetics Chapter 94 Integration of Genetics Into Pediatric Practice Diagnostic Testing Predictive Testing

Predispositional Testing Pharmacogenetic Testing Talking to Families Genetic Counseling Physiologic Therapies Replacement Therapies Bibliography Chapter 95 The Genetic Approach in Pediatric Medicine The Burden of Genetic Disorders in Childhood The Changing Paradigm of Genetics in Medicine Ethics Issues Bibliography Chapter 96 The Human Genome Fundamentals of Molecular Genetics Genetic Variation Genotype-Phenotype Correlations in Genetic Disease Human Genome Project Bibliography Chapter 97 Patterns of Genetic Transmission

Family History and Pedigree Notation Mendelian Inheritance Y-Linked Inheritance Inheritance Associated With Pseudoautosomal Regions Digenic Inheritance Pseudogenetic Inheritance and Familial Clustering Nontraditional Inheritance Multifactorial and Polygenic Inheritance Bibliography Chapter 98 Cytogenetics Bibliography Aneuploidy and Polyploidy Down Syndrome Bibliography Translocations Inversions Deletions and Duplications Insertions Isochromosomes Marker and Ring Chromosomes

Bibliography Turner Syndrome Klinefelter Syndrome 47,XYY Bibliography Bibliography Pallister-Killian Syndrome Hypomelanosis of Ito Uniparental Disomy Imprinting Bibliography Chapter 99 Genetics of Common Disorders Linkage Mapping Genetic Association Bibliography Chapter 100 Epigenome-Wide Association Studies and Disease Epigenetic Mechanisms of Disease: Viable Yellow Mouse Model Epigenetics and Regulation of Gene Expression Pediatric Diseases Involving Epigenetic Processes Epigenome-Wide Association Studies: DNA Methylation

Cell Fate Variability as Model for Epigenetics and Disease Epigenetic Disease and Therapeutic Interventions Bibliography Chapter 101 Genetic Approaches to Rare and Undiagnosed Diseases Scope of Genetic Disease Clinical Evaluation Single Nucleotide Polymorphism Arrays Exome Sequencing Gene Function Studies Pediatric Issues The Diagnostic Spectrum Bibliography

Part X Metabolic Disorders Chapter 102 An Approach to Inborn Errors of Metabolism Newborn Screening Clinical Manifestations of Genetic Metabolic Diseases Treatment Bibliography Chapter 103 Defects in Metabolism of Amino Acids

Keywords Severe Phenylalanine Hydroxylase Deficiency (Classic Phenylketonuria) Hyperphenylalaninemia Caused by Deficiency of the Cofactor Tetrahydrobiopterin Tetrahydrobiopterin Defects Without Hyperphenylalaninemia Bibliography Keywords Tyrosinemia Type I (Fumarylacetoacetate Hydrolase Deficiency, Hepatorenal Tyrosinemia) Tyrosinemia Type II (Tyrosine Aminotransferase Deficiency, RichnerHanhart Syndrome, Oculocutaneous Tyrosinemia) Tyrosinemia Type III (Primary Deficiency of 4Hydroxyphenylpyruvate Dioxygenase) Hawkinsinuria Transient Tyrosinemia of the Newborn Alkaptonuria Tyrosine Hydroxylase Deficiency Albinism Bibliography Keywords Homocystinuria (Homocystinemia) Hypermethioninemia

Primary Cystathioninemia (Cystathioninuria) Bibliography Keywords Sulfite Oxidase Deficiency and Molybdenum Cofactor Deficiency Bibliography Keywords Hartnup Disorder Bibliography Keywords Maple Syrup Urine Disease Branched-Chain α-Ketoacid Dehydrogenase Kinase Deficiency Branched-Chain Amino Acid Transporter Deficiency Isovaleric Acidemia Multiple Carboxylase Deficiencies (Defects of Biotin Cycle) 3-Methylcrotonyl-CoA Carboxylase Deficiency 3-Methylglutaconic Acidurias β-Ketothiolase (3-Oxothiolase) Deficiency (Mitochondrial Acetoacetyl-CoA Thiolase [T2 ] Deficiency) Cytosolic Acetoacetyl-CoA Thiolase Deficiency Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency (3-Hydroxy-3-

Methylglutaric Aciduria) Succinyl-CoA:3-Oxoacid-CoA Transferase Deficiency Mevalonate Kinase Deficiency Propionic Acidemia (Propionyl-CoA Carboxylase Deficiency) Isolated Methylmalonic Acidemias Combined Methylmalonic Aciduria and Homocystinuria (cbl C, cbl D, cbl F, cbl J, and cbl X Defects) Isolated Homocystinuria Combined Malonic and Methylmalonic Aciduria (ACSF3 -Related Disorder) Bibliography Hypoglycinemia Hyperglycinemia Nonketotic Hyperglycinemia (Glycine Encephalopathy) Sarcosinemia Primary Trimethylaminuria Hyperoxaluria and Oxalosis Bibliography Keywords 3-Phosphoglycerate Dehydrogenase Deficiency Phosphoserine Aminotransferase Deficiency

3-Phosphoserine Phosphatase Deficiency Bibliography Keywords Hyperprolinemia Type I Hyperprolinemia Type II Prolidase Deficiency Disorders of De Novo Proline Synthesis Bibliography Keywords Glutathione Synthetase Deficiency γ-Glutamyl Transpeptidase Deficiency (Glutathionemia) Genetic Disorders of Metabolism of γ-Aminobutyric Acid Bibliography Keywords Tyrosine Hydroxylase Deficiency (Infantile Parkinsonism, Autosomal Recessive Dopa-Responsive Dystonia, Autosomal Recessive Segawa Syndrome) Aromatic l-Amino Acid Decarboxylase Deficiency Tetrahydrobiopterin Deficiency Dopamine β-Hydroxylase Deficiency Monoamine Oxidase a Deficiency

Disorders of γ-Aminobutyric Acid (GABA) Metabolism Defects in Neurotransmitter Transporter Proteins Histidine Decarboxylase Deficiency Hyperprolinemia 3-Phosphoglycerate Dehydrogenase Deficiency Phosphoserine Aminotransferase Deficiency Nonketotic Hyperglycinemia Bibliography Keywords Genetic Causes of Hyperammonemia Clinical Manifestations of Hyperammonemia Diagnosis Treatment of Acute Hyperammonemia Carbamoyl Phosphate Synthetase 1 and N -Acetylglutamate Synthase Deficiencies Ornithine Transcarbamylase Deficiency Citrullinemia Argininosuccinate Lyase Deficiency (Argininosuccinic Aciduria) Arginase 1 Deficiency (Hyperargininemia) Transient Hyperammonemia of the Newborn Disorders of Ornithine Metabolism

Congenital Glutamine Deficiency Bibliography Keywords Bibliography Keywords Pyridoxine (Vitamin B6 )–Dependent Epilepsy Glutaric Aciduria Type 1 (Glutaryl-CoA Dehydrogenase Deficiency) Lysinuric Protein Intolerance (Familial Protein Intolerance) Bibliography Keywords Etiology and Pathology Clinical Manifestations Atypical Canavan Disease Diagnosis Treatment and Prevention Bibliography Chapter 104 Defects in Metabolism of Lipids Keywords Defects in the β-Oxidation Cycle Defects in the Carnitine Cycle

Defects in the Electron Transfer Pathway Defects in the Ketone Synthesis Pathway Defects in Ketone Body Utilization Bibliography Keywords Peroxisomal Disorders Adrenoleukodystrophy Bibliography Keywords Epidemiology of Blood Lipids and Cardiovascular Disease Blood Lipids and Atherogenesis Plasma Lipoprotein Metabolism and Transport Hyperlipoproteinemias Bibliography Keywords GM1 Gangliosidosis The GM2 Gangliosidoses Gaucher Disease Niemann-Pick Disease Fabry Disease

Fucosidosis Schindler Disease Metachromatic Leukodystrophy Multiple-Sulfatase Deficiency Krabbe Disease Farber Disease Wolman Disease and Cholesterol Ester Storage Disease Bibliography Keywords I-Cell Disease Pseudo-Hurler Polydystrophy Bibliography Chapter 105 Defects in Metabolism of Carbohydrates Keywords Liver Glycogenoses Muscle Glycogenoses Bibliography Keywords Galactose-1-Phosphate Uridyl Transferase Deficiency Galactosemia Galactokinase Deficiency

Uridine Diphosphate Galactose-4-Epimerase Deficiency Bibliography Keywords Deficiency of Fructokinase (Essential or Benign Fructosuria) Deficiency of Fructose-1,6-Bisphosphate Aldolase (Aldolase B, Hereditary Fructose Intolerance) Bibliography Keywords Disorders of Gluconeogenesis Disorders of Pyruvate Metabolism Bibliography Keywords Essential Pentosuria Transaldolase Deficiency Ribose-5-Phosphate Isomerase Deficiency Bibliography Sialidosis and Galactosialidosis Aspartylglucosaminuria α-Mannosidosis Bibliography Keywords

Congenital Disorders of Protein N -Glycosylation Congenital Disorders of Protein O -Glycosylation Defects in Lipid Glycosylation and in Glycosylphosphatidylinositol Anchor Biosynthesis Defects in Multiple Glycosylation Pathways and in Other Pathways, Including Dolicholphosphate Biosynthesis Defects Congenital Disorders of Deglycosylation Therapeutic Summary Bibliography Chapter 106 Mitochondrial Disease Diagnosis Overview of Mitochondrial Disease When to Suspect Mitochondrial Disease Mitochondrial Disease Inheritance Diagnostic Testing for Mitochondrial Disease Treatment Principles for Mitochondrial Disease Bibliography Chapter 107 Mucopolysaccharidoses Disease Entities Diagnosis and Differential Diagnosis Treatment

Bibliography Chapter 108 Disorders of Purine and Pyrimidine Metabolism Gout Abnormalities in Purine Salvage Disorders Linked to Purine Nucleotide Synthesis Disorders Resulting From Abnormalities in Purine Catabolism Disorders of Pyrimidine Metabolism Bibliography Chapter 109 Hutchinson-Gilford Progeria Syndrome (Progeria) Clinical Manifestations Laboratory Findings Molecular Pathogenesis Diagnosis and Differential Diagnosis Treatment and Prognosis Patient Resources Bibliography Chapter 110 The Porphyrias The Heme Biosynthetic Pathway Classification and Diagnosis of Porphyrias

δ-Aminolevulinic Acid Dehydratase Deficient Porphyria Acute Intermittent Porphyria Congenital Erythropoietic Porphyria Porphyria Cutanea Tarda Hepatoerythropoietic Porphyria Hereditary Coproporphyria Variegate Porphyria Erythropoietic Protoporphyria and X-Linked Protoporphyria Dual Porphyria Porphyria Resulting From Tumors Bibliography Chapter 111 Hypoglycemia Definition Significance and Sequelae Substrate, Enzyme, and Hormonal Integration of Glucose Homeostasis Clinical Manifestations Classification of Hypoglycemia in Infants and Children Diagnosis and Differential Diagnosis Treatment

Prognosis Bibliography

Part XI The Fetus and the Neonatal Infant Chapter 112 Overview of Morbidity and Mortality Infant Mortality Major Causes of Infant Death Infant Mortality Reduction Bibliography Chapter 113 The Newborn Infant General Appearance Skin Skull Face Neck Chest Lungs Heart Abdomen Genitals

Anus Extremities Neurologic Examination Bibliography Maintenance of Body Heat Antiseptic Skin and Cord Care Newborn Prophylaxis and Screening Bibliography Bibliography Rooming-in and Breastfeeding Bibliography Chapter 114 High-Risk Pregnancies Genetic Factors Maternal Factors Bibliography Chapter 115 The Fetus Bibliography Bibliography Infectious Diseases Noninfectious Diseases (see Table 114.2)

Bibliography Bibliography Bibliography Bibliography Bibliography Chapter 116 Fetal Intervention and Surgery Fetal Therapy Ethics Obstructive Uropathy Nonobstructive Renal Disease Congenital Diaphragmatic Hernia Congenital Pulmonary Airway Malformation Myelomeningocele Other Indications Fetal Centers Bibliography Chapter 117 The High-Risk Infant Keywords Monozygotic vs Dizygotic Twins Incidence Etiology

Atypical Twinning Complications Twin Syndromes (TRAP, TTTS) Diagnosis Prognosis Treatment Bibliography Keywords Incidence Etiology Assessment of Gestational Age Nursery Care Immaturity of Drug Metabolism Morbidity and Mortality Bibliography Keywords Moderate Preterm Infant Late Preterm Infant Bibliography Keywords

Small for Gestational Age and IUGR Large-for-Gestational-Age Infants Postterm Infants Bibliography Keywords Discharge From the Hospital Postdischarge Follow-Up Bibliography Chapter 118 Transport of the Critically Ill Newborn Regionalized Care of Newborns Levels of Neonatal Care Transport of the Critically Ill Neonate Bibliography Chapter 119 Clinical Manifestations of Diseases in the Newborn Period Abnormal Movements Altered Mental Status Apnea Congenital Anomalies Cyanosis Gastrointestinal Disturbances

Hypotension Jaundice Pain Bibliography Bibliography Bibliography Bibliography Bibliography Chapter 120 Nervous System Disorders Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Prognosis Prevention Treatment Bibliography Etiology Pathophysiology and Pathology

Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Bibliography Brachial Palsy Phrenic Nerve Paralysis Facial Nerve Palsy Bibliography Chapter 121 Neonatal Resuscitation and Delivery Room Emergencies Neonatal Resuscitation Resuscitation of the Preterm Infant Special Circumstances in the Delivery Room Injury During Delivery Ongoing Care After Resuscitation Bibliography Chapter 122 Respiratory Tract Disorders Keywords The First Breath

Breathing Patterns in Newborns Keywords Apnea of Prematurity Treatment Prognosis Apnea of Prematurity and Sudden Infant Death Syndrome Bibliography Keywords Incidence Etiology and Pathophysiology Clinical Manifestations Diagnosis Prevention Treatment Complications Bibliography Keywords Incidence Etiology and Pathophysiology Clinical Manifestations

Diagnosis Prevention Treatment Prognosis Bibliography Keywords Incidence and Pathophysiology Clinical Manifestations Treatment Bibliography Keywords Bibliography Keywords Keywords Clinical Manifestations Prevention Treatment Prognosis Bibliography Keywords

Pathophysiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Keywords Congenital Diaphragmatic Hernia (Bochdalek) Bibliography Bibliography Keywords Etiology and Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Keywords Bibliography Chapter 123 Digestive System Disorders Keywords

Meconium Plugs Meconium Ileus Meconium Peritonitis Bibliography Keywords Pathology and Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Keywords Etiology Clinical Manifestations Differential Diagnosis Physiologic Jaundice (Icterus Neonatorum) Pathologic Hyperbilirubinemia Jaundice Associated With Breastfeeding Neonatal Cholestasis

Congenital Atresia of the Bile Ducts Bibliography Keywords Clinical Manifestations Incidence and Prognosis Prevention Treatment of Hyperbilirubinemia Bibliography Chapter 124 Blood Disorders Keywords Normal Hematocrit and Hemoglobin Concentrations in Newborn Infants Classification of Anemia and Diagnostic Evaluation Treatment Options for Neonatal Anemia Bibliography Keywords Hemolytic Disease Caused by Rh Incompatibility Hemolytic Disease Caused by Blood Group A and B Incompatibility Other Forms of Hemolytic Disease Bibliography

Keywords Bibliography Keywords Vitamin K Deficiency Bleeding Disseminated Intravascular Coagulopathy Neonatal Thrombocytopenia Bibliography Keywords Bibliography Chapter 125 The Umbilicus Umbilical Cord Hemorrhage Granuloma Infections Umbilical Hernia Congenital Omphalocele Tumors Bibliography Chapter 126 Abstinence Syndromes Keywords

Treatment Bibliography Keywords Bibliography Keywords Epidemiology Diagnostic Criteria Clinical Features Interventions and Treatment Outcomes The Pediatrician's Role Bibliography Chapter 127 The Endocrine System Keywords Pathophysiology Clinical Manifestations Treatment Prognosis Bibliography Bibliography

Chapter 128 Dysmorphology Classification of Birth Defects Molecular Mechanisms of Malformations Approach to the Dysmorphic Child Bibliography Chapter 129 Epidemiology of Infections Incidence and Epidemiology Pathogenesis Clinical Manifestations Laboratory Findings General Approach to Management Prevention Bibliography Chapter 130 Healthcare-Acquired Infections Incidence Epidemiology Pathogenesis Types of Infection Prevention Bibliography

Chapter 131 Congenital and Perinatal Infections General Approach Pathogenesis Clinical Manifestations Diagnosis Specific Infectious Agents General Approach Pathogenesis Clinical Manifestations Specific Infectious Agents Diagnosis Bibliography

Part XII Adolescent Medicine Chapter 132 Adolescent Physical and Social Development Physical Development Neurologic, Cognitive, and Moral Development Psychosocial Development Implications for Providers, Parents, and Policymakers Bibliography

Chapter 133 Gender and Sexual Identity Terms and Definitions Factors That Influence Sexual Identity Development Nonconformity in Gender Expression Among Children and Adolescents Transgender and Gender-Nonconforming Identities Among Children and Adolescents Bibliography Chapter 134 Gay, Lesbian, and Bisexual Adolescents Prevalence of Homosexuality and Bisexuality in Youth Development of Sexual Orientation in Childhood and Adolescence Stigma, Risk, and Resilience Health Recommendations for Care Bibliography Chapter 135 Transgender Care Cultural and Clinical Competence Gender Literacy Assessment Treatment

Families Bibliography Chapter 136 The Epidemiology of Adolescent Health Problems Access to Healthcare Bibliography Chapter 137 Delivery of Healthcare to Adolescents Bibliography Interviewing the Adolescent Psychosocial Assessment Physical Examination Bibliography Bibliography Chapter 138 Transitioning to Adult Care Bibliography Chapter 139 Violent Behavior Epidemiology Etiology Clinical Manifestations Diagnosis

Treatment Prevention Bibliography Chapter 140 Substance Abuse Etiology Epidemiology Clinical Manifestations Screening for Substance Abuse Disorders Diagnosis Complications Treatment Prognosis Prevention Pharmacology and Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Keywords Cigarettes

Pharmacology Clinical Manifestations Electronic Cigarettes (E-Cigarettes) Hookah Treatment Bibliography Keywords Clinical Manifestations Synthetic Marijuana Bibliography Keywords Clinical Manifestations Complications Diagnosis Treatment Bibliography Keywords Lysergic Acid Diethylamide Methylenedioxymethamphetamine Phencyclidine

Bibliography Clinical Manifestations Treatment Bibliography Clinical Manifestations Treatment Bibliography Clinical Manifestations Treatment Bibliography Clinical Manifestations Withdrawal Overdose Syndrome Treatment Bibliography Clinical Manifestations Treatment Bibliography Bibliography Chapter 141 The Breast

Female Disorders Male Disorders Bibliography Chapter 142 Menstrual Problems Normal Menstruation Menstrual Irregularities Keywords History and Physical Examination Laboratory Studies Treatment Bibliography Keywords Irregular Menstrual Bleeding Heavy and Prolonged Menstrual Bleeding Laboratory Findings Treatment Bibliography Keywords Bibliography Keywords

Bibliography Bibliography Chapter 143 Contraception Contraceptive Effectiveness Keywords Sexual Activity Use of Contraception Among Teens Bibliography Keywords Bibliography Keywords Intrauterine Devices Implants Bibliography Keywords Depo-Provera Progestin-Only Pills Bibliography Keywords Combined Oral Contraceptives

Transdermal Patch Vaginal Ring Contraindications Bibliography Keywords Copper IUD Ulipristal Acetate Levonorgestrel Bibliography Keywords Condoms Bibliography Keywords Diaphragm, Cervical Cap, and Sponge Keywords Spermicides Withdrawal Fertility Awareness–Based Methods Lactational Amenorrhea Method Bibliography

Chapter 144 Adolescent Pregnancy Epidemiology Etiology Clinical Manifestations Diagnosis Pregnancy Counseling and Initial Management Adolescent Fathers Medical Complications of Mothers and Babies Psychosocial Outcomes/Risks for Mother and Child Prevention of Teen Pregnancies Bibliography Chapter 145 Adolescent Sexual Assault Epidemiology Types of Rape Clinical Manifestations Interview and Physical Examination Laboratory Data Treatment Prevention Bibliography

Chapter 146 Sexually Transmitted Infections Etiology Epidemiology Pathogenesis Screening Common Infections and Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 147 Chronic Overlapping Pain Conditions Prevalence Symptom/Disorder Overlap Psychiatric Comorbidities Predisposing Factors Natural History Proposed Pathophysiology Treatment Keywords Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Management Prognosis Bibliography Bibliography

Part XIII Immunology Section 1 Evaluation of the Immune System Chapter 148 Evaluation of Suspected Immunodeficiency Advanced Testing Bibliography

Section 2 The T-, B-, and NK-Cell Systems Chapter 149 Lymphocyte Development and Function Lymphopoiesis in the Fetus Postnatal Lymphocyte Behavior Inheritance of Abnormalities in T-, B-, and NK-Cell Development

Bibliography Chapter 150 Primary Defects of Antibody Production X-Linked Agammaglobulinemia Common Variable Immunodeficiency Selective IgA Deficiency IgG Subclass Deficiencies Immunoglobulin Heavy- and Light-Chain Deletions Transient Hypogammaglobulinemia of Infancy Class Switch Defects X-Linked Lymphoproliferative Disease Bibliography Bibliography Chapter 151 Primary Defects of Cellular Immunity Chromosome 22Q11.2 Deletion Syndrome T-Cell Activation Defects Chronic Mucocutaneous Candidiasis Autoimmune Polyendocrinopathy-Candidiasis–Ectodermal Dysplasia Bibliography Chapter 152 Immunodeficiencies Affecting Multiple Cell Types

Keywords Pathogenesis Clinical Manifestations Treatment Genetics Bibliography Keywords Cartilage-Hair Hypoplasia Wiskott-Aldrich Syndrome Ataxia-Telangiectasia Autosomal Dominant Hyper-IgE Syndrome DOCK8 Deficiency Bibliography Keywords Interferon-γ Receptors 1 and 2, IL-12 Receptor β1 , and IL-12P40 Defects IL-1R–Associated Kinase 4 Deficiency and Myeloid Differentiation Factor 88 Natural Killer Cell Deficiency Defects in Innate Responses to Viral Infection Defects in Innate Responses to Fungi

Bibliography Keywords Autoimmune Lymphoproliferative Syndrome Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Deficiency Lipopolysaccharide (Lps)-Responsive Beige-Like Anchor Protein (LRBA) Deficiency Activated Phosphoinositide 3-Kinase (PI3K) δ Syndromes Signal Transducer and Activator of Transcription (STAT) Pathway Defects Nuclear Factor-κB Pathway Defects Tetratricopeptide Repeat Domain 7A (TTC7A) Deficiency Deficiency of Adenosine Deaminase 2 (DADA2) Bibliography

Section 3 The Phagocytic System Chapter 153 Neutrophils The Phagocytic Inflammatory Response Hematopoiesis Neutrophil Maturation and Kinetics

Neutrophil Function Bibliography Chapter 154 Monocytes, Macrophages, and Dendritic Cells Development Activation Functional Activities Dendritic Cells Abnormalities of Monocyte-Macrophage or Dendritic Cell Function Bibliography Chapter 155 Eosinophils Diseases Associated With Eosinophilia Bibliography Chapter 156 Disorders of Phagocyte Function Leukocyte Adhesion Deficiency Treatment Prognosis Chédiak-Higashi Syndrome Myeloperoxidase Deficiency Chronic Granulomatous Disease

Bibliography Chapter 157 Leukopenia Neutropenia Lymphopenia Bibliography Chapter 158 Leukocytosis Neutrophilia Additional Forms of Leukocytosis Bibliography

Section 4 The Complement System Chapter 159 Complement Components and Pathways Classical and Lectin Pathways Alternative Pathway Membrane Attack Complex Control Mechanisms Participation in Host Defense Bibliography

Chapter 160 Disorders of the Complement System Keywords Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography

Section 5 Hematopoietic Stem Cell Transplantation Chapter 161 Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation HSCT From an HLA-Identical Sibling Donor Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Chronic Myelogenous Leukemia Juvenile Myelomonocytic Leukemia

Myelodysplastic Syndromes Other Than Juvenile Myelomonocytic Leukemia Non-Hodgkin Lymphoma and Hodgkin Disease Acquired Aplastic Anemia Inherited Bone Marrow Failure Syndromes Thalassemia Sickle Cell Disease Immunodeficiency Disorders Inherited Metabolic Diseases Bibliography Chapter 162 Hematopoietic Stem Cell Transplantation From Alternative Sources and Donors Unrelated Donor Transplants Umbilical Cord Blood Transplants Haploidentical Transplants Donor Versus Recipient NK-Cell Alloreactivity Autologous Hematopoietic Stem Cell Transplantation Bibliography Chapter 163 Graft-Versus-Host Disease, Rejection, and Venoocclusive Disease Acute Graft-Versus-Host Disease

Chronic Graft-Versus-Host Disease Graft Failure Venoocclusive Disease Bibliography Chapter 164 Infectious Complications of Hematopoietic Stem Cell Transplantation Bibliography Chapter 165 Late Effects of Hematopoietic Stem Cell Transplantation Endocrine Effects Cardiovascular Effects Secondary Malignancy Graft-Versus-Host Disease Other Effects Special Considerations Bibliography

Part XIV Allergic Disorders Chapter 166 Allergy and the Immunologic Basis of Atopic Disease Key Elements of Allergic Diseases Mechanisms of Allergic Tissue Inflammation

Genetic Basis of Atopy Bibliography Chapter 167 Diagnosis of Allergic Disease Allergy History Physical Examination Diagnostic Testing Bibliography Chapter 168 Allergic Rhinitis Etiology and Classification Pathogenesis Clinical Manifestations Differential Diagnosis Complications Laboratory Findings Treatment Prognosis Bibliography Chapter 169 Childhood Asthma Etiology

Epidemiology Pathogenesis Clinical Manifestations and Diagnosis Differential Diagnosis Laboratory Findings Treatment Prognosis Prevention Bibliography Chapter 170 Atopic Dermatitis (Atopic Eczema) Etiology Pathology Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Treatment Avoiding Triggers Complications Prognosis

Prevention Bibliography Chapter 171 Insect Allergy Etiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 172 Ocular Allergies Clinical Manifestations Diagnosis Treatment Bibliography Chapter 173 Urticaria (Hives) and Angioedema Etiology and Pathogenesis Physical Urticaria Chronic Idiopathic Urticaria and Angioedema

Treatment Hereditary Angioedema Bibliography Chapter 174 Anaphylaxis Etiology Epidemiology Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Treatment Prevention Bibliography Chapter 175 Serum Sickness Etiology Pathogenesis Clinical Manifestations Differential Diagnosis Diagnosis Treatment

Prevention Bibliography Chapter 176 Food Allergy and Adverse Reactions to Foods Genetics Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 177 Adverse Reactions to Drugs Epidemiology Pathogenesis and Clinical Manifestations Diagnosis Treatment Bibliography

Part XV Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases)

Chapter 178 Evaluation of Suspected Rheumatic Disease Symptoms Suggestive of Rheumatic Disease Signs Suggestive of Rheumatic Disease Laboratory Testing Imaging Studies Bibliography Chapter 179 Treatment of Rheumatic Diseases Pediatric Rheumatology Teams and Primary Care Physicians Therapeutics Bibliography Chapter 180 Juvenile Idiopathic Arthritis Epidemiology Etiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Laboratory Findings Treatment Prognosis

Bibliography Chapter 181 Ankylosing Spondylitis and Other Spondyloarthritides Epidemiology Etiology and Pathogenesis Clinical Manifestations and Diagnosis Laboratory Findings Differential Diagnosis Treatment Prognosis Bibliography Chapter 182 Reactive and Postinfectious Arthritis Pathogenesis Clinical Manifestations and Differential Diagnosis Diagnosis Treatment Complications and Prognosis Bibliography Chapter 183 Systemic Lupus Erythematosus Etiology

Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Laboratory Findings Treatment Complications Prognosis Keywords Bibliography Bibliography Chapter 184 Juvenile Dermatomyositis Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis

Laboratory Findings Treatment Complications Prognosis Bibliography Chapter 185 Scleroderma and Raynaud Phenomenon Etiology and Pathogenesis Classification Epidemiology Clinical Manifestations Diagnosis Differential Diagnosis Laboratory Findings Treatment Prognosis Bibliography Chapter 186 Behçet Disease Epidemiology Etiology and Pathogenesis Clinical Manifestations and Diagnosis

Treatment and Prognosis Bibliography Chapter 187 Sjögren Syndrome Epidemiology Etiology and Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment Complications and Prognosis Bibliography Chapter 188 Hereditary Periodic Fever Syndromes and Other Systemic Autoinflammatory Diseases Classification of Autoinflammatory Disorders Autoinflammatory Diseases With Periodic or Prominent Fevers Other Mendelian Autoinflammatory Diseases Genetically Complex Autoinflammatory Diseases Bibliography Chapter 189 Amyloidosis Etiology

Epidemiology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Treatment Prognosis Prevention Bibliography Chapter 190 Sarcoidosis Etiology Epidemiology Pathology and Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Differential Diagnosis Treatment Prognosis Bibliography

Chapter 191 Kawasaki Disease Etiology Epidemiology Pathology Clinical Manifestations Laboratory and Radiology Findings Diagnosis Differential Diagnosis Treatment Complications Prognosis Bibliography Chapter 192 Vasculitis Syndromes Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Treatment

Complications Prognosis Bibliography Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Laboratory Findings Treatment Complications Prognosis Bibliography Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis

Laboratory Findings Treatment Complications Prognosis Bibliography Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Laboratory Findings Treatment Complications Prognosis Bibliography Bibliography Bibliography Chapter 193 Musculoskeletal Pain Syndromes Clinical Manifestations

Diagnosis and Differential Diagnosis Treatment Complications and Prognosis Bibliography Bibliography Bibliography Bibliography Bibliography Bibliography Chapter 194 Miscellaneous Conditions Associated With Arthritis Relapsing Polychondritis Mucha-Habermann Disease/Pityriasis Lichenoides Et Varioliformis Acuta Sweet Syndrome Hypertrophic Osteoarthropathy Plant Thorn Synovitis Pigmented Villonodular Synovitis Bibliography

Part XVI Infectious Diseases

Section 1 General Considerations Chapter 195 Diagnostic Microbiology Specimen Collection Laboratory Diagnosis of Bacterial and Fungal Infections Antimicrobial Susceptibility Testing Point-of-Care Diagnostics Laboratory Detection of Parasitic Infections Serologic Diagnosis Laboratory Diagnosis of Viral Infections Bibliography Chapter 196 The Microbiome and Pediatric Health Measuring the Microbiome Early Childhood Development of the Microbiome The Microbiome and Physiologic Development Contributions of Microbiome to Disease Therapeutic Manipulation of the Microbiome Bibliography

Section 2 Preventive Measures

Chapter 197 Immunization Practices Passive Immunity Active Immunization Vaccination System in the United States Recommended Immunization Schedule Vaccines Recommended in Special Situations Precautions and Contraindications Medical Exemptions Improving Immunization Coverage Vaccine Hesitancy Bibliography Bibliography Chapter 198 Infection Prevention and Control Hand Hygiene Standard Precautions Isolation Additional Measures Surgical Prophylaxis Employee Health

Bibliography Chapter 199 Childcare and Communicable Diseases Epidemiology Respiratory Tract Infections Gastrointestinal Tract Infections Skin Diseases Invasive Organisms Herpesviruses Bloodborne Pathogens Antibiotic Use and Bacterial Resistance Prevention Standards Bibliography Chapter 200 Health Advice for Children Traveling Internationally The Pediatric Travel Medicine Consultation Safety and Preventive Counseling Topics Routine Childhood Vaccinations Required for Pediatric Travel Specialized Pediatric Travel Vaccinations Traveler's Diarrhea Insect-Borne Infections

Malaria Chemoprophylaxis The Returning Traveler The Adolescent Traveler Bibliography Chapter 201 Fever Pathogenesis Etiology Clinical Features Evaluation Management Bibliography Chapter 202 Fever Without a Focus in the Neonate and Young Infant Etiology and Epidemiology Clinical Manifestations Diagnosis Laboratory Diagnosis Treatment Prognosis Bibliography

Chapter 203 Fever in the Older Child Diagnosis General Approach Evaluation Management Bibliography Chapter 204 Fever of Unknown Origin Etiology Diagnosis Management Prognosis Bibliography Chapter 205 Infections in Immunocompromised Persons Abnormalities of the Phagocytic System Defective Splenic Function, Opsonization, or Complement Activity B Cell Defects (Humoral Immunodeficiencies) T Cell Defects (Cell-Mediated Immunodeficiencies) Combined B Cell and T Cell Defects Bibliography Acquired Immunodeficiency From Infectious Agents

Malignancies Fever and Neutropenia Fever Without Neutropenia Transplantation Bibliography Bibliography Chapter 206 Infection Associated With Medical Devices Intravascular Access Devices Cerebrospinal Fluid Shunts Urinary Catheters Peritoneal Dialysis Catheters Orthopedic Prostheses Bibliography

Section 3 Antibiotic Therapy Chapter 207 Principles of Antibacterial Therapy Age- and Risk-Specific Use of Antibiotics in Children Antibiotics Commonly Used in Pediatric Practice Bibliography

Section 4 Gram-Positive Bacterial Infections Chapter 208 Staphylococcus Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Chapter 209 Streptococcus pneumoniae (Pneumococcus) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Chapter 210 Group A Streptococcus Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Complications Prognosis Prevention Keywords Etiology Epidemiology Pathogenesis Clinical Manifestations and Diagnosis Treatment Complications Prognosis Prevention Bibliography Bibliography Chapter 211 Group B Streptococcus Etiology

Epidemiology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Treatment Prognosis Prevention Bibliography Chapter 212 Non–Group A or B Streptococci Bibliography Chapter 213 Enterococcus Etiology Epidemiology Pathogenesis Clinical Manifestations Treatment Prevention Bibliography

Chapter 214 Diphtheria (Corynebacterium diphtheriae ) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Complications Treatment Supportive Care Prognosis Prevention Bibliography Chapter 215 Listeria monocytogenes Etiology Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Treatment

Prognosis Prevention Bibliography Chapter 216 Actinomyces Etiology and Epidemiology Pathogenesis Diagnosis Clinical Manifestations Differential Diagnosis Treatment Prognosis Bibliography Chapter 217 Nocardia Etiology Epidemiology Pathogenesis Clinical and Radiographic Manifestations Diagnosis Treatment Prognosis

Bibliography

Section 5 Gram-Negative Bacterial Infections Chapter 218 Neisseria meningitidis (Meningococcus) Etiology Epidemiology Pathogenesis and Pathophysiology Clinical Manifestations Diagnosis Treatment Complications Prognosis Prevention Bibliography Chapter 219 Neisseria gonorrhoeae (Gonococcus) Etiology Epidemiology Pathogenesis and Pathology Clinical Manifestations

Diagnosis Treatment Complications Prevention Bibliography Chapter 220 Kingella kingae Etiology Epidemiology Pathogenesis Clinical Disease Spondylodiscitis Diagnosis Treatment Prevention Bibliography Chapter 221 Haemophilus influenzae Etiology Epidemiology Pathogenesis Diagnosis

Clinical Manifestations and Treatment Prevention Bibliography Chapter 222 Chancroid (Haemophilus ducreyi) Etiology and Epidemiology Clinical Manifestations Diagnosis Treatment Complications Bibliography Chapter 223 Moraxella catarrhalis Etiology Epidemiology Pathogenesis of Infection Clinical Manifestations Diagnosis Treatment Prevention Bibliography

Chapter 224 Pertussis (Bordetella pertussis and Bordetella parapertussis ) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Complications Prevention Bibliography Chapter 225 Salmonella Etiology Epidemiology Pathogenesis Clinical Manifestations Complications Diagnosis Treatment Prognosis Prevention

Bibliography Etiology Epidemiology Pathogenesis Clinical Manifestations Complications Diagnosis Differential Diagnosis Treatment Prognosis Prevention Bibliography Chapter 226 Shigella Etiology Epidemiology Pathogenesis Immunity Clinical Manifestations and Complications Differential Diagnosis Diagnosis

Treatment Prevention Bibliography Chapter 227 Escherichia coli Enterotoxigenic Escherichia coli Enteroinvasive Escherichia coli Enteropathogenic Escherichia coli Shiga Toxin–Producing Escherichia coli Enteroaggregative Escherichia coli Diffusely Adherent Escherichia coli Enteroaggregative Hemorrhagic Escherichia coli Diagnosis Treatment Prevention of Illness Bibliography Chapter 228 Cholera Etiology Epidemiology Pathogenesis Clinical Manifestations

Laboratory Findings Diagnosis and Differential Diagnosis Complications Treatment Prevention Bibliography Chapter 229 Campylobacter Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Complications Prognosis Prevention Bibliography Chapter 230 Yersinia Keywords Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Complications Prevention Bibliography Keywords Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Complications Prevention Bibliography Keywords Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 231 Aeromonas and Plesiomonas Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis

Treatment Bibliography Chapter 232 Pseudomonas, Burkholderia, and Stenotrophomonas Keywords Etiology Epidemiology Pathology Clinical Manifestations Diagnosis Treatment Supportive Care Prognosis Prevention Bibliography Keywords Burkholderia mallei (Glanders) Burkholderia pseudomallei (Melioidosis) Bibliography Keywords Bibliography

Chapter 233 Tularemia (Francisella tularensis) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Chapter 234 Brucella Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography

Chapter 235 Legionella Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 236 Bartonella Keywords Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Treatment Complications Prognosis

Prevention Bibliography Keywords Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Keywords Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Bibliography Keywords Bacillary Angiomatosis

Bacillary Peliosis Bacteremia and Endocarditis Diagnosis Treatment Prevention Bibliography Bibliography

Section 6 Anaerobic Bacterial Infections Chapter 237 Botulism (Clostridium botulinum) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Supportive Care Complications Prognosis Prevention

Bibliography Chapter 238 Tetanus (Clostridium tetani) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Supportive Care Complications Prognosis Prevention Bibliography Chapter 239 Clostridium difficile Infection Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment

Prognosis Prevention Bibliography Chapter 240 Other Anaerobic Infections Clinical Manifestations Diagnosis Treatment Common Anaerobic Pathogens Bibliography

Section 7 Mycobacterial Infections Chapter 241 Principles of Antimycobacterial Therapy Agents Used Against Mycobacterium Tuberculosis Agents Used Against Mycobacterium Leprae Agents Used Against Nontuberculous Mycobacteria Bibliography Chapter 242 Tuberculosis (Mycobacterium tuberculosis) Etiology Epidemiology

Transmission Pathogenesis Clinical Manifestations Diagnostic Tools Mycobacterial Sampling, Susceptibility and Culture Treatment Prevention Bibliography Chapter 243 Hansen Disease (Mycobacterium leprae) Microbiology Epidemiology Pathogenesis Disease Classification Clinical Manifestations Diagnosis Treatment Long-Term Complications Prevention Bibliography Chapter 244 Nontuberculous Mycobacteria

Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography

Section 8 Spirochetal Infections Chapter 245 Syphilis (Treponema pallidum) Etiology Epidemiology Clinical Manifestations and Laboratory Findings Diagnosis Treatment Prevention Bibliography Chapter 246 Nonvenereal Treponemal Infections Bibliography

Bibliography Bibliography Chapter 247 Leptospira Etiology Epidemiology Pathology and Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 248 Relapsing Fever (Borrelia) Etiology Epidemiology Pathology and Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention

Bibliography Chapter 249 Lyme Disease (Borrelia burgdorferi) Etiology Epidemiology Transmission Pathology and Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Treatment Prognosis Prevention Bibliography

Section 9 Mycoplasmal Infections Chapter 250 Mycoplasma pneumoniae The Organism Epidemiology Pathogenesis

Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 251 Genital Mycoplasmas (Mycoplasma hominis, Mycoplasma genitalium , and Ureaplasma urealyticum ) Etiology Epidemiology Transmission Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography

Section 10 Chlamydial Infections Chapter 252 Chlamydia pneumoniae Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 253 Chlamydia trachomatis Keywords Bibliography Keywords Epidemiology Clinical Manifestations Diagnosis Treatment Complications Prevention Bibliography Keywords Epidemiology Diagnosis

Treatment Prevention Bibliography Keywords Clinical Manifestations Diagnosis Treatment Bibliography Chapter 254 Psittacosis (Chlamydia psittaci) Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography

Section 11 Rickettsial Infections

Chapter 255 Spotted Fever Group Rickettsioses Etiology Epidemiology Transmission Pathology and Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Differential Diagnosis Treatment Supportive Care Complications Prognosis Prevention Bibliography Etiology Epidemiology Transmission Pathology and Pathogenesis Clinical Manifestations and Laboratory Findings

Diagnosis Differential Diagnosis Treatment and Supportive Care Complications Prevention Bibliography Bibliography Bibliography Chapter 256 Scrub Typhus (Orientia tsutsugamushi) Etiology Epidemiology Transmission Pathology and Pathogenesis Clinical Manifestations and Laboratory Findings Diagnosis and Differential Diagnosis Treatment and Supportive Care Complications Prevention Bibliography Chapter 257 Typhus Group Rickettsioses

Keywords Etiology Epidemiology Transmission Pathology and Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Treatment Supportive Care Complications Prevention Bibliography Keywords Etiology Epidemiology Transmission Clinical Manifestations Treatment Prevention

Bibliography Bibliography Chapter 258 Ehrlichiosis and Anaplasmosis Etiology Epidemiology Transmission Pathology and Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Differential Diagnosis Treatment Complications and Prognosis Prevention Bibliography Chapter 259 Q Fever (Coxiella burnetii) Etiology Epidemiology Transmission Pathology and Pathogenesis

Clinical Manifestations and Complications Laboratory Findings Diagnosis and Differential Diagnosis Treatment Prevention Bibliography

Section 12 Fungal Infections Chapter 260 Principles of Antifungal Therapy Polyenes Pyrimidine Analogs Azoles Echinocandins Bibliography Chapter 261 Candida Keywords Epidemiology Pathogenesis Clinical Manifestations

Diagnosis Prophylaxis Treatment Prognosis Bibliography Keywords Oral Candidiasis Diaper Dermatitis Ungual and Periungual Infections Vulvovaginitis Bibliography Keywords Etiology Clinical Manifestations Diagnosis Treatment Primary Immune Defects Bibliography Chapter 262 Cryptococcus neoformans and Cryptococcus gattii Etiology

Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 263 Malassezia Bibliography Chapter 264 Aspergillus Asthma Extrinsic Alveolar Alveolitis Allergic Bronchopulmonary Aspergillosis Allergic Aspergillus Sinusitis Bibliography Keywords Pulmonary Aspergilloma Chronic Pulmonary Aspergillosis Sinusitis Otomycosis

Bibliography Keywords Invasive Pulmonary Aspergillosis Cutaneous Aspergillosis Invasive Sinonasal Disease Central Nervous System Eye Bone Heart Empirical Antifungal Therapy Bibliography Chapter 265 Histoplasmosis (Histoplasma capsulatum) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 266 Blastomycosis (Blastomyces dermatitidis and Blastomyces

gilchristii ) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 267 Coccidioidomycosis (Coccidioides Species) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 268 Paracoccidioides brasiliensis Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 269 Sporotrichosis (Sporothrix schenckii) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 270 Mucormycosis Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment

Bibliography Chapter 271 Pneumocystis jirovecii Etiology Epidemiology Pathogenesis Pathology Clinical Manifestations Laboratory Findings Diagnosis Treatment Supportive Care Complications Prognosis Prevention Bibliography

Section 13 Viral Infections Chapter 272 Principles of Antiviral Therapy Antivirals Used for Herpesviruses

Antivirals Used for Respiratory Viral Infections Antivirals Used for Hepatitis Antiviral Immune Globulins Bibliography Chapter 273 Measles Etiology Epidemiology Transmission Pathology Pathogenesis Clinical Manifestations Modified Measles Infection Laboratory Findings Diagnosis Differential Diagnosis Complications Treatment Prognosis Prevention Bibliography

Chapter 274 Rubella Etiology Epidemiology Pathology Pathogenesis Clinical Manifestations Laboratory Findings Diagnoses Differential Diagnoses Complications Treatment Supportive Care Prognosis Prevention Vaccination Bibliography Chapter 275 Mumps Etiology Epidemiology Pathology and Pathogenesis

Clinical Manifestations Diagnosis Differential Diagnosis Complications Treatment Prognosis Prevention Bibliography Chapter 276 Polioviruses Etiology Epidemiology Transmission Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment Complications Prognosis Prevention

Bibliography Chapter 277 Nonpolio Enteroviruses Etiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment Complications and Prognosis Bibliography Chapter 278 Parvoviruses Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment Complications Prevention

Bibliography Chapter 279 Herpes Simplex Virus Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Treatment Prognosis Prevention Bibliography Chapter 280 Varicella-Zoster Virus* Etiology Epidemiology Pathogenesis Clinical Manifestations Complications Diagnosis Treatment

Prognosis Prevention Bibliography Chapter 281 Epstein-Barr Virus Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Complications Oncogenesis Treatment Prognosis Prevention Bibliography Chapter 282 Cytomegalovirus The Virus and Its Interaction With the Host Epidemiology Clinical Manifestations Diagnosis

Treatment Prevention Bibliography Chapter 283 Roseola (Human Herpesviruses 6 and 7) Etiology Epidemiology Pathology/Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Complications Treatment Prognosis Prevention Bibliography Chapter 284 Human Herpesvirus 8 Etiology Epidemiology Pathology and Pathogenesis Clinical Manifestations

Diagnosis Treatment Bibliography Chapter 285 Influenza Viruses* Etiology Epidemiology Pathogenesis Clinical Manifestations Complications Laboratory Findings Diagnosis and Differential Diagnosis Treatment Supportive Care Prognosis Prevention Bibliography Chapter 286 Parainfluenza Viruses* Etiology Epidemiology Pathogenesis

Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Complications Prognosis Prevention Bibliography Chapter 287 Respiratory Syncytial Virus Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Chapter 288 Human Metapneumovirus Etiology Etiology

Epidemiology Pathology Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Complications Treatment Prognosis Prevention Bibliography Chapter 289 Adenoviruses Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Complications Treatment Prevention

Bibliography Chapter 290 Rhinoviruses Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Complications Treatment Prevention Bibliography Chapter 291 Coronaviruses Etiology Epidemiology Pathogenesis of SARS and MERS Clinical Manifestations Diagnosis Treatment and Prevention Bibliography

Chapter 292 Rotaviruses, Caliciviruses, and Astroviruses Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Differential Diagnosis Treatment Prognosis Prevention Bibliography Chapter 293 Human Papillomaviruses Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment

Complications Prognosis Prevention Bibliography Chapter 294 Arboviral Infections Etiology Diagnosis Prevention Bibliography Bibliography Bibliography Bibliography Bibliography Epidemiology Clinical Features Management Laboratory Diagnosis Prognosis Differential Diagnosis Prevention

Bibliography Bibliography Chapter 295 Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Laboratory Findings Treatment Complications Prognosis Prevention Bibliography Chapter 296 Yellow Fever Etiology Epidemiology Pathogenesis Clinical Manifestations

Diagnosis Treatment Complications Prevention Bibliography Chapter 297 Ebola and Other Viral Hemorrhagic Fevers Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 298 Lymphocytic Choriomeningitis Virus Etiology Epidemiology Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis

Complications Treatment Prognosis Prevention Bibliography Chapter 299 Hantavirus Pulmonary Syndrome Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment Prognosis Prevention Bibliography Chapter 300 Rabies Epidemiology Transmission Pathogenesis

Clinical Manifestations Differential Diagnosis Diagnosis Treatment and Prognosis Prevention Bibliography Chapter 301 Polyomaviruses Bibliography Chapter 302 Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Chapter 303 Human T-Lymphotropic Viruses (1 and 2)

Etiology Epidemiology and Modes of Transmission Diagnosis Clinical Manifestations Adult T-Cell Leukemia/Lymphoma Human T-Cell Lymphotropic Virus-1–Associated Myelopathy Human T-Cell Lymphotropic Virus-2 Prevention Bibliography Chapter 304 Transmissible Spongiform Encephalopathies Etiology Epidemiology Pathogenesis and Pathology Clinical Manifestations Diagnosis Laboratory Findings Treatment Genetic Counseling Prognosis Family Support

Prevention Bibliography

Section 14 Antiparasitic Therapy Chapter 305 Principles of Antiparasitic Therapy Selected Antiparasitic Drugs for Protozoans Selected Antiparasitic Drugs for Helminths and Ectoparasites

Section 15 Protozoan Diseases Chapter 306 Primary Amebic Meningoencephalitis Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 307 Amebiasis Etiology

Epidemiology Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Complications Treatment Prognosis Prevention Bibliography Chapter 308 Giardiasis and Balantidiasis Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Bibliography

Chapter 309 Cryptosporidium, Cystoisospora, Cyclospora, and Microsporidia Cryptosporidium Diagnosis Cystoisospora Cyclospora Microsporidia Bibliography Chapter 310 Trichomoniasis (Trichomonas vaginalis) Epidemiology Pathogenesis Clinical Manifestations Diagnosis Complications Treatment Prevention Bibliography Chapter 311 Leishmaniasis (Leishmania) Etiology Epidemiology Pathology

Pathogenesis Clinical Manifestations Laboratory Findings Differential Diagnosis Diagnosis Treatment Prevention Bibliography Chapter 312 African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei Complex) Etiology Life Cycle Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 313 American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi )

Etiology Life Cycle Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 314 Malaria (Plasmodium) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Complications of Plasmodium Falciparum MALARIA Prevention Bibliography Chapter 315 Babesiosis (Babesia)

Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography Chapter 316 Toxoplasmosis (Toxoplasma gondii) Etiology Epidemiology Pathogenesis Clinical Manifestations Systemic Signs Diagnosis Treatment Prognosis Prevention Acknowledgment

Bibliography

Section 16 Helminthic Diseases Chapter 317 Ascariasis (Ascaris lumbricoides) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 318 Hookworms (Necator americanus and Ancylostoma spp.) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment

Prevention Keywords Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Bibliography Bibliography Chapter 319 Trichuriasis (Trichuris trichiura) Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 320 Enterobiasis (Enterobius vermicularis) Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 321 Strongyloidiasis (Strongyloides stercoralis) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 322 Lymphatic Filariasis (Brugia malayi, Brugia timori, and Wuchereria bancrofti ) Etiology Epidemiology Clinical Manifestations

Diagnosis Treatment Bibliography Chapter 323 Other Tissue Nematodes Onchocerciasis (Onchocerca Volvulus) Loiasis (Loa Loa) Infection With Animal Filariae Angiostrongylus Cantonensis Angiostrongylus Costaricensis Dracunculiasis (Dracunculus Medinensis) Gnathostoma Spinigerum Bibliography Chapter 324 Toxocariasis (Visceral and Ocular Larva Migrans) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention

Bibliography Chapter 325 Trichinellosis (Trichinella spiralis) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 326 Schistosomiasis (Schistosoma) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography

Chapter 327 Flukes (Liver, Lung, and Intestinal) Liver Flukes Lung Flukes Intestinal Flukes Bibliography Chapter 328 Adult Tapeworm Infections Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Diphyllobothriasis (Diphyllobothrium Spp.) Hymenolepiasis (Hymenolepis) Dipylidiasis (Dipylidium Caninum) Bibliography Chapter 329 Cysticercosis Etiology Epidemiology

Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Bibliography Chapter 330 Echinococcosis (Echinococcus granulosus and Echinococcus multilocularis ) Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Prevention Bibliography

Volume 2 Part XVII The Digestive System

Section 1 Clinical Manifestations of Gastrointestinal Disease Chapter 331 Normal Digestive Tract Phenomena Bibliography Chapter 332 Major Symptoms and Signs of Digestive Tract Disorders Dysphagia Regurgitation Anorexia Vomiting Diarrhea Constipation Abdominal Pain Gastrointestinal Hemorrhage Abdominal Distention and Abdominal Masses Bibliography

Section 2 The Oral Cavity Chapter 333 Development and Developmental Anomalies of the Teeth

Development of Teeth Bibliography Chapter 334 Disorders of the Oral Cavity Associated With Other Conditions Chapter 335 Malocclusion Variations in Growth Patterns Crossbite Open and Closed Bites Dental Crowding Digit Sucking Chapter 336 Cleft Lip and Palate Incidence and Epidemiology Clinical Manifestations Treatment Postoperative Management Sequelae Velopharyngeal Dysfunction Bibliography Chapter 337 Syndromes With Oral Manifestations Bibliography

Chapter 338 Dental Caries Etiology Epidemiology Clinical Manifestations Complications Treatment Prevention Bibliography Chapter 339 Periodontal Diseases Gingivitis Aggressive Periodontitis in Children (Prepubertal Periodontitis) Aggressive Periodontitis in Adolescents Cyclosporine- or Phenytoin-Induced Gingival Overgrowth Acute Pericoronitis Necrotizing Periodontal Disease (Acute Necrotizing Ulcerative Gingivitis) Bibliography Chapter 340 Dental Trauma Injuries to Teeth Injuries to Periodontal Structures

Prevention Additional Considerations Bibliography Chapter 341 Common Lesions of the Oral Soft Tissues Oropharyngeal Candidiasis Aphthous Ulcers Herpetic Gingivostomatitis Recurrent Herpes Labialis Parulis Cheilitis Ankyloglossia Geographic Tongue Fissured Tongue Developmental (Normal) Variations Bibliography Chapter 342 Diseases of the Salivary Glands and Jaws Parotitis Ranula Mucocele Congenital Lip Pits

Eruption Cyst Xerostomia Salivary Gland Tumors Histiocytic Disorders Tumors of the Jaw Bibliography Chapter 343 Diagnostic Radiology in Dental Assessment Bibliography

Section 3 The Esophagus Chapter 344 Embryology, Anatomy, and Function of the Esophagus Embryology Anatomy Function Keywords Diagnostic Aids Bibliography Bibliography Chapter 345 Congenital Anomalies

Keywords Presentation Diagnosis Management Outcome Bibliography Bibliography Keywords Bibliography Chapter 346 Obstructing and Motility Disorders of the Esophagus Extrinsic Intrinsic Bibliography Chapter 347 Dysmotility Upper Esophageal and Upper Esophageal Sphincter Dysmotility (Striated Muscle) Lower Esophageal and Lower Esophageal Sphincter Dysfunction (Smooth Muscle) Bibliography Chapter 348 Hiatal Hernia

Chapter 349 Gastroesophageal Reflux Disease Pathophysiology Epidemiology and Natural History Clinical Manifestations Diagnosis Management Keywords Esophageal: Esophagitis and Sequelae—Stricture, Barrett Esophagus, Adenocarcinoma Nutritional Extraesophageal: Respiratory (“Atypical”) Presentations Apnea and Stridor Bibliography Bibliography Chapter 350 Eosinophilic Esophagitis, Pill Esophagitis, and Infective Esophagitis Eosinophilic Esophagitis Infective Esophagitis Pill Esophagitis Bibliography

Chapter 351 Esophageal Perforation Bibliography Chapter 352 Esophageal Varices Bibliography Chapter 353 Ingestions Bibliography Keywords Bibliography

Section 4 Stomach and Intestines Chapter 354 Normal Development, Structure, and Function of the Stomach and Intestines Development Digestion and Absorption Chapter 355 Pyloric Stenosis and Other Congenital Anomalies of the Stomach Etiology Clinical Manifestations Differential Diagnosis Treatment

Acknowledgment Bibliography Clinical Manifestations Diagnosis Treatment Acknowledgment Bibliography Acknowledgment Bibliography Pathogenesis Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Acknowledgment Bibliography Chapter 356 Intestinal Atresia, Stenosis, and Malrotation Clinical Manifestations and Diagnosis Treatment Bibliography Clinical Manifestation and Diagnosis

Treatment Bibliography Clinical Manifestations Treatment Acknowledgment Bibliography Chapter 357 Intestinal Duplications, Meckel Diverticulum, and Other Remnants of the Omphalomesenteric Duct Clinical Manifestations Clinical Manifestations Diagnosis Bibliography Chapter 358 Motility Disorders and Hirschsprung Disease Clinical Manifestations Diagnosis Treatment Bibliography Bibliography Clinical Manifestations Diagnosis

Treatment Bibliography Pathology Clinical Manifestations Diagnosis Treatment Bibliography Bibliography Acknowledgment Bibliography Chapter 359 Ileus, Adhesions, Intussusception, and Closed-Loop Obstructions Bibliography Acknowledgment Bibliography Etiology and Epidemiology Pathology Clinical Manifestations Diagnosis Differential Diagnosis Treatment

Prognosis Bibliography Bibliography Chapter 360 Foreign Bodies and Bezoars Bibliography Bibliography Chapter 361 Peptic Ulcer Disease in Children Pathogenesis Clinical Manifestations Diagnosis Primary Ulcers Secondary Ulcers “Stress” Ulceration Treatment Bibliography Bibliography Chapter 362 Inflammatory Bowel Disease Keywords Clinical Manifestations

Differential Diagnosis Diagnosis Treatment Prognosis Bibliography Keywords Clinical Manifestations Differential Diagnosis Diagnosis Treatment Prognosis Bibliography Keywords Bibliography Chapter 363 Eosinophilic Gastroenteritis Bibliography Chapter 364 Disorders of Malabsorption Clinical Approach Keywords Investigations for Carbohydrate Malabsorption

Investigations for Fat Malabsorption Investigations for Protein-Losing Enteropathy Investigations for Exocrine Pancreatic Function Investigations for Intestinal Mucosal Disorders Imaging Procedures Bibliography Keywords Etiology and Epidemiology Genetics and Pathogenesis Clinical Presentation and Associated Disorders Diagnosis Treatment The Spectrum of Gluten-Related Disorders Bibliography Keywords Defects of Enterocyte Differentiation and Polarization Microvillus Inclusion Disease (Congenital Microvillus Atrophy) Tufting Enteropathy (Congenital Tufting Enteropathy) Tricho-Hepato-Enteric Syndrome (Syndromic Diarrhea) Defects in Enteroendocrine Cells Differentiation

Enteric Anendocrinosis Proprotein Convertase 1/3 Deficiency Mitchell-Riley Syndrome Aristaless-Related Homeobox Gene Mutations Autoimmune Enteropathy Autoimmune Polyglandular Syndrome Type 1 Abetalipoproteinemia Homozygous Hypobetalipoproteinemia Chylomicron Retention Disease (Anderson Disease) DGAT1 Mutation Wolman Disease Tangier Disease Sitosterolemia Bile Acid Malabsorption Protein-Losing Enteropathy Bibliography Keywords Postinfectious Diarrhea Proximal Intestinal Bacterial Overgrowth Environmental Enteropathy (Tropical Sprue)

Whipple Disease Bibliography Keywords Bibliography Keywords Bibliography Keywords Treatment Complications Bibliography Keywords Bibliography Keywords Carbohydrate Malabsorption Lactase Deficiency Fructose Malabsorption Sucrase-Isomaltase Deficiency Glucose-Galactose Malabsorption Exocrine Pancreatic Insufficiency Enterokinase (Enteropeptidase) Deficiency

Trehalase Deficiency Trypsinogen Deficiency Bibliography Keywords Keywords Disorders of Carbohydrate Absorption Disorders of Amino Acid and Peptide Absorption Disorders of Fat Transport Disorders of Vitamin Absorption Disorders of Electrolyte and Mineral Absorption Bibliography Chapter 365 Intestinal Transplantation in Children With Intestinal Failure Indications for Intestinal Transplant Transplantation Operation Postoperative Management Bibliography Chapter 366 Acute Gastroenteritis in Children Burden of Childhood Diarrhea Pathogens Epidemiology in the United States and Other Middle- and High-

Income Countries Epidemiology in Low- and Middle-Income Countries Pathogenesis of Infectious Diarrhea Clinical Manifestation of Diarrhea Intestinal and Extraintestinal Complications Differential Diagnosis Treatment Prevention Keywords Treatment Prevention Bibliography Bibliography Chapter 367 Chronic Diarrhea Definition of Epidemiology Pathophysiology Etiology Evaluation of Patients Investigations Treatment

KeyWords Bibliography Bibliography Chapter 368 Functional Gastrointestinal Disorders Functional Gastrointestinal Disorders in Children and Adolescents Functional Abdominal Pain Disorders Functional Defecation Disorders Bibliography Chapter 369 Cyclic Vomiting Syndrome Bibliography Chapter 370 Acute Appendicitis Epidemiology Pathophysiology Appendicitis Risk Scoring Systems Laboratory Findings Imaging Studies Diagnosis and Treatment Differential Diagnosis Antibiotics

Surgical Intervention Perforated Appendicitis Nonoperative Management of Uncomplicated Appendicitis Recurrent Appendicitis Interval Appendectomy Incidental Appendicoliths Bibliography Chapter 371 Surgical Conditions of the Anus and Rectum Keywords Embryology Associated Anomalies Manifestations and Diagnosis Approach to the Patient Operative Repair Outcome Bibliography Keywords Clinical Manifestations Treatment Bibliography

Keywords Clinical Manifestations Treatment Bibliography Keywords Clinical Manifestations Treatment Bibliography Keywords Clinical Manifestations Treatment Bibliography Keywords Bibliography Chapter 372 Tumors of the Digestive Tract Hamartomatous Tumors Adenomatous Tumors Other Gastrointestinal Tumors Bibliography Chapter 373 Inguinal Hernias

Embryology and Pathogenesis Evaluation of Acute Inguinal–Scrotal Swelling Direct Inguinal Hernia Femoral Hernia Complications Bibliography

Section 5 Exocrine Pancreas Chapter 374 Embryology, Anatomy, and Physiology of the Pancreas Bibliography Bibliography Bibliography Chapter 375 Pancreatic Function Tests Direct Test Bibliography Chapter 376 Disorders of the Exocrine Pancreas Disorders Associated With Pancreatic Insufficiency Cystic Fibrosis (see Chapter 432) Shwachman-Diamond Syndrome (see Chapter 157)

Pearson Syndrome Johanson-Blizzard Syndrome Isolated Enzyme Deficiencies Other Syndromes Associated With Pancreatic Insufficiency Bibliography Chapter 377 Treatment of Pancreatic Insufficiency Bibliography Chapter 378 Pancreatitis Keywords Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Keywords Bibliography Chapter 379 Pancreatic Fluid Collections Treatment of Fluid Collections and Necrosis Bibliography

Chapter 380 Pancreatic Tumors Bibliography

Section 6 The Liver and Biliary System Chapter 381 Morphogenesis of the Liver and Biliary System Hepatic Ultrastructure Metabolic Functions of the Liver Bibliography Chapter 382 Manifestations of Liver Disease Pathologic Manifestations Clinical Manifestations Keywords Biochemical Tests Liver Biopsy Hepatic Imaging Procedures Diagnostic Approach to Infants With Jaundice Bibliography Bibliography Chapter 383 Cholestasis

Mechanisms Evaluation Intrahepatic Cholestasis Bile Acid-Coenzyme a Ligase Deficiency Disorders of Embryogenesis Biliary Atresia Management of Chronic Cholestasis Prognosis Bibliography Chapter 384 Metabolic Diseases of the Liver Crigler-Najjar Syndrome Type I (Glucuronyl Transferase Deficiency) Crigler-Najjar Syndrome Type II (Partial Glucuronyl Transferase Deficiency) Inherited Conjugated Hyperbilirubinemia Dubin-Johnson Syndrome Bibliography Pathogenesis Clinical Manifestations Pathology Diagnosis

Treatment Prognosis Bibliography Bibliography Bibliography α1 -Antitrypsin Deficiency Citrin Deficiency Bibliography Chapter 385 Viral Hepatitis Issues Common to All Forms of Viral Hepatitis Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Approach to Acute or Chronic Hepatitis Bibliography Chapter 386 Liver Abscess Bibliography

Chapter 387 Liver Disease Associated With Systemic Disorders Inflammatory Bowel Disease Bacterial Sepsis Celiac Disease Cardiac Disease Cholestasis Associated With Chronic Total Parenteral Nutrition Cystic Fibrosis Bone Marrow Transplantation Hemoglobinopathies Histiocytic Disorders Bibliography Bibliography Chapter 388 Mitochondrial Hepatopathies Epidemiology Clinical Manifestations Primary Mitochondrial Hepatopathies Diagnostic Evaluation Treatment of Mitochondrial Hepatopathies Bibliography Chapter 389 Autoimmune Hepatitis

Autoimmune Hepatitis Etiology Pathology Clinical Manifestations Laboratory Findings Diagnosis Treatment Prognosis Bibliography Chapter 390 Drug- and Toxin-Induced Liver Injury Treatment Prognosis Prevention Bibliography Chapter 391 Acute Hepatic Failure Etiology Pathology Pathogenesis Clinical Manifestations Laboratory Findings

Treatment Prognosis Bibliography Chapter 392 Cystic Diseases of the Biliary Tract and Liver Choledochal Cysts Autosomal Dominant Polycystic Kidney Disease Autosomal Dominant Polycystic Liver Disease Bibliography Chapter 393 Diseases of the Gallbladder Anomalies Acute Hydrops Cholecystitis and Cholelithiasis Biliary Dyskinesia Bibliography Chapter 394 Portal Hypertension and Varices Etiology Pathophysiology Clinical Manifestations Diagnosis

Treatment Prognosis Bibliography Chapter 395 Liver Transplantation Indications Technical Innovations Immunosuppression Complications Outcomes Bibliography

Section 7 Peritoneum Chapter 396 Peritoneal Malformations Acknowledgment Bibliography Chapter 397 Ascites Bibliography Chapter 398 Peritonitis

Etiology and Epidemiology Clinical Manifestations Diagnosis and Treatment Bibliography Clinical Manifestations Treatment Bibliography Etiology Clinical Manifestations Treatment Bibliography Bibliography Chapter 399 Epigastric Hernia Clinical Presentation Bibliography

Part XVIII The Respiratory System Section 1 Development and Function Chapter 400 Diagnostic Approach to Respiratory Disease

History Physical Examination Blood Gas Analysis Transillumination of the Chest Radiographic Techniques Pulmonary Function Testing Microbiology: Examination of Lung Secretions The Microbiome (see Chapter 196) Airway Visualization and Lung Specimen–Based Diagnostic Tests Bibliography Chapter 401 Chronic or Recurrent Respiratory Symptoms Judging the Seriousness of Chronic Respiratory Complaints Recurrent or Persistent Cough Frequently Recurring or Persistent Stridor Recurrent or Persistent Wheeze Recurrent and Persistent Lung Infiltrates Evaluation Bibliography Bibliography Chapter 402 Sudden Infant Death Syndrome

Epidemiology Pathology Environmental Risk Factors Genetic Risk Factors Gene-Environment Interactions Infant Groups at Increased Risk for Sudden Infant Death Syndrome Clinical Strategies Keywords Epidemiology Pathogenesis Risk Factors Diagnosis and Differential Diagnosis Outcome Treatment Prevention Bibliography Bibliography Chapter 403 Brief Resolved Unexplained Events and Other Acute Events in Infants Background

Definition Epidemiology Initial History Bibliography

Section 2 Disorders of the Respiratory Tract Chapter 404 Congenital Disorders of the Nose Normal Newborn Nose Physiology Congenital Disorders Choanal Atresia Congenital Defects of the Nasal Septum Pyriform Aperture Stenosis Congenital Midline Nasal Masses Diagnosis and Treatment Bibliography Chapter 405 Acquired Disorders of the Nose Keywords Etiology

Diagnosis Treatment Complications Prevention Bibliography Keywords Anatomy Etiology Clinical Manifestations Treatment Prevention Bibliography Chapter 406 Nasal Polyps Etiology Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Bibliography Chapter 407 The Common Cold Etiology

Epidemiology Pathogenesis Clinical Manifestations Diagnosis Laboratory Findings Treatment Complications Prevention Bibliography Chapter 408 Sinusitis Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Complications Prevention Bibliography Chapter 409 Acute Pharyngitis

Infectious Etiologies Diagnosis Treatment Chronic Group a Streptococcus Carriers Recurrent Pharyngitis Complications and Prognosis Prevention Bibliography Chapter 410 Retropharyngeal Abscess, Lateral Pharyngeal (Parapharyngeal) Abscess, and Peritonsillar Cellulitis/Abscess Retropharyngeal and Lateral Pharyngeal Abscess Peritonsillar Cellulitis and/or Abscess Bibliography Chapter 411 Tonsils and Adenoids Anatomy Normal Function Pathology Clinical Manifestations Treatment Complications

Chronic Airway Obstruction Bibliography Chapter 412 Acute Inflammatory Upper Airway Obstruction (Croup, Epiglottitis, Laryngitis, and Bacterial Tracheitis) Etiology and Epidemiology Clinical Manifestations Differential Diagnosis Complications Treatment Prognosis Bibliography Clinical Manifestations Diagnosis Treatment Complications Prognosis Bibliography Chapter 413 Congenital Anomalies of the Larynx, Trachea, and Bronchi Keywords Clinical Manifestations

Diagnosis Treatment Bibliography Keywords Clinical Manifestations Diagnosis Bibliography Keywords Diagnosis Treatment Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Bibliography Keywords Bibliography

Bibliography Bibliography Bibliography Chapter 414 Foreign Bodies in the Airway Epidemiology and Etiology Clinical Manifestations Diagnosis Treatment Bibliography Chapter 415 Laryngotracheal Stenosis and Subglottic Stenosis Keywords Keywords Clinical Manifestations Diagnosis Treatment Bibliography Chapter 416 Bronchomalacia and Tracheomalacia Clinical Manifestations Diagnosis

Treatment Prognosis Bibliography Chapter 417 Neoplasms of the Larynx, Trachea, and Bronchi Keywords Keywords Clinical Manifestations Treatment Bibliography Keywords Clinical Manifestations Treatment Bibliography Keywords Bibliography Keywords Keywords Bibliography Keywords Bibliography

Chapter 418 Wheezing, Bronchiolitis, and Bronchitis Keywords General Pathophysiology of Wheezing in Infants Clinical Manifestations Prognosis Prevention Bibliography Keywords Acute Bronchitis Chronic Bronchitis Cigarette Smoking and Air Pollution Bibliography Chapter 419 Plastic Bronchitis Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Complications and Prognosis Bibliography

Chapter 420 Emphysema and Overinflation Localized Obstructive Overinflation Generalized Obstructive Overinflation Bibliography Chapter 421 α1 -Antitrypsin Deficiency and Emphysema Pathogenesis Clinical Manifestations Laboratory Findings Treatment Supportive Therapy Bibliography Chapter 422 Other Distal Airway Diseases Keywords Epidemiology Pathogenesis Clinical Manifestations and Diagnosis Treatment Prognosis Bibliography

Keywords Bibliography Keyword Epidemiology and Etiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 423 Congenital Disorders of the Lung Etiology and Pathology Clinical Manifestations and Prognosis Diagnosis and Treatment Bibliography Etiology and Pathology Clinical Manifestations Diagnosis and Treatment Bibliography Pathology Etiology

Diagnosis Clinical Manifestations Treatment Bibliography Pathophysiology Clinical Manifestations and Diagnosis Treatment Bibliography Etiology and Pathology Clinical Manifestations and Treatment Bibliography Etiology and Pathology Clinical Manifestations and Treatment Bibliography Etiology and Pathology Clinical Manifestations and Treatment Bibliography Congenital Lobar Emphysema and Pulmonary Cysts Pulmonary Arteriovenous Malformation Bronchobiliary Fistula

Bibliography Chapter 424 Pulmonary Edema Pathophysiology Etiology Clinical Manifestations Treatment Bibliography Chapter 425 Aspiration Syndromes Aspiration Syndromes Gastric Contents Hydrocarbon Aspiration Bibliography Chapter 426 Chronic Recurrent Aspiration Etiology Diagnosis Treatment Bibliography Chapter 427 Immune and Inflammatory Lung Disease Keywords

Etiology Pathogenesis Clinical Manifestations and Classification Laboratory Treatment Bibliography Keywords Classification and Pathogenesis Treatment Bibliography Keywords Granulomatosis With Polyangiitis Sarcoidosis Berylliosis Granulomatous Lung Disease in Primary Immune Deficiency Bibliography Keywords Etiology Pathology and Pathogenesis Clinical Manifestations

Löffler Syndrome Acute Eosinophilic Pneumonia Chronic Eosinophilic Pneumonia Eosinophilic Granulomatosis With Polyangiitis (the Churg-Strauss Syndrome) Allergic Bronchopulmonary Aspergillosis Hypereosinophilic Syndrome Bibliography Keywords Classification and Pathology Clinical Manifestations Diagnosis Treatment Prognosis Anti-Glomerular Basement Membrane Disease (Anti-GBM Disease) Bibliography Keywords Background/Summary Epidemiology Pathophysiology Clinical Presentation

Diagnosis Natural Course and Treatment Bibliography Keywords Clinical Presentation Evaluation Treatment Outcomes Bibliography Chapter 428 Community-Acquired Pneumonia Epidemiology Etiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Complications Prevention Bibliography

Chapter 429 Pleurisy, Pleural Effusions, and Empyema Etiology Pathology and Pathogenesis Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography Keywords Etiology Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Complications Treatment Bibliography Keywords Etiology Epidemiology

Pathology Clinical Manifestations Laboratory Findings Complications Treatment Bibliography Chapter 430 Bronchiectasis Pathophysiology and Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 431 Pulmonary Abscess Pathology and Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Bibliography

Chapter 432 Cystic Fibrosis Genetics Pathogenesis Pathology Clinical Manifestations Diagnosis and Assessment Treatment Treatment of Pulmonary Complications Treatment of Intestinal Complications Other Complications Prognosis Bibliography Chapter 433 Primary Ciliary Dyskinesia (Immotile Cilia Syndrome, Kartagener Syndrome) Normal Ciliary Ultrastructure and Function Genetics of Primary Ciliary Dyskinesia Clinical Manifestations of Primary Ciliary Dyskinesia Diagnosis of Primary Ciliary Dyskinesia Treatment Prognosis

Bibliography Chapter 434 Diffuse Lung Diseases in Childhood Pathology Deficiency of Surfactant Protein B (Surfactant Metabolism Dysfunction, Pulmonary, 1; Smdp1; Omim #265120) Surfactant Protein C Gene Abnormalities (Surfactant Metabolism Dysfunction, Pulmonary, 2; Smdp2; Omim #610913) Disease Caused by Mutations in ABCA3 (Surfactant Metabolism Dysfunction, Pulmonary, 3; Smdp3; Omim #610921) Disease Caused by Mutations in NKX2-1 (Thyroid Transcription Factor 1, Choreoathetosis, Hypothyroidism, and Neonatal Respiratory Distress, Omim #600635) Treatment of Surfactant Dysfunction Disorders Bibliography Etiology and Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Chapter 435 Pulmonary Hemosiderosis Etiology Epidemiology

Pathology Pathophysiology Clinical Manifestations Laboratory Findings and Diagnosis Treatment Prognosis Bibliography Chapter 436 Pulmonary Embolism, Infarction, and Hemorrhage Keywords Etiology Epidemiology Pathophysiology Clinical Manifestations Laboratory Findings and Diagnosis Treatment Prognosis Bibliography Etiology Epidemiology Pathophysiology

Clinical Manifestations Laboratory Findings and Diagnosis Treatment Bibliography Chapter 437 Atelectasis Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Chapter 438 Pulmonary Tumors Etiology Clinical Manifestations and Evaluation Bibliography Chapter 439 Pneumothorax Etiology and Epidemiology Pathogenesis Clinical Manifestations Diagnosis and Differential Diagnosis

Treatment Bibliography Chapter 440 Pneumomediastinum Etiology Pathogenesis Clinical Manifestations Laboratory Findings Treatment Complications Bibliography Chapter 441 Hydrothorax Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography Chapter 442 Hemothorax Etiology Clinical Manifestations

Diagnosis Treatment Bibliography Chapter 443 Chylothorax Etiology Clinical Manifestations Laboratory Findings Treatment Complications Bibliography Chapter 444 Bronchopulmonary Dysplasia Bronchopulmonary Dysplasia Clinical Manifestations Treatment Prognosis Bibliography Chapter 445 Skeletal Diseases Influencing Pulmonary Function Keywords Etiology

Epidemiology Clinical Manifestations Laboratory Findings Treatment Bibliography Keywords Pectus Carinatum Treatment Sternal Clefts Bibliography Keywords Etiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Keyword Etiology Clinical Manifestations

Diagnosis Treatment Prognosis Bibliography Keywords Etiology Clinical Manifestations Diagnosis Treatment Bibliography Keyword Clinical Manifestations Diagnosis Treatment Bibliography Chapter 446 Chronic Respiratory Insufficiency Epidemiology Modalities for Respiratory Support Other Management Considerations Preparing for Discharge

Care by the General Pediatrician Care by the Subspecialty Team Weaning Off the Ventilator Psychosocial Considerations Adult Transition Bibliography Keywords Genetics Clinical Manifestations Differential Diagnosis Management Bibliography Myelomeningocele With Arnold-Chiari Type II Malformation Management Rapid-Onset Obesity, Hypothalamic Dysfunction, and Autonomic Dysregulation Obesity Hypoventilation Syndrome Management Acquired Alveolar Hypoventilation Obstructive Sleep Apnea Spinal Cord Injury

Metabolic Disease Keywords Goals and Decision-Making Noninvasive and Transtracheal Supports Augmented Secretion Clearance Aerodigestive and Communication Considerations Gas-Exchange Goals and Ventilator Strategies Cardiopulmonary Interactions Chest Wall/Thoracic Configuration Nutrition and Weight Gain Developmental Considerations Projected Interventions and Needs Monitoring Transitioning From Acute Care to Rehabilitation or Community Setting Routine Health Maintenance Long-Term Mechanical Ventilation Weaning and Tracheal Decannulation Bibliography

Part XIX The Cardiovascular System

Section 1 Developmental Biology of the Cardiovascular System Chapter 447 Cardiac Development Bibliography Chapter 448 The Fetal to Neonatal Circulatory Transition Keywords Bibliography

Section 2 Evaluation of the Cardiovascular System and the Child with A Heart Murmur Chapter 449 History and Physical Examination in Cardiac Evaluation History General Physical Examination Cardiac Examination Bibliography Chapter 450 Laboratory Cardiac Evaluation Keywords Developmental Changes

Rate and Rhythm P Waves QRS Complex P-R and Q-T Intervals ST Segment and T-Wave Abnormalities Bibliography M-Mode Echocardiography Two-Dimensional Echocardiography Doppler Echocardiography Three-Dimensional Echocardiography Transesophageal Echocardiography Fetal Echocardiography Bibliography Bibliography Bibliography Diagnostic Cardiac Catheterization Thermodilution Measurement of Cardiac Output Angiocardiography Interventional Cardiac Catheterization Bibliography

Section 3 Congenital Heart Disease Chapter 451 Epidemiology and Genetic Basis of Congenital Heart Disease Prevalence Etiology Next-Generation Genome Sequencing and Congenital Heart Disease Genetic Counseling Bibliography Chapter 452 Evaluation and Screening of the Infant or Child With Congenital Heart Disease Acyanotic Congenital Heart Lesions Cyanotic Congenital Heart Lesions Bibliography Chapter 453 Acyanotic Congenital Heart Disease Bibliography Pathophysiology Clinical Manifestations Diagnosis Complications Treatment

Prognosis Pathophysiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Pathophysiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Pathophysiology Clinical Manifestations Diagnosis Prognosis and Complications Treatment Patent Ductus Arteriosus in Low-Birthweight Infants Bibliography

Chapter 454 Acyanotic Congenital Heart Disease Pathophysiology Clinical Manifestations and Laboratory Findings Treatment Prognosis and Complications Bibliography Pathophysiology Clinical Manifestations Laboratory Findings and Diagnosis Treatment Prognosis Bibliography Pathophysiology Clinical Manifestations Diagnosis Treatment Postcoarctectomy Syndrome Prognosis Bibliography Bibliography

Chapter 455 Acyanotic Congenital Heart Disease Keywords Bibliography Bibliography Bibliography Chapter 456 Cyanotic Congenital Heart Disease Cardiac Disease Leading to Cyanosis Differential Diagnosis Chapter 457 Cyanotic Congenital Heart Disease Pathophysiology Clinical Manifestations Diagnosis Complications Associated Anomalies Treatment Prognosis Bibliography Pathophysiology Clinical Manifestations Diagnosis

Treatment Bibliography Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Pathophysiology Clinical Manifestations Diagnosis Prognosis and Complications Treatment Bibliography Chapter 458 Cyanotic Congenital Heart Disease Clinical Manifestations

Diagnosis Treatment Clinical Manifestations Diagnosis Bibliography Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Pathophysiology Clinical Manifestations Diagnosis Prognosis and Complications Treatment Bibliography Pathophysiology Clinical Manifestations Diagnosis Prognosis and Complications

Treatment Pathophysiology Clinical Manifestations Diagnosis Prognosis and Complications Treatment Prevention Bibliography Bibliography Chapter 459 Other Congenital Heart and Vascular Malformations Right Aortic Arch Vascular Rings Bibliography Anomalous Origin of Left Coronary Artery From Pulmonary Artery Anomalous Origin of Right Coronary Artery From Pulmonary Artery Ectopic Origin of a Coronary Artery From the Aorta With Aberrant Proximal Course Bibliography Bibliography Chapter 460 Pulmonary Hypertension

Pathophysiology Clinical Manifestations Diagnosis Prognosis and Treatment Pathophysiology Pathology and Pathophysiology Clinical Manifestations Diagnosis Treatment Bibliography Chapter 461 General Principles of Treatment of Congenital Heart Disease Postoperative Management Interstage Management Long-Term Management Keywords Long-Term Medical Considerations Specific Lesions Pregnancy and Congenital Heart Disease Contraception Adolescent Transition

Bibliography Bibliography

Section 4 Cardiac Arrhythmias Chapter 462 Disturbances of Rate and Rhythm of the Heart Clinical Manifestations Treatment Bibliography Chapter 463 Sudden Death Mechanism of Sudden Death Congenital Heart Disease Cardiomyopathy Cardiac Arrhythmia Miscellaneous Causes Evaluation and Therapy for Resuscitated Patients Medication for Attention-Deficit/Hyperactivity Disorder Prevention of Sudden Death Bibliography

Section 5 Acquired Heart Disease Chapter 464 Infective Endocarditis Etiology Epidemiology Clinical Manifestations Diagnosis Prognosis and Complications Treatment Prevention Bibliography Chapter 465 Rheumatic Heart Disease Patterns of Valvular Disease Bibliography

Section 6 Diseases of the Myocardium and Pericardium Chapter 466 Diseases of the Myocardium Keywords

Etiology and Epidemiology Pathogenesis Clinical Manifestations Laboratory Findings Prognosis and Management Bibliography Keywords Etiology and Epidemiology Pathogenesis Clinical Manifestations Diagnosis Prognosis and Management Bibliography Keywords Etiology and Epidemiology Pathogenesis Clinical Manifestations Diagnosis Prognosis and Management Bibliography

Keywords Bibliography Keywords Etiology and Epidemiology Pathophysiology Clinical Manifestations Diagnosis Differential Diagnosis Treatment Prognosis Bibliography Chapter 467 Diseases of the Pericardium Keywords Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Keywords Bibliography Chapter 468 Tumors of the Heart

Bibliography

Section 7 Cardiac Therapeutics Chapter 469 Heart Failure Pathophysiology Clinical Manifestations Diagnosis Treatment Electrophysiologic Approaches to Heart Failure Management Mechanical Circulatory Support Bibliography Chapter 470 Pediatric Heart and Heart-Lung Transplantation Indications Recipient and Donor Selection Perioperative Management Diagnosis and Management of Acute Graft Rejection Complications of Immunosuppression Bibliography Bibliography

Section 8 Diseases of the Peripheral Vascular System Chapter 471 Diseases of the Blood Vessels (Aneurysms and Fistulas) Keywords Clinical Manifestations Treatment Arterial Calcifications Caused by Deficiency of CD73 Bibliography Chapter 472 Systemic Hypertension Prevalence of Hypertension in Children Definition of Hypertension Blood Pressure Measurement in Children Etiology and Pathophysiology Clinical Manifestations Diagnosis Prevention Treatment Bibliography

Part XX Diseases of the Blood

Section 1 The Hematopoietic System Chapter 473 Development of the Hematopoietic System Hematopoiesis in the Human Embryo and Fetus Fetal Granulocytopoiesis Fetal Thrombopoiesis Fetal Erythropoiesis Red Cell Life Span in the Fetus and Neonate Bibliography Chapter 474 The Anemias History and Physical Examination Laboratory Studies Differential Diagnosis Bibliography

Section 2 Anemias of Inadequate Production Chapter 475 Congenital Hypoplastic Anemia (Diamond-Blackfan Anemia) Etiology Epidemiology

Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Prognosis Bibliography Chapter 476 Pearson Syndrome Bibliography Chapter 477 Acquired Pure Red Blood Cell Anemia Transient Erythroblastopenia of Childhood Red Cell Aplasia Associated With Parvovirus B19 Infection Other Red Cell Aplasias in Children Bibliography Chapter 478 Anemia of Chronic Disease and Renal Disease Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography

Etiology Laboratory Findings Treatment Bibliography Chapter 479 Congenital Dyserythropoietic Anemias Congenital Dyserythropoietic Anemia Type I Congenital Dyserythropoietic Anemia Type II Congenital Dyserythropoietic Anemia Type III Bibliography Chapter 480 Physiologic Anemia of Infancy Treatment Bibliography Chapter 481 Megaloblastic Anemias Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography Keywords

Metabolism Etiology Clinical Manifestations Laboratory Findings Diagnosis Treatment Bibliography Keywords Bibliography Chapter 482 Iron-Deficiency Anemia Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Prevention Treatment Keywords Etiology Clinical Manifestations Laboratory Findings

Differential Diagnosis Treatment Bibliography Bibliography Chapter 483 Other Microcytic Anemias Infantile Poikilocytosis and Hereditary Pyropoikilocytosis Copper Deficiency Defects of Iron Metabolism Bibliography

Section 3 Hemolytic Anemias Chapter 484 Definitions and Classification of Hemolytic Anemias Bibliography Chapter 485 Hereditary Spherocytosis Etiology Clinical Manifestations Diagnosis Differential Diagnosis Treatment

Bibliography Chapter 486 Hereditary Elliptocytosis, Hereditary Pyropoikilocytosis, and Related Disorders Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography Chapter 487 Hereditary Stomatocytosis Hereditary Xerocytosis Hereditary Hydrocytosis Intermediate Syndromes and Other Variants Other Disorders Associated With Stomatocytosis Bibliography Chapter 488 Paroxysmal Nocturnal Hemoglobinuria and Acanthocytosis Paroxysmal Nocturnal Hemoglobinuria Acanthocytosis Bibliography Chapter 489 Hemoglobinopathies

Hemoglobin Disorders Pathophysiology Diagnosis and Epidemiology Clinical Manifestations and Treatment of Sickle Cell Anemia (HbSS) Therapeutic Considerations Other Sickle Cell Syndromes Anticipatory Guidance Bibliography Bibliography Hemoglobin C Hemoglobin E Hemoglobin D Epidemiology Pathophysiology Homozygous β-Thalassemia (Thalassemia Major, Cooley Anemia) Other β-Thalassemia Syndromes α-Thalassemia Syndromes Bibliography Chapter 490 Enzymatic Defects Keywords

Etiology Clinical Manifestations and Laboratory Findings Treatment Keywords Deficiencies of Enzymes of Hexose Monophosphate Pathway Keywords Episodic or Induced Acute Hemolytic Anemia Chronic Hemolytic Anemias Associated With Deficiency of G6PD or Related Factors Bibliography Chapter 491 Hemolytic Anemias Resulting from Extracellular Factors—Immune Hemolytic Anemias Immune Hemolytic Anemias Autoimmune Hemolytic Anemias Associated With “Warm” Antibodies Autoimmune Hemolytic Anemias Associated With “Cold” Antibodies Bibliography Chapter 492 Hemolytic Anemias Secondary to Other Extracellular Factors Fragmentation Hemolysis Thermal Injury Renal Disease

Liver Disease Toxins and Venoms Wilson Disease Bibliography

Section 4 Polycythemia (Erythrocytosis) Chapter 493 Polycythemia Clonal (Primary) Polycythemia (Polycythemia Vera) Bibliography Chapter 494 Nonclonal Polycythemia Pathogenesis Diagnosis Treatment Bibliography

Section 5 The Pancytopenias Chapter 495 Inherited Bone Marrow Failure Syndromes With Pancytopenia Fanconi Anemia Shwachman-Diamond Syndrome

Dyskeratosis Congenita Congenital Amegakaryocytic Thrombocytopenia Other Inherited Aplastic Anemias Other Inherited Syndromes With Occasional Significant Bone Marrow Failure Unclassified Inherited Bone Marrow Failure Syndromes Bibliography Chapter 496 The Acquired Pancytopenias Etiology and Epidemiology Pathology and Pathogenesis Clinical Manifestations, Laboratory Findings, and Differential Diagnosis Treatment Complications Prognosis Pancytopenia Caused by Marrow Replacement Bibliography

Section 6 Blood Component Transfusions Chapter 497 Red Blood Cell Transfusions and Erythropoietin Therapy

RBC Transfusion in Children and Adolescents RBC Transfusion in Preterm Infants and Neonates RBC Product and Dose Storage Age of RBC Units Bibliography Chapter 498 Platelet Transfusions Children and Adolescents Infants and Neonates Platelet Products and Dosing Bibliography Chapter 499 Neutrophil (Granulocyte) Transfusions Granulocyte Transfusions for Children Granulocyte Transfusion for Neonates Granulocyte Product Bibliography Chapter 500 Plasma Transfusions Plasma Products and Patient Testing Plasma Transfusion in Children Plasma Transfusion in Neonates

Bibliography Chapter 501 Risks of Blood Transfusions Infectious Risks of Transfusion Noninfectious Risks of Transfusion Bibliography

Section 7 Hemorrhagic and Thrombotic Diseases Chapter 502 Hemostasis The Hemostatic Process Pathology Keywords Clinical History Physical Examination Laboratory Tests Developmental Hemostasis Bibliography Chapter 503 Hereditary Clotting Factor Deficiencies (Bleeding Disorders) Keywords Pathophysiology

Clinical Manifestations Laboratory Findings and Diagnosis Differential Diagnosis Genetics and Classification Treatment Prophylaxis Supportive Care Chronic Complications Comprehensive Care Bibliography Keywords Bibliography Keywords Keywords Bibliography Keywords Bibliography Keywords Bibliography Keywords

Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Chapter 504 Von Willebrand Disease Pathophysiology Classification Laboratory Diagnosis Treatment Bibliography Chapter 505 Hereditary Predisposition to Thrombosis Bibliography Chapter 506 Thrombotic Disorders in Children Epidemiology

Clinical Manifestations Diagnosis Laboratory Testing Treatment Complications Keywords Unfractionated Heparin Low-Molecular-Weight Heparin Warfarin Direct Oral Anticoagulants Thrombolytic Therapy Thromboprophylaxis Antiplatelet Therapy Bibliography Chapter 507 Postneonatal Vitamin K Deficiency Bibliography Chapter 508 Liver Disease Bibliography Chapter 509 Acquired Inhibitors of Coagulation

Laboratory Findings Treatment Bibliography Chapter 510 Disseminated Intravascular Coagulation Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography Chapter 511 Platelet and Blood Vessel Disorders Megakaryopoiesis Thrombocytopenia Keywords Epidemiology Pathogenesis Clinical Manifestations Outcome Laboratory Findings Diagnosis and Differential Diagnosis Treatment

Chronic Autoimmune Thrombocytopenic Purpura Bibliography Keywords Bibliography Keywords Keywords Bibliography Keywords Bibliography Keywords Keywords Bibliography Keywords Bibliography Keywords Keywords Bibliography Keywords Bibliography Keywords

Other Hereditary Disorders of Platelet Function Treatment of Patients With Platelet Dysfunction Bibliography Keywords Henoch-Schönlein Purpura Ehlers-Danlos Syndrome Other Acquired Disorders Bibliography

Section 8 The Spleen Chapter 512 Anatomy and Function of the Spleen Anatomy Function Bibliography Chapter 513 Splenomegaly Clinical Manifestations Differential Diagnosis Bibliography Chapter 514 Hyposplenism, Splenic Trauma, and Splenectomy

Hyposplenism Splenic Trauma Splenectomy Bibliography

Section 9 The Lymphatic System Chapter 515 Anatomy and Function of the Lymphatic System Bibliography Chapter 516 Abnormalities of Lymphatic Vessels Lymphatic Malformations Lymphangiectasia Lymphedema Lymphangioleiomyomatosis Lymphangitis Bibliography Chapter 517 Lymphadenopathy Diagnosis Treatment Keywords

Bibliography Keywords Bibliography Keywords Bibliography Bibliography

Part XXI Cancer and Benign Tumors Chapter 518 Epidemiology of Childhood and Adolescent Cancer Influencing the Incidence of Cancer Bibliography Chapter 519 Molecular and Cellular Biology of Cancer Genes Involved in Oncogenesis Syndromes Predisposing to Cancer Other Factors Associated With Oncogenesis Bibliography Chapter 520 Principles of Cancer Diagnosis Signs and Symptoms Physical Examination Age-Related Manifestations

Early Detection Ensuring the Diagnosis Staging Bibliography Chapter 521 Principles of Cancer Treatment Diagnosis and Staging A Multimodal, Multidisciplinary Approach Discussing the Treatment Plan With the Patient and Family Treatments Acute Toxic Effects and Supportive Care Late Adverse Effects Palliative Care Bibliography Chapter 522 The Leukemias Epidemiology Etiology Cellular Classification Clinical Manifestations Diagnosis Differential Diagnosis

Treatment Supportive Care Prognosis Bibliography Keywords Epidemiology Cellular Classification Clinical Manifestations Diagnosis Prognosis and Treatment Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Chapter 523 Lymphoma

Keywords Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Relapse Prognosis Bibliography Keywords Epidemiology Pathogenesis Clinical Manifestations Laboratory Findings Treatment Complications Prognosis Bibliography Keywords Chapter 524 Brain Tumors in Childhood

Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Specific Tumors Complications and Long-Term Management Bibliography Chapter 525 Neuroblastoma Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 526 Neoplasms of the Kidney Keywords Epidemiology Etiology: Genetics and Molecular Biology

Clinical Presentation Diagnosis and Differential Diagnosis Treatment Recurrent Disease Prognosis Late Effects Keywords Mesoblastic Nephroma Clear Cell Sarcoma of the Kidney Rhabdoid Tumor of the Kidney Renal Cell Carcinoma Bibliography Chapter 527 Soft Tissue Sarcomas Rhabdomyosarcoma Other Soft Tissue Sarcomas Bibliography Chapter 528 Neoplasms of Bone Keywords Osteosarcoma Ewing Sarcoma

Keywords Characteristic Lesions of the Tibia Histiocytosis Diagnostic Considerations Vascular Tumors of Bone Bibliography Chapter 529 Retinoblastoma Epidemiology Pathogenesis Screening Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 530 Gonadal and Germ Cell Neoplasms Epidemiology Pathogenesis Clinical Manifestations and Diagnosis Treatment

Prognosis Bibliography Chapter 531 Neoplasms of the Liver Hepatoblastoma Hepatocellular Carcinoma Bibliography Chapter 532 Benign Vascular Tumors Keywords Clinical Manifestations Treatment Bibliography Keywords Bibliography Chapter 533 Rare Tumors Keywords Benign Thyroid Tumors Malignant Thyroid Tumors Bibliography Keywords

Bibliography Keywords Bibliography Keywords Bibliography Keywords Bibliography Chapter 534 Histiocytosis Syndromes of Childhood Classification and Pathology Keywords Clinical Manifestations Treatment and Prognosis Bibliography Keywords Clinical Manifestations Treatment and Prognosis Bibliography Keywords Bibliography

Part XXII Nephrology

Section 1 Glomerular Disease Chapter 535 Introduction to Glomerular Diseases Bibliography Bibliography Pathogenesis Pathology Bibliography

Section 2 Conditions Particularly Associated with Hematuria Chapter 536 Clinical Evaluation of the Child With Hematuria Bibliography Chapter 537 Isolated Glomerular Diseases Associated With Recurrent Gross Hematuria Pathology and Pathologic Diagnosis Clinical and Laboratory Manifestations Prognosis and Treatment Bibliography Genetics

Pathology Clinical Manifestations Diagnosis Prognosis and Treatment Bibliography Bibliography Etiology and Epidemiology Pathology Pathogenesis Clinical Manifestations Diagnosis Complications Prevention Treatment Prognosis Bibliography Pathology Pathogenesis Clinical Manifestations Diagnosis

Prognosis and Treatment Bibliography Pathology Pathogenesis Clinical Manifestations Differential Diagnosis Prognosis and Treatment Bibliography Classification Pathology and Pathogenesis Clinical Manifestations Diagnosis and Differential Diagnosis Prognosis and Treatment Bibliography Chapter 538 Multisystem Disease Associated With Hematuria Bibliography Keywords Pathogenesis and Pathology Clinical Manifestations Diagnosis

Treatment Prognosis Bibliography Keywords Pathogenesis and Pathology Clinical and Laboratory Manifestations Prognosis and Treatment Bibliography Keywords Pathology Clinical Manifestations Diagnosis and Differential Diagnosis Prognosis and Treatment Bibliography Keywords Etiology Pathology Pathogenesis Clinical Manifestations Diagnosis and Differential Diagnosis

Prognosis and Treatment Bibliography Keywords Bibliography Keywords Background Etiology Pathogenesis Clinical Manifestations Laboratory and Radiologic Findings Treatment Prognosis Bibliography Chapter 539 Tubulointerstitial Disease Associated With Hematuria Keywords Acute Tubulointerstitial Nephritis Chronic Tubulointerstitial Nephritis Bibliography Keywords Pathogenesis and Pathology

Clinical Manifestations Diagnosis Treatment and Prognosis Bibliography Keywords Pathogenesis and Pathology Clinical Manifestations Diagnosis Treatment and Prognosis (see also Chapter 550.1) Bibliography Chapter 540 Vascular Diseases Associated with Hematuria Keywords Bibliography Keywords Epidemiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment

Prognosis Bibliography Keywords Etiology Pathology Clinical Manifestations Treatment Prognosis Bibliography Keywords Diagnosis Treatment Bibliography Chapter 541 Anatomic Abnormalities Associated With Hematuria Keywords Pathology Pathogenesis Clinical Manifestations Diagnosis Treatment

Prognosis Bibliography Keywords Pathology Pathogenesis Clinical Presentation Diagnosis Treatment and Prognosis Bibliography Keywords Bibliography Chapter 542 Lower Urinary Tract Causes of Hematuria Keywords Bibliography Keywords Bibliography

Section 3 Conditions Particularly Associated with Proteinuria

Chapter 543 Clinical Evaluation of the Child With Proteinuria Normal Physiology Pathophysiology of Proteinuria Measurement of Urine Protein Clinical Considerations Bibliography Chapter 544 Conditions Associated With Proteinuria Keywords Bibliography Bibliography Keywords Glomerular Proteinuria Tubular Proteinuria Bibliography Chapter 545 Nephrotic Syndrome Etiology Pathogenesis Clinical Consequences of Nephrotic Syndrome Keywords Pathology

Minimal Change Nephrotic Syndrome Bibliography Keywords Bibliography Keywords Bibliography Bibliography

Section 4 Tubular Disorders Chapter 546 Tubular Function Sodium Potassium Calcium Phosphate Magnesium Acidification and Concentrating Mechanisms Developmental Considerations Bibliography Chapter 547 Renal Tubular Acidosis

Normal Urinary Acidification Pathogenesis Clinical Manifestations of Proximal Renal Tubular Acidosis and Fanconi Syndrome Pathogenesis Clinical Manifestations Pathogenesis Clinical Manifestations Diagnostic Approach to Renal Tubular Acidosis Treatment and Prognosis Bibliography Chapter 548 Nephrogenic Diabetes Insipidus Pathogenesis Clinical Manifestations Diagnosis Treatment and Prognosis Bibliography Chapter 549 Inherited Tubular Transport Abnormalities Pathogenesis Clinical Manifestations

Diagnosis Treatment and Prognosis Pathogenesis Clinical Manifestations Diagnosis Treatment Bibliography Chapter 550 Renal Failure Keywords Pathogenesis Clinical Manifestations and Diagnosis Laboratory Findings Treatment Dialysis Prognosis Bibliography Keywords Etiology Pathogenesis Clinical Manifestations

Laboratory Findings Treatment and Management Bibliography Keywords Bibliography Chapter 551 Renal Transplantation Incidence and Etiology of End-Stage Renal Disease Indications for Renal Transplantation Characteristics of Kidney Donors and Recipients Evaluation and Preparing for Kidney Transplantation Immunosuppression Fluid Management in Infants and Small Children Following Kidney Transplantation Rejection of Kidney Transplant Graft Survival of Kidneys Complications of Immunosuppression Long-Term Outcome of Kidney Transplantation Bibliography

Part XXIII Urologic Disorders in Infants and Children

Chapter 552 Congenital Anomalies and Dysgenesis of the Kidneys Embryonic and Fetal Development Renal Agenesis Renal Dysgenesis: Dysplasia, Hypoplasia, and Cystic Anomalies Renal Cysts in Children Anomalies in Shape and Position Associated Physical Findings Bibliography Chapter 553 Urinary Tract Infections Prevalence and Etiology Clinical Manifestations and Classification Pathogenesis and Pathology Diagnosis Imaging Findings Treatment Imaging Studies in Children With a Febrile UTI Prevention of Recurrences Bibliography Chapter 554 Vesicoureteral Reflux Classification

Clinical Manifestations Diagnosis Natural History Treatment Current Vesicoureteral Reflux Guidelines Bibliography Chapter 555 Obstruction of the Urinary Tract Etiology Clinical Manifestations Diagnosis Physical Findings Imaging Studies Specific Types of Urinary Tract Obstruction and Their Treatment Bibliography Chapter 556 Anomalies of the Bladder Bladder Exstrophy Other Exstrophy Anomalies Bladder Diverticula Urachal Anomalies Bibliography

Chapter 557 Neuropathic Bladder Neural Tube Defects Associated Disorders Bibliography Chapter 558 Enuresis and Voiding Dysfunction Normal Voiding and Toilet Training Diurnal Incontinence Overactive Bladder (Diurnal Urge Syndrome) Nonneurogenic Neurogenic Bladder (Hinman Syndrome) Infrequent Voiding (Underactive Bladder) Vaginal Voiding Other Causes of Incontinence in Females Voiding Disorders Without Incontinence Nocturnal Enuresis Bibliography Chapter 559 Anomalies of the Penis and Urethra Hypospadias Chordee Without Hypospadias Phimosis and Paraphimosis Circumcision

Penile Torsion Inconspicuous Penis Micropenis Priapism Other Penile Anomalies Meatal Stenosis Other Male Urethral Anomalies Urethral Prolapse (Female) Other Female Urethral Lesions Bibliography Chapter 560 Disorders and Anomalies of the Scrotal Contents Undescended Testis (Cryptorchidism) Scrotal Swelling Testicular (Spermatic Cord) Torsion Torsion of the Appendix Testis/Epididymis Epididymitis Varicocele Spermatocele Hydrocele Inguinal Hernia

Testicular Microlithiasis Testicular Tumor Bibliography Chapter 561 Trauma to the Genitourinary Tract Etiology Diagnosis Treatment Bibliography Chapter 562 Urinary Lithiasis Stone Formation Clinical Manifestations Diagnosis Metabolic Evaluation Pathogenesis of Specific Renal Calculi Treatment Stone Prevention Bibliography

Part XXIV Gynecologic Problems of Childhood Chapter 563 Gynecologic History and Physical Examination

History Gynecologic Examination Bibliography Chapter 564 Vulvovaginitis Etiology Epidemiology Clinical Manifestations Diagnosis and Differential Diagnosis Treatment and Prevention Bibliography Chapter 565 Vaginal Bleeding in the Prepubertal Child Bibliography Chapter 566 Breast Concerns Breast Development Breast Evaluation Breast Self-Awareness Abnormal Development Breast Masses Cosmetic Surgery

Bibliography Chapter 567 Polycystic Ovary Syndrome and Hirsutism Polycystic Ovary Syndrome Hirsutism Bibliography Chapter 568 Gynecologic Neoplasms and Adolescent Prevention Methods for Human Papillomavirus Overview of Gynecologic Malignancies in Children and Adolescents Impact of Cancer Therapy on Fertility Ovarian Neoplasms Uterine Malignancies Vaginal Malignancies Vulvar Malignancies Cervical Malignancies and Their Prevention Bibliography Chapter 569 Vulvovaginal and Müllerian Anomalies Embryology Epidemiology Clinical Manifestations Laboratory Findings

Uterine Anomalies Vaginal Anomalies Cervical Anomalies Vulvar and Other Anomalies Bibliography Chapter 570 Gynecologic Care for Girls With Special Needs Sexuality and Sexual Education Abuse Pelvic Examination Menstruation Contraception Bibliography Chapter 571 Female Genital Mutilation Background Complications Clinical Management of FGM Bibliography

Part XXV The Endocrine System

Section 1 Disorders of the Hypothalamus and Pituitary Gland Chapter 572 Hormones of the Hypothalamus and Pituitary Anatomy Embryology Vascular Supply Anterior Pituitary Cell Types Posterior Pituitary Cell Types Bibliography Chapter 573 Hypopituitarism Multiple Pituitary Hormone Deficiency Isolated Growth Hormone Deficiency and Insensitivity Growth Hormone Insensitivity Clinical Manifestations Laboratory Findings Radiologic Findings Differential Diagnosis Treatment Complications and Adverse Effects of Growth Hormone Treatment

Bibliography Chapter 574 Diabetes Insipidus Physiology of Water Balance Approach to the Patient With Polyuria, Polydipsia, and Hypernatremia Causes of Hypernatremia Treatment of Central Diabetes Insipidus Treatment of Nephrogenic Diabetes Insipidus Bibliography Chapter 575 Other Abnormalities of Arginine Vasopressin Metabolism and Action Causes of Hyponatremia Treatment Bibliography Chapter 576 Hyperpituitarism, Tall Stature, and Overgrowth Syndromes Hyperpituitarism Tall Stature Sotos Syndrome (Cerebral Gigantism) Treatment of Normal Variant Tall Stature Excess Growth Hormone Secretion and Pituitary Gigantism

Hypersecretion of Other Pituitary Hormones Bibliography Chapter 577 Physiology of Puberty Bibliography Chapter 578 Disorders of Pubertal Development Keywords Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography Keywords Etiology Clinical Manifestations Treatment Bibliography Keywords Treatment Bibliography Keywords

Keywords Hepatic Tumors Intracranial Tumors Tumors in Other Locations Peripheral Precocious Puberty Bibliography Keywords Extragonadal Manifestations Bibliography Keywords Treatment Bibliography Keywords Premature Thelarche Premature Pubarche (Adrenarche) Premature Menarche Bibliography Keywords Keywords Differential Diagnosis

Diagnostic Approach to Delayed Puberty Treatment of Delayed Puberty Bibliography

Section 2 Disorders of the Thyroid Gland Chapter 579 Thyroid Development and Physiology Fetal Development Thyroid Physiology Thyroid Regulation Serum Thyroid Hormones Fetal and Newborn Thyroid Serum Thyroxine-Binding Globulin Radionuclide Studies Thyroid Ultrasonography Bibliography Bibliography Chapter 580 Disorders of Thyroxine-Binding Globulin Bibliography Chapter 581 Hypothyroidism

Congenital Hypothyroidism Acquired Hypothyroidism Bibliography Chapter 582 Thyroiditis Thyroiditis With Pain Thyroiditis Without Pain Other Causes of Thyroiditis Bibliography Chapter 583 Goiter Keywords Bibliography Keywords Keywords Etiology Clinical Manifestations Pathogenesis Treatment Bibliography Keywords Iodide Goiter

Simple Goiter (Colloid Goiter) Multinodular Goiter Toxic Goiter (Hyperthyroidism) Bibliography Chapter 584 Thyrotoxicosis Keywords Epidemiology Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography Keywords Etiology and Pathogenesis Clinical Manifestations Treatment Prognosis Bibliography Chapter 585 Carcinoma of the Thyroid

Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prognosis Medullary Thyroid Carcinoma Bibliography Bibliography Chapter 586 Autoimmune Polyglandular Syndromes Monogenic Autoimmune Polyglandular Syndromes Autoimmune Polyglandular Syndrome Type 1 Immune Dysregulation-Polyendocrinopathy-Enteropathy X-Linked Other Monogenic Immune Dysregulation Disorders Polygenic Autoimmune Polyglandular Syndrome (APS-2) Chromosomal Abnormalities Associated With Autoimmune Polyglandular Syndrome Nongenetic Autoimmune Causes of Multiple Endocrinopathy Bibliography Chapter 587 Multiple Endocrine Neoplasia Syndromes

Multiple Endocrine Neoplasia Type 1 Multiple Endocrine Neoplasia Type 2 Multiple Endocrine Neoplasia Type 2A Multiple Endocrine Neoplasia Type 2B Familial Medullary Thyroid Carcinoma Management of Multiple Endocrine Neoplasia Type 2 Bibliography

Section 3 Disorders of the Parathyroid Gland Chapter 588 Hormones and Peptides of Calcium Homeostasis and Bone Metabolism Parathyroid Hormone Parathyroid Hormone–Related Peptide Vitamin D Calcitonin Bibliography Chapter 589 Hypoparathyroidism Etiology Aplasia or Hypoplasia of the Parathyroid Glands X-Linked Recessive Hypoparathyroidism

Autosomal Recessive Hypoparathyroidism With Dysmorphic Features Hypoparathyroidism, Sensorineural Deafness, and Renal Anomaly Syndrome Suppression of Neonatal Parathyroid Hormone Secretion Because of Maternal Hyperparathyroidism Autosomal Dominant Hypoparathyroidism Hypoparathyroidism Associated With Mitochondrial Disorders Surgical Hypoparathyroidism Autoimmune Hypoparathyroidism Idiopathic Hypoparathyroidism Bibliography Chapter 590 Pseudohypoparathyroidism Type Ia Type Ib Acrodysostosis With Hormone Resistance Bibliography Chapter 591 Hyperparathyroidism Etiology Clinical Manifestations Laboratory Findings

Differential Diagnosis Treatment Prognosis Familial Hypocalciuric Hypercalcemia (Familial Benign Hypercalcemia) Granulomatous Diseases Hypercalcemia of Malignancy Miscellaneous Causes of Hypercalcemia Bibliography

Section 4 Disorders of the Adrenal Gland Chapter 592 Physiology of the Adrenal Gland Keywords Bibliography Keywords Zona Glomerulosa Zona Fasciculata Zona Reticularis Fetoplacental Unit Bibliography

Keywords Regulation of Cortisol Secretion Regulation of Aldosterone Secretion Regulation of Adrenal Androgen Secretion Bibliography Keywords Actions of Glucocorticoids Metabolic Effects Actions of Mineralocorticoids Actions of the Adrenal Androgens Bibliography Keywords Bibliography Chapter 593 Adrenocortical Insufficiency Keywords Inherited Etiologies Acquired Etiologies Laboratory Findings Differential Diagnosis Treatment

Bibliography Keywords Etiology Clinical Presentation Laboratory Findings Treatment Bibliography Keywords Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography Keywords Generalized Glucocorticoid Resistance Cortisone Reductase Deficiency Altered End-Organ Sensitivity to Mineralocorticoids Apparent Mineralocorticoid Excess Liddle Syndrome Bibliography

Chapter 594 Congenital Adrenal Hyperplasia and Related Disorders Keywords Etiology Epidemiology Genetics Pathogenesis and Clinical Manifestations Laboratory Findings Differential Diagnosis Prenatal Diagnosis Newborn Screening Treatment Bibliography Keywords Etiology Epidemiology Clinical Manifestations Laboratory Findings Treatment Bibliography Keywords

Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography Keywords Etiology Clinical Manifestations and Laboratory Findings Treatment Bibliography Keywords Etiology Clinical Manifestations Laboratory Findings Treatment Bibliography Keywords Etiology, Pathogenesis, and Clinical Manifestations Epidemiology

Laboratory Findings Differential Diagnosis Bibliography Keywords Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography Keywords Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Genetic Counseling Bibliography Chapter 595 Adrenocortical Tumors and Masses Epidemiology

Keywords Etiology Clinical Manifestations Pathologic Findings Differential Diagnosis Treatment Keywords Bibliography Chapter 596 Virilizing and Feminizing Adrenal Tumors Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Chapter 597 Cushing Syndrome Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography

Chapter 598 Primary Aldosteronism Etiology Epidemiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography Chapter 599 Pheochromocytoma Etiology Clinical Manifestations Laboratory Findings Differential Diagnosis Treatment Bibliography

Section 5 Disorders of the Gonads Chapter 600 Development and Function of the Gonads Genetic Control of Embryonic Gonadal Differentiation

Function of the Testes Function of the Ovaries Diagnostic Testing Therapeutic Use of Sex Steroids Bibliography Chapter 601 Hypofunction of the Testes Keywords Etiology Clinical Manifestations Diagnosis Noonan Syndrome Klinefelter Syndrome XX Males 45,X Males 47,XXX Males Bibliography Keywords Etiology Diagnosis Bibliography

Chapter 602 Pseudoprecocity Resulting From Tumors of the Testes Bibliography Chapter 603 Gynecomastia Physiologic Forms of Gynecomastia Evaluation of Gynecomastia Treatment Bibliography Chapter 604 Hypofunction of the Ovaries Keywords Turner Syndrome XX Gonadal Dysgenesis 45,X/46,XY Gonadal Dysgenesis XXX, XXXX, and XXXXX Females Noonan Syndrome Other Ovarian Defects Bibliography Keywords Etiology Diagnosis Bibliography

Chapter 605 Pseudoprecocity Resulting From Lesions of the Ovary Estrogenic Lesions of the Ovary Androgenic Lesions of the Ovary Bibliography Chapter 606 Disorders of Sex Development Sex Differentiation Diagnostic Approach to the Patient With Atypical or Ambiguous Genitalia Keywords Congenital Adrenal Hyperplasia Aromatase Deficiency Cortisol Resistance Due to Glucocorticoid Receptor Gene Mutation Virilizing Maternal Tumors Exposure to Androgenic Drugs by Women During Pregnancy Bibliography Keywords Defects in Testicular Differentiation Defiency of Testicular Hormone Production Defects in Androgen Action Undetermined Causes

Bibliography Keywords Diagnosis and Management of Disorders of Sex Development Bibliography Bibliography

Section 6 Diabetes Mellitus in Children Chapter 607 Diabetes Mellitus Keywords Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Other Specific Types of Diabetes Other Etiologies of Diabetes Prediabetes Keywords Epidemiology Genetics Environmental Factors Pathogenesis and Natural History of Type 1 Diabetes Mellitus Prediction and Prevention

Pathophysiology Clinical Manifestations Diagnosis Treatment Initiation of Subcutaneous Insulin Therapy Cognitive Function Coping Styles Nonadherence Anxiety and Depression Fear of Self-Injecting and Self-Testing Eating Disorders Long-Term Complications: Relation to Glycemic Control Diabetic Neuropathy Prognosis Pancreas and Islet Transplantation and Regeneration Natural History Epidemiology Genetics Epigenetics and Fetal Programming Environmental and Lifestyle-Related Risk Factors

Clinical Features Treatment Complications Prevention Keywords Genetic Defects of β-Cell Function Genetic Defects of Insulin Action Cystic Fibrosis–Related Diabetes Endocrinopathies Drugs Genetic Syndromes Associated With Diabetes Mellitus Autoimmune Diseases Associated With T1DM Bibliography

Part XXVI The Nervous System Chapter 608 Neurologic Evaluation History Neurologic Examination General Examination Special Diagnostic Procedures Bibliography

Chapter 609 Congenital Anomalies of the Central Nervous System Hydrocephalus Etiology Prevention Clinical Manifestations Treatment Prognosis Bibliography Bibliography Lissencephaly Schizencephaly Neuronal Heterotopias Polymicrogyrias Focal Cortical Dysplasias Porencephaly Bibliography Holoprosencephaly Bibliography Congenital Cranial Dysinnervation Disorders Brainstem and Cerebellar Disorders

Bibliography Etiology Clinical Manifestations and Diagnosis Treatment Bibliography Physiology Pathophysiology and Etiology Clinical Manifestations Diagnosis and Differential Diagnosis Megalencephaly Hydranencephaly Treatment Prognosis Bibliography Development and Etiology Clinical Manifestations and Treatment Bibliography Bibliography Chapter 610 Deformational Plagiocephaly Epidemiology and Etiology

Examination and Differentiating Between Deformational Plagiocephaly and Craniosynostosis Treatment Outcomes Bibliography Chapter 611 Seizures in Childhood Evaluation of the First Seizure Keywords Genetic and Other Factors Leading to Febrile Seizures Evaluation Treatment Bibliography Keywords History and Examination Differential Diagnosis Long-Term Approach to the Patient and Additional Testing Bibliography Keywords Focal Seizures With Preserved Awareness Focal Seizures With Impaired Awareness

Focal to Bilateral Tonic-Clonic Seizures Benign Epilepsy Syndromes With Focal Seizures Severe Epilepsy Syndromes With Focal Seizures Bibliography Keywords Absence Seizures Generalized Motor Seizures Benign Generalized Epilepsies Severe Generalized Epilepsies Keywords Bibliography Keywords Deciding on Long-Term Therapy Counseling Mechanisms of Action of Antiepileptic Drugs Choice of Drug According to Seizure Type and Epilepsy Syndrome Choice of Drug: Other Considerations Initiating and Monitoring Therapy Side Effects Additional Treatments

Approach to Epilepsy Surgery Discontinuation of Therapy Sudden Unexpected Death in Epilepsy (SUDEP) Bibliography Keywords Pathophysiology Types of Neonatal Seizures Etiology Diagnosis Prognosis Treatment Bibliography Keywords Etiology Mechanisms Therapy Bibliography Keyword Bibliography Keywords

Bibliography Chapter 612 Conditions That Mimic Seizures Syncope and Other Generalized Paroxysms Movement Disorders and Other Paroxysmal Movements and Postures Oculomotor and Visual Abnormalities Sleep-Related Disorders Bibliography Chapter 613 Headaches Epidemiology Classification and Clinical Manifestations Diagnosis and Differential Diagnosis Treatment Bibliography Bibliography Bibliography Chapter 614 Neurocutaneous Syndromes Clinical Manifestations and Diagnosis Management Genetic Counseling

Bibliography Clinical Manifestations and Diagnosis Management Bibliography Etiology Clinical Manifestations Diagnosis Management Bibliography Bibliography Bibliography Bibliography Clinical Manifestations and Diagnosis Management Bibliography Chapter 615 Movement Disorders Bibliography Bibliography Bibliography Keywords

Inherited Primary Dystonias Drug-Induced Dystonias Cerebral Palsy Metabolic Disorders Other Disorders Treatment Bibliography Bibliography Chapter 616 Encephalopathies Epidemiology and Etiology Clinical Manifestations Diagnosis Treatment Bibliography Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes Myoclonic Epilepsy and Ragged Red Fibers Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) Syndrome Leber Hereditary Optic Neuropathy (LHON) Kearns-Sayre Syndrome (KSS)

Reversible Infantile Cytochrome C Oxidase Deficiency Myopathy Leigh Disease (Subacute Necrotizing Encephalomyopathy) Mitochondrial DNA Depletion Syndrome Reye Syndrome Bibliography Human Immunodeficiency Virus (HIV) Encephalopathy Lead Encephalopathy Burn Encephalopathy Hypertensive Encephalopathy Radiation Encephalopathy Acute Necrotizing Encephalopathy Cystic Leukoencephalopathy Bibliography Keywords Anti-N -Methyl-D-Aspartate Receptor Encephalitis Other Types of Encephalitis Associated With Antibodies Against Neuronal Cell Surface Antigens Acquired Demyelinating Syndromes With Encephalopathy Hashimoto Encephalopathy Opsoclonus–Myoclonus and Other Types of Brainstem–Cerebellar Encephalitis

Bickerstaff Encephalitis Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids Autoimmune Encephalopathies Associated With Epilepsy and Status Epilepticus Other Suspected Types of Autoimmune Encephalitis Bibliography Chapter 617 Neurodegenerative Disorders of Childhood Keywords Gangliosidoses Krabbe Disease (Globoid Cell Leukodystrophy) Metachromatic Leukodystrophy Bibliography Keywords Bibliography Keywords Bibliography Keywords Pelizaeus-Merzbacher Disease Alexander Disease Canavan Spongy Degeneration

Other Leukodystrophies Menkes Disease Rett Syndrome Neurodegeneration With Brain Iron Accumulation Bibliography Chapter 618 Demyelinating Disorders of the Central Nervous System Epidemiology Pathogenesis Clinical Manifestations Neuroimaging Laboratory Findings Differential Diagnosis Treatment Prognosis Bibliography Epidemiology and Clinical Presentation Diagnostic Evaluation Treatment Prognosis Bibliography

Epidemiology Clinical Manifestations Diagnostic Evaluation Treatment Prognosis Bibliography Epidemiology and Risk Factors Pathogenesis Clinical Manifestations Imaging and Laboratory Findings Diagnosis and Differential Diagnosis Treatment Prognosis Bibliography Epidemiology Pathogenesis Clinical Manifestations Imaging and Laboratory Findings Diagnosis and Differential Diagnosis Treatment

Prognosis Bibliography Clinical Presentation Imaging and Laboratory Findings Treatment Prognosis Bibliography Bibliography Chapter 619 Pediatric Stroke Perinatal Arterial Ischemic Stroke Bibliography Keywords Bibliography Keywords Vasculitic Processes: Systemic Lupus Erythematosus Spinal Cord Embolism Treatment Bibliography Keywords Bibliography

Migraine Seizure Infection Demyelination Hypoglycemia Global Hypoxic-Ischemic Encephalopathy Hypertensive Encephalopathy Inborn Errors of Metabolism Vestibulopathy and Ataxia Channelopathies Alternating Hemiplegia of Childhood Chapter 620 Central Nervous System Vasculitis Epidemiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 621 Central Nervous System Infections Epidemiology

Pathology and Pathophysiology Pathogenesis Clinical Manifestations Diagnosis Differential Diagnosis Treatment Complications Prognosis Prevention Bibliography Etiology Epidemiology Pathogenesis and Pathology Clinical Manifestations Diagnosis Differential Diagnosis Treatment Prognosis Prevention Bibliography

Etiology Epidemiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 622 Brain Abscess Pathology Etiology Clinical Manifestations Diagnosis Treatment Prognosis Bibliography Chapter 623 Idiopathic Intracranial Hypertension (Pseudotumor Cerebri) Etiology Clinical Manifestations Treatment Bibliography

Chapter 624 Spinal Cord Disorders Clinical Manifestations Diagnostic Evaluation Treatment Outcome Bibliography Clinical Manifestations Diagnostic Evaluation Treatment Bibliography Clinical Manifestations Diagnostic Evaluation Treatment Bibliography Clinical Manifestations Diagnostic Evaluation Treatment Outcome Bibliography Diagnostic Evaluation

Treatment Bibliography

Part XXVII Neuromuscular Disorders Chapter 625 Evaluation and Investigation of Neuromuscular Disorders Genetic Testing Clinical Manifestations Laboratory Findings Imaging of Muscles and the Central Nervous System Muscle Biopsy Nerve Biopsy Cardiac Assessment Bibliography Chapter 626 Developmental Disorders of Muscle Myogenic Regulatory Genes and Genetic Loci of Inherited Diseases of Muscle Treatment of Congenital Myopathies Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis

Genetics Treatment Prognosis Bibliography Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Genetics Treatment Bibliography Clinical Manifestations Laboratory Findings Genetics Treatment and Prognosis Bibliography Clinical Manifestations Laboratory Findings Genetics Treatment and Prognosis

Bibliography Clinical Manifestations and MFM Subtypes According to Genetic Background Laboratory Findings Treatment Bibliography Bibliography Bibliography Bibliography Bibliography Fetal Movement and the Link to Arthrogryposis Basic Categories, Etiologies, and Classifications Diagnostic Approach and Laboratory Evaluation Differential Diagnosis Genetic Counseling and Prenatal Diagnosis Management Bibliography Bibliography Chapter 627 Muscular Dystrophies Clinical Manifestations

Laboratory Findings Diagnosis Genetic Etiology and Pathogenesis Treatment Bibliography Genetics Diagnostics Bibliography Clinical Manifestations Laboratory Findings Diagnosis Genetics Treatment Other Myotonic Syndromes Bibliography Bibliography Clinical Manifestations Laboratory Findings Diagnosis and Differential Diagnosis Treatment

Bibliography Clinical Manifestations Laboratory Findings Diagnosis Treatment Bibliography Chapter 628 Endocrine and Toxic Myopathies Thyroid Myopathies Steroid-Hormone Induced Myopathy Statin-Induced Rhabdomyolysis With Myoglobinuria Mitochondrial Dysfunction in Toxic Myopathies Critical Illness Myopathy Bibliography Chapter 629 Metabolic Myopathies and Channelopathies Treatment Other Muscle Channelopathies Bibliography Bibliography Bibliography Investigations

Treatment Bibliography Bibliography Bibliography Chapter 630 Disorders of Neuromuscular Transmission and of Motor Neurons Autoimmune Myasthenia Gravis Clinical Manifestations Congenital Myasthenic Syndromes Rare Other Causes of Myasthenia Laboratory Findings and Diagnosis Treatment Complications Prognosis Other Causes of Neuromuscular Blockade Bibliography Etiology Clinical Manifestations and Course Laboratory Findings Diagnosis Genetics

Management Bibliography Bibliography Chapter 631 Hereditary Motor-Sensory Neuropathies Clinical Manifestations Laboratory Findings and Diagnosis Treatment Bibliography Bibliography Bibliography Bibliography Clinical Manifestations Laboratory Findings Treatment Bibliography Bibliography Bibliography Bibliography Chapter 632 Toxic Neuropathies Bibliography

Chapter 633 Autonomic Neuropathies Pathology Clinical Manifestations Laboratory Findings Diagnosis Treatment Prognosis Bibliography Congenital Insensitivity to Pain and Anhidrosis Allgrove Syndrome (Triple a Syndrome) Bibliography Chapter 634 Guillain-Barré Syndrome Clinical Manifestations Laboratory Findings and Diagnosis Treatment Prognosis Bibliography Chapter 635 Bell Palsy Clinical Manifestations Treatment

Prognosis Facial Palsy at Birth Bibliography

Part XXVIII Disorders of the Eye Chapter 636 Growth and Development of the Eye Bibliography Chapter 637 Examination of the Eye Visual Acuity Visual Field Assessment Color Vision Testing Pupillary Examination Ocular Motility Binocular Vision External Examination Biomicroscopy (Slit-Lamp Examination) Fundus Examination (Ophthalmoscopy) Refraction Tonometry Bibliography

Chapter 638 Abnormalities of Refraction and Accommodation Hyperopia Myopia Astigmatism Anisometropia Accommodation Bibliography Chapter 639 Disorders of Vision Amblyopia Diplopia Suppression Amaurosis Nyctalopia Psychogenic Disturbances Dyslexia Bibliography Chapter 640 Abnormalities of Pupil and Iris Aniridia Coloboma of the Iris Microcoria

Congenital Mydriasis Dyscoria and Corectopia Anisocoria Dilated Fixed Pupil Tonic Pupil Marcus Gunn Pupil Horner Syndrome Paradoxical Pupil Reaction Persistent Pupillary Membrane Heterochromia Other Iris Lesions Leukocoria Bibliography Chapter 641 Disorders of Eye Movement and Alignment Strabismus Congenital Ocular Motor Apraxia Nystagmus Other Abnormal Eye Movements Bibliography Chapter 642 Abnormalities of the Lids

Ptosis Epicanthal Folds Lagophthalmos Lid Retraction Ectropion, Entropion, and Epiblepharon Blepharospasm Blepharitis Hordeolum (Stye) Chalazion Coloboma of the Eyelid Tumors of the Lid Bibliography Chapter 643 Disorders of the Lacrimal System The Tear Film Dacryostenosis Alacrima and “Dry Eye” Bibliography Chapter 644 Disorders of the Conjunctiva Conjunctivitis Bibliography

Chapter 645 Abnormalities of the Cornea Megalocornea Microcornea Keratoconus Neonatal Corneal Opacities Sclerocornea Peters Anomaly Corneal Dystrophies Dermoids Dendritic Keratitis Corneal Ulcers Phlyctenules Interstitial Keratitis Corneal Manifestations of Systemic Disease Bibliography Chapter 646 Abnormalities of the Lens Cataracts Ectopia Lentis Other Disorders of the Lens Bibliography

Chapter 647 Disorders of the Uveal Tract Uveitis (Iritis, Cyclitis, Chorioretinitis) Bibliography Chapter 648 Disorders of the Retina and Vitreous Retinopathy of Prematurity Persistent Fetal Vasculature Retinoblastoma Retinitis Pigmentosa Stargardt Disease (Fundus Flavimaculatus) Best Vitelliform Degeneration Cherry-Red Spot Phakomas Retinoschisis Retinal Detachment Coats Disease Familial Exudative Vitreoretinopathy Hypertensive Retinopathy Diabetic Retinopathy Subacute Bacterial Endocarditis Blood Disorders

Trauma-Related Retinopathy Myelinated Nerve Fibers Coloboma of the Fundus Bibliography Chapter 649 Abnormalities of the Optic Nerve Optic Nerve Aplasia Optic Nerve Hypoplasia Optic Nerve Coloboma Morning Glory Disc Anomaly Tilted Disc Drusen of the Optic Nerve Papilledema Optic Neuritis Leber Optic Neuropathy Optic Atrophy Optic Nerve Glioma Traumatic Optic Neuropathies Bibliography Chapter 650 Childhood Glaucoma Clinical Manifestations

Diagnosis and Treatment Bibliography Chapter 651 Orbital Abnormalities Hypertelorism and Hypotelorism Exophthalmos and Enophthalmos Orbital Inflammation Tumors of the Orbit Bibliography Chapter 652 Orbital Infections Dacryoadenitis Dacryocystitis Preseptal Cellulitis Orbital Cellulitis Bibliography Chapter 653 Injuries to the Eye Ecchymosis and Swelling of the Eyelids Lacerations of the Eyelids Superficial Abrasions of the Cornea Foreign Body Involving the Ocular Surface

Hyphema Open Globe Optic Nerve Trauma Chemical Injuries Orbital Fractures Penetrating Wounds of the Orbit Child Abuse Fireworks-Related Injuries Sports-Related Ocular Injuries and Their Prevention Handheld Laser Retinal Injury Bibliography

Part XXIX The Ear Chapter 654 General Considerations and Evaluation of the Ear Clinical Manifestations Facial Paralysis Physical Examination Bibliography Chapter 655 Hearing Loss Incidence and Prevalence

Types of Hearing Loss Etiology Effects of Hearing Impairment Hearing Screening Identification of Hearing Impairment Clinical Audiologic Evaluation Treatment Genetic Counseling Bibliography Chapter 656 Congenital Malformations of the Ear Pinna Malformations Congenital Stenosis or Atresia of the External Auditory Canal Congenital Middle-Ear Malformations Congenital Inner Ear Malformations Congenital Cholesteatoma Bibliography Chapter 657 External Otitis (Otitis Externa) Etiology Clinical Manifestations Diagnosis

Treatment Prevention Other Diseases of the External Ear Bibliography Chapter 658 Otitis Media Epidemiology Etiology Pathogenesis Clinical Manifestations Examination of the Tympanic Membrane Prevention Immunoprophylaxis and Vaccination Status Treatment Antimicrobial Prophylaxis Management of Otitis Media With Effusion Intracranial Complications Possible Developmental Sequelae Bibliography Chapter 659 Acute Mastoiditis Anatomy

Epidemiology Microbiology Clinical Manifestations Imaging Management Special Situations Bibliography Chapter 660 The Inner Ear and Diseases of the Bony Labyrinth Other Diseases of the Inner Ear Bibliography Chapter 661 Traumatic Injuries of the Ear and Temporal Bone Auricle and External Auditory Canal Tympanic Membrane and Middle Ear Temporal Bone Fractures Acoustic Trauma Bibliography Chapter 662 Tumors of the Ear and Temporal Bone Bibliography

Part XXX The Skin

Chapter 663 Morphology of the Skin Epidermis Dermis Subcutaneous Tissue Appendageal Structures Bibliography Chapter 664 Dermatologic Evaluation of the Patient History and Physical Examination Biopsy of Skin Wood Lamp Potassium Hydroxide Preparation Tzanck Smear Immunofluorescence Studies Connective Tissue Diseases Vasculitides Gastrointestinal Diseases Cutaneous Manifestations of Malignancy Cutaneous Reactions in the Setting of Immunosuppression Drug Rash With Eosinophilia and Systemic Symptoms (DRESS Syndrome)

Serum Sickness–Like Reaction Acute Generalized Exanthematous Pustulosis Bibliography Chapter 665 Principles of Dermatologic Therapy Wet Dressings Bath Oils, Colloids, Soaps Lubricants Shampoos Shake Lotions Powders Pastes Keratolytic Agents Tar Compounds Antifungal Agents Topical Antibiotics Topical Corticosteroids Topical Nonsteroidal Antiinflammatory Agents Sunscreens Laser Therapy Bibliography

Chapter 666 Dermatologic Diseases of the Neonate Sebaceous Hyperplasia Milia Sucking Blisters Cutis Marmorata Harlequin Color Change Nevus Simplex (Salmon Patch) Dermal Melanocytosis (Mongolian Spots) Erythema Toxicum Transient Neonatal Pustular Melanosis Infantile Acropustulosis Eosinophilic Pustular Folliculitis Bibliography Chapter 667 Cutaneous Defects Skin Dimples Redundant Skin Amniotic Constriction Bands Preauricular Sinuses and Pits Accessory Tragi Branchial Cleft and Thyroglossal Cysts and Sinuses

Supernumerary Nipples Aplasia Cutis Congenita (Congenital Absence of Skin) Focal Facial Dermal Dysplasias Focal Dermal Hypoplasia (Goltz-Gorlin Syndrome) Dyskeratosis Congenita (Zinsser-Engman-Cole Syndrome) Cutis Verticis Gyrata Bibliography Chapter 668 Ectodermal Dysplasias Hypohidrotic Ectodermal Dysplasia Hidrotic Ectodermal Dysplasia (Clouston Syndrome) Bibliography Chapter 669 Vascular Disorders Vascular Malformations Lymphatic Malformations Arteriovenous Malformation Klippel-Trenaunay and Parkes-Weber Syndromes Phakomatosis Pigmentovascularis Nevus Anemicus Vascular Tumors Bibliography

Chapter 670 Cutaneous Nevi Acquired Melanocytic Nevus Atypical Melanocytic Nevus Congenital Melanocytic Nevus Melanoma Halo Nevus Spitz Nevus (Spindle and Epithelioid Cell Nevus) Zosteriform Lentiginous Nevus (Agminated Lentigines) Nevus Spilus (Speckled Lentiginous Nevus) Nevus of Ota and Nevus of Ito Blue Nevi Nevus Depigmentosus (Achromic Nevus) Epidermal Nevi Nevus Comedonicus Connective Tissue Nevus Smooth Muscle Hamartoma Bibliography Chapter 671 Hyperpigmented Lesions Disorders of Pigment Ephelides (Freckles)

Lentigines Café-Au-Lait Spots Incontinentia Pigmenti (Bloch-Sulzberger Disease) PostInflammatory Pigmentary Changes Bibliography Chapter 672 Hypopigmented Lesions Albinism Melanoblast Migration Abnormalities Bibliography Chapter 673 Vesiculobullous Disorders Keywords Etiology Clinical Manifestations Bibliography Keywords Etiology Bibliography Keywords Epidemiology and Etiology Clinical Manifestations

Treatment Bibliography Keywords Epidermolysis Bullosa Epidermolysis Bullosa Simplex Junctional Epidermolysis Bullosa Dystrophic Epidermolysis Bullosa Kindler Syndrome Bibliography Keywords Pemphigus Vulgaris Pemphigus Foliaceus Bullous Pemphigoid Bibliography Keywords Etiology/Pathogenesis Clinical Manifestations Pathology Differential Diagnosis Treatment

Bibliography Keywords Etiology/Pathogenesis Clinical Manifestations Pathology Differential Diagnosis Treatment Bibliography Chapter 674 Eczematous Disorders Irritant Contact Dermatitis Diaper Dermatitis Allergic Contact Dermatitis Bibliography Bibliography Bibliography Bibliography Etiology Clinical Manifestations Differential Diagnosis Treatment

Bibliography Chapter 675 Photosensitivity Acute Sunburn Reaction Photosensitive Reactions Porphyrias Colloid Milium Hydroa Vacciniforme Solar Urticaria Polymorphous Light Eruption Actinic Prurigo Cockayne Syndrome Xeroderma Pigmentosum Rothmund-Thomson Syndrome Bloom Syndrome Hartnup Disease Bibliography Chapter 676 Diseases of the Epidermis Etiology/Pathogenesis Clinical Manifestations Differential Diagnosis

Pathology Treatment Prognosis Bibliography Etiology/Pathogenesis Clinical Manifestations Pathology Differential Diagnosis Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations Differential Diagnosis Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations Differential Diagnosis Histology Treatment

Bibliography Etiology/Pathogenesis Clinical Manifestations Histology Differential Diagnosis Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations Differential Diagnosis Histology Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations Differential Diagnosis Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations

Histology Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations Histology Differential Diagnosis Treatment Prognosis Bibliography Etiology/Pathogenesis Clinical Manifestations Histology Differential Diagnosis Treatment Bibliography Etiology/Pathogenesis Clinical Manifestations Histology Treatment

Bibliography Chapter 677 Disorders of Keratinization Disorders of Cornification Collodion Baby Nonsyndromic Ichthyoses Autosomal Recessive Congenital Ichthyoses Keratinopathic Ichthyoses Other Nonsyndromic Ichthyoses Syndromic Ichthyoses Other Syndromes With Ichthyosis Bibliography Chapter 678 Diseases of the Dermis Keloid Striae Cutis Distensae (Stretch Marks) Corticosteroid-Induced Atrophy Granuloma Annulare Necrobiosis Lipoidica Lichen Sclerosus Morphea Scleredema (Scleredema Adultorum, Scleredema of Buschke)

Lipoid Proteinosis (Urbach-Wiethe Disease, Hyalinosis Cutis Et Mucosae) Macular Atrophy (Anetoderma) Cutis Laxa (Dermatomegaly, Generalized Elastolysis) Pseudoxanthoma Elasticum Elastosis Perforans Serpiginosa Reactive Perforating Collagenosis Xanthomas Fabry Disease Mucopolysaccharidoses Mastocytosis Keywords Bibliography Bibliography Chapter 679 Ehlers-Danlos Syndrome Classification of the 6 Most Common Subtypes of Ehlers-Danlos Syndrome Differential Diagnosis General Approach to Management Bibliography

Chapter 680 Diseases of Subcutaneous Tissue Corticosteroid-Induced Atrophy Erythema Nodosum Post-Steroid Panniculitis Lupus Erythematosus Profundus (Lupus Erythematosus Panniculitis) Alpha1 -Antitrypsin Deficiency Pancreatic Panniculitis Subcutaneous Fat Necrosis Sclerema Neonatorum Cold Panniculitis Chilblains (Pernio) Factitial Panniculitis Bibliography Partial Lipodystrophy Generalized Lipodystrophy Bibliography Chapter 681 Disorders of the Sweat Glands Anhidrosis Hyperhidrosis Miliaria

Bromhidrosis Hidradenitis Suppurativa Fox-Fordyce Disease Bibliography Chapter 682 Disorders of Hair Hypertrichosis Hypotrichosis and Alopecia Traumatic Alopecia (Traction Alopecia, Hair Pulling, Trichotillomania) Alopecia Areata Acquired Diffuse Hair Loss Congenital Diffuse Hair Loss Bibliography Chapter 683 Disorders of the Nails Abnormalities in Nail Shape or Size Changes in Nail Color Nail Separation Nail Changes Associated With Skin Disease Trachyonychia (20-Nail Dystrophy) Nail Infection Paronychial Inflammation

Paronychial Tumors Bibliography Chapter 684 Disorders of the Mucous Membranes Angular Cheilitis Aphthous Stomatitis (Canker Sores) Fordyce Spots Epstein Pearls (Gingival Cysts of the Newborn) Mucocele Fissured Tongue Geographic Tongue (Benign Migratory Glossitis) Black Hairy Tongue Oral Hairy Leukoplakia Acute Necrotizing Ulcerative Gingivitis (Vincent Stomatitis, Fusospirochetal Gingivitis, Trench Mouth) Noma Cowden Syndrome (Multiple Hamartoma Syndrome) Bibliography Chapter 685 Cutaneous Bacterial Infections Etiology/Pathogenesis Clinical Manifestations

Complications Treatment Bibliography Cellulitis Necrotizing Fasciitis Bibliography Etiology and Pathogenesis Clinical Manifestations Differential Diagnosis Histology Treatment Bibliography Bibliography Blastomycosis-Like Pyoderma (Pyoderma Vegetans) Blistering Distal Dactylitis Perianal Infectious Dermatitis Erysipelas Folliculitis Abscesses and Furuncles Pitted Keratolysis

Erythrasma Erysipeloid Tuberculosis of the Skin Bibliography Chapter 686 Cutaneous Fungal Infections Tinea Versicolor Dermatophytoses Candidal Infections (Candidosis, Candidiasis, and Moniliasis) Bibliography Chapter 687 Cutaneous Viral Infections Wart (Verruca) Molluscum Contagiosum Bibliography Chapter 688 Arthropod Bites and Infestations Clinical Manifestations Treatment Bibliography Etiology and Pathogenesis Clinical Manifestations

Differential Diagnosis Treatment Norwegian (Crusted) Scabies Canine Scabies Other Types of Scabies Bibliography Bibliography Chapter 689 Acne Acne Vulgaris Drug-Induced Acne Halogen Acne Chloracne Neonatal Acne Infantile Acne Mid-Childhood Acne Tropical Acne Acne Conglobata Acne Fulminans (Acute Febrile Ulcerative Acne) Bibliography Chapter 690 Tumors of the Skin

Epidermal Inclusion Cyst (Epidermoid Cyst) Milium Fibrofolliculomas Pilar Cyst (Trichilemmal Cyst) Pilomatricoma (Pilomatrixoma) Trichoepithelioma Eruptive Vellus Hair Cysts Steatocystoma Multiplex Syringoma Infantile Digital Fibroma Dermatofibroma (Histiocytoma) Juvenile Xanthogranuloma Lipoma Basal Cell Carcinoma Nevoid Basal Cell Carcinoma Syndrome (Basal Cell Nevus Syndrome, Gorlin Syndrome) Melanoma Mucosal Neuroma Syndrome (Multiple Endocrine Neoplasia Type Iib) Bibliography Chapter 691 Nutritional Dermatoses

Acrodermatitis Enteropathica Essential Fatty Acid Deficiency Kwashiorkor Cystic Fibrosis Pellagra Scurvy (Vitamin C or Ascorbic Acid Deficiency) Vitamin a Deficiency Bibliography

Part XXXI Bone and Joint Disorders Section 1 Orthopedic Problems Chapter 692 Growth and Development In Utero Positioning Growth and Development Centers of Ossification Gait/Functional Maturation Bibliography Chapter 693 Orthopedic Evaluation of the Child History

Physical Examination Limping Back Pain Neurologic Evaluation Radiographic Assessment Laboratory Studies Bibliography Chapter 694 The Foot and Toes Clinical Manifestations Radiographic Evaluation Treatment Bibliography Clinical Manifestations Radiographic Evaluation Treatment Bibliography Clinical Manifestations Radiographic Evaluation Treatment Bibliography

Clinical Manifestations Radiographic Evaluation Treatment Bibliography Clinical Manifestations Radiographic Evaluation Treatment Bibliography Clinical Manifestations Radiographic Evaluation Treatment Bibliography Treatment Bibliography Bibliography Bibliography Juvenile Hallux Valgus (Bunion) Curly Toes Overlapping 5Th Toe Polydactyly

Syndactyly Hammer Toe Mallet Toe Claw Toe Annular Bands Macrodactyly Subungual Exostosis Ingrown Toenail Bibliography Bibliography Chapter 695 Torsional and Angular Deformities of the Limb Keywords Bibliography Keywords Foot Progression Angle Femoral Anteversion Tibial Rotation Foot Shape and Position Bibliography Keywords

Femoral Anteversion Medial Tibial Torsion External Femoral Torsion Lateral Tibial Torsion Metatarsus Adductus Bibliography Keywords Genu Varum Tibia Vara Genu Valgum (Knock-Knees) Bibliography Keywords Posteromedial Tibial Bowing Anteromedial Tibial Bowing (Postaxial Hemimelia) Anterolateral Tibial Bowing Tibial Longitudinal Deficiency Bibliography Chapter 696 Leg-Length Discrepancy Diagnosis and Clinical Findings Radiographic Evaluation

Treatment Bibliography Chapter 697 The Knee Normal Development of the Knee Anatomy and Range of Motion Clinical Manifestations and Diagnosis Treatment Bibliography Clinical Manifestations and Diagnosis Treatment Bibliography Clinical Manifestations and Diagnosis Treatment Bibliography Clinical Manifestations and Diagnosis Treatment Bibliography Clinical Manifestations and Diagnosis Treatment Bibliography

Clinical Manifestations and Diagnosis Treatment Bibliography Clinical Manifestations and Diagnosis Treatment Bibliography Chapter 698 The Hip Growth and Development Vascular Supply Keywords Classification Etiology and Risk Factors Epidemiology Pathoanatomy Clinical Findings Diagnostic Testing Treatment Complications Bibliography Keywords

Etiology Clinical Manifestations Diagnosis Treatment Bibliography Keywords Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Classification Natural History and Prognosis Treatment Bibliography Keywords Classification Etiology and Pathogenesis Epidemiology Clinical Manifestations

Diagnostic Studies Treatment Complications Bibliography Chapter 699 The Spine Normal Spinal Curvatures Keywords Definition Etiology Epidemiology Classification of Idiopathic Scoliosis Clinical Presentation of Idiopathic Scoliosis Physical Examination of Idiopathic Scoliosis Radiographic Evaluation of Idiopathic Scoliosis Natural History of Idiopathic Scoliosis Treatment of Idiopathic Scoliosis Bibliography Keywords Definition Etiology

Associated Conditions Classification of Congenital Scoliosis Natural History of Congenital Scoliosis Treatment of Congenital Scoliosis Special Circumstance: Thoracic Insufficiency Syndrome Bibliography Keywords Neuromuscular Scoliosis Syndromes and Genetic Disorders Compensatory Scoliosis Bibliography Keywords Flexible Kyphosis (Postural Kyphosis) Structural Kyphosis Congenital Kyphosis Bibliography Keywords Clinical Evaluation Medical Decision Making Radiographic and Laboratory Evaluation

Bibliography Keywords Clinical Manifestations Physical Exam Radiographic Evaluation Treatment Bibliography Keywords Clinical Manifestations Radiographic Evaluation Treatment Bibliography Keywords Apophysis Etiology Clinical Manifestations Radiographic Evaluation Treatment Bibliography Keywords

Bibliography Chapter 700 The Neck Keywords Congenital Muscular Torticollis Other Causes of Torticollis Atlantoaxial Rotatory Displacement Bibliography Keywords Etiology and Classification Clinical Presentation Physical Examination Radiologic Investigation Treatment Bibliography Keywords OS Odontoideum Bibliography Chapter 701 The Upper Limb Shoulder Elbow

Wrist Hand Bibliography Chapter 702 Arthrogryposis Etiology Classification Management of Orthopedic Problems of Arthrogryposis Foot Problems Knee Problems Hip Problems Upper-Extremity Problems Bibliography Chapter 703 Common Fractures Keywords Fracture Remodeling Overgrowth Progressive Deformity Rapid Healing Bibliography Keywords

Plastic Deformation Buckle or Torus Fracture Greenstick Fracture Complete Fractures Epiphyseal Fractures Child Abuse Bibliography Keywords Phalangeal Fractures Forearm Fractures Distal Humeral Fractures Proximal Humerus Fractures Clavicular Fractures Bibliography Keywords Hip Fracture Femoral Shaft Fractures Proximal Tibia Fractures Tibia and Fibula Shaft Fractures Toddler Fracture

Triplane and Tillaux Fractures Metatarsal Fractures Toe Phalangeal Fractures Bibliography Keywords Surgical Techniques Bibliography Keywords Complications Resulting From Injury Complications of Treatment Late Complications of Trauma Chapter 704 Osteomyelitis Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Radiographic Evaluation Differential Diagnosis Treatment

Prognosis Bibliography Chapter 705 Septic Arthritis Etiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Radionuclide Imaging Differential Diagnosis Treatment Prognosis Bibliography

Section 2 Sports Medicine Chapter 706 Epidemiology and Prevention of Injuries Preparticipation Sports Examination Bibliography Chapter 707 Management of Musculoskeletal Injury

Mechanism of Injury Initial Evaluation of the Injured Extremity Transition From Immediate Management to Return to Play Imaging Differential Diagnoses of Musculoskeletal Pain Bibliography Clavicle Fractures Acromioclavicular Joint Separation Anterior Glenohumeral Dislocation Rotator Cuff Injury Bibliography Acute Injuries Bibliography Spondylolysis, Spondylolisthesis, and Facet Syndrome Lumbar Disk Herniation, Strain, and Contusion Other Causes Bibliography Bibliography Initial Treatment of Acute Knee Injuries Chronic Injuries

Bibliography Bibliography Examination and Injury Grading Scale Radiographs Initial Treatment of Ankle Sprains Bibliography Bibliography Bibliography Chapter 708 Sports-Related Traumatic Brain Injury (Concussion) Epidemiology Pathophysiology Assessment of the Injured Player Management and Treatment Prevention Bibliography Chapter 709 Cervical Spine Injuries Soft Tissue Injury Spear Tackler's Spine Cervical Fractures Stingers (Burners)

Transient Quadriparesis Congenital Spinal Stenosis Spinal Cord Injury Bibliography Chapter 710 Heat Injuries Bibliography Chapter 711 Female Athletes Bibliography Chapter 712 Performance-Enhancing Aids Bibliography Chapter 713 Specific Sports and Associated Injuries Sports Participation, Early Specialization, Injury Risk and Burnout Football Baseball/Softball Basketball/Volleyball Tennis Lacrosse Swimming/Diving Soccer

Ice Hockey Field Hockey Skiing and Snowboarding Skateboarding Cycling and Motocross Wrestling Running Cheerleading Gymnastics Dance Adaptive Sports Bibliography

Section 3 The Skeletal Dysplasias Chapter 714 General Considerations in Skeletal Dysplasias Clinical Manifestations Diagnosis Molecular Genetics Pathophysiology Treatment

Bibliography Chapter 715 Disorders Involving Cartilage Matrix Proteins Spondyloepiphyseal Dysplasias/Type 2 Collagenopathies Kniest Dysplasia Late-Onset Spondyloepiphyseal Dysplasia Aggrecan-Related Spondyloepiphyseal Dysplasias Stickler Syndrome/Dysplasia (Hereditary Osteoarthroophthalmopathy) Schmid Metaphyseal Dysplasia Pseudoachondroplasia and Multiple Epiphyseal Dysplasia Bibliography Chapter 716 Disorders Involving Transmembrane Receptors Achondroplasia Group Jansen Metaphyseal Dysplasia Bibliography Chapter 717 Disorders Involving Ion Transporters Autosomal Recessive Multiple Epiphyseal Dysplasia Bibliography Chapter 718 Disorders Involving Transcription Factors

Campomelic Dysplasia Cleidocranial Dysplasia Nail-Patella Syndrome Bibliography Chapter 719 Disorders Involving Defective Bone Resorption Osteopetrosis Clinical Manifestations Treatment Pyknodysostosis Bibliography Chapter 720 Other Inherited Disorders of Skeletal Development Ellis–Van Creveld Syndrome Asphyxiating Thoracic Dystrophy (See Also Chapter 445.3) Short-Rib Polydactyly Syndromes Cartilage-Hair Hypoplasia–Anauxetic Spectrum Disorders Metatropic Dysplasia Spondylometaphyseal Dysplasia, Kozlowski Type Disorders Involving Filamins Juvenile Osteochondroses Caffey Disease (Infantile Cortical Hyperostosis)

Fibrodysplasia Ossificans Progressiva Bibliography Chapter 721 Osteogenesis Imperfecta Etiology Epidemiology Pathology Pathogenesis Clinical Manifestations Other Genes for Osteogenesis Imperfecta Laboratory Findings Complications Treatment Prognosis Genetic Counseling Bibliography Chapter 722 Marfan Syndrome Epidemiology Pathogenesis Clinical Manifestations Diagnosis

Differential Diagnosis Laboratory Findings Management Current Therapies Emerging Therapeutic Strategies Prognosis Genetic Counseling Bibliography

Section 4 Metabolic Bone Disease Chapter 723 Bone Structure, Growth, and Hormonal Regulation Bibliography Chapter 724 Hypophosphatasia Bibliography Chapter 725 Hyperphosphatasia Bibliography Chapter 726 Osteoporosis Bibliography

Part XXXII Rehabilitation Medicine Chapter 727 Evaluation of the Child for Rehabilitative Services Child Characteristics Family Characteristics The Physical Environment The Previously Healthy Child Chapter 728 Rehabilitation for Severe Traumatic Brain Injury Pathophysiology Severity Medical Complications Spasticity Bibliography Chapter 729 Spinal Cord Injury and Autonomic Dysreflexia Management Clinical Manifestations Prognosis Bibliography Chapter 730 Spasticity Oral Medications

Surgical Management Bibliography Chapter 731 Birth Brachial Plexus Palsy Physical Examination Evaluation Treatment Bibliography Chapter 732 Meningomyelocele (Spina Bifida) Etiology Prevention Prenatal Screening Clinical Implications Adolescence and Transition to Adulthood Bibliography Chapter 733 Ambulation Assistance Orthoses Prostheses Assistive Mobility Devices Wheelchair

Bibliography Chapter 734 Health and Wellness for Children With Disabilities Health Promotion Definitions and Background for Disability Anticipatory Guidance, Counseling, and Preventive Care Physical Activity and Exercise Nutrition and Obesity Emotional Health and Leisure Activities Dental Care Role of Healthcare Providers Keywords Preparation Community Resources Subacute Care Emergency and Acute Care Quality of Life Bibliography Bibliography

Part XXXIII Environmental Health Chapter 735 Overview of Environmental Health and Children

Global Climate Change Localized Environmental Hazards Toxins Versus Toxicants Mycotoxins Food-Borne Diseases Caused by Environmental Exposures Bibliography Chapter 736 Biologic Effects of Ionizing Radiation on Children Basic Principles Biologic Effects of Radiation Radiation Exposure in Diagnostic Imaging of Children Decreasing Unnecessary Diagnostic Radiation in Children While Still Obtaining Diagnostic Images Radiation Therapy—Acute and Late Effects Whole-Body Irradiation Internal Contamination External Contamination Bibliography Chapter 737 Chemical Pollutants Synthetic Chemicals and Human Health Children's Unique Susceptibility to Synthetic Chemicals

Safety Testing of Synthetic Chemicals Synthetic Chemicals and Disease in Children Chemical Pollutants of Major Concern Health Hazards of Unconventional Natural Gas Development (Fracking) The Physician's Role Keywords Composition of Second-Hand Smoke and Toxicities Tobacco Use and Exposure Is A Health Risk Disparity Maternal Smoking During Pregnancy and Tobacco Smoke Exposure During Pregnancy Postnatal Second-Hand Smoke Exposure—Effects on the Child Treatment for Second-Hand Tobacco Smoke Exposure Bibliography Bibliography Chapter 738 Heavy Metal Intoxication Arsenic Mercury Treatment of Arsenic and Mercury Intoxication Bibliography

Chapter 739 Lead Poisoning Public Health History Sources of Exposure Metabolism Clinical Effects Clinical Symptoms Diagnosis Treatment Bibliography Chapter 740 Nonbacterial Food Poisoning Keywords Gastrointestinal: Delayed Onset Renal: Delayed Onset Autonomic Nervous System: Rapid Onset Central Nervous System: Rapid Onset Gastrointestinal: Rapid Onset Bibliography Keywords Bibliography Keywords

Ciguatera Fish Poisoning Scombroid (Pseudoallergic) Fish Poisoning Paralytic Shellfish Poisoning Neurotoxic Shellfish Poisoning Diarrhetic Shellfish Poisoning Amnesic Shellfish Poisoning Pufferfish Poisoning Azaspiracid Poisoning Bibliography Keywords Bibliography Chapter 741 Biologic and Chemical Terrorism* Etiology Epidemiology and Pediatric-Specific Concerns Clinical Manifestations Diagnosis Prevention Treatment Bibliography Chapter 742 Mass Psychogenic Illness

Clinical Features and Diagnosis Treatment Strategies Bibliography Chapter 743 Animal and Human Bites Epidemiology Clinical Manifestations Diagnosis Complications Treatment Prevention Bibliography Chapter 744 Rat Bite Fever Etiology Clinical Course Diagnosis Treatment Bibliography Chapter 745 Monkeypox Etiology

Clinical Course Treatment Bibliography Chapter 746 Envenomations General Approach to the Envenomated Child Snake Bites Spider Bites Scorpion Stings Hymenoptera Stings Marine Envenomation Bibliography

Part XXXIV Laboratory Medicine Chapter 747 Laboratory Testing in Infants and Children Accuracy and Precision of Laboratory Tests Sensitivity, Accuracy, and Analytic Testing Predictive Value of Laboratory Tests Neonatal Screening Tests Testing in Refining a Differential Diagnosis Bibliography

Chapter 748 Reference Intervals for Laboratory Tests and Procedures Bibliography (for Table 748.5) Index

Copyright NELSON TEXTBOOK OF PEDIATRICS, TWENTY-FIRST EDITION ISBN: 978-0-323-52950-1 IE ISBN: 978-0-323-56890-6 Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher's permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions . This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Previous editions copyrighted 2016, 2011, 2007, 2004, 2000, 1996, 1992, 1987, 1983, 1979, 1975, 1969, 1964, 1959 Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of

each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. The Publisher Library of Congress Control Number: 2018952009 Senior Content Strategist: Sarah Barth Senior Content Development Specialist: Jennifer Shreiner Publishing Services Manager: Catherine Jackson Senior Project Manager: John Casey Senior Book Designer: Renee Duenow Printed in Canada 9 8 7 6 5 4 3 2 1

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Dedication To the Child's Physician who through their expressed confidence in past editions of this book have provided the stimulus for this revision. May we continue to be a resource of helpful information for clinicians who care for all of our children. R.M. Kliegman

Contributors Nadia Y. Abidi MD Resident Physician Department of Dermatology University of Missouri School of Medicine Columbia, Missouri

Cutaneous Defects Ectodermal Dysplasias Mark J. Abzug MD Professor of Pediatrics Vice Chair for Academic Affairs University of Colorado School of Medicine Section of Pediatric Infectious Diseases Children's Hospital Colorado Aurora, Colorado

Nonpolio Enteroviruses David R. Adams MD, PhD Associate Investigator, Undiagnosed Diseases Program Senior Staff Clinician National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

Genetic Approaches to Rare and Undiagnosed Diseases Nicholas S. Adams MD

Plastic Surgery Resident Spectrum Health Hospitals Michigan State University Grand Rapids, Michigan

Deformational Plagiocephaly Stewart L. Adelson MD Assistant Clinical Professor Department of Psychiatry Columbia University College of Physicians and Surgeons Adjunct Clinical Assistant Professor Weill Cornell Medical College of Cornell University New York, New York

Gay, Lesbian, and Bisexual Adolescents Shawn K. Ahlfeld MD Assistant Professor of Pediatrics University of Cincinnati College of Medicine Attending Neonatologist, Perinatal Institute Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Respiratory Tract Disorders Osman Z. Ahmad MD Fellow in Pediatric Gastroenterology University of Alabama at Birmingham School of Medicine Birmingham, Alabama

Clostridium difficile Infection John J. Aiken MD, FACS, FAAP Professor of Surgery Division of Pediatric General and Thoracic Surgery Medical College of Wisconsin The Children's Hospital of Wisconsin Milwaukee, Wisconsin

Acute Appendicitis Inguinal Hernias Epigastric Hernia Incisional Hernia Cezmi A. Akdis MD Professor of Immunology Swiss Institute of Allergy and Asthma Research Christine Kühne Center for Allergy Research and Education Davos, Switzerland; Medical Faculty, University of Zurich Zurich, Switzerland

Allergy and the Immunologic Basis of Atopic Disease Evaline A. Alessandrini MD, MSCE Professor of Clinical Pediatrics University of Cincinnati College of Medicine Division of Emergency Medicine Director, Quality Scholars Program in Health Care Transformation Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Outcomes and Risk Adjustment of Emergency Medical Services Michael A. Alexander MD Professor of Pediatrics and Rehabilitation Medicine Thomas Jefferson Medical College Philadelphia, Pennsylvania; Emeritus Medical Staff Nemours Alfred I. duPont Hospital for Children Wilmington, Delaware

Evaluation of the Child for Rehabilitative Services Omar Ali MD

Pediatric Endocrinology Valley Children's Hospital Madera, California

Hyperpituitarism, Tall Stature, and Overgrowth Syndromes Hypofunction of the Testes Pseudoprecocity Resulting from Tumors of the Testes Gynecomastia Karl E. Anderson MD, FACP Professor of Preventive Medicine and Community Health and Internal Medicine Director, Porphyria Laboratory and Center University of Texas Medical Branch Galveston, Texas

The Porphyrias Kelly K. Anthony PhD, PLLC Assistant Professor Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, North Carolina

Musculoskeletal Pain Syndromes Alia Y. Antoon MD, DCH Senior Fellow American Academy of Pediatrics Honorary Pediatrician MassGeneral Hospital for Children Boston, Massachusetts

Burn Injuries Cold Injuries Susan D. Apkon MD

Professor Department of Physical Medicine and Rehabilitation University of Colorado Denver, Colorado; Chief, Pediatric Rehabilitation Children's Hospital Colorado Aurora, Colorado

Ambulation Assistance Stacy P. Ardoin MD, MHS Associate Professor of Clinical Medicine Division of Adult and Pediatric Rheumatology The Ohio State University Wexner Medical Center Nationwide Children's Hospital Columbus, Ohio

Systemic Lupus Erythematosus Vasculitis Syndromes Alexandre Arkader MD Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Common Fractures Thaís Armangué MD, PhD Pediatric Neurologist Neuroimmunology Program IDIBAPS—Hospital Clinic–Hospital Sant Joan de Déu (Barcelona) University of Barcelona Barcelona, Spain

Autoimmune Encephalitis Carola A.S. Arndt MD Professor of Pediatrics

Department of Pediatrics and Adolescent Medicine Division of Pediatric Hematology-Oncology Mayo Clinic Rochester, Minnesota

Soft Tissue Sarcomas Paul L. Aronson MD Associate Professor of Pediatrics and Emergency Medicine Yale School of Medicine New Haven, Connecticut

Fever in the Older Child David M. Asher MD Supervisory Medical Officer and Chief Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents Division of Emerging and Transfusion-Transmitted Diseases US Food and Drug Administration Silver Spring, Maryland

Transmissible Spongiform Encephalopathies Ann Ashworth PhD, Hon FRCPCH Professor Emeritus Department of Population Health Nutrition Group London School of Hygiene and Tropical Medicine London, United Kingdom

Nutrition, Food Security, and Health Amit Assa MD Associate Professor of Pediatrics Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel; Head, IBD Unit Institute of Gastroenterology, Nutrition, and Liver Diseases

Schneider Children's Medical Center Petah Tikva, Israel

Immunodeficiency Disorders Barbara L. Asselin MD Professor of Pediatrics and Oncology Department of Pediatrics University of Rochester School of Medicine and Dentistry Golisano Children's Hospital and Wilmot Cancer Institute Rochester, New York

Epidemiology of Childhood and Adolescent Cancer Christina M. Astley MD, ScD Instructor in Pediatrics Harvard Medical School Attending Physician Division of Endocrinology Boston Children's Hospital Boston, Massachusetts

Autoimmune Polyglandular Syndromes Joann L. Ater MD Professor Department of Pediatrics Patient Care University of Texas MD Anderson Cancer Center Houston, Texas

Brain Tumors in Childhood Neuroblastoma Norrell Atkinson MD, FAAP Assistant Professor of Pediatrics Drexel University College of Medicine Child Protection Program St. Christopher's Hospital for Children

Philadelphia, Pennsylvania

Adolescent Sexual Assault Erika U. Augustine MD Associate Professor of Neurology and Pediatrics Associate Director, Center for Health + Technology University of Rochester Medical Center Rochester, New York

Dystonia Marilyn C. Augustyn MD Professor of Pediatrics Boston University School of Medicine Boston Medical Center Boston, Massachusetts

Impact of Violence on Children Yaron Avitzur MD Associate Professor Department of Pediatrics University of Toronto Faculty of Medicine Division of Gastroenterology, Hepatology, and Nutrition The Hospital for Sick Children Toronto, Canada

Short Bowel Syndrome Carlos A. Bacino MD Professor and Vice Chair of Clinical Affairs Department of Molecular and Human Genetics Baylor College of Medicine Director, Pediatrics Genetics Clinic Texas Children's Hospital Houston, Texas

Cytogenetics

Zinzi D. Bailey ScD, MSPH Assistant Scientist University of Miami Miller School of Medicine Miami, Florida

Racism and Child Health Binod Balakrishnan MBBS Assistant Professor Department of Pediatrics Medical College of Wisconsin Division of Pediatric Critical Care Children's Hospital of Wisconsin Milwaukee, Wisconsin

Brain Death Frances B. Balamuth MD, PhD, MSCE Assistant Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Associate Director of Research Division of Emergency Medicine Co-Director, Pediatric Sepsis Program Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Triage of the Acutely Ill Child Robert N. Baldassano MD Colman Family Chair in Pediatric Inflammatory Bowel Disease and Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Director, Center for Pediatric Inflammatory Bowel Disease Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Inflammatory Bowel Disease Eosinophilic Gastroenteritis

Keith D. Baldwin MD, MSPT, MPH Assistant Professor Department of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Physician Neuromuscular Orthopaedics and Orthopaedic Trauma Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Growth and Development Evaluation of the Child Torsional and Angular Deformities Common Fractures Christina Bales MD Associate Professor of Clinical Pediatrics University of Pennsylvania Perelman School of MedicineMedical Director, Intestinal Rehabilitation Program Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Intestinal Atresia, Stenosis, and Malrotation William F. Balistreri MD Medical Director Emeritus, Pediatric Liver Care Center Division of Pediatric Gastroenterology, Hepatology, and Nutrition Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Morphogenesis of the Liver and Biliary System Manifestations of Liver Disease Cholestasis Metabolic Diseases of the Liver Viral Hepatitis

Liver Disease Associated with Systemic Disorders Mitochondrial Hepatopathies Allison Ballantine MD, MEd Associate Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Co-Director Med Ed Program, Graduate School of Education Section Chief, Inpatient Services Division of General Pediatrics Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Malnutrition Robert S. Baltimore MD Professor of Pediatrics and Epidemiology Clinical Professor of Nursing Professor of Pediatrics and Epidemiology Clinical Professor of Nursing Yale School of Medicine Associate Director of Hospital Epidemiology (for Pediatrics) Yale–New Haven Hospital New Haven, Connecticut

Listeria monocytogenes Pseudomonas, Burkholderia, and Stenotrophomonas Infective Endocarditis Manisha Balwani MBBS, MS Associate Professor of Medicine and Genetics and Genomic Sciences Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

The Porphyrias Vaneeta Bamba MD Associate Professor of Clinical Pediatrics

University of Pennsylvania Perelman School of Medicine Medical Director, Diagnostic and Research Growth Center Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Assessment of Growth Brenda L. Banwell MD Professor of Neurology Grace R. Loeb Endowed Chair in Neurosciences University of Pennsylvania Perelman School of Medicine Chief, Division of Neurology Director, Pediatric Multiple Sclerosis Clinic Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Central Nervous System Vasculitis Sarah F. Barclay PhD Department of Medical Genetics Cumming School of Medicine at University of Calgary Alberta Children's Hospital Research Institute Calgary, Alberta, Canada

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Maria E. Barnes-Davis MD, PhD Assistant Professor of Pediatrics University of Cincinnati College of Medicine Attending Neonatologist Division of Neonatology and Pulmonary Biology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

The High-Risk Infant

Karyl S. Barron MD Deputy Director Division of Intramural Research National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland

Amyloidosis Donald Basel MBBCh Associate Professor of Pediatrics and Genetics Chief, Medical Genetics Division Medical College of Wisconsin Milwaukee, Wisconsin

Ehlers-Danlos Syndrome Dorsey M. Bass MD Associate Professor of Pediatrics Stanford University School of Medicine Division of Pediatric Gastroenterology Lucile Salter Packard Children's Hospital Palo Alto, California

Rotaviruses, Caliciviruses, and Astroviruses Mary T. Bassett MD, MPH FXB Professor of the Practice of Public Health and Human Rights Harvard T.H. Chan School of Public Health Boston, Massachusetts

Racism and Child Health Christian P. Bauerfeld MD Assistant Professor of Pediatrics Wayne State University School of Medicine Division of Pediatric Critical Care Medicine Children's Hospital of Michigan Detroit, Michigan

Mechanical Ventilation Rebecca A. Baum MD Clinical Associate Professor of Pediatrics The Ohio State University College of Medicine Chief, Developmental Behavioral Pediatrics Nationwide Children's Hospital Columbus, Ohio

Positive Parenting and Support Michael J. Bell MD Professor, Pediatrics and Critical Care Medicine Chief, Critical Care Medicine Children's National Medical Center The George Washington University School of Medicine Washington, DC

Neurologic Emergencies and Stabilization Nicole R. Bender MD Resident Physician Department of Dermatology Medical College of Wisconsin Milwaukee, Wisconsin

Morphology of the Skin Dermatologic Evaluation of the Patient Eczematous Disorders Photosensitivity Diseases of the Epidermis Daniel K. Benjamin Jr, MD, PhD, MPH Kiser-Arena Professor of Pediatrics Duke Clinical Research Institute Duke University Medical Center Durham, North Carolina

Principles of Antifungal Therapy Candida Michael J. Bennett PhD, FRCPath, FACB Professor of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Director, Michael J. Palmieri Metabolic Disease Laboratory Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Disorders of Mitochondrial Fatty Acid β-Oxidation Daniel Bernstein MD Alfred Woodley Salter and Mabel G. Salter Endowed Professor in Pediatrics Associate Dean for Curriculum and Scholarship Stanford University School of Medicine Palo Alto, California

Cardiac Development The Fetal to Neonatal Circulatory Transition History and Physical Examination in Cardiac Evaluation Laboratory Cardiac Evaluation Epidemiology and Genetic Basis of Congenital Heart Disease Evaluation and Screening of the Infant or Child with Congenital Heart Disease Acyanotic Congenital Heart Disease: Left-to-Right Shunt Lesions Acyanotic Congenital Heart Disease: The Obstructive Lesions Acyanotic Congenital Heart Disease: Regurgitant

Lesions Cyanotic Congenital Heart Disease: Evaluation of the Critically Ill Neonate with Cyanosis and Respiratory Distress Cyanotic Congenital Heart Lesions: Lesions Associated with Decreased Pulmonary Blood Flow Cyanotic Congenital Heart Disease: Lesions Associated with Increased Pulmonary Blood Flow Other Congenital Heart and Vascular Malformations Pulmonary Hypertension General Principles of Treatment of Congenital Heart Disease Diseases of the Blood Vessels (Aneurysms and Fistulas) Henry H. Bernstein DO, MHCM, FAAP Professor of Pediatrics Zucker School of Medicine at Hofstra/Northwell Cohen Children's Medical Center of New York New Hyde Park, New York

Immunization Practices Diana X. Bharucha-Goebel MD Assistant Professor, Neurology and Pediatrics Children's National Medical Center Washington, DC; Clinical Research Collaborator National Institutes of Health/NINDS Neurogenetics Branch/NNDCS Bethesda, Maryland

Muscular Dystrophies

Myasthenia Gravis Giant Axonal Neuropathy Holly M. Biggs MD, MPH Medical Epidemiologist Respiratory Viruses Branch, Division of Viral Diseases National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta, Georgia

Parainfluenza Viruses Samra S. Blanchard MD Associate Professor Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

Peptic Ulcer Disease in Children Joshua A. Blatter MD, MPH Assistant Professor of Pediatrics, Allergy, Immunology, and Pulmonary Medicine Researcher, Patient Oriented Research Unit Washington University School of Medicine in St. Louis St. Louis, Missouri

Congenital Disorders of the Lung Archie Bleyer MD, FRCP (Glasg) Clinical Research Professor Knight Cancer Center Oregon Health & Science University Chair, Institutional Review Board for St. Charles Health System Portland, Oregon; Professor of Pediatrics University of Texas MD Anderson Cancer Center Houston, Texas

Principles of Cancer Treatment The Leukemias Nathan J. Blum MD William H. Bennett Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Chief, Division of Developmental and Behavioral Pediatrics Children's Hospital of Philadelphia Philadelphia, Pennsylvania Steven R. Boas MD, FAAP, FACSM Director, The Cystic Fibrosis Center of Chicago President and CEO, The Cystic Fibrosis Institute Glenview, Illinois; Clinical Professor of Pediatrics Northwestern University Feinberg School of Medicine Chicago, Illinois

Emphysema and Overinflation α1-Antitrypsin Deficiency and Emphysema Other Distal Airway Diseases Skeletal Diseases Influencing Pulmonary Function Walter O. Bockting PhD Professor of Medical Psychology (in Psychiatry and Nursing) Research Scientist, New York State Psychiatric Institute Division of Gender, Sexuality, and Health Department of Psychiatry Columbia University Vagelos College of Physicians and Surgeons New York, New York

Gender and Sexual Identity Transgender Care Mark Boguniewicz MD Professor of Pediatrics

Division of Allergy-Immunology Department of Pediatrics University of Colorado School of Medicine National Jewish Health Denver, Colorado

Ocular Allergies Michael J. Boivin PhD, MPH Professor of Psychiatry and of Neurology and Ophthalmology Michigan State University College of Osteopathic Medicine East Lansing, Michigan

Nodding Syndrome Daniel J. Bonthius MD, PhD Professor of Pediatrics and Neurology University of Iowa Carver College of Medicine Iowa City, Iowa

Lymphocytic Choriomeningitis Virus Brett J. Bordini MD, FAAP Associate Professor of Pediatrics Division of Hospital Medicine Nelson Service for Undiagnosed and Rare Diseases Director, Medical Spanish Curriculum Medical College of Wisconsin Milwaukee, Wisconsin

Plastic Bronchitis Kristopher R. Bosse MD Instructor in Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician Division of Oncology Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Molecular and Cellular Biology of Cancer Bret L. Bostwick MD Assistant Professor Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas

Genetics of Common Disorders Kenneth M. Boyer MD Professor and Woman's Board Chair, Emeritus Department of Pediatrics Rush University Medical Center Chicago, Illinois

Toxoplasmosis (Toxoplasma gondii) Jennifer M. Brady MD Assistant Professor of Pediatrics University of Cincinnati College of Medicine Perinatal Institute Division of Neonatology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

The High-Risk Infant Transport of the Critically Ill Newborn Neonatal Resuscitation and Delivery Room Emergencies Patrick W. Brady MD, MSc Associate Professor of Pediatrics University of Cincinnati College of Medicine Attending Physician, Division of Hospital Medicine Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Safety in Healthcare for Children Rebecca C. Brady MD Professor of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Congenital and Perinatal Infections Coccidioidomycosis (Coccidioides Species) Samuel L. Brady MS, PhD Clinical Medical Physicist Cincinnati Children's Hospital Associate Professor of Radiology University of Cincinnati Cincinnati, Ohio

Biologic Effects of Ionizing Radiation on Children Amanda M. Brandow DO, MS Associate Professor Department of Pediatrics Division of Pediatric Hematology/Oncology Medical College of Wisconsin Milwaukee, Wisconsin

Enzymatic Defects Hemolytic Anemias Resulting from Extracellular Factors—Immune Hemolytic Anemias Hemolytic Anemias Secondary to Other Extracellular Factors Polycythemia Nonclonal Polycythemia

David T. Breault MD, PhD Associate Professor of Pediatrics Harvard Medical School Division of Endocrinology Boston Children's Hospital Boston, Massachusetts

Diabetes Insipidus Other Abnormalities of Arginine Vasopressin Metabolism and Action Cora Collette Breuner MD, MPH Professor of Pediatrics Adjunct Professor of Orthopedics and Sports Medicine University of Washington School of Medicine Division of Adolescent Medicine Department of Orthopedics and Sports Medicine Seattle Children's Hospital Seattle, Washington

Substance Abuse Adolescent Pregnancy Carolyn Bridgemohan MD Associate Professor of Pediatrics Harvard Medical School Co-Director Autism Spectrum Center Division of Developmental Medicine Boston Children's Hospital Boston, Massachusetts

Autism Spectrum Disorder William J. Britt MD Charles A. Alford Professor of Pediatrics Professor of Microbiology and Neurobiology University of Alabama Birmingham School of Medicine

Division of Pediatric Infectious Diseases Children's of Alabama Birmingham, Alabama

Cytomegalovirus Laura Brower MD Assistant Professor of Pediatrics University of Cincinnati College of Medicine Division of Hospital Medicine Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Fever Without a Focus in the Neonate and Young Infant Rebeccah L. Brown MD Professor of Clinical Surgery and Pediatrics University of Cincinnati College of Medicine Co-Director of Pectus Program Associate Director of Trauma Services Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Meconium Ileus, Peritonitis, and Intestinal Obstruction Necrotizing Enterocolitis J. Naylor Brownell MD Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Feeding Healthy Infants, Children, and Adolescents Meghen B. Browning MD Associate Professor of Pediatrics The Medical College of Wisconsin

Division of Pediatric Hematology-Oncology Children's Hospital of Wisconsin Milwaukee, Wisconsin

Pancreatic Tumors Nicola Brunetti-Pierri MD Associate Professor Department of Translational Medicine University of Naples Federico II Associate Investigator, Telethon Institute of Genetics and Medicine (TIGEM) Naples, Italy

Management and Treatment of Genetic Disorders Phillip R. Bryant DO Professor Department of Pediatrics University of Pennsylvania Perelman School of Medicine Division of Rehabilitation Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Rehabilitation for Severe Traumatic Brain injury Spinal Cord Injury and Autonomic Dysreflexia Management Rebecca H. Buckley MD J. Buren Sidbury Professor of Pediatrics Professor of Immunology Duke University School of Medicine Durham, North Carolina

Evaluation of Suspected Immunodeficiency The T-, B-, and NK-Cell Systems T Lymphocytes, B Lymphocytes, and Natural Killer Cells

Primary Defects of Antibody Production Treatment of B-Cell Defects Primary Defects of Cellular Immunity Immunodeficiencies Affecting Multiple Cell Types Cynthia Etzler Budek MS, APN/NP, CPNP-AC/PC Pediatric Nurse Practitioner Department of Pulmonary and Critical Care Medicine Transitional Care/Pulmonary Habilitation Unit Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Other Conditions Affecting Respiration Supinda Bunyavanich MD, MPH, MPhil Associate Professor Associate Director, Jaffe Food Allergy Institute Department of Pediatrics Department of Genetics and Genomic Sciences Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Diagnosis of Allergic Disease Carey-Ann D. Burnham PhD D(ABMM), FIDSA, F(AAM) Professor of Pathology and Immunology, Molecular Microbiology, Pediatrics, and Medicine Washington University School of Medicine in St. Louis Medical Director, Microbiology Barnes Jewish Hospital St. Louis, Missouri

Diagnostic Microbiology Gale R. Burstein MD, MPH Clinical Professor Department of Pediatrics

University at Buffalo Jacobs School of Medicine and Biomedical Sciences Commissioner, Erie County Department of Health Buffalo, New York

The Epidemiology of Adolescent Health Problems Transitioning to Adult Care The Breast Menstrual Problems Contraception Sexually Transmitted Infections Amaya L. Bustinduy MD, PhD, MPH Associate Professor in Tropical Pediatrics Department of Clinical Research London School of Hygiene and Tropical Medicine London, United Kingdom

Schistosomiasis (Schistosoma) Flukes (Liver, Lung, and Intestinal) Jill P. Buyon MD Professor of Medicine (Rheumatology) Director, Division of Rheumatology New York University School of Medicine NYU Langone Medical Center New York, New York

Neonatal Lupus Miguel M. Cabada MD, MSc Assistant Professor Division of Infectious Diseases The University of Texas Medical Branch at Galveston Galveston, Texas

Echinococcosis (Echinococcus granulosus and

Echinococcus multilocularis) Michaela Cada MD, FRCPC, FAAP, MPH Assistant Professor Department of Pediatrics University of Toronto Faculty of Medicine Director, Education Training Program Division of Hematology/Oncology The Hospital for Sick Children Toronto, Ontario, Canada

Inherited Bone Marrow Failure Syndromes with Pancytopenia Derya Caglar MD Associate Professor Fellowship Director, Pediatric Emergency Medicine Department of Pediatrics University of Washington School of Medicine Attending Physician Division of Emergency Medicine Seattle Children's Hospital Seattle, Washington

Drowning and Submersion Injury Mitchell S. Cairo MD Professor Departments of Pediatrics, Medicine, Pathology, Microbiology, and Immunology and Cell Biology and Anatomy New York Medical College Chief, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation Maria Fareri Children's Hospital at Westchester Medical Center New York Medical College Valhalla, New York

Lymphoma

Diane P. Calello MD Associate Professor of Emergency Medicine Rutgers University New Jersey Medical School Executive and Medical Director New Jersey Poison Information and Education System Newark, New Jersey

Nonbacterial Food Poisoning Lauren E. Camarda MD Pediatric Pulmonology Advocate Children's Hospital Park Ridge, Illinois

Bronchitis Lindsay Hatzenbuehler Cameron MD, MPH Assistant Professor of Pediatrics Baylor College of Medicine Pediatric Infectious Diseases Texas Children's Hospital Houston, Texas

Tuberculosis (Mycobacterium tuberculosis) Bruce M. Camitta MD Rebecca Jean Slye Professor of Pediatrics Division of Pediatric Hematology/Oncology Medical College of Wisconsin Midwest Children's Cancer Center Milwaukee, Wisconsin

Polycythemia Nonclonal Polycythemia Anatomy and Function of the Spleen Splenomegaly Hyposplenism, Splenic Trauma, and Splenectomy

Anatomy and Function of the Lymphatic System Abnormalities of Lymphatic Vessels Lymphadenopathy Angela J.P. Campbell MD, MPH Medical Officer Epidemiology and Prevention Branch, Influenza Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta, Georgia

Influenza Viruses Parainfluenza Viruses Rebecca F. Carlin MD Attending Physician Division of General and Community Pediatrics Children's National Health System Assistant Professor of Pediatrics George Washington University School of Medicine and Health Sciences Washington, DC

Sudden Infant Death Syndrome Michael R. Carr MD Assistant Professor of Pediatrics Division of Cardiology Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Rheumatic Heart Disease Robert B. Carrigan MD Assistant Clinical Professor Department of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine

Pediatric Hand Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Upper Limb Michael S. Carroll Research Assistant Professor of Pediatrics Northwestern University Feinberg School of Medicine Chicago, Illinois

Congenital Central Hypoventilation Syndrome Rebecca G. Carter MD Assistant Professor Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

The Second Year The Preschool Years Mary T. Caserta MD Professor of Pediatrics University of Rochester School of Medicine and Dentistry Division of Pediatric Infectious Diseases Golisano Children's Hospital Rochester, New York

Roseola (Human Herpesviruses 6 and 7) Human Herpesvirus 8 Jennifer I. Chapman MD Assistant Professor of Pediatrics George Washington University School of Medicine and Health Sciences Program Director, Pediatric Emergency Medicine Fellowship Children's National Medical Center Washington, DC

Principles Applicable to the Developing World Ira M. Cheifetz MD, FCCM, FAARC Professor of Pediatrics and Anesthesiology Duke University School of Medicine Executive Director and Chief Medical Officer Duke Children's Hospital Associate Chief Medical Officer Duke University Hospital Durham, North Carolina

Pediatric Emergencies and Resuscitation Shock Gisela G. Chelimsky MD Professor of Pediatrics Medical College of Wisconsin Division of Pediatric Gastroenterology Children's Hospital Milwaukee Milwaukee, Wisconsin

Chronic Overlapping Pain Conditions Postural Tachycardia Syndrome Thomas C. Chelimsky MD Professor of Neurology Medical College of Wisconsin Milwaukee, Wisconsin

Chronic Overlapping Pain Conditions Postural Tachycardia Syndrome Wassim Chemaitilly MD Associate Member and Director Division of Endocrinology Department of Pediatric Medicine St. Jude Children's Research Hospital

Memphis, Tennessee

Physiology of Puberty Disorders of Pubertal Development Yuan-Tsong Chen MD, PhD Professor of Pediatrics and Genetics Duke University Medical Center Durham, North Carolina

Defects in Metabolism of Carbohydrates Jennifer A. Chiriboga PhD Pediatric and School Psychologist Assistant Professor Department of Counseling, Psychology, and Special Education Duquesne University School of Psychology Pittsburgh, Pennsylvania

Anxiety Disorders Yvonne E. Chiu MD Associate Professor of Dermatology and Pediatrics Medical College of Wisconsin Department of Dermatology Division of Pediatric Dermatology Children's Hospital of Wisconsin Milwaukee, Wisconsin

Morphology of the Skin Dermatologic Evaluation of the Patient Eczematous Disorders Photosensitivity Diseases of the Epidermis Christine B. Cho MD Assistant Professor of Pediatrics

Division of Allergy-Immunology Department of Pediatrics University of Colorado School of Medicine National Jewish Health Denver, Colorado

Ocular Allergies Adverse Reactions to Drugs Hey Jin Chong MD, PhD Assistant Professor of Pediatrics University of Pittsburgh School of Medicine Chief, Division of Pediatric Allergy and Immunology UPMC Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania

Infections in Immunocompromised Persons Stella T. Chou MD Associate Professor Department of Pediatrics University of Pennsylvania Perelman School of Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Development of the Hematopoietic System John C. Christenson MD Professor of Clinical Pediatrics Ryan White Center for Pediatric Infectious Diseases and Global Health Indiana University School of Medicine Indianapolis, Indiana

Health Advice for Children Traveling Internationally Robert H. Chun MD Associate Professor of Pediatric Otolaryngology Department of Otolaryngology and Communication Sciences

Medical College of Wisconsin Milwaukee, Wisconsin

Acute Mastoiditis Michael J. Chusid MD Professor (Infectious Disease) Department of Pediatrics Medical College of Wisconsin Medical Director, Infection Prevention and Control Children's Hospital of Wisconsin Milwaukee, Wisconsin

Infection Prevention and Control Other Anaerobic Infections Theodore J. Cieslak MD, MPH, FAAP, FIDSA Associate Professor of Epidemiology Associate Director, Center for Biosecurity, Biopreparedness, and Emerging Infectious Diseases University of Nebraska Medical Center College of Public Health Omaha, Nebraska

Biologic and Chemical Terrorism Donna J. Claes MD, MS, BS Pharm Assistant Professor of Pediatrics University of Cincinnati College of Medicine Division of Pediatric Nephrology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Chronic Kidney Disease End-Stage Renal Disease Jeff A. Clark MD Associate Professor

Department of Pediatrics Wayne State University School of Medicine Children's Hospital of Michigan Detroit, Michigan

Respiratory Distress and Failure John David Clemens MD, PhD (Hon) Professor and Vice Chair Department of Epidemiology Founding Director, Center for Global Infectious Diseases UCLA Fielding School of Public Health Los Angeles, California; International Centre for Diarrhoeal Disease Research Dhaka, Bangladesh

International Immunization Practices Thomas D. Coates MD Professor of Pediatrics and Pathology University of Southern California Keck School of Medicine Head, Section of Hematology Children's Center for Cancer and Blood Diseases Children's Hospital of Los Angeles Los Angeles, California

Neutrophils Disorders of Phagocyte Function Susan E. Coffin MD, MPH Professor of Pediatrics Distinguished Chair in the Department of Pediatrics University of Pennsylvania Perelman School of Medicine Associate Chief, Division of Infectious Diseases Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Childcare and Communicable Diseases

Joanna S. Cohen MD Associate Professor of Pediatrics and Emergency Medicine George Washington University School of Medicine Division of Pediatric Emergency Medicine Children's National Medical Center Washington, DC

Care of Abrasions and Minor Lacerations Mitchell B. Cohen MD Katharine Reynolds Ireland Endowed Chair in Pediatrics Professor and Chair, Department of Pediatrics University of Alabama at Birmingham School of Medicine Physician-in-Chief Children's of Alabama Birmingham, Alabama

Clostridium difficile Infection Michael Cohen-Wolkowiez MD Professor of Pediatrics Duke Clinical Research Institute Duke University Medical Center Durham, North Carolina

Principles of Antifungal Therapy Robert A. Colbert MD, PhD Acting Clinical Director National Institute of Arthritis and Musculoskeletal and Skin Diseases Chief, Pediatric Translational Branch National Institutes of Health Bethesda, Maryland

Ankylosing Spondylitis and Other Spondylarthritides Reactive and Postinfectious Arthritis F. Sessions Cole III, MD

Assistant Vice-Chancellor for Children's Health Park J. White Professor of Pediatrics Professor of Cell Biology and Physiology Washington University School of Medicine in St. Louis Chief Medical Officer Vice-Chairman, Department of Pediatrics Director of Newborn Medicine St. Louis Children's Hospital St. Louis, Missouri

Inherited Disorders of Surfactant Metabolism Pulmonary Alveolar Proteinosis J. Michael Collaco MD, MS, MBA, MPH, PhD Associate Professor of Pediatrics Eudowood Division of Pediatric Respiratory Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

Bronchopulmonary Dysplasia John L. Colombo MD Professor of Pediatrics University of Nebraska College of Medicine Division of Pediatric Pulmonology Nebraska Regional Cystic Fibrosis Center University of Nebraska Medical Center Omaha, Nebraska

Aspiration Syndromes Chronic Recurrent Aspiration Joseph A. Congeni MD Director, Sports Medicine Center Akron Children's Hospital Akron, Ohio; Associate Professor of Pediatrics and Sports Medicine Northeast Ohio Medical University

Rootstown, Ohio; Clinical Associate Professor of Pediatrics and Sports Medicine Ohio University College of Osteopathic Medicine Athens, Ohio

Sports-Related Traumatic Brain Injury (Concussion) Cervical Spinal Spine Injuries Lindsay N. Conner MD, MPH Department of Obstetrics and Gynecology Benefis Health System Great Falls, Montana

Breast Concerns Sarah M. Creighton MBBS Professor and Consultant Gynaecologist Department of Women's Health University College London Hospitals London, United Kingdom

Female Genital Mutilation James E. Crowe Jr, MD Ann Scott Carell Chair and Professor of Pediatrics Division of Pediatric Infectious Diseases Professor of Pathology, Microbiology, and Immunology Director, Vanderbilt Vaccine Center Vanderbilt University School of Medicine Nashville, Tennessee

Respiratory Syncytial Virus Human Metapneumovirus Steven J. Czinn MD Professor and Chair Department of Pediatrics University of Maryland School of Medicine

Baltimore, Maryland

Peptic Ulcer Disease in Children Aarti S. Dalal DO Assistant Professor of Pediatrics Washington University School of Medicine in St. Louis Division of Pediatric Cardiology St Louis Children's Hospital St. Louis, Missouri

Syncope Disturbances of Rate and Rhythm of the Heart Sudden Death Josep O. Dalmau MD, PhD Research Professor ICREA-IDIBAPS Service of Neurology Hospital Clinic University of Barcelona Barcelona, Spain; Adjunct Professor of Neurology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Autoimmune Encephalitis Lara A. Danziger-Isakov MD, MPH Professor of Pediatrics University of Cincinnati College of Medicine Director, Immunocompromised Host Infectious Disease Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Histoplasmosis (Histoplasma capsulatum) Toni Darville MD Professor of Pediatrics and Microbiology and Immunology

University of North Carolina at Chapel Hill Chief, Division of Infectious Diseases Vice-Chair of Pediatric Research North Carolina Children's Hospital Chapel Hill, North Carolina

Neisseria gonorrhoeae (Gonococcus) Robert S. Daum MD, CM, MSc Professor of Medicine Center for Vaccine Development and Global Health University of Maryland School of Medicine Baltimore, Maryland

Haemophilus influenzae Loren T. Davidson MD Clinical Professor Department of Physical Medicine and Rehabilitation University of California, Davis School of Medicine Davis, California; Director, Spinal Cord Injury Shriners Hospital for Children Sacramento, California

Spasticity Richard S. Davidson MD Emeritus Professor of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Foot and Toes Leg-Length Discrepancy Arthrogryposis

H. Dele Davies MD, MS, MHCM Vice-Chancellor for Academic Affairs Dean for Graduate Studies University of Nebraska Medical Center Omaha, Nebraska

Chancroid (Haemophilus ducreyi) Syphilis (Treponema pallidum) Nonvenereal Treponemal Infections Leptospira Relapsing Fever (Borrelia) Najat C. Daw MD Professor Division of Pediatrics University of Texas MD Anderson Cancer Center Houston, Texas

Neoplasms of the Kidney Shannon L. Dean MD, PhD Instructor in Neurology and Pediatrics University of Rochester Medical Center Rochester, New York

Dystonia Helen M. Oquendo Del Toro, MD Pediatric and Adolescent Gynecology Clinical Assistant Professor University of New Mexico Department of Obstetrics and Gynecology Albuquerque, New Mexico

Vulvovaginitis David R. DeMaso MD

Psychiatrist-in-Chief The Leon Eisenberg Chair in Psychiatry Boston Children's Hospital; George P. Gardner and Olga E. Monks Professor of Child Psychiatry Professor of Pediatrics Harvard Medical School Boston, Massachusetts

Psychosocial Assessment and Interviewing Psychopharmacology Psychotherapy and Psychiatric Hospitalization Somatic Symptom and Related Disorders Rumination and Pica Motor Disorders and Habits Anxiety Disorders Mood Disorders Suicide and Attempted Suicide Disruptive, Impulse-Control, and Conduct Disorders Tantrums and Breath-Holding Spells Lying, Stealing, and Truancy Aggression Self-Injurious Behavior Childhood Psychoses Mark R. Denison MD Craig-Weaver Professor of Pediatrics Professor of Pathology, Microbiology, and Immunology Vanderbilt University Medical Center Monroe Carell Jr Children's Hospital at Vanderbilt Nashville, Tennessee

Coronaviruses

Arlene E. Dent MD, PhD Associate Professor of Pediatrics Center for Global Health and Diseases Case Western Reserve University School of Medicine Cleveland, Ohio

Ascariasis (Ascaris lumbricoides) Trichuriasis (Trichuris trichiura) Enterobiasis (Enterobius vermicularis) Strongyloidiasis (Strongyloides stercoralis) Lymphatic Filariasis (Brugia malayi, Brugia timori, and Wuchereria bancrofti) Other Tissue Nematodes Toxocariasis (Visceral and Ocular Larva Migrans) Trichinellosis (Trichinella spiralis) Robert J. Desnick MD, PhD Dean for Genetics and Genomic Medicine Professor and Chair Emeritus, Genetics and Genomic Sciences Professor, Departments of Pediatrics, Oncological Sciences, and Obstetrics, Gynecology and Reproductive Science Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Lipidoses (Lysosomal Storage Disorders) Mucolipidoses Disorders of Glycoprotein Degradation and Structure The Porphyrias Robin R. Deterding MD Professor of Pediatrics University of Colorado School of Medicine Chief, Pediatric Pulmonary Medicine Director, Breathing Institute

Co-Chair, Children's Interstitial and Diffuse Lung Disease Research Network Medical Director, Children's Colorado Innovation Center Children's Hospital Colorado Aurora, Colorado

Fibrotic Lung Disease Prasad Devarajan MD, FAAP Louise M. Williams Endowed Chair Professor of Pediatrics and Developmental Biology University of Cincinnati College of Medicine Director of Nephrology and Hypertension CEO, Dialysis Unit Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Multisystem Disease Associated with Hematuria Tubulointerstitial Disease Associated with Hematuria Vascular Disease Associated with Hematuria Anatomic Abnormalities Associated with Hematuria Lower Urinary Tract Causes of Hematuria Acute Kidney Injury Gabrielle A. deVeber MD, MHSc Professor of Pediatrics University of Toronto Faculty of Medicine Children's Stroke Program Division of Neurology Senior Scientist Emeritus, Research Institute Hospital for Sick Children Toronto, Ontario, Canada

Pediatric Stroke Vineet Dhar BDS, MDS, PhD, Clinical Professor and Chairman

Department of Orthodontics and Pediatric Dentistry Director, Advanced Specialty Education Program, Pediatric Dentistry Diplomate, American Board of Pediatric Dentistry University of Maryland School of Dentistry Baltimore, Maryland

Development and Developmental Anomalies of the Teeth Disorders of the Oral Cavity Associated with Other Conditions Malocclusion Cleft Lip and Palate Syndromes with Oral Manifestations Dental Caries Periodontal Diseases Dental Trauma Common Lesions of the Oral Soft Tissues Diseases of the Salivary Glands and Jaws Diagnostic Radiology in Dental Assessment Anil Dhawan MD, FRCPCH Professor of Pediatric Hepatology Pediatric Liver GI and Nutrition Centre MowatLabs King's College London School of Medicine at King's College Hospital NSH Foundation Trust London, United Kingdom

Liver and Biliary Disorders Causing Malabsorption André A.S. Dick MD, MPH, FACS Associate Professor of Surgery Division of Transplantation University of Washington School of Medicine

Section of Pediatric Transplantation Seattle Children's Hospital Seattle, Washington

Intestinal Transplantation in Children with Intestinal Failure Harry C. Dietz III, MD Victor A. McKusick Professor of Medicine and Genetics Departments of Pediatrics, Medicine, and Molecular Biology and Genetics Investigator, Howard Hughes Medical Institute Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore, Maryland

Marfan Syndrome Daren A. Diiorio MD Resident Physician Department of Dermatology Medical College of Wisconsin Milwaukee, Wisconsin

Principles of Dermatologic Therapy Cutaneous Bacterial Infections Cutaneous Fungal Infections Cutaneous Viral Infections Arthropod Bites and Infestations Linda A. DiMeglio MD, MPH Professor Department of Pediatrics Indiana University School of Medicine Indiana University Clinical and Translational Science Institute Riley Hospital for Children Indianapolis, Indiana

Hypophosphatasia Hyperphosphatasia Bradley P. Dixon MD, FASN Associate Professor of Pediatrics and Medicine Renal Section, Department of Pediatrics University of Colorado School of Medicine Kidney Center Children's Hospital Colorado Aurora, Colorado

Tubular Function Renal Tubular Acidosis Nephrogenic Diabetes Insipidus Inherited Tubular Transport Abnormalities Nomazulu Dlamini MBBS, PhD Assistant Professor of Pediatrics University of Toronto Faculty of Medicine Staff Physician in Neurology Director, Children's Stroke Program Hospital for Sick Children Toronto, Ontario, Canada

Pediatric Stroke Sonam N. Dodhia MD Resident Physician New York-Presbyterian Hospital New York, New York

Congenital Disorders of the Nose Acquired Disorders of the Nose Nasal Polyps General Considerations and Evaluation of the Ear

Hearing Loss Congenital Malformations of the Ear External Otitis (Otitis Externa) The Inner Ear and Diseases of the Bony Labyrinth Traumatic Injuries of the Ear and Temporal Bone Tumors of the Ear and Temporal Bone Patricia A. Donohoue MD Professor of Pediatrics Chief, Pediatric Endocrinology Medical College of Wisconsin Medical Director, Pediatric Endocrinology Children's Hospital of Wisconsin Milwaukee, Wisconsin

Development and Function of the Gonads Hypofunction of the Testes Pseudoprecocity Resulting from Tumors of the Testes Gynecomastia Hypofunction of the Ovaries Pseudoprecocity Resulting from Lesions of the Ovary Disorders of Sex Development Kevin J. Downes MD Assistant Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician, Division of Infectious Diseases Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Tularemia (Francisella tularensis) Brucella

Alexander J. Doyle MBBS, MDRes, FRCA William Harvey Research Institute Barts and The London School of Medicine Queen Mary University of London London, United Kingdom

Marfan Syndrome Daniel A. Doyle MD Associate Professor of Pediatrics Thomas Jefferson University Sidney Kimmel Medical College Philadelphia, Pennsylvania; Chief, Division of Pediatric Endocrinology Nemours Alfred I. duPont Hospital for Children Wilmington, Delaware

Hormones and Peptides of Calcium Homeostasis and Bone Metabolism Hypoparathyroidism Pseudohypoparathyroidism (Albright Hereditary Osteodystrophy) Hyperparathyroidism Jefferson J. Doyle MBBChir, PhD, MHS Assistant Professor of Ophthalmology Wilmer Eye Institute Johns Hopkins Hospital Affiliate Member, Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore, Maryland

Marfan Syndrome Stephen C. Dreskin MD, PhD Professor of Medicine and Immunology Division of Allergy and Clinical Immunology

Department of Medicine University of Colorado School of Medicine Aurora, Colorado

Urticaria (Hives) and Angioedema Sherilyn W. Driscoll MD Division Chair, Pediatric Rehabilitation Departments of Physical Medicine and Rehabilitation and Pediatric and Adolescent Medicine Mayo Clinic Children's Center Rochester, Minnesota

Specific Sports and Associated Injuries Yigal Dror MD, FRCPC Professor Department of Pediatrics University of Toronto Faculty of Medicine Head, Hematology Section Director, Marrow Failure and Myelodysplasia Program The Hospital for Sick Children Toronto, Ontario, Canada

The Inherited Pancytopenias Jill N. D'Souza MD Assistant Professor Baylor College of Medicine Division of Pediatric Otolaryngology – Head and Neck Surgery Texas Children's Hospital Houston, Texas

Congenital Anomalies of the Larynx, Trachea, and Bronchi Howard Dubowitz MD, MS, FAAP Professor of Pediatrics

Head, Division of Child Protection Director, Center for Families University of Maryland School of Medicine Baltimore, Maryland

Abused and Neglected Children J. Stephen Dumler MD Professor and Chair Joint Department of Pathology Uniformed Services University of the Health Sciences Walter Reed National Military Medical Center Bethesda, Maryland

Spotted Fever Group Rickettsioses Scrub Typhus (Orientia tsutsugamushi) Typhus Group Rickettsioses Ehrlichioses and Anaplasmosis Q Fever (Coxiella burnetii) Janet Duncan MSN, CPNP Department of Psychosocial Oncology and Palliative Care Boston Children's Hospital Dana-Farber Cancer Institute Boston, Massachusetts

Pediatric Palliative Care Jeffrey A. Dvergsten MD Assistant Professor of Pediatrics Duke University School of Medicine Division of Pediatric Rheumatology Duke University Health System Durham, North Carolina

Treatment of Rheumatic Diseases

Michael G. Earing MD Professor of Internal Medicine and Pediatrics Division of Adult Cardiovascular Medicine and Division of Pediatric Cardiology Medical College of Wisconsin Director, Wisconsin Adult Congenital Heart Disease Program (WAtCH) Children's Hospital of Wisconsin Milwaukee, Wisconsin

Congenital Heart Disease in Adults Matthew D. Eberly MD Associate Professor of Pediatrics Program Director, Pediatric Infectious Diseases Fellowship Uniformed Services University of the Health Sciences Bethesda, Maryland

Primary Amebic Meningoencephalitis S. Derrick Eddy MD Sports Medicine Education Director Akron Children's Hospital Clinical Assistant Professor of Pediatrics Northeast Ohio Medical University Akron, Ohio

Cervical Spinal Spine Injuries Marie E. Egan MD Professor of Pediatrics (Respiratory) and Cellular and Molecular Physiology Director, Cystic Fibrosis Center Vice Chair for Research Department of Pediatrics Yale School of Medicine New Haven, Connecticut

Cystic Fibrosis Jack S. Elder MD, FACS Chief of Pediatric Urology

Massachusetts General Hospital Boston, Massachusetts

Congenital Anomalies and Dysgenesis of the Kidneys Urinary Tract Infections Vesicoureteral Reflux Obstruction of the Urinary Tract Anomalies of the Bladder Neuropathic Bladder Enuresis and Voiding Dysfunction Anomalies of the Penis and Urethra Disorders and Anomalies of the Scrotal Contents Trauma to the Genitourinary Tract Urinary Lithiasis Elizabeth Englander PhD Professor of Psychology Founder and Director, Massachusetts Aggression Reduction Center Bridgewater State University Bridgewater, Massachusetts

Bullying, Cyberbullying, and School Violence Elizabeth Enlow MD, MS Assistant Professor of Pediatrics University of Cincinnati College of Medicine Division of Neonatology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Clinical Manifestations of Diseases in the Newborn Period Stephen C. Eppes MD

Professor of Pediatrics Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia, Pennsylvania; Vice Chair, Department of Pediatrics Division of Pediatric Infectious Diseases Christiana Care Health System Newark, Delaware

Lyme Disease (Borrelia burgdorferi) Jessica Ericson MD Assistant Professor of Pediatrics Pennsylvania State University College of Medicine Division of Pediatric Infectious Disease Milton S. Hershey Medical Center Hershey, Pennsylvania

Candida Elif Erkan MD, MS Associate Professor of Pediatrics University of Cincinnati College of Medicine Division of Pediatric Nephrology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Nephrotic Syndrome Yokabed Ermias MPH Fellow, Division of Reproductive Health Centers for Disease Control and Prevention Atlanta, Georgia

Contraception Ashley M. Eskew MD Fellow, Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Washington University School of Medicine in St. Louis

St. Louis, Missouri

Vulvovaginal and Müllerian Anomalies Ruth A. Etzel MD, PhD Milken Institute School of Public Health George Washington University Washington, DC

Overview of Environmental Health and Children Matthew P. Fahrenkopf MD Plastic Surgery Resident Spectrum Health Hospitals Michigan State University Grand Rapids, Michigan

Deformational Plagiocephaly Marni J. Falk MD Associate Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Executive Director, Mitochondrial Medicine Frontier Program Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Mitochondrial Disease Diagnosis John J. Faria MD Assistant Professor of Otolaryngology and Pediatrics University of Rochester Rochester, New York

Acute Mastoiditis John H. Fargo DO Division of Pediatric Hematology/Oncology Showers Family Center for Childhood Cancer and Blood Disorders Akron Children's Hospital

Akron, Ohio

The Acquired Pancytopenias Kristen A. Feemster MD, MPH, MSPHR Director of Research for the Vaccine Education Center Children's Hospital of Philadelphia Medical Director of the Immunization Program and Acute Communicable Diseases Philadelphia Department of Public Health Adjunct Associate Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Human Papillomaviruses Susan Feigelman MD Professor, Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

Developmental and Behavioral Theories Assessment of Fetal Growth and Development The First Year The Second Year The Preschool Years Middle Childhood Jeffrey A. Feinstein MD, MPH Dunlevie Family Professor of Pulmonary Vascular Disease Division of Pediatric Cardiology Stanford University School of Medicine Professor, by courtesy, of Bioengineering Medical Director, Pediatric Pulmonary Hypertension Program Lucile Packard Children's Hospital at Stanford Palo Alto, California

Pulmonary Hypertension Amy G. Feldman MD, MSCS Assistant Professor of Pediatrics University of Colorado School of Medicine Denver, Colorado; Program Director, Liver Transplant Fellowship Children's Hospital Colorado Research Institute Aurora, Colorado

Drug- and Toxin-Induced Liver Injury Acute Hepatic Failure Eric I. Felner MD, MS Professor of Pediatrics Division of Pediatric Endocrinology Director, Pediatric Clerkships Emory University School of Medicine Atlanta, Georgia

Hormones of the Hypothalamus and Pituitary Hypopituitarism Edward C. Fels MD Clinical Assistant Professor of Medicine Tufts University School of Medicine Boston, Massachusetts; Maine Medical Center Portland, Maine

Vasculitis Syndromes Sing-Yi Feng MD, FAAP Associate Professor Division of Emergency Medicine Department of Pediatrics Children's Medical Center of Dallas

Medical Toxicologist North Texas Poison Center Parkland Memorial Hospital The University of Texas Southwestern Medical Center at Dallas Dallas, Texas

Envenomations Thomas W. Ferkol Jr, MD Alexis Hartmann Professor of Pediatrics Director, Division of Pediatric Allergy, Immunology, and Pulmonary Medicine Washington University School of Medicine in St. Louis St. Louis, Missouri

Primary Ciliary Dyskinesia (Immotile Cilia Syndrome, Kartagener Syndrome) Karin E. Finberg MD, PhD Assistant Professor Department of Pathology Yale School of Medicine New Haven, Connecticut

Iron-Refractory Iron-Deficiency Anemia Jonathan D. Finder MD Professor of Pediatrics The University of Tennessee Health Science Center Attending Pediatric Pulmonologist Division of Pediatric Pulmonology Le Bonheur Children's Hospital Memphis, Tennessee

Bronchomalacia and Tracheomalacia Congenital Disorders of the Lung Laura H. Finkelstein MD Assistant Professor, Department of Pediatrics

University of Maryland School of Medicine Baltimore, Maryland

Assessment of Fetal Growth and Development Middle Childhood Kristin N. Fiorino MD Associate Professor of Clinical Pediatrics Suzie and Scott Lustgarten Motility Center Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine

Motility Disorders and Hirschsprung Disease Philip R. Fischer MD Professor of Pediatrics Department of Pediatric and Adolescent Medicine Mayo Clinic Rochester, Minnesota

Adult Tapeworm Infections Cysticercosis Echinococcosis (Echinococcus granulosus and Echinococcus multilocularis) Brian T. Fisher DO, MSCE Assistant Professor of Pediatrics and Epidemiology University of Pennsylvania Perelman School of Medicine Fellowship Program Director Division of Infectious Diseases Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Actinomyces Nocardia

Veronica H. Flood MD Associate Professor Department of Pediatrics Division of Pediatric Hematology/Oncology Medical College of Wisconsin Milwaukee, Wisconsin

Hemostasis Hereditary Clotting Factor Deficiencies (Bleeding Disorders) von Willebrand Disease Postneonatal Vitamin K Deficiency Liver Disease Acquired Inhibitors of Coagulation Platelet and Blood Vessel Disorders Francisco X. Flores MD Associate Professor of Pediatrics University of Cincinnati College of Medicine Medical Director, Clinical Services and MARS Program Division of Nephrology and Hypertension Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Clinical Evaluation of the Child with Hematuria Isolated Renal Disease Associated with Hematuria Clinical Evaluation of the Child with Proteinuria Conditions Associated with Proteinuria Joseph T. Flynn MD, MS Dr. Robert O. Hickman Endowed Chair in Pediatric Nephrology Professor of Pediatrics University of Washington School of Medicine Chief, Division of Nephrology

Seattle Children's Hospital Seattle, Washington

Systemic Hypertension Patricia M. Flynn MD Senior Vice President and Medical Director of Quality and Patient Care Deputy Clinical Director Member, Department of Infectious Diseases Arthur Ashe Chair in Pediatric AIDS Research St. Jude Children's Research Hospital Memphis, Tennessee

Infection Associated with Medical Devices Cryptosporidium, Isospora, Cyclospora, and Microsporidia Joel A. Forman MD Associate Professor of Pediatrics and Preventive Medicine Vice-Chair for Education Department of Pediatrics Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Chemical Pollutants Michael M. Frank MD Professor Emeritus of Pediatrics, Medicine, and Immunology Duke University School of Medicine Durham, North Carolina

Urticaria (Hives) and Angioedema Robert W. Frenck Jr, MD Professor of Pediatrics University of Cincinnati College of Medicine Medical Director, Division of Infectious Diseases Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio

Liver Abscess Deborah M. Friedman MD Pediatric Cardiology New York Medical College Maria Fareri Children's Hospital Westchester Medical Center Valhalla, New York

Neonatal Lupus Erika Friehling MD Assistant Professor of Pediatrics University of Pittsburgh School of Medicine Division of Pediatric Hematology/Oncology UPMC Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania

Principles of Cancer Diagnosis Principles of Cancer Treatment The Leukemias Stephanie A. Fritz MD, MSCI Associate Professor of Pediatrics University of Washington School of Medicine in St. Louis Division of Infectious Diseases St. Louis Children's Hospital St. Louis, Missouri

Diphtheria (Corynebacterium diphtheriae) Donald P. Frush MD, FACR, FAAP Professor of Radiology Lucile Packard Children's Hospital at Stanford Stanford University School of Medicine Stanford, California

Biologic Effects of Ionizing Radiation on Children Anne M. Gadomski MD, MPH Director, Bassett Research Institute Bassett Medical Center Cooperstown, New York; Associate Professor of Pediatrics Columbia University Medical Center New York, New York

Strategies for Health Behavior Change James T. Gaensbauer MD, MScPH Assistant Professor of Pediatrics University of Colorado School of Medicine Pediatric Infectious Diseases Denver Health Medical Center and Children's Hospital Colorado Denver, Colorado

Staphylococcus Sheila Gahagan MD, MPH Professor of Clinical Pediatrics Chief, Division of Academic General Pediatrics, Child Development, and Community Health Martin Stein Endowed Chair, Developmental-Behavioral Pediatrics University of California, San Diego School of Medicine La Jolla, California

Overweight and Obesity William A. Gahl MD, PhD Clinical Director, National Human Genome Research Institute Director, NIH Undiagnosed Diseases Program National Institutes of Health Bethesda, Maryland

Genetic Approaches to Rare and Undiagnosed

Diseases Patrick G. Gallagher MD Professor of Pediatrics, Genetics, and Pathology Yale University School of Medicine Attending Physician Yale New Haven Children's Hospital New Haven, Connecticut

Definitions and Classification of Hemolytic Anemias Hereditary Spherocytosis Hereditary Elliptocytosis, Hereditary Pyropoikilocytosis, and Related Disorders Hereditary Stomatocytosis Paroxysmal Nocturnal Hemoglobinuria and Acanthocytosis Hayley A. Gans MD Clinical Professor of Pediatrics Stanford University School of Medicine Division of Pediatric Infectious Diseases Stanford, California

Measles Rubella Mumps Cristina Garcia-Mauriño MD Physician Scientist Center for Vaccines and Immunity The Research Institute at Nationwide Children's Hospital Columbus, Ohio

Hansen Disease (Mycobacterium leprae)

Paula M. Gardiner MD, MPH Associate Professor Associate Research Director Department of Family Medicine and Community Health University of Massachusetts Medical School Worcester, Massachusetts

Complementary Therapies and Integrative Medicine Luigi R. Garibaldi MD Professor of Pediatrics University of Pittsburgh School of Medicine Clinical Director Division of Pediatric Endocrinology Children's Hospital of UPMC Pittsburgh, Pennsylvania

Physiology of Puberty Disorders of Pubertal Development Gregory M. Gauthier MD, MS Associate Professor of Medicine Division of Infectious Diseases University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Blastomycosis (Blastomyces dermatitidis) Jeffrey S. Gerber MD, PhD Associate Professor of Pediatrics and Epidemiology University of Pennsylvania Perelman School of Medicine Division of Infectious Diseases Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Legionella Anne A. Gershon MD

Professor of Pediatrics Columbia University College of Physicians and Surgeons Division of Pediatric Infectious Diseases NewYork-Presbyterian Morgan Stanley Children's Hospital New York, New York Saied Ghadersohi MD Resident Physician Department of Otolaryngology – Head and Neck Surgery Northwestern University Feinberg School of Medicine Chicago, Illinois

Neoplasms of the Larynx, Trachea, and Bronchi Mark Gibson MD Professor (Clinical) Emeritus Department of Obstetrics and Gynecology Chief, Division of Reproductive Endocrinology University of Utah School of Medicine Salt Lake City, Utah

Polycystic Ovary Syndrome and Hirsutism Francis Gigliotti MD Professor and Chief of Pediatric Infectious Diseases and Microbiology and Immunology Vice Chair for Academic Affairs University of Rochester Medical Center School of Medicine and Dentistry Rochester, New York

Pneumocystis jirovecii Walter S. Gilliam MSEd, PhD Professor of Child Psychiatry and Psychology Child Study Center Director, The Edward Zigler Center in Child Development and Social Policy Yale School of Medicine

New Haven, Connecticut

Childcare Salil Ginde MD, MPH Assistant Professor of Pediatrics Division of Pediatric Cardiology Medical College of Wisconsin Milwaukee, Wisconsin

Congenital Heart Disease in Adults John A. Girotto MD Section Chief Pediatric Plastic Surgery and Dermatology Center Helen DeVos Children's Hospital Grand Rapids, Michigan

Deformational Plagiocephaly Samuel B. Goldfarb MD Medical Director Pediatric Lung and Heart/Lung Transplant Programs Division of Pulmonary Medicine Medical Director, Solid Organ Transplant Center Children's Hospital of Philadelphia Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Heart-Lung and Lung Transplantation David L. Goldman MD Associate Professor of Pediatrics and Microbiology and Immunology Albert Einstein College of Medicine Division of Pediatric Infectious Disease Montefiore Medical Center Bronx, New York

Cryptococcus neoformans and Cryptococcus gattii Stanton C. Goldman MD Division of Pediatric Hematology, Oncology, and Stem Cell Transplant Medical City Children's Hospital Texas Oncology, PA Dallas, Texas Neal D. Goldstein PhD, MBI Assistant Research Professor of Epidemiology and Biostatistics Drexel University Dornsife School of Public Health Philadelphia, Pennsylvania; Infectious Disease Epidemiologist Christiana Care Health System Newark, Delaware

Lyme Disease (Borrelia burgdorferi) Stuart L. Goldstein MD, FAAP, FNKF Clark D. West Endowed Chair and Professor of Pediatrics University of Cincinnati College of Medicine Director, Center for Acute Care Nephrology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

End-Stage Renal Disease Joseph Gonzalez-Heydrich MD Associate Professor of Psychiatry Harvard Medical School Senior Attending Psychiatrist Boston Children's Hospital Boston, Massachusetts

Childhood Psychoses Denise M. Goodman MD, MS Professor of Pediatrics

Northwestern University Feinberg School of Medicine Attending Physician, Division of Critical Care Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Bronchitis Chronic Respiratory Failure and Long-Term Mechanical Ventilation Tracy S. Goodman MA Technical Officer, Expanded Programme on Immunization Department of Immunization, Vaccines, and Biologicals World Health Organization Geneva, Switzerland

International Immunization Practices Catherine M. Gordon MD, MSc Professor Department of Pediatrics Harvard Medical School Chief, Division of Adolescent/Young Adult Medicine Robert P. Masland Jr. Chair of Adolescent Medicine Boston Children's Hospital Boston, Massachusetts

Bone Structure, Growth, and Hormonal Regulation Osteoporosis Leslie B. Gordon MD, PhD Professor of Pediatrics Research Hasbro Children's Hospital and Warren Alpert Medical School of Brown University Providence, Rhode Island; Department of Pediatrics Boston Children's Hospital and Harvard Medical School Boston, Massachusetts;

Medical Director, The Progeria Research Foundation Peabody, Massachusetts

Hutchinson-Gilford Progeria Syndrome (Progeria) Collin S. Goto MD Professor of Pediatrics The University of Texas Southwestern Medical Center Attending Physician Division of Pediatric Emergency Medicine Children's Medical Center Dallas, Texas

Envenomations W. Adam Gower MD, MS Associate Professor of Pediatrics University of North Carolina School of Medicine Chapel Hill, North Carolina

Neuroendocrine Cell Hyperplasia of Infancy Neera K. Goyal MD Associate Professor of Pediatrics Sidney Kimmel College of Medicine at Thomas Jefferson University Philadelphia, Pennsylvania

The Newborn Infant Jaundice and Hyperbilirubinemia in the Newborn Kernicterus Nicholas P. Goyeneche MD Department of Physical Medicine and Rehabilitation Ochsner Health Center–Covington Covington, Louisiana

Management of Musculoskeletal Injury

Kevin W. Graepel PhD Medical Scientist Training Program Vanderbilt University School of Medicine Vanderbilt University Medical Center Nashville, Tennessee

Coronaviruses Robert J. Graham MD Associate Professor Department of Anesthesiology, Critical Care, and Pain Medicine Harvard Medical School Division of Pediatric Critical Care Medicine Boston Children's Hospital Boston, Massachusetts

Home Mechanical Ventilation and Technology Dependence John M. Greally DMed, PhD, FACMG Professor of Genetics, Medicine, and Pediatrics Albert Einstein College of Medicine Department of Genetics Children's Hospital at Montefiore Bronx, New York

Epigenome-Wide Association Studies and Disease Cori M. Green MD, MSc Assistant Professor of Clinical Pediatrics Weill Cornell Medicine New York-Presbyterian Komansky Children's Hospital New York, New York

Strategies for Health Behavior Change Michael Green MD, MPH Professor of Pediatrics, Surgery, and Clinical and Translational Science

University of Pittsburgh School of Medicine Division of Infectious Diseases Director, Antimicrobial Stewardship and Infection Prevention UPMC Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania

Infections in Immunocompromised Persons Larry A. Greenbaum MD, PhD Marcus Professor of Pediatrics Director, Division of Pediatric Nephrology Emory University School of Medicine Children's Healthcare of Atlanta Atlanta, Georgia

Vitamin D Deficiency (Rickets) and Excess Vitamin E Deficiency Vitamin K Deficiency Micronutrient Mineral Deficiencies Electrolyte and Acid-Base Disorders Maintenance and Replacement Therapy Deficit Therapy V. Jordan Greenbaum MD International Centre for Missing and Exploited Children Alexandria, Virginia

Child Trafficking for Sex and Labor James M. Greenberg MD Professor of Pediatrics Director, Division of Neonatology University of Cincinnati College of Medicine Co-Director, Perinatal Institute Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Overview of Morbidity and Mortality Clinical Manifestations of Diseases in the Newborn Period Anne G. Griffiths MD Pediatric Pulmonologist Children's Respiratory and Critical Care Specialists Director, Primary Ciliary Dyskinesia Center Children's Minnesota Minneapolis, Minnesota

Chronic or Recurrent Respiratory Symptoms Kenneth L. Grizzle PhD Associate Professor of Pediatrics Medical College of Wisconsin Child Development Center Children's Hospital of Wisconsin Milwaukee, Wisconsin

Math and Writing Disabilities Child-Onset Fluency Disorder Judith A. Groner MD Clinical Professor of Pediatrics The Ohio State University College of Medicine Section of Ambulatory Pediatrics Nationwide Children's Hospital Columbus, Ohio

Tobacco Alfredo Guarino MD Professor of Pediatrics Department of Translational Medical Sciences University of Naples Federico II Napoli, Italy

Intestinal Infections and Infestations Associated with Malabsorption Juan P. Gurria MD Fellow in Pediatric Trauma Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Meconium Ileus, Peritonitis, and Intestinal Obstruction Anat Guz-Mark MD Attending Physician Institute of Gastroenterology, Nutrition and Liver Disease Schneider Children's Medical Center of Israel Petah Tikva, Israel; Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel;

Chronic Diarrhea Gabriel G. Haddad MD Distinguished Professor of Pediatrics and Neuroscience Chairman, Department of Pediatrics University of California, San Diego School of Medicine Physician-in-Chief and Chief Scientific Officer Rady Children's Hospital–San Diego

Diagnostic Approach to Respiratory Disease Joseph Haddad Jr, MD Lawrence Savetsky Professor Emeritus Columbia University Irving Medical Center New York, New York

Congenital Disorders of the Nose

Acquired Disorders of the Nose Nasal Polyps General Considerations and Evaluation of the Ear Hearing Loss Congenital Malformations of the Ear External Otitis (Otitis Externa) The Inner Ear and Diseases of the Bony Labyrinth Traumatic Injuries of the Ear and Temporal Bone Tumors of the Ear and Temporal Bone Joseph F. Hagan Jr, MD, FAAP Clinical Professor Department of Pediatrics The Robert Larner College of Medicine at the University of Vermont College of Medicine Hagan, Rinehart, and Connolly Pediatricians, PLLC Burlington, Vermont

Maximizing Children's Health: Screening, Anticipatory Guidance, and Counseling James S. Hagood MD Professor of Pediatrics (Pulmonology) Director, Program in Rare and Interstitial Lung Disease University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Diagnostic Approach to Respiratory Disease Suraiya K. Haider MD Sleep Physician Fairfax Neonatal Associates Fairfax, Virginia

Pleurisy, Pleural Effusions, and Empyema

Goknur Haliloglu MD Professor of Pediatrics Department of Pediatric Neurology Hacettepe University Children's Hospital Ankara, Turkey

Nemaline Rod Myopathy Core Myopathies Myofibrillar Myopathies Brain Malformations and Muscle Development Arthrogryposis Spinal Muscular Atrophies Other Motor Neuron Diseases Scott B. Halstead MD Adjunct Professor Department of Preventive Medicine and Biostatistics Uniformed Services University of the Health Sciences Bethesda, Maryland

Arboviral Infections Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue Yellow Fever Ebola and Other Viral Hemorrhagic Fevers Hantavirus Pulmonary Syndrome Allison R. Hammer MSN, APRN, CPNP-PC Advanced Practice Nurse Department of Otolaryngology – Head and Neck Surgery Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Foreign Bodies in the Airway

Margaret R. Hammerschlag MD Professor of Pediatrics and Medicine Director, Pediatric Infectious Disease Fellowship Program SUNY Down State Medical Center Brooklyn, New York

Chlamydia pneumoniae Chlamydia trachomatis Psittacosis (Chlamydia psittaci) Aaron Hamvas MD Raymond and Hazel Speck Barry Professor of Neonatology Northwestern University Feinberg School of Medicine Head, Division of Neonatology Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Inherited Disorders of Surfactant Metabolism Pulmonary Alveolar Proteinosis James C. Harris MD Professor of Pediatrics, Psychiatry and Behavioral Sciences, Mental Health, and History of Medicine Division of Child and Adolescent Psychiatry Director, Developmental Neuropsychiatry Johns Hopkins University School of Medicine Baltimore, Maryland

Disorders of Purine and Pyrimidine Metabolism Douglas J. Harrison MD, MS Associate Professor of Pediatrics Director of Patient Care and Programs Co-Chair Pediatric Solid Tumor and Sarcoma Team The Children's Cancer Hospital of MD Anderson The University of Texas MD Anderson Cancer Center Houston, Texas

Neuroblastoma Corina Hartman MD Pediatric Gastroenterology and Nutrition Unit Lady Davis Carmel Medical Center Haifa, Israel

Other Malabsorptive Syndromes Mary E. Hartman MD, MPH Assistant Professor of Pediatrics Washington University School of Medicine in St. Louis Division of Pediatric Critical Care Medicine St. Louis Children's Hospital St. Louis, Missouri

Pediatric Emergencies and Resuscitation David B. Haslam MD Associate Professor of Pediatrics University of Cincinnati College of Medicine Director, Antimicrobial Stewardship Program Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Epidemiology of Infections Healthcare-Acquired Infections Non–Group A or B Streptococci Enterococcus H. Hesham Abdel-Kader Hassan MD, MSc Professor of Pediatrics Chief, Division of Pediatric Gastroenterology and Nutrition The University of Arizona College of Medicine Tucson, Arizona

Cholestasis

Fern R. Hauck MD, MS Spencer P. Bass MD Twenty-First Century Professor of Family Medicine Departments of Family Medicine and Public Health Sciences University of Virginia School of Medicine Charlottesville, Virginia

Sudden Infant Death Syndrome Fiona P. Havers MD, MHS Medical Epidemiologist Epidemiology and Prevention Branch, Influenza Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta, Georgia

Influenza Viruses Ericka V. Hayes MD Associate Professor Department of Pediatrics Division of Infectious Diseases Washington University School of Medicine in St. Louis Medical Director, Pediatric and Adolescent HIV Program Medical Director, Infection Prevention St. Louis Children's Hospital St. Louis, Missouri

Campylobacter Yersinia Nontuberculous Mycobacteria Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Jacqueline T. Hecht PhD Professor and Division Head Pediatric Research Center Vice-Chair for Research

Leah L. Lewis Distinguished Chair Department of Pediatrics McGovern Medical School at UTHealth Associate Dean for Research UTHealth School of Dentistry Houston, Texas

General Considerations in Skeletal Dysplasias Disorders Involving Cartilage Matrix Proteins Disorders Involving Transmembrane Receptors Disorders Involving Ion Transporters Disorders Involving Transcription Factors Disorders Involving Defective Bone Resorption Other Inherited Disorders of Skeletal Development Sabrina M. Heidemann MD Professor Department of Pediatrics Wayne State University School of Medicine Director, Intensive Care Unit Co-Director of Transport Children's Hospital of Michigan Detroit, Michigan

Respiratory Distress and Failure Jennifer R. Heimall MD Assistant Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician Division of Allergy and Immunology Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Immunodeficiencies Affecting Multiple Cell Types

Cheryl Hemingway MBChB, PhD Consultant Pediatric Neurologist Great Ormond Street Hospital for Children London, United Kingdom

Demyelinating Disorders of the Central Nervous System J. Owen Hendley MD † Professor of Pediatric Infectious Diseases University of Virginia School of Medicine Charlottesville, Virginia

Sinusitis Retropharyngeal Abscess, Lateral Pharyngeal (Parapharyngeal) Abscess, and Peritonsillar Cellulitis/Abscess Michelle L. Hernandez MD Associate Professor of Pediatrics University of North Carolina School of Medicine Chief Medical Officer UNC Center for Environmental Medicine, Asthma, and Lung Biology Chapel Hill, North Carolina

Hypersensitivity Pneumonia Occupational and Environmental Lung Disease Andrew D. Hershey MD, PhD, FAAN, FAHS Professor of Pediatrics University of Cincinnati College of Medicine Endowed Chair and Director, Division of Neurology Headache Medicine Specialist Cincinnati Children's Medical Center Cincinnati, Ohio

Headaches

Cynthia E. Herzog MD Professor of Pediatrics University of Texas MD Anderson Cancer Center Houston, Texas

Retinoblastoma Gonadal and Germ Cell Neoplasms Neoplasms of the Liver Benign Vascular Tumors Melanoma Nasopharyngeal Carcinoma Adenocarcinoma of the Colon and Rectum Desmoplastic Small Round Cell Tumor Jesse P. Hirner MD Resident Physician Department of Dermatology University of Missouri School of Medicine Columbia, Missouri

Tumors of the Skin Jessica Hochberg MD Assistant Professor of Clinical Pediatrics Division of Pediatric Hematology, Oncology, and Stem Cell Transplant New York Medical College Maria Fareri Children's Hospital at Westchester Medical Center Valhalla, New York

Lymphoma Deborah Hodes MBBS, BSc, DRCOG, FRCPCH Consultant Community Paediatrician Department of Paediatrics University College London Hospitals London, United Kingdom

Female Genital Mutilation Holly R. Hoefgen MD Assistant Professor Pediatric and Adolescent Gynecology Washington University School of Medicine in St. Louis Co-Director, Integrated Care and Fertility Preservation Program St. Louis Children's Hospital St. Louis, Missouri

Vulvovaginitis Lauren D. Holinger MD, FAAP, FACS Paul H. Holinger MD Professor Division of Pediatric Otolaryngology Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Other Laryngeal Neoplasms Tracheal Neoplasms Cynthia M. Holland-Hall MD, MPH Associate Professor of Clinical Pediatrics The Ohio State University College of Medicine Section of Adolescent Medicine Nationwide Children's Hospital Columbus, Ohio

Adolescent Physical and Social Development Transitioning to Adult Care The Breast David K. Hooper MD, MS Associate Professor of Pediatrics University of Cincinnati College of Medicine Medical Director of Kidney Transplantation

Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Renal Transplantation Julie E. Hoover-Fong MD, PhD Associate Professor Department of Pediatrics McKusick-Nathans Institute of Genetic Medicine Director, Greenberg Center for Skeletal Dysplasias Johns Hopkins University School of Medicine Baltimore, Maryland

General Considerations in Skeletal Dysplasias Disorders Involving Transmembrane Receptors Jeffrey D. Hord MD The LOPen Charities and Mawaka Family Chair in Pediatric Hematology/Oncology Director, Showers Family Center for Childhood Cancer and Blood Disorders Akron Children's Hospital Akron, Ohio

The Acquired Pancytopenias B. David Horn MD Associate Professor Department of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Hip Helen M. Horstmann MD Associate Professor Department of Orthopaedic Surgery

University of Pennsylvania Perelman School of Medicine Attending Physician Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Arthrogryposis William A. Horton MD Professor Department of Molecular Medical Genetics Oregon Health & Science University Director Emeritus of Research Shriners Hospitals for Children Portland, Oregon

General Considerations in Skeletal Dysplasias Disorders Involving Cartilage Matrix Proteins Disorders Involving Transmembrane Receptors Disorders Involving Ion Transporters Disorders Involving Transcription Factors Disorders Involving Defective Bone Resorption Other Inherited Disorders of Skeletal Development Peter J. Hotez MD, PhD Dean, National School of Tropical Medicine Professor, Pediatrics and Molecular Virology and Microbiology Head, Section of Pediatric Tropical Medicine Baylor College of Medicine; Endowed Chair of Tropical Pediatrics Center for Vaccine Development Texas Children's Hospital; Professor, Department of Biology Baylor University Waco, Texas; Baker Institute Fellow in Disease and Poverty Rice University

Houston, Texas

Hookworms (Necator americanus and Ancylostoma spp.) Samantha A. House DO Assistant Professor of Pediatrics Geisel School of Medicine at Dartmouth and The Dartmouth Institute Hanover, New Hampshire

Wheezing in Infants: Bronchiolitis Evelyn Hsu MD Associate Professor of Pediatrics University of Washington School of Medicine Medical Director, Liver Transplantation Seattle Children's Hospital Seattle, Washington

Liver Transplantation Katherine Hsu MD, MPH, FAAP Associate Professor of Pediatrics Section of Pediatric Infectious Diseases Boston University Medical Center Boston, Massachusetts; Medical Director, Division of STD Prevention and HIV/AIDS Surveillance Director, Ratelle STD/HIV Prevention Training Center Bureau of Infectious Disease and Laboratory Sciences Massachusetts Department of Public Health Jamaica Plain, Massachusetts

Neisseria gonorrhoeae (Gonococcus) Felicia A. Scaggs Huang, MD Clinical Fellow Division of Infectious Diseases Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio

Congenital and Perinatal Infections Heather G. Huddleston MD Assistant Professor Department of Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco School of Medicine San Francisco, California

Polycystic Ovary Syndrome and Hirsutism Sarah P. Huepenbecker MD Resident Physician Department of Obstetrics and Gynecology Washington University School of Medicine in St. Louis St. Louis, Missouri

Gynecologic Neoplasms and Adolescent Prevention Methods for Human Papillomavirus Vicki Huff PhD Professor Department of Genetics University of Texas MD Anderson Cancer Center Houston, Texas

Neoplasms of the Kidney Winston W. Huh MD Assistant Professor of Clinical Care Children's Hospital of Los Angeles Los Angeles, California

Gonadal and Germ Cell Neoplasms Adenocarcinoma of the Colon and Rectum Stephen R. Humphrey MD

Assistant Professor Department of Dermatology Medical College of Wisconsin Children's Hospital of Wisconsin Milwaukee, Wisconsin

Principles of Dermatologic Therapy Cutaneous Bacterial Infections Cutaneous Fungal Infections Cutaneous Viral Infections Arthropod Bites and Infestations Stephen P. Hunger MD Professor and Jeffrey E. Perelman Distinguished Chair Department of Pediatrics University of Pennsylvania Perelman School of Medicine Chief, Division of Pediatric Oncology Director, Center for Childhood Cancer Research Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Molecular and Cellular Biology of Cancer David A. Hunstad MD Professor of Pediatrics and Molecular Microbiology Washington University School of Medicine in St. Louis St. Louis, Missouri

Central Nervous System Infections Animal and Human Bites Rat Bite Fever Monkeypox Carl E. Hunt MD Research Professor of Pediatrics Uniformed Services University of the Health Sciences

Division of Neonatology Walter Reed National Military Medical Center Bethesda, Maryland; Adjunct Professor of Pediatrics George Washington University School of Medicine and Health Sciences Washington, DC

Sudden Infant Death Syndrome Stacey S. Huppert PhD Associate Professor of Pediatrics University of Cincinnati College of Medicine Division of Gastroenterology, Hepatology, and Nutrition Division of Developmental Biology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Morphogenesis of the Liver and Biliary System Anna R. Huppler MD Assistant Professor Pediatric Infectious Diseases Medical College of Wisconsin Children's Hospital of Wisconsin Milwaukee, Wisconsin

Infectious Complications of Hematopoietic Stem Cell Transplantation Patricia I. Ibeziako MBBS Assistant Professor of Psychiatry Harvard Medical School Director, Psychiatry Consultation Service Boston Children's Hospital Boston, Massachusetts

Somatic Symptom and Related Disorders

Samar H. Ibrahim MBChB Assistant Professor of Pediatrics Division of Pediatric Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota

Mitochondrial Hepatopathies Allison M. Jackson MD, MPH, FAAP Division Chief, Child and Adolescent Protection Center Children's National Health System Washington Children's Foundation Professor of Child and Adolescent Protection Associate Professor of Pediatrics The George Washington University School of Medicine and Health Sciences Washington, DC

Adolescent Sexual Assault Elizabeth C. Jackson MD Professor Emerita of Pediatrics University of Cincinnati College of Medicine Division of Nephrology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Urinary Tract Infections Mary Anne Jackson MD Clinical Professor of Pediatrics University of Missouri–Kansas City School of Medicine Department of Pediatric Infectious Diseases Children's Mercy Hospitals and Clinics Kansas City, Missouri

Orbital Infections Ashlee Jaffe MD, MEd Assistant Professor of Clinical Pediatrics

Department of Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician, Division of Rehabilitation Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Spinal Cord Injury and Autonomic Dysreflexia Management Andrew B. Janowski MD Instructor in Infectious Diseases Department of Pediatrics Washington University School of Medicine in St. Louis St. Louis, Missouri

Central Nervous System Infections Tara C. Jatlaoui MD, MPH Medical Epidemiologist Division of Reproductive Health Centers for Disease Control and Prevention Atlanta, Georgia

Contraception Elena J. Jelsing MD Assistant Professor Departments of Physical Medicine and Rehabilitation and Division of Sports Medicine Mayo Clinic Sports Medicine Center Minneapolis, Minnesota

Specific Sports and Associated Injuries M. Kyle Jensen MD Associate Professor Department of Pediatrics University of Utah School of Medicine

Division of Pediatric Gastroenterology Primary Children's Hospital Salt Lake City, Utah

Viral Hepatitis Brian P. Jenssen MD, MSHP Assistant Professor Department of Pediatrics University of Pennsylvania Perelman School of Medicine Division of General Pediatrics Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Tobacco and Electronic Nicotine Delivery Systems Karen E. Jerardi MD, MEd Associate Professor of Pediatrics University of Cincinnati College of Medicine Attending Physician, Division of Hospital Medicine Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Urinary Tract Infections Chandy C. John MD, MS Ryan White Professor of Pediatrics Director, Ryan White Center for Pediatric Infectious Diseases and Global Health Indiana University School of Medicine Indianapolis, Indiana

Health Advice for Children Traveling Internationally Giardiasis and Balantidiasis Malaria (Plasmodium) Brian D. Johnston MD, MPH Professor of Pediatrics Associate Chief of Clinical Services

Division of General Pediatrics University of Washington School of Medicine Chief of Service, Department of Pediatrics Harborview Medical Center Seattle, Washington

Injury Control Michael V. Johnston MD Executive Vice President and Chief Medical Officer Kennedy Krieger Institute Professor of Pediatrics and Neurology Johns Hopkins University School of Medicine Baltimore, Maryland

Congenital Anomalies of the Central Nervous System Encephalopathies Richard B. Johnston Jr, MD Professor Emeritus of Pediatrics University of Colorado School of Medicine Aurora, Colorado; National Jewish Health Denver, Colorado

Monocytes, Macrophages, and Dendritic Cells The Complement System Disorders of the Complement System Bridgette L. Jones MD Associate Professor of Pediatrics Division of Allergy, Asthma, and Immunology University of Missouri – Kansas City School of Medicine Division of Allergy, Asthma, and Immunology Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation Children's Mercy Kansas City, Missouri

Principles of Drug Therapy Marsha Joselow MSW, LICSW Department of Psychosocial Oncology and Palliative Care Boston Children's Hospital Dana-Farber Cancer Institute Boston, Massachusetts

Pediatric Palliative Care Cassandra D. Josephson MD Professor of Pathology and Pediatrics Emory University School of Medicine Director of Clinical Research, Center for Transfusion and Cellular Therapies Program Director, Transfusion Medicine Fellowship Medical Director Children's Healthcare of Atlanta Blood, Tissue, and Apheresis Services Atlanta, Georgia

Red Blood Cell Transfusions and Erythropoietin Therapy Platelet Transfusions Neutrophil (Granulocyte) Transfusions Plasma Transfusions Risks of Blood Transfusions Nicholas Jospe MD Professor of Pediatrics University of Rochester School of Medicine and Dentistry Chief, Division of Pediatric Endocrinology Golisano Children's Hospital Rochester, New York

Diabetes Mellitus Joel C. Joyce MD

Pediatric Dermatologist NorthShore University Health System Skokie, Illinois; Clinical Assistant Professor of Dermatology University of Chicago Pritzker School of Medicine Chicago, Illinois

Hyperpigmented Lesions Hypopigmented Lesions Vesiculobullous Disorders Nutritional Dermatoses Marielle A. Kabbouche MD, FAHS Professor of Pediatrics University of Cincinnati College of Medicine Director, Acute and Inpatient Headache Program Division of Neurology Cincinnati Children's Medical Center Cincinnati, Ohio

Headaches Joanne Kacperski MD, FAHS Assistant Professor of Pediatrics University of Cincinnati College of Medicine Headache Medicine Specialist, Division of Neurology Director, Post-Concussion Headache Program Director, Headache Medicine Fellowship Cincinnati Children's Medical Center Cincinnati, Ohio

Headaches Deepak Kamat MD, PhD Professor of Pediatrics Vice Chair for Education Wayne State University School of Medicine

Designated Institutional Official Detroit, Michigan

Fever Beena D. Kamath-Rayne MD, MPH Associate Professor of Pediatrics University of Cincinnati College of Medicine Attending Neonatologist, Division of Neonatology and Pulmonary Biology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Neonatal Resuscitation and Delivery Room Emergencies Alvina R. Kansra MD Associate Professor of Pediatrics Medical College of Wisconsin Division of Pediatric Endocrinology Children's Hospital of Wisconsin Milwaukee, Wisconsin

Hypofunction of the Ovaries Pseudoprecocity Resulting From Lesions of the Ovary David M. Kanter MD Assistant Professor Department of Physical Medicine and Rehabilitation State University of New York SUNY Upstate Medical University Syracuse, New York

Health and Wellness for Children With Disabilities Aaron M. Karlin MD Clinical Associate Professor Department of Physical Medicine and Rehabilitation Louisiana State University School of Medicine

Chair, Department of Physical Medicine and Rehabilitation Section Head, Pediatric Rehabilitation Ochsner Clinic Medical Center Ochsner Children's Health Center New Orleans, Louisiana

Management of Musculoskeletal Injury Jacob Kattan MD, MSCR Assistant Professor Department of Pediatrics Jaffe Food Allergy Institute Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Diagnosis of Allergic Disease James W. Kazura MD Distinguished University Professor Adel A. Mahmoud Professorship in Global Health and Vaccines Director, Center for Global Health and Diseases Case Western Reserve University School of Medicine Cleveland, Ohio

Ascariasis (Ascaris lumbricoides) Trichuriasis (Trichuris trichiura) Enterobiasis (Enterobius vermicularis) Strongyloidiasis (Strongyloides stercoralis) Lymphatic Filariasis (Brugia malayi, Brugia timori, and Wuchereria bancrofti) Other Tissue Nematodes Toxocariasis (Visceral and Ocular Larva Migrans) Trichinellosis (Trichinella spiralis) Gregory L. Kearns PharmD, PhD, FAAP

President, Arkansas Children's Research Institute Senior Vice President and Chief Research Officer Arkansas Children's Ross and Mary Whipple Family Distinguished Research Scientist Professor of Pediatrics University of Arkansas for Medical Sciences Little Rock, Arkansas

Principles of Drug Therapy Andrea Kelly MD, MSCE Associate Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Assessment of Growth Desmond P. Kelly MD Professor of Pediatrics University of South Carolina School of Medicine Greenville Chief Medical Research Officer Health Sciences Center Prisma Health-Upstate Greenville, South Carolina

Neurodevelopmental and Executive Function and Dysfunction Kevin J. Kelly MD Professor of Pediatrics (Emeritus) Department of Pediatrics University of North Carolina School of Medicine Chapel Hill, North Carolina

Hypersensitivity Pneumonia Occupational and Environmental Lung Disease

Granulomatous Lung Disease Eosinophilic Lung Disease Interstitial Lung Disease Matthew S. Kelly MD, MPH Assistant Professor of Pediatrics Division of Infectious Diseases Duke University School of Medicine Durham, North Carolina

Community-Acquired Pneumonia Michael Kelly MD, PhD Chief Research Officer Akron Children's Hospital Akron, Ohio

Anatomy and Function of the Lymphatic System Abnormalities of Lymphatic Vessels Lymphadenopathy Kimberly M. Ken MD Resident Physician Department of Dermatology University of Missouri School of Medicine Columbia, Missouri

Disorders of the Sweat Glands Disorders of Hair Disorders of the Nails Melissa A. Kennedy MD Assistant Professor of Clinical Pediatrics Division of Gastroenterology, Hepatology, and Nutrition University of Pennsylvania Perelman School of Medicine Children's Hospital of Philadelphia

Philadelphia, Pennsylvania

Intestinal Duplications, Meckel Diverticulum, and Other Remnants of the Omphalomesenteric Duct Eitan Kerem MD Professor and Chair Department of Pediatrics Hadassah University Medical Center Jerusalem, Israel

Effects of War on Children Joseph E. Kerschner MD Dean of the Medical School, Provost and Executive Vice President Professor of Otolaryngology and Microbiology and Immunology Medical College of Wisconsin Milwaukee, Wisconsin

Otitis Media Seema Khan MD Associate Professor of Pediatrics Division of Gastroenterology and Nutrition George Washington University School of Medicine and Health Sciences Children's National Medical Center Washington, DC

Embryology, Anatomy, and Function of the Esophagus Congenital Anomalies Obstructing and Motility Disorders of the Esophagus Dysmotility Hiatal Hernia Gastroesophageal Reflux Disease Eosinophilic Esophagitis, Pill Esophagitis, and Infective Esophagitis

Esophageal Perforation Esophageal Varices Ingestions Ameneh Khatami BHB, MBChB, MD Clinical Senior Lecturer Discipline of Child and Adolescent Health University of Sydney Department of Microbiology and Infectious Diseases The Children's Hospital at Westmead Sydney, Australia

Aeromonas and Plesiomonas Soumen Khatua MD Associate Professor of Pediatrics Section Chief, Neuro-Oncology Department of Pediatrics Patient Care The University of Texas MD Anderson Cancer Center Houston, Texas

Brain Tumors in Childhood Alexandra Kilinsky DO Fellow, Pediatric Hospital Medicine Department of Pediatrics Cohen Children's Medical Center of New York New Hyde Park, New York

Immunization Practices Chong-Tae Kim MD, PhD Associate Professor Department of Pediatrics University of Pennsylvania Perelman School of Medicine Division of Rehabilitation Medicine Children's Hospital of Philadelphia

Philadelphia, Pennsylvania

Rehabilitation for Severe Traumatic Brain Injury Wendy E. Kim DO Assistant Professor of Internal Medicine and Pediatrics Division of Pediatric Dermatology Loyola University Chicago Stritch School of Medicine Evanston, Illinois

Diseases of the Dermis Diseases of Subcutaneous Tissue Disorders of the Mucous Membranes Acne Charles H. King MD Professor Emeritus of International Health Center for Global Health and Diseases Case Western Reserve University School of Medicine Cleveland, Ohio

Schistosomiasis (Schistosoma) Flukes (Liver, Lung, and Intestinal) Paul S. Kingma MD, PhD Associate Professor of Pediatrics University of Cincinnati of College of Medicine Neonatal Director, Cincinnati Fetal Center Co-Director, Cincinnati Bronchopulmonary Dysplasia Center The Perinatal Institute Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Fetal Intervention and Surgery Stephen L. Kinsman MD Associate Professor of Pediatrics

Medical University of South Carolina Charleston, South Carolina

Congenital Anomalies of the Central Nervous System Priya S. Kishnani MD, MBBS C.L. and Su Chen Professor of Pediatrics Chief, Division of Medical Genetics Duke University Medical Center Durham, North Carolina

Defects in Metabolism of Carbohydrates Bruce L. Klein MD Associate Professor of Pediatrics Johns Hopkins University School of Medicine Interim Director, Pediatric Emergency Medicine Director, Pediatric Transport Johns Hopkins Children's Center Baltimore, Maryland

Interfacility Transport of the Seriously Ill or Injured Pediatric Patient Acute Care of Multiple Trauma Care of Abrasions and Minor Lacerations Bruce S. Klein MD Professor of Pediatrics, Internal Medicine, and Medical Microbiology and Immunology Chief, Pediatric Infectious Disease Division University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Blastomycosis (Blastomyces dermatitidis) Robert M. Kliegman MD Professor and Chairman Emeritus Department of Pediatrics

Medical College of Wisconsin Children's Hospital of Wisconsin Milwaukee, Wisconsin

Culture-Specific Beliefs Refeeding Syndrome Generalized Arterial Calcification of Infancy/Idiopathic Infantile Arterial Calcification Arterial Tortuosity William C. Koch MD Associate Professor of Pediatrics Virginia Commonwealth University School of Medicine Division of Pediatric Infectious Diseases Children's Hospital of Richmond at VCU Richmond, Virginia

Parvoviruses Patrick M. Kochanek MD, MCCM Ake N. Grenvik Professor of Critical Care Medicine Vice Chair, Department of Critical Care Medicine Professor of Anesthesiology, Pediatrics, Bioengineering, and Clinical and Translational Science Director, Safar Center for Resuscitation Research UPMC Children's Hospital of Pittsburgh John G. Rangos Research Center Pittsburgh, Pennsylvania

Neurologic Emergencies and Stabilization Eric Kodish MD Professor of Pediatrics Lerner College of Medicine Cleveland Clinic Cleveland, Ohio

Ethics in Pediatric Care Stephan A. Kohlhoff MD Associate Professor of Pediatrics and Medicine Chief, Pediatric Infectious Diseases SUNY Downstate Medical Center Brooklyn, New York

Chlamydia pneumoniae Psittacosis (Chlamydia psittaci) Mark A. Kostic MD Professor of Emergency Medicine and Pediatrics Medical College of Wisconsin Associate Medical Director Wisconsin Poison Center Milwaukee, Wisconsin

Poisoning Karen L. Kotloff MD Professor of Pediatrics Division Head, Infectious Disease and Tropical Pediatrics Center for Vaccine Development and Global Health University of Maryland School of Medicine Baltimore, Maryland

Acute Gastroenteritis in Children Elliot J. Krane MD, FAAP Professor of Pediatrics, and Anesthesiology, Perioperative, and Pain Medicine Stanford University School of Medicine Chief, Pediatric Pain Management Stanford Children's Health Lucile Packard Children's Hospital at Stanford Stanford, California

Pediatric Pain Management

Peter J. Krause MD Senior Research Scientist in Epidemiology (Microbial Diseases), Medicine (Infectious Diseases), and Pediatrics (Infectious Diseases) Lecturer in Epidemiology (Microbial Diseases) Yale School of Public Health New Haven, Connecticut

Babesiosis (Babesia) Richard E. Kreipe MD, FAAAP, FSAHM, FAED Dr. Elizabeth R. McArnarney Professor in Pediatrics funded by Roger and Carolyn Friedlander Department of Pediatrics, Division of Adolescent Medicine University of Rochester Medical Center Golisano Children's Hospital Director, New York State ACT for Youth Center of Excellence Medical Director, Western New York Comprehensive Care Center for Eating Disorders Rochester, New York

Eating Disorders Steven E. Krug MD Professor of Pediatrics Northwestern University Feinberg School of Medicine Division of Pediatric Emergency Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Emergency Medical Services for Children Janet L. Kwiatkowski MD, MSCE Professor Department of Pediatrics University of Pennsylvania Perelman School of Medicine Division of Hematology Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Hemoglobinopathies Jennifer M. Kwon MD Professor of Child Neurology Department of Neurology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Neurodegenerative Disorders of Childhood Catherine S. Lachenauer MD Assistant Professor of Pediatrics Harvard Medical School Director, Infectious Diseases Outpatient Practice Boston Children's Hospital Boston, Massachusetts

Group B Streptococcus Stephan Ladisch MD Professor of Pediatrics and Biochemistry/Molecular Biology George Washington University School of Medicine Center for Cancer and Immunology Research and Center for Cancer and Blood Disorders Children's Research Institute Children's National Medical Center Washington, DC

Histiocytosis Syndromes of Childhood Oren J. Lakser MD Assistant Professor of Pediatrics Northwestern University Feinberg School of Medicine Associate Clinician Specialist Division of Pulmonary Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Bronchiectasis Pulmonary Abscess Philip J. Landrigan MD, MSc, FAAP Director, Global Public Health Program Schiller Institute for Integrated Science and Society Professor of Biology Boston College Chestnut Hill, Massachusetts

Chemical Pollutants Gregory L. Landry MD Professor Emeritus Department of Pediatrics University of Wisconsin – Madison School of Medicine and Public Health Madison, Wisconsin

Epidemiology and Prevention of Injuries Heat Injuries Female Athletes: Menstrual Problems and the Risk of Osteopenia Performance-Enhancing Aids Wendy G. Lane MD, MPH, FAAP Associate Professor Department Epidemiology and Public Health Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

Abused and Neglected Children A. Noelle Larson MD Associate Professor, Orthopedic Surgery

Division of Pediatric Orthopedic Surgery Mayo Clinic Rochester, Minnesota

Benign Tumors and Tumor-Like Processes of Bone Phillip S. LaRussa MD Professor of Pediatrics Columbia University College of Physicians and Surgeons Division of Pediatric Infectious Diseases NewYork-Presbyterian Morgan Stanley Children's Hospital New York, New York

Varicella-Zoster Virus Oren J. Lakser MD Assistant Professor of Pediatrics Northwestern University Feinberg School of Medicine Division of Pulmonary Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Bronchiectasis Pulmonary Abscess J. Todd R. Lawrence MD, PhD Assistant Professor Department of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Knee Brendan Lee MD, PhD Robert and Janice McNair Endowed Chair in Molecular and Human Genetics

Professor and Chairman Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas

Integration of Genetics into Pediatric Practice The Genetic Approach in Pediatric Medicine The Human Genome Patterns of Genetic Transmission Cytogenetics Genetics of Common Disorders K. Jane Lee MD, MA Associate Professor Department of Pediatrics Medical College of Wisconsin Division of Pediatric Special Needs Children's Hospital of Wisconsin Milwaukee, Wisconsin

Brain Death J. Steven Leeder PharmD, PhD Marion Merrell Dow / Missouri Endowed Chair in Pediatric Pharmacology Chief, Division of Pediatric Pharmacology and Medical Toxicology Children's Mercy Hospitals and Clinics Kansas City, Missouri; Adjunct Professor Department of Pharmacology, Toxicology, and Therapeutics Kansas University School of Medicine Kansas City, Kansas

Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics Jennifer W. Leiding MD

Assistant Professor of Pediatrics University of South Florida College of Medicine St. Petersburg, Florida

Immunodeficiencies Affecting Multiple Cell Types Michael J. Lentze MD Professor Emeritus of Pediatrics Zentrum für Kinderheilkunde Universitätsklinikum Bonn Bonn, Germany

Enzyme Deficiencies Steven O. Lestrud MD Assistant Professor of Pediatrics Northwestern University Feinberg School of Medicine Medical Director, Respiratory Care Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Bronchopulmonary Dysplasia Chronic Respiratory Failure and Long-Term Mechanical Ventilation Donald Y.M. Leung MD, PhD Edelstein Family Chair of Pediatric Allergy-Immunology National Jewish Health Professor of Pediatrics University of Colorado School of Medicine Denver, Colorado

Atopic Dermatitis (Atopic Eczema) Michael N. Levas MD Associate Professor of Pediatrics Medical College of Wisconsin Division of Pediatric Emergency Medicine

Children's Hospital of Wisconsin Milwaukee, Wisconsin

Violent Behavior Rona L. Levy MSW, PhD, MPH Professor and Director Behavioral Medicine Research Group Assistant Dean for Research School of Social Work University of Washington Seattle, Washington

Pediatric Pain Management B U.K. Li MD Clinical Professor of Pediatrics Medical College of Wisconsin Division of Pediatric Gastroenterology Children's Hospital of Wisconsin Milwaukee, Wisconsin

Cyclic Vomiting Syndrome Chris A. Liacouras MD Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Co-Director, Center for Pediatric Eosinophilic Disorders Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Normal Digestive Tract Phenomena Major Symptoms and Signs of Digestive Tract Disorders Normal Development, Structure, and Function of the Stomach and Intestines Pyloric Stenosis and Other Congenital Anomalies of

the Stomach Intestinal Atresia, Stenosis, and Malrotation Intestinal Duplications, Meckel Diverticulum, and Other Remnants of the Omphalomesenteric Duct Motility Disorders and Hirschsprung Disease Ileus, Adhesions, Intussusception, and Closed-Loop Obstructions Foreign Bodies and Bezoars Functional Abdominal Pain Cyclic Vomiting Syndrome Malformations Ascites Peritonitis Christopher W. Liebig MD Clinical Assistant Professor of Pediatrics Northeast Ohio Medical University Rootstown, Ohio; Director, Sports Medicine in Mahoning Valley Akron Children's Hospital Boardman, Ohio

Sports-Related Traumatic Brain Injury (Concussion) Paul H. Lipkin MD Associate Professor of Pediatrics Director, Medical Informatics Director, Interactive Autism Network Kennedy Krieger Institute Johns Hopkins University School of Medicine Baltimore, Maryland

Developmental and Behavioral Surveillance and

Screening Deborah R. Liptzin MD, MS Assistant Professor of Pediatrics University of Colorado School of Medicine Associate Director, Colorado chILD Children's Hospital Colorado Aurora, Colorado

Fibrotic Lung Disease Andrew H. Liu MD Professor Department of Pediatrics Children's Hospital Colorado University of Colorado School of Medicine Aurora, Colorado

Childhood Asthma Lucinda Lo MD Clinical Assistant Professor of Pediatrics Physician Advisor, CDI and CM University of Pennsylvania Perelman School of Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Malnutrition Stanley F. Lo PhD Associate Professor of Pathology Medical College of Wisconsin Technical Director, Clinical Chemistry, POCT, and Biochemical Genetics Director, Reference Standards Library Children's Hospital of Wisconsin Milwaukee, Wisconsin

Laboratory Testing in Infants and Children

Reference Intervals for Laboratory Tests and Procedures Kathleen A. Long MD Department of Child Health University of Missouri School of Medicine Columbia, Missouri

Dermatologic Diseases of the Neonate Sarah S. Long MD Professor of Pediatrics Drexel University College of Medicine Division of Infectious Diseases St. Christopher's Hospital for Children Philadelphia, Pennsylvania

Pertussis (Bordetella pertussis and Bordetella parapertussis) Anna Lena Lopez MD, MPH Director, Institute of Child Health and Human Development Research Associate Professor University of the Philippines Manila–National Institutes of Health Manila, Philippines

Cholera Santiago M.C. Lopez MD Assistant Professor of Pediatrics University of South Dakota School of Medicine Pediatric Infectious Diseases Sanford Children's Hospital/Specialty Clinic Sioux Falls, South Dakota

The Common Cold Steven V. Lossef MD

Associate Professor of Radiology George Washington University School of Medicine and Health Sciences Head, Pediatric Interventional Radiology Division of Diagnostic Imaging and Radiology Children's National Medical Center Washington, DC

Pertussis (Bordetella pertussis and Bordetella parapertussis) Pleurisy, Pleural Effusions, and Empyema Jennifer A. Lowry MD Professor of Pediatrics University of Missouri – Kansas City School of Medicine Director, Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation Children's Mercy Kansas City, Missouri

Principles of Drug Therapy Ian R. Macumber MD, MS Assistant Professor of Pediatrics University of Connecticut School of Medicine Division of Nephrology Connecticut Children's Medical Center Hartford, Connecticut

Systemic Hypertension Mark R. Magnusson MD, PhD Co-Director, Diagnostic and Complex Care Center Medical Director, Spina Bifida Program Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Chronic Fatigue Syndrome

Pilar L. Magoulas MS Assistant Professor, Clinical Program Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas

Genetic Counseling Prashant V. Mahajan MD, MPH, MBA Professor of Emergency Medicine and Pediatrics Vice-Chair, Department of Emergency Medicine Division Chief, Pediatric Emergency Medicine University of Michigan Ann Arbor, Michigan

Heavy Metal Intoxication Joseph A. Majzoub MD Thomas Morgan Rotch Professor of Pediatrics Harvard Medical School Division of Endocrinology Boston Children's Hospital Boston, Massachusetts

Diabetes Insipidus Other Abnormalities of Arginine Vasopressin Metabolism and Action Robert J. Mann MD The Karl and Patricia Betz Family Endowed Director of Research Helen DeVos Children's Hospital Grand Rapids, Michigan

Deformational Plagiocephaly Irini Manoli MD, PhD National Human Genome Research Institute

National Institutes of Health Bethesda, Maryland

Isoleucine, Leucine, Valine, and Related Organic Acidemias Asim Maqbool MD Associate Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Nutritional Requirements Normal Digestive Tract Phenomena Major Symptoms and Signs of Digestive Tract Disorders Normal Development, Structure, and Function of the Stomach and Intestines Pyloric Stenosis and Other Congenital Anomalies of the Stomach Intestinal Atresia, Stenosis, and Malrotation Intestinal Duplications, Meckel Diverticulum, and Other Remnants of the Omphalomesenteric Duct Motility Disorders and Hirschsprung Disease Ileus, Adhesions, Intussusception, and Closed-Loop Obstructions Foreign Bodies and Bezoars Cyclic Vomiting Syndrome Peritoneal Malformations Ascites

Peritonitis Ashley M. Maranich MD Program Director, Pediatrics Residency Tripler Army Medical Center Honolulu, Hawaii

Malassezia Nicole Marcantuono MD Associate Professor Department of Pediatrics Thomas Jefferson Medical College Philadelphia, Pennsylvania; Attending Physician Alfred I. du Pont Hospital for Children Wilmington, Delaware

Evaluation of the Child for Rehabilitative Services David Margolis MD Professor and Associate Chair Department of Pediatrics Medical College of Wisconsin Program Director, Bone Marrow Transplantation Children's Hospital of Wisconsin Milwaukee, Wisconsin

Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cell Transplantation from Alternative Sources and Donors Graft-Versus-Host Disease, Rejection, and Venoocclusive Disease Late Effects of Hematopoietic Stem Cell

Transplantation Mona Marin MD Division of Viral Diseases National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta, Georgia

Varicella-Zoster Virus Joan C. Marini MD, PhD Chief, Bone and Extracellular Matrix Branch National Institute for Child Health and Development National Institutes of Health Bethesda, Maryland

Osteogenesis Imperfecta Thomas C. Markello MD, PhD Associate Staff Clinician, Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

Genetic Approaches to Rare and Undiagnosed Diseases Morri Markowitz MD Professor of Pediatrics and Medicine Albert Einstein College of Medicine Director, Lead Poisoning Prevention and Treatment Program The Children's Hospital at Montefiore Bronx, New York

Lead Poisoning Stacene R. Maroushek MD, PhD, MPH

Assistant Professor of Pediatrics Divisions of Pediatric Infectious Diseases and General Pediatrics University of Minnesota Medical School Hennepin County Medical Center Minneapolis, Minnesota

Medical Evaluation of the Foreign-Born Child Principles of Antimycobacterial Therapy Justin D. Marsh MD Assistant Professor of Pediatric Ophthalmology University of Missouri-Kansas City School of Medicine Kansas City, Missouri

Growth and Development of the Eye Examination of the Eye Abnormalities of Refraction and Accommodation Disorders of Vision Abnormalities of Pupil and Iris Disorders of Eye Movement and Alignment Abnormalities of the Lids Disorders of the Lacrimal System Disorders of the Conjunctiva Abnormalities of the Cornea Abnormalities of the Lens Disorders of the Uveal Tract Disorders of the Retina and Vitreous Abnormalities of the Optic Nerve Childhood Glaucoma Orbital Abnormalities Orbital Infections

Injuries to the Eye Kari L. Martin MD Assistant Professor of Dermatology and Child Health University of Missouri School of Medicine Columbia, Missouri

Dermatologic Diseases of the Neonate Cutaneous Defects Ectodermal Dysplasias Vascular Disorders Cutaneous Nevi Disorders of Keratinization Disorders of the Sweat Glands Disorders of Hair Disorders of the Nails Tumors of the Skin Maria G. Martinez MD Clinical Fellow, Pediatric Rehabilitation Medicine Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Health and Wellness for Children With Disabilities Wilbert H. Mason MD, MPH Professor Emeritus of Clinical Pediatrics University of Southern California Keck School of Medicine Chief, Pediatric Infectious Diseases Children's Hospital of Los Angeles Los Angeles, California

Measles Rubella

Mumps Reuben K. Matalon MD, PhD Professor of Pediatrics and Genetics University of Texas Medical Branch University of Texas Children's Hospital Galveston, Texas

N-Acetylaspartic Acid Aspartic Acid (Canavan Disease) Sravan Kumar Reddy Matta, MD Assistant Professor of Pediatrics Division of Gastroenterology and Nutrition Children's National Medical Center Washington, DC

Embryology, Anatomy, and Function of the Esophagus Congenital Anomalies Obstructing and Motility Disorders of the Esophagus Dysmotility Hiatal Hernia Gastroesophageal Reflux Disease Aletha Maybank MD, MPH Deputy Commissioner Founding Director, Center for Health Equity New York City Department of Health and Mental Hygiene Long Island City, New York

Racism and Child Health Robert L. Mazor MD Clinical Associate Professor Department of Pediatrics University of Washington School of Medicine

Division of Critical Care and Cardiac Surgery Clinical Director, CICU Seattle Children's Hospital and Regional Medical Center Seattle, Washington

Pulmonary Edema Jennifer McAllister MD, IBCLC Assistant Professor of Pediatrics University of Cincinnati College of Medicine Medical Director, West Chester Hospital Special Care Nursery and University of Cincinnati Medical Center Newborn Nursery Medical Director, NICU Follow Up Clinic–NAS Clinic Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Maternal Selective Serotonin Reuptake Inhibitors and Neonatal Behavioral Syndromes Megan E. McCabe MD, FAAP Director, Pediatric Residency Program Director, Pediatric Critical Care Fellowship Program The Children's Hospital at Montefiore The University Hospital for Albert Einstein College of Medicine Bronx, New York

Loss, Separation, and Bereavement Megan E. McClean MD Resident Physician Department of Dermatology University of Missouri School of Medicine Columbia, Missouri

Cutaneous Nevi Susanna A. McColley MD Professor of Pediatrics

Northwestern University Feinberg School of Medicine Associate Chief Research Officer for Clinical Trials Stanley Manne Children's Research Institute Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Extrapulmonary Diseases with Pulmonary Manifestations Pulmonary Tumors Patrick T. McGann MD, MS Associate Professor of Pediatrics University of Cincinnati College of Medicine Division of Hematology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Anemia in the Newborn Infant Margaret M. McGovern MD, PhD Knapp Professor of Pediatrics Physician-in-Chief Stony Brook Children's Hospital Dean for Clinical Affairs Stony Brook University School of Medicine Stony Brook, New York

Lipidoses (Lysosomal Storage Disorders) Mucolipidoses Disorders of Glycoprotein Degradation and Structure Sharon A. McGrath-Morrow MD, MBA Professor of Pediatrics Eudowood Division of Pediatric Respiratory Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

Bronchopulmonary Dysplasia Jeffrey S. McKinney MD, PhD Professor of Pediatrics Vice Chair for Education Harry W. Bass Jr. Professorship in Pediatric Education Distinguished Teaching Professor Division of Pediatric Infectious Diseases UT Southwestern Medical Center Dallas, Texas

Salmonella Matthew J. McLaughlin MD Assistant Professor of Pediatrics University of Missouri–Kansas City School of Medicine Division of Pediatric Physical Medicine and Rehabilitation Children's Mercy Hospitals and Clinics Kansas City, Missouri

Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics Rima McLeod MD Professor of Ophthalmology and Visual Science and Pediatrics Medical Director, Toxoplasmosis Center University of Chicago Medicine Chicago, Illinois

Toxoplasmosis (Toxoplasma gondii) Asuncion Mejias MD, PhD, MSCS Associate Professor of Pediatrics Division of Infectious Diseases The Ohio State University College of Medicine Principal Investigator, Center for Vaccines and Immunity The Research Institute at Nationwide Children's Hospital Columbus, Ohio

Hansen Disease (Mycobacterium leprae) Mycoplasma pneumoniae Genital Mycoplasmas (Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum) Peter C. Melby MD Professor of Internal Medicine (Infectious Diseases), Microbiology and Immunology, and Pathology Director, Division of Infectious Diseases Director, Center for Tropical Diseases University of Texas Medical Branch (UTMB) Galveston, Texas

Leishmaniasis (Leishmania) Marlene D. Melzer-Lange MD Professor of Pediatrics Medical College of Wisconsin Program Director, Project Ujima Children's Hospital of Wisconsin Milwaukee, Wisconsin

Violent Behavior Matthew D. Merguerian MD, PhD Fellow, Division of Pediatric Oncology Department of Oncology Johns Hopkins Hospital Pediatric Oncology Branch National Cancer Institute Baltimore, Maryland

Definitions and Classification of Hemolytic Anemias Hereditary Spherocytosis Hereditary Elliptocytosis, Hereditary

Pyropoikilocytosis, and Related Disorders Hereditary Stomatocytosis Paroxysmal Nocturnal Hemoglobinuria and Acanthocytosis Stephanie L. Merhar MD, MS Assistant Professor of Pediatrics University of Cincinnati College of Medicine Attending Neonatologist, Division of Neonatology and Pulmonary Biology Research Director, NICU Follow-Up Clinic Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Nervous System Disorders Diane F. Merritt MD Professor Department of Obstetrics and Gynecology Director, Pediatric and Adolescent Gynecology Washington University School of Medicine in St. Louis St. Louis, Missouri

Gynecologic History and Physical Examination Vaginal Bleeding in the Prepubertal Child Breast Concerns Neoplasms and Adolescent Prevention Methods for Human Papillomavirus Vulvovaginal and Müllerian Anomalies Kevin Messacar MD Assistant Professor of Pediatrics University of Colorado School of Medicine Section of Pediatric Infectious Diseases Section of Hospital Medicine Children's Hospital Colorado

Aurora, Colorado

Nonpolio Enteroviruses Marian G. Michaels MD, MPH Professor of Pediatrics and Surgery University of Pittsburgh School of Medicine UPMC Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania

Infections in Immunocompromised Persons Thomas F. Michniacki Pediatric Hematology/Oncology Fellow Division of Pediatric Hematology/Oncology University of Michigan Medical School Ann Arbor, Michigan

Leukopenia Leukocytosis Mohamad A. Mikati MD Wilburt C. Davison Professor of Pediatrics Professor of Neurobiology Chief, Division of Pediatric Neurology Duke University Medical Center Durham, North Carolina

Seizures in Childhood Conditions That Mimic Seizures Henry Milgrom MD Professor of Pediatrics National Jewish Health University of Colorado School of Medicine Denver, Colorado

Allergic Rhinitis

Jonathan W. Mink MD, PhD Frederick A. Horner MD Endowed Professor in Pediatric Neurology Professor of Neurology and Pediatrics Chief, Division of Child Neurology Vice-Chair, Department of Neurology University of Rochester Medical Center Rochester, New York

Mass Psychogenic Illness Movement Disorders R. Justin Mistovich MD Assistant Professor Department of Orthopaedic Surgery Case Western Reserve University School of Medicine MetroHealth Medical Center University Hospitals Rainbow and Babies Children's Hospital Cleveland, Ohio

The Spine The Neck Jonathan A. Mitchell PhD, MsC Research Assistant Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia

Nutritional Requirements Feeding Healthy Infants, Children, and Adolescents Mark M. Mitsnefes MD, MS Professor of Pediatrics University of Cincinnati College of Medicine Director, Clinical and Translational Research Center Division of Pediatric Nephrology Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio

Chronic Kidney Disease Sindhu Mohandas MD Assistant Professor of Pediatrics Division of Infectious Diseases Keck School of Medicine University of Southern California Los Angeles, California

Other Anaerobic Infections Rachel Y. Moon MD Professor of Pediatrics Head, Division of General Pediatrics University of Virginia School of Medicine Charlottesville, Virginia

Sudden Infant Death Syndrome Joan P. Moran BSN, RN Infection Preventionist Infection Prevention and Control Children's Hospital of Wisconsin Milwaukee, Wisconsin

Infection Prevention and Control Eva Morava MD, PhD Professor of Pediatrics Tulane University Medical School Clinical Biochemical Geneticist Hayward Genetics Center New Orleans, Louisiana

Congenital Disorders of Glycosylation Megan A. Moreno MD, MSEd, MPH

Professor of Pediatrics Division Chief, General Pediatrics and Adolescent Medicine Vice Chair of Digital Health University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Bullying, Cyberbullying, and School Violence Media Violence Esi Morgan MD, MSCE Associate Professor of Pediatrics University of Cincinnati College of Medicine Division of Rheumatology James M. Anderson Center for Health Systems Excellence Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Treatment of Rheumatic Diseases Peter E. Morrison DO Senior Instructor Department of Neurology University of Rochester Medical Center Rochester, New York

Ataxias Lovern R. Moseley PhD Clinical Assistant Professor of Psychiatry Boston University School of Medicine Boston, Massachusetts

Tantrums and Breath-Holding Spells Lying, Stealing, and Truancy Aggression Self-Injurious Behavior

Yael Mozer-Glassberg MD Head, Pediatric Liver Transplant Program Institute of Gastroenterology, Nutrition, and Liver Diseases Schneider Children's Medical Center of Israel Petah Tikva, Israel

Immunoproliferative Small Intestinal Disease Louis J. Muglia MD, PhD Professor of Pediatrics University of Cincinnati College of Medicine Co-Director, Perinatal Institute Director, Center for Prevention of Preterm Birth Director, Division of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

The Endocrine System Kevin P. Murphy MD Medical Director, Pediatric Rehabilitation Sanford Health Systems Bismarck, North Dakota; Medical Director, Gillette Children's Specialty Healthcare Duluth Clinic Duluth, Minnesota

Management of Musculoskeletal Injury Specific Sports and Associated Injuries Timothy F. Murphy MD SUNY Distinguished Professor of Medicine Senior Associate Dean for Clinical and Translational Research Jacobs School of Medicine and Biomedical Sciences University at Buffalo, State University of New York Buffalo, New York

Moraxella catarrhalis

Karen F. Murray MD Professor and Interim-Chair Chief, Division of Gastroenterology and Hepatology Department of Pediatrics University of Washington School of Medicine Interim Pediatrician-In-Chief Seattle Children's Hospital Seattle, Washington

Tumors of the Digestive Tract Thomas S. Murray MD, PhD Associate Professor of Medical Sciences Quinnipiac University Frank H Netter MD School of Medicine Hamden, Connecticut

Listeria monocytogenes Pseudomonas, Burkholderia, and Stenotrophomonas Infective Endocarditis Sona Narula MD Assistant Professor of Clinical Neurology Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Central Nervous System Vasculitis Mindo J. Natale PsyD Assistant Professor of Psychology University of South Carolina School of Medicine Senior Staff Psychologist GHS Children's Hospital Greenville, South Carolina

Neurodevelopmental and Executive Function and Dysfunction

Amy T. Nathan MD Associate Professor of Pediatrics University of Cincinnati College of Medicine Medical Director, Perinatal Institute Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

The Umbilicus Dipesh Navsaria MD, MPH, MSLIS, FAAP Associate Professor of Pediatrics University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Maximizing Children's Health: Screening, Anticipatory Guidance, and Counseling William A. Neal MD Professor Emeritus of Pediatrics Division of Pediatric Cardiology West Virginia University School of Medicine Morgantown, West Virginia

Disorders of Lipoprotein Metabolism and Transport Grace Nehme MD Fellow, Department of Pediatrics University of Texas MD Anderson Cancer Center Houston, Texas

Neoplasms of the Kidney Edward J. Nehus MD, MS Assistant Professor of Clinical Pediatrics University of Cincinnati College of Medicine Division of Nephrology and Hypertension Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Introduction to Glomerular Diseases Maureen R. Nelson MD Associate Professor of Physical Medicine & Rehabilitation and Pediatrics Baylor College of Medicine Medical Director, Physical Medicine & Rehabilitation The Children's Hospital of San Antonio San Antonio, Texas

Birth Brachial Plexus Palsy Caitlin M. Neri MD Assistant Professor of Pediatrics Boston University School of Medicine Boston, Massachusetts

Complementary Therapies and Integrative Medicine Mark I. Neuman MD, MPH Associate Professor of Pediatrics and Emergency Medicine Harvard Medical School Department of Emergency Medicine Boston Children's Hospital Boston, Massachusetts

Fever in the Older Child Mary A. Nevin MD, FAAP, FCCP Associate Professor of Pediatrics Northwestern University Feinberg School of Medicine Department of Pediatrics, Division of Pulmonary Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Pulmonary Hemosiderosis Pulmonary Embolism, Infarction, and Hemorrhage Jane W. Newburger MD

Commonwealth Professor of Pediatrics Harvard Medical School Associate Cardiologist-in-Chief, Research and Education Director, Cardiac Neurodevelopmental Program Boston Children's Hospital Boston, Massachusetts

Kawasaki Disease Jonathan Newmark MD, MM, FAAN Adjunct Professor of Neurology F. Edward Hebert School of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland; Clinical Assistant Professor of NeurologyGeorge Washington University School of Medicine and Health Sciences Staff Neurologist Washington DC VA Medical Center Washington, DC

Biologic and Chemical Terrorism Linda S. Nield MD Assistant Dean for Admissions Professor of Medical Education and Pediatrics West Virginia University School of Medicine Morgantown, West Virginia

Fever Omar Niss MD Assistant Professor of Pediatrics University of Cincinnati College of Medicine Division of Hematology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Hemolytic Disease of the Newborn

Neonatal Polycythemia Zehava L. Noah MD Associate Professor of Pediatrics Northwestern University Feinberg School of Medicine Division of Pediatric Critical Care Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Other Conditions Affecting Respiration James J. Nocton MD Professor of Pediatrics Section of Pediatric Rheumatology Medical College of Wisconsin Milwaukee, Wisconsin

Mast Cell Activation Syndrome Lawrence M. Nogee MD Professor of Pediatrics Eudowood Neonatal Pulmonary Division Johns Hopkins University School of Medicine Baltimore, Maryland

Inherited Disorders of Surfactant Metabolism Pulmonary Alveolar Proteinosis Corina Noje MD Assistant Professor Pediatric Critical Care Medicine Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Medical Director, Pediatric Transport Johns Hopkins Bloomberg Children's Center Baltimore, Maryland

Interfacility Transport of the Seriously Ill or Injured

Pediatric Patient Laura E. Norton MD, MS Assistant Professor of Pediatrics Division of Pediatric Infectious Diseases and Immunology University of Minnesota Medical School Minneapolis, Minnesota

Botulism (Clostridium botulinum) Anna Nowak-Węgrzyn MD, PhD Professor of Pediatrics Jaffe Food Allergy Institute Division of Allergy and Immunology Department of Pediatrics Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Serum Sickness Food Allergy and Adverse Reactions to Foods Stephen K. Obaro MD, PhD Professor of Pediatric Infectious Diseases Director, Pediatric International Research University of Nebraska Medical Center Omaha, Nebraska

Nonvenereal Treponemal Infections Relapsing Fever (Borrelia) Makram M. Obeid MD Assistant Professor of Pediatrics and Adolescent Medicine Pediatric Epileptologist, Division of Child Neurology Department of Pediatrics and Adolescent Medicine Department of Anatomy, Cell Biology and Physiology American University of Beirut Beirut, Lebanon

Conditions That Mimic Seizures Hope L. O'Brien MD, MBA, FAHS, FAAN Associate Professor of Pediatrics University of Cincinnati College of Medicine Program Director, Headache Medicine Education Co-Director Young Adult Headache Program Cincinnati Children's Medical Center Cincinnati, Ohio

Headaches Jean-Marie Okwo-Bele MD, MPH Director, Department of Immunization, Vaccines, and Biologicals World Health Organization Geneva, Switzerland

International Immunization Practices Joyce L. Oleszek MD Associate Professor Department of Physical Medicine and Rehabilitation University of Colorado School of Medicine Children's Hospital Colorado Denver, Colorado

Spasticity Scott E. Olitsky MD Professor of Ophthalmology University of Kansas School of Medicine University of Missouri – Kansas City School of Medicine Section Chief, Ophthalmology Children's Mercy Hospitals and Clinics Kansas City, Missouri

Growth and Development of the Eye Examination of the Eye

Abnormalities of Refraction and Accommodation Disorders of Vision Abnormalities of Pupil and Iris Disorders of Eye Movement and Alignment Abnormalities of the Lids Disorders of the Lacrimal System Disorders of the Conjunctiva Abnormalities of the Cornea Abnormalities of the Lens Disorders of the Uveal Tract Disorders of the Retina and Vitreous Abnormalities of the Optic Nerve Childhood Glaucoma Orbital Abnormalities Orbital Infections Injuries to the Eye John M. Olsson MD, CPE Professor of Pediatrics Medical Director, Well Newborn Services Division of General Pediatrics University of Virginia School of Medicine Charlottesville, Virginia

The Newborn Amanda K. Ombrello MD Associate Research Physician National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

Amyloidosis Meghan E. O'Neill MD Fellow in Neurodevelopment Disabilities Kennedy Krieger Institute Baltimore, Maryland

Developmental Delay and Intellectual Disability Mutiat T. Onigbanjo MD Assistant Professor Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

The First Year Walter A. Orenstein MD, DSc (Hon) Professor of Medicine, Pediatrics, and Global Health Emory University Associate Director, Emory Vaccines Center Atlanta, Georgia; Former Deputy Director for Immunization Programs Bill & Melinda Gates Foundation Seattle, Washington; Former Director, National Immunization Program Centers for Disease Control and Prevention Atlanta, Georgia

Immunization Practices Rachel C. Orscheln MD Associate Professor of Pediatrics Washington University School of Medicine in St. Louis Director, Ambulatory Pediatric Infectious Diseases Director, International Adoption Center St. Louis Children's Hospital St. Louis, Missouri

Bartonella Marisa Osorio DO Assistant Professor Department of Rehabilitation Medicine University of Washington School of Medicine Seattle Children's Hospital Seattle, Washington

Ambulation Assistance Christian A. Otto MD, MMSc Director of TeleOncology Associate Attending Physician Memorial Sloan Kettering Cancer Center New York, New York

Altitude-Associated Illness in Children (Acute Mountain Sickness) Judith A. Owens MD, MPH Professor of Neurology Harvard Medical School Director of Sleep Medicine Boston Children's Hospital Boston, Massachusetts

Sleep Medicine Seza Özen MD Professor of Paediatrics Divisions of Paediatric Rheumatology Hacettepe University Ankara, Turkey

Behçet Disease Lee M. Pachter DO

Professor of Pediatrics and Population Health Sidney Kimmel Medical College and Jefferson College of Population Health Thomas Jefferson University Director, Community and Clinical Integration Nemours Alfred I. duPont Hospital for Children Wilmington, Delaware; Director, Health Policy Program Jefferson College of Population Health Philadelphia, Pennsylvania

Overview of Pediatrics Child Health Disparities Cultural Issues in Pediatric Care Amruta Padhye MD Assistant Professor of Clinical Child Health Division of Pediatric Infectious Diseases University of Missouri School of Medicine Columbia, Missouri

Diphtheria (Corynebacterium diphtheriae) Suzinne Pak-Gorstein MD, PhD, MPH Associate Professor of Pediatrics Adjunct Associate Professor of Global Health University of Washington School of Medicine Seattle, Washington

Global Child Health Jennifer Panganiban MD Assistant Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Director, Non Alcoholic Fatty Liver Disease Clinic Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Nutritional Requirements Diane E. Pappas MD, JD Professor of Pediatrics Director of Child Advocacy University of Virginia School of Medicine Charlottesville, Virginia

Sinusitis Retropharyngeal Abscess, Lateral Pharyngeal (Parapharyngeal) Abscess, and Peritonsillar Cellulitis/Abscess John J. Parent MD, MSCR Assistant Professor of Pediatrics Indiana University School of Medicine Section of Cardiology Riley Hospital for Children at Indiana University Health Indianapolis, Indiana

Diseases of the Myocardium Diseases of the Pericardium Tumors of the Heart Alasdair P.J. Parker MBBS (Lond), MRCP, MD, MA (Camb) Consultant in Pediatric Neurology Addenbrooke's Hospital Associate Lecturer University of Cambridge School of Clinical Medicine Cambridge, United Kingdom

Idiopathic Intracranial Hypertension (Pseudotumor Cerebri) Elizabeth Prout Parks MD, MSCE Assistant Professor of Pediatrics

University of Pennsylvania Perelman School of Medicine Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Nutritional Requirements Feeding Healthy Infants, Children, and Adolescents Briana C. Patterson MD, MS Associate Professor of Pediatrics Division of Pediatric Endocrinology Director, Pediatric Endocrine Fellowship Program Emory University School of Medicine Atlanta, Georgia

Hormones of the Hypothalamus and Pituitary Hypopituitarism Maria Jevitz Patterson MD, PhD Professor Emeritus of Microbiology and Molecular Genetics Michigan State University College of Human Medicine East Lansing, Michigan

Syphilis (Treponema pallidum) Anna L. Peters MD, PhD Clinical Fellow Division of Gastroenterology, Hepatology, and Nutrition Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Metabolic Diseases of the Liver Timothy R. Peters MD Professor of Pediatrics Wake Forest School of Medicine Division of Pediatric Infectious Diseases Wake Forest Baptist Medical Center

Winston-Salem, North Carolina

Streptococcus pneumoniae (Pneumococcus) Rachel A. Phelan MD, MPH Assistant Professor of Pediatrics Medical College of Wisconsin Division of Hematology/Oncology/BMT Children's Hospital of Wisconsin Milwaukee, Wisconsin

Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cell Transplantation from Alternative Sources and Donors Graft-Versus-Host Disease, Rejection, and Venoocclusive Disease Late Effects of Hematopoietic Stem Cell Transplantation Anna Pinto MD, PhD Lecturer of Neurology Harvard Medical School Co-Director, Sturge Weber Clinic Department of Neurology Boston Children's Hospital Boston, Massachusetts

Neurocutaneous Syndromes Brenda B. Poindexter MD, MS Professor of Pediatrics University of Cincinnati College of Medicine Director of Clinical and Translational Research Perinatal Institute Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio

The High-Risk Infant Transport of the Critically Ill Newborn Andrew J. Pollard FRCPCH, PhD, FMedSci Professor of Paediatric Infection and Immunity Department of Paediatrics University of Oxford Children's Hospital Oxford, United Kingdom

Neisseria meningitidis (Meningococcus) Diego Preciado MD, PhD Professor of Pediatrics, Surgery, and Integrative Systems Biology George Washington University School of Medicine and Health Sciences Vice-Chief, Division of Pediatric Otolaryngology Children's National Health System Washington, DC

Otitis Media Mark R. Proctor MD Franc D. Ingraham Professor of Neurosurgery Harvard Medical School Neurosurgeon-in-Chief Boston Children's Hospital Boston, Massachusetts

Spinal Cord Injuries in Children Spinal Cord Disorders Howard I. Pryor II, MD Instructor of Surgery Division of Pediatric Surgery Johns Hopkins University School of Medicine Johns Hopkins Children's Center

Baltimore, Maryland

Acute Care of Multiple Trauma Lee A. Pyles MD, MS Associate Professor of Pediatrics Division of Pediatric Cardiology West Virginia University School of Medicine Morgantown, West Virginia

Disorders of Lipoprotein Metabolism and Transport Molly Quinn MD Fellow, Reproductive Endocrinology and Infertility Department of Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco San Francisco, California

Polycystic Ovary Syndrome and Hirsutism Elisabeth H. Quint MD Professor of Obstetrics and Gynecology Director, Fellowship in Pediatric and Adolescent Gynecology University of Michigan Medical School Ann Arbor, Michigan

Gynecologic Care for Girls with Special Needs Amy E. Rabatin MD Fellow, Pediatric Rehabilitation and Board Certified Sports Medicine Department of Physical Medicine and Rehabilitation Mayo Clinic Children's Center Rochester, Minnesota

Specific Sports and Associated Injuries C. Egla Rabinovich MD, MPH Professor of Pediatrics Duke University School of Medicine

Co-Chief, Division of Pediatric Rheumatology Duke University Health System Durham, North Carolina

Evaluation of Suspected Rheumatic Disease Treatment of Rheumatic Diseases Juvenile Idiopathic Arthritis Scleroderma and Raynaud Phenomenon Sjögren Syndrome Miscellaneous Conditions Associated With Arthritis Leslie J. Raffini MD Associate Professor Department of Pediatrics University of Pennsylvania Perelman School of Medicine Division of Hematology Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Hemostasis Hereditary Predisposition to Thrombosis Thrombotic Disorders in Children Disseminated Intravascular Coagulation Shawn L. Ralston MD, MS Associate Professor and Vice Chair for Clinical Affairs Department of Pediatrics Geisel School of Medicine at Dartmouth Chief, Section of Pediatric Hospital Medicine Children's Hospital at Dartmouth-Hitchcock Hanover, New Hampshire

Wheezing in Infants: Bronchiolitis Sanjay Ram MD

Professor of Medicine University of Massachusetts Medical School Division of Infectious Diseases and Immunology UMass Memorial Medical Center Worcester, Massachusetts

Neisseria gonorrhoeae (Gonococcus) Octavio Ramilo MD Professor of Pediatrics Henry G. Cramblett Chair in Medicine The Ohio State University College of Medicine Chief, Division of Infectious Diseases Nationwide Children's Hospital Columbus, Ohio

Mycoplasma pneumoniae Kacy A. Ramirez MD Assistant Professor of Pediatrics Wake Forest School of Medicine Division of Pediatric Infectious Diseases Wake Forest Baptist Medical Center Winston-Salem, North Carolina

Streptococcus pneumoniae (Pneumococcus) Casey M. Rand BS Project Manager, Center for Autonomic Medicine in Pediatrics Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Congenital Central Hypoventilation Syndrome Adam J. Ratner MD, MPH

Associate Professor of Pediatrics and Microbiology New York University School of Medicine Chief, Division of Pediatric Infectious Diseases New York University Langone Medical Center New York, New York

Aeromonas and Plesiomonas Lee Ratner MD, PhD Professor of Medicine Professor of Molecular Microbiology and of Pathology and Immunology Washington University School of Medicine in St. Louis St. Louis, Missouri

Human T-Lymphotropic Viruses (1 and 2) Gerald V. Raymond MD Professor of Neurology University of Minnesota School of Medicine Chief of Pediatric Neurology University of Minnesota Medical Center, Fairview Minneapolis, Minnesota

Disorders of Very-Long-Chain Fatty Acids and Other Peroxisomal Functions Ann M. Reed MD Professor of Pediatrics Chair, Department of Pediatrics Physician-in-Chief Duke Children's Duke University Durham, North Carolina

Juvenile Dermatomyositis Shimon Reif MD Chairman, Department of Pediatrics

Hadassah Medical Center Hebrew University Jerusalem, Israel

Diarrhea From Neuroendocrine Tumors Megan E. Reller MD, PhD, MPH Associate Professor of Medicine Associate Research Professor of Global Health Duke University Medical Center Durham, North Carolina

Spotted Fever Group Rickettsioses Scrub Typhus (Orientia tsutsugamushi) Typhus Group Rickettsioses Ehrlichioses and Anaplasmosis Q Fever (Coxiella burnetii) Caroline H. Reuter MD, MSCI Associate Medical Director, Pharmacovigilance Bioverativ Waltham, Massachusetts

Group A Streptococcus Jorge D. Reyes MD Professor and Roger K. Giesecke Distinguished Chair Department of Surgery University of Washington School of Medicine Chief, Division of Transplant Surgery Seattle Children's Hospital Seattle, Washington

Intestinal Transplantation in Children with Intestinal Failure Liver Transplantation

Firas Rinawi MD Attending Physician Institute of Gastroenterology, Nutrition, and Liver Diseases Schneider Children's Medical Center of Israel Petah Tikva, Israel

Evaluation of Children with Suspected Intestinal Malabsorption A. Kim Ritchey MD Professor and Vice-Chair of International Affairs Department of Pediatrics University of Pittsburgh School of Medicine Division of Hematology/Oncology UPMC Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania

Principles of Cancer Diagnosis Principles of Cancer Treatment The Leukemias Frederick P. Rivara MD, MPH Seattle Children's Guild Endowed Chair in Pediatrics Professor and Vice-Chair, Department of Pediatrics University of Washington School of Medicine Seattle, Washington

Injury Control Eric Robinette MD Attending Physician in Infectious Diseases Akron Children's Hospital Akron, Ohio

Osteomyelitis Septic Arthritis

Angela Byun Robinson MD, MPH Associate Professor Cleveland Clinic Lerner College of Medicine Staff, Pediatrics Institute Cleveland Clinic Children's Cleveland, Ohio

Juvenile Dermatomyositis Miscellaneous Conditions Associated with Arthritis Kristine Knuti Rodrigues MD, MPH Assistant Professor of Pediatrics University of Colorado School of Medicine Department of Pediatrics Denver Health Medical Center Denver, Colorado

Acute Inflammatory Upper Airway Obstruction (Croup, Epiglottitis, Laryngitis, and Bacterial Tracheitis) David F. Rodriguez-Buritica MD Assistant Professor Department of Pediatrics Division of Medical Genetics McGovern Medical School at UTHealth Houston, Texas

Disorders Involving Ion Transporters Disorders Involving Transcription Factors Disorders Involving Defective Bone Resorption Rosa Rodríguez-Fernández MD, PhD Hospital General Universitario Gregorio Marañón Instituto de Investigación Sanitaria Gregorio Marañón (IISGM) Madrid, Spain;

Center for Vaccines and Immunity The Research Institute at Nationwide Children's Hospital The Ohio State University College of Medicine Columbus, Ohio

Genital Mycoplasmas (Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum) Genie E. Roosevelt MD, MPH Professor of Emergency Medicine University of Colorado School of Medicine Department of Emergency Medicine Denver Health Medical Center Denver, Colorado

Acute Inflammatory Upper Airway Obstruction (Croup, Epiglottitis, Laryngitis, and Bacterial Tracheitis) David R. Rosenberg MD Chair, Department of Psychiatry and Behavioral Neurosciences Chief of Child Psychiatry and Psychology Wayne State University School of Medicine Detroit, Michigan

Anxiety Disorders Cindy Ganis Roskind MD Program Director Pediatric Emergency Medicine Fellowship Children's Hospital of New York–Presbyterian Associate Professor of Pediatrics Columbia University Irving Medical Center Columbia University College of Physicians and Surgeons New York, New York

Acute Care of Multiple Trauma A. Catharine Ross PhD Professor and Dorothy Foehr Huck Chair Department of Nutritional Sciences The Pennsylvania State University College of Health and Human Development University Park, Pennsylvania

Vitamin A Deficiencies and Excess Joseph W. Rossano MD, MS Chief, Division of Cardiology Co-Executive Director, The Cardiac Center Jennifer Terker Endowed Chair in Pediatric Cardiology Associate Professor of Pediatrics Children's Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Heart Failure Pediatric Heart and Heart-Lung Transplantation Jennifer A. Rothman MD Associate Professor Department of Pediatrics Division of Pediatric Hematology/Oncology Duke University Medical Center Durham, North Carolina

Iron-Deficiency Anemia Other Microcytic Anemias Ranna A. Rozenfeld MD Professor of Pediatrics The Warren Alpert Medical School Brown University

Division of Pediatric Critical Care Medicine Hasbro Children's Hospital Providence, Rhode Island

Atelectasis Colleen A. Ryan MD Instructor in Psychiatry Harvard Medical School Boston Children's Hospital Boston, Massachusetts

Motor Disorders and Habits Monique M. Ryan M Med BS, FRACP Professor of Paediatric Neurology Director, Department of Neurology Honorary Fellow, Murdoch Children's Research Institute University of Melbourne Royal Children's Hospital Parkville, Victoria, Australia

Autonomic Neuropathies Guillain-Barré Syndrome Bell Palsy Julie Ryu MD Professor of Pediatrics University of California, San Diego School of Medicine Interim Chief, Division of Respiratory Medicine Chief Research Informatics Officer Department of Pediatrics Rady Children's Hospital–San Diego San Diego, California H.P.S. Sachdev MD, FIAP, FAMS, FRCPCH Senior Consultant Departments of Pediatrics and Clinical Epidemiology

Sitaram Bhartia Institute of Science and Research New Delhi, India

Vitamin B Complex Deficiencies and Excess Vitamin C (Ascorbic Acid) Manish Sadarangani MRCPCH, DPHIL, BM.BCh, MA Assistant Professor of Pediatrics Sauder Family Chair in Pediatric Infectious Diseases University of British Columbia Faculty of Medicine Director, Vaccine Evaluation Center British Columbia Children's Hospital Vancouver, British Columbia, Canada

Neisseria meningitidis (Meningococcus) Rebecca E. Sadun MD, PhD Assistant Professor of Adult and Pediatric Rheumatology Departments of Medicine and Pediatrics Duke University School of Medicine Durham, North Carolina

Systemic Lupus Erythematosus Mustafa Sahin MD, PhD Professor of Neurology Harvard Medical School Director, Translational Neuroscience Center Boston Children's Hospital Boston, Massachusetts

Neurocutaneous Syndromes Nina N. Sainath MD Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Feeding Healthy Infants, Children, and Adolescents

Robert A. Salata MD Professor and Chairman, Department of Medicine Case Western Reserve University School of Medicine Physician-in-Chief University Hospitals Case Medical Center Cleveland, Ohio

Amebiasis Trichomoniasis (Trichomonas vaginalis) African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei complex) American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi) Edsel Maurice T. Salvana MD Clinical Associate Professor of Medicine University of the Philippines College of Medicine Director, Institute of Molecular Biology and Biotechnology National Institutes of Health Manila, The Philippines; Adjunct Professor of Global Health University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Amebiasis Trichomoniasis (Trichomonas vaginalis) African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei complex) American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi) Hugh A. Sampson MD Kurt Hirschhorn Professor of Pediatrics Jaffe Food Allergy Institute

Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Anaphylaxis Food Allergy and Adverse Reactions to Foods Chase B. Samsel MD Instructor in Psychiatry Harvard Medical School Boston Children's Hospital Boston, Massachusetts

Rumination and Pica Thomas J. Sandora MD, MPH Associate Professor of Pediatrics Harvard Medical School Hospital Epidemiologist Division of Infectious Diseases Boston Children's Hospital Boston, Massachusetts

Community-Acquired Pneumonia Tracy L. Sandritter PharmD Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation Children's Mercy Adjunct Clinical Professor University of Missouri – Kansas City School of Pharmacy Kansas City, Missouri

Principles of Drug Therapy Wudbhav N. Sankar MD Associate Professor Department of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon

Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Hip Eric J. Sarkissian MD Resident Physician Department of Orthopaedic Surgery Stanford University School of Medicine Stanford, California

Osgood-Schlatter Disease and Sinding-LarsenJohansson Syndrome Ajit A. Sarnaik MD Associate Professor of Pediatrics Wayne State University School of Medicine Director, Pediatric Critical Care Medicine Fellowship Program Children's Hospital of Michigan Detroit, Michigan

Mechanical Ventilation Ashok P. Sarnaik MD Professor and Former Interim Chair Department of Pediatrics Wayne State University School of Medicine Former Pediatrician-in-Chief Children's Hospital of Michigan Detroit, Michigan

Respiratory Distress and Failure Harvey B. Sarnat MD, MS, FRCPC Professor of Pediatrics, Pathology (Neuropathology), and Clinical Neurosciences University of Calgary Cumming School of Medicine Division of Pediatric Neurology Alberta Children's Hospital Research Institute

Calgary, Alberta, Canada

Evaluation and Investigation of Neuromuscular Disorders Developmental Disorders of Muscle Endocrine and Toxic Myopathies Metabolic Myopathies Hereditary Motor-Sensory Neuropathies Toxic Neuropathies Joshua K. Schaffzin MD, PhD Assistant Professor of Pediatrics University of Cincinnati College of Medicine Director, Infection Prevention and Control Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Liver Abscess Laura E. Schanberg MD Professor of Pediatrics Duke University School of Medicine Division of Pediatric Rheumatology Duke University Medical Center Durham, North Carolina

Systemic Lupus Erythematosus Musculoskeletal Pain Syndromes Michael S. Schechter MD, MPH Professor of Pediatrics Virginia Commonwealth University School of Medicine Chief, Division of Pulmonary Medicine Director, Cystic Fibrosis Center Director, UCAN Community Asthma Program Children's Hospital of Richmond at VCU

Richmond, Virginia

Cystic Fibrosis Mark R. Schleiss MD Professor of Pediatrics American Legion and Auxiliary Heart Research Foundation Endowed Chair Division of Pediatric Infectious Diseases and Immunology University of Minnesota Medical School Minneapolis, Minnesota

Principles of Antibacterial Therapy Botulism (Clostridium botulinum) Tetanus (Clostridium tetani) Principles of Antiviral Therapy Principles of Antiparasitic Therapy Nina F. Schor MD, PhD Deputy Director National Institute of Neurological Disorders and Stroke National Institute of Health Bethesda, Maryland

Neurologic Evaluation James W. Schroeder Jr, MD, FACS, FAAP Associate Professor Department of Otolaryngology – Head and Neck Surgery Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Congenital Anomalies of the Larynx, Trachea, and Bronchi Foreign Bodies in the Airway Laryngotracheal Stenosis and Subglottic Stenosis

Neoplasms of the Larynx, Trachea, and Bronchi Elaine E. Schulte MD, MPH Professor of Pediatrics Albert Einstein College of Medicine Vice Chair, Academic Affairs and Faculty Development Division of Academic General Pediatrics The Children's Hospital at Montefiore Bronx, New York

Domestic and International Adoption Mark A. Schuster MD, PhD Founding Dean and CEO Professor Kaiser Permanente School of Medicine Pasadena, California

Gay, Lesbian, and Bisexual Adolescents Daryl A. Scott MD, PhD Assistant Professor Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas

The Genetic Approach in Pediatric Medicine The Human Genome Patterns of Genetic Transmission J. Paul Scott MD Professor Department of Pediatrics Division of Pediatric Hematology/Oncology Medical College of Wisconsin Blood Center of Southeastern Wisconsin Milwaukee, Wisconsin

Hemostasis Hereditary Clotting Factor Deficiencies (Bleeding Disorders) von Willebrand Disease Hereditary Predisposition to Thrombosis Thrombotic Disorders in Children Postneonatal Vitamin K Deficiency Liver Disease Acquired Inhibitors of Coagulation Disseminated Intravascular Coagulation Platelet and Blood Vessel Disorders John P. Scott MD Associate Professor of Anesthesiology and Pediatrics Divisions of Pediatric Anesthesiology and Pediatric Critical Care Medical College of Wisconsin Children's Hospital of Wisconsin Milwaukee, Wisconsin

Anesthesia and Perioperative Care Procedural Sedation Patrick C. Seed MD, PhD, FAAP, FIDSA Children's Research Fund Chair in Basic Science Professor of Pediatrics, Microbiology and Immunology Northwestern University Feinberg School of Medicine Division Head, Pediatric Infectious Diseases Associate Chief Research Officer of Basic Science Stanley Manne Children's Research Institute Director, Host-Microbial Interactions, Inflammation, and Immunity (HMI3) Program Ann & Robert H. Lurie Children's Hospital Chicago, Illinois

The Microbiome and Pediatric Health Shigella Escherichia coli Janet R. Serwint MD Professor Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland

Loss, Separation, and Bereavement Apurva S. Shah MD, MBA Assistant Professor Department of Orthopedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Common Fractures Dheeraj Shah MD, FIAP, MAMS Professor Department of Pediatrics University College of Medical Sciences Guru Teg Bahadur Hospital New Delhi, India

Vitamin B Complex Deficiencies and Excess Vitamin C (Ascorbic Acid) Samir S. Shah MD, MSCE Professor of Pediatrics University of Cincinnati College of Medicine Director, Division of Hospital Medicine Chief Metrics Officer

James M. Ewell Endowed Chair Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Quality and Value in Healthcare for Children Fever Without a Focus in the Neonate and Young Infant Osteomyelitis Septic Arthritis Ala Shaikhkhalil MD Pediatric Nutrition Fellow Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Nutritional Requirements Feeding Healthy Infants, Children, and Adolescents Raanan Shamir MD Professor of Pediatrics Sackler Faculty of Medicine Tel-Aviv University Tel Aviv, Israel; Chairman, Institute of Gastroenterology, Nutrition, and Liver Diseases Schneider Children's Medical Center of Petah Tikva, Israel

Disorders of Malabsorption Chronic Diarrhea Christina M. Shanti MD Chief, Division of Pediatric Surgery Children's Hospital of Michigan Detroit, Michigan

Surgical Conditions of the Anus and Rectum Bruce K. Shapiro MD Professor of Pediatrics The Arnold J. Capute MD, MPH Chair in Neurodevelopmental Disabilities The Johns Hopkins University School of Medicine Vice-President, Training Kennedy Krieger Institute Baltimore, Maryland

Developmental Delay and Intellectual Disability Erin E. Shaughnessy MD, MSHCM Division Chief, Hospital Medicine Phoenix Children's Hospital Phoenix, Arizona

Jaundice and Hyperbilirubinemia in the Newborn Kernicterus Bennett A. Shaywitz MD Charles and Helen Schwab Professor in Dyslexia and Learning Development Co-Director, Center for Dyslexia and Creativity Chief, Child Neurology Yale University School of Medicine New Haven, Connecticut

Dyslexia Sally E. Shaywitz MD Audrey G. Ratner Professor in Learning Development Co-Director, Center for Dyslexia and Creativity Department of Pediatrics Yale University School of Medicine New Haven, Connecticut

Dyslexia

Oleg A. Shchelochkov MD Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

An Approach to Inborn Errors of Metabolism Nicole M. Sheanon MD, MS Assistant Professor of Pediatrics University of Cincinnati College of Medicine Division of Endocrinology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

The Endocrine System Benjamin L. Shneider MD Professor of Pediatrics Texas Children's Hospital Baylor College of Medicine Houston, Texas

Autoimmune Hepatitis Stanford T. Shulman MD Virginia H. Rogers Professor of Pediatric Infectious Diseases Northwestern University Feinberg School of Medicine Chief Emeritus, Division of Pediatric Infectious Diseases Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Group A Streptococcus Rheumatic Heart Disease Scott H. Sicherer MD Elliot and Roslyn Jaffe Professor of Pediatrics, Allergy, and Immunology Director, Jaffe Food Allergy Institute

Department of Pediatrics Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Allergy and the Immunologic Basis of Atopic Disease Diagnosis of Allergic Disease Allergic Rhinitis Childhood Asthma Atopic Dermatitis (Atopic Eczema) Insect Allergy Ocular Allergies Urticaria (Hives) and Angioedema Anaphylaxis Serum Sickness Food Allergy and Adverse Reactions to Foods Adverse Reactions to Drugs Mark D. Simms MD, MPH Professor of Pediatrics Medical College of Wisconsin Medical Director Child Development Center Children's Hospital of Wisconsin Milwaukee, Wisconsin

Language Development and Communication Disorders Adoption Jeffery M. Simmons MD, MSc Associate Professor of Pediatrics University of Cincinnati College of Medicine Associate Division Director for Quality

Division of Hospital Medicine Safety Officer Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Quality and Value in Healthcare for Children Safety in Healthcare for Children Eric A.F. Simões MBBS, DCH, MD Professor of Pediatrics University of Colorado School of Medicine Division of Pediatric Infectious Diseases Children's Hospital Colorado Aurora, Colorado

Polioviruses Kari A. Simonsen MD Professor of Pediatrics Division of Pediatric Infectious Disease University of Nebraska Medical Center Omaha, Nebraska

Leptospira Keneisha Sinclair-McBride PhD Assistant Professor of Psychology Department of Psychiatry Harvard Medical School Staff Psychologist Boston Children's Hospital Boston, Massachusetts

Tantrums and Breath-Holding Spells Lying, Stealing, and Truancy Aggression Self-Injurious Behavior

Vidya Sivaraman MD Clinical Assistant Professor of Pediatrics Division of Adult and Pediatric Rheumatology The Ohio State University Wexner Medical Center Nationwide Children's Hospital Columbus, Ohio

Vasculitis Syndromes Anne M. Slavotinek MB BS, PhD Professor of Clinical Pediatrics University of California San Francisco School of Medicine Director, Medical Genetics and Genomics UCSF Benioff Children's Hospital San Francisco, California

Dysmorphology Jessica R. Smith MD Assistant Professor of Pediatrics Harvard Medical School Clinical Director, Thyroid Program Boston Children's Hospital Boston, Massachusetts

Thyroid Development and Physiology Disorders of Thyroxine-Binding Globulin Hypothyroidism Thyroiditis Goiter Thyrotoxicosis Carcinoma of the Thyroid Autoimmune Polyglandular Syndromes Multiple Endocrine Neoplasia Syndrome

Stephanie H. Smith MD Resident Physician Department of Obstetrics and Gynecology Washington University School of Medicine in St. Louis St. Louis, Missouri

Gynecologic Neoplasms and Adolescent Prevention Methods for Human Papillomavirus Kim Smith-Whitley MD Professor, Department of Pediatrics University of Pennsylvania Perelman School of Medicine Clinical Director, Division of Hematology Director, Comprehensive Sickle Cell Center Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Hemoglobinopathies Mary Beth F Son MD Assistant Professor in Pediatrics Harvard Medical School Staff Physician, Division of Immunology Boston Children's Hospital Boston, Massachusetts

Kawasaki Disease Laura Stout Sosinsky PhD Research Scientist Research and Evaluation Group Public Health Management Corporation Philadelphia, Pennsylvania

Childcare Emily Souder MD Drexel University College of Medicine

St. Christopher's Hospital for Children Philadelphia, Pennsylvania

Pertussis (Bordetella pertussis and Bordetella parapertussis) Joseph D. Spahn MD Professor Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado

Childhood Asthma Paul Spearman MD Albert B. Sabin Professor of Pediatrics University of Cincinnati College of Medicine Director, Division of Infectious Diseases Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Human T-Lymphotropic Viruses (1 and 2) Mark A. Sperling MD Professor Emeritus and Chair Department of Pediatrics University of Pittsburgh School of Medicine Professorial Lecturer Department of Pediatrics Division of Endocrinology and Diabetes Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Hypoglycemia David A. Spiegel MD Professor Department of Orthopaedic Surgery

University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Pediatric Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Spine The Neck Jaclyn B. Spitzer PhD Professor Emerita of Audiology and Speech Pathology in Otolaryngology Columbia University Irving Medical Center New York, New York Jürgen W. Spranger MD Professor Emeritus of Pediatrics University of Mainz School of Medicine Children's Hospital Mainz, Germany

Mucopolysaccharidoses James E. Squires MD, MS Assistant Professor in Pediatrics Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania

Manifestations of Liver Disease Siddharth Srivastava MD, PhD Instructor in Neurology Harvard Medical School Department of Neurology Boston Children's Hospital Boston, Massachusetts

Neurocutaneous Syndromes Joseph W. St Geme III, MD

Professor of Pediatrics and Microbiology and Chair of the Department of Pediatrics University of Pennsylvania Perelman School of Medicine Chair of the Department of Pediatrics and Physician-in-Chief Leonard and Madlyn Abramson Endowed Chair in Pediatrics Children's Hospital of Philadelphia Philadelphia, Pennsylvania Amy P. Stallings MD Assistant Professor of Pediatrics Division of Pediatric Allergy and Immunology Duke University School of Medicine Durham, North Carolina

Urticaria (Hives) and Angioedema Virginia A. Stallings MD Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Director, Nutrition Center Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Nutritional Requirements Feeding Healthy Infants, Children, and Adolescents Kathryn C. Stambough MD Resident Physician Department of Obstetrics and Gynecology Washington University School of Medicine in St. Louis St. Louis, Missouri

Gynecologic History and Physical Examination Lawrence R. Stanberry MD, PhD Associate Dean for International Programs Department of Pediatrics

Columbia University Vagelos College of Physicians and Surgeons New York, New York

Herpes Simplex Virus Charles A. Stanley MD Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Division of Endocrinology Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Disorders of Mitochondrial Fatty Acid β-Oxidation Jeffrey R. Starke MD Professor of Pediatrics Baylor College of Medicine Pediatric Infectious Diseases Texas Children's Hospital Houston, Texas

Tuberculosis (Mycobacterium tuberculosis) Taylor B. Starr DO, MPH Associate Professor of Pediatrics Division of Adolescent Medicine University of Rochester Medical Center Rochester, New York

Eating Disorders Andrew P. Steenhoff MBBCh, DCH, FAAP Assistant Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Medical Director, Global Health Center Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Fever of Unknown Origin

Paracoccidioides brasiliensis Sporotrichosis (Sporothrix schenckii) Ronen E. Stein MD Assistant Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Inflammatory Bowel Disease Eosinophilic Gastroenteritis William J. Steinbach MD Professor of Pediatrics, Molecular Genetics, and Microbiology Chief, Pediatric Infectious DiseasesDuke University Medical Center Durham, North Carolina

Principles of Antifungal Therapy Aspergillus Mucormycosis Janet Stewart MD Associate Professor Emerita Department of Pediatrics University of Colorado School of Medicine Spina Bifida Clinic Children's Hospital Colorado Denver, Colorado

Meningomyelocele (Spina Bifida) Gregory A. Storch MD Ruth L. Siteman Professor of Pediatrics Washington University School of Medicine in St. Louis St. Louis Children's Hospital

St. Louis, Missouri

Diagnostic Microbiology Polyomaviruses Ronald G. Strauss MD Professor Emeritus Departments of Pediatrics and Pathology University of Iowa Carver College of Medicine Iowa City, Iowa; Medical Director, Vitalant (formerly LifeSource) Rosemont, Illinois

Red Blood Cell Transfusions and Erythropoietin Therapy Platelet Transfusions Neutrophil (Granulocyte) Transfusions Plasma Transfusions Risks of Blood Transfusions Gina S. Sucato MD, MPH Director, Adolescent Center Washington Permanente Medical Group Adjunct Investigator, Kaiser Permanente Washington Health Research Institute Seattle, Washington

Menstrual Problems Frederick J. Suchy MD Professor of Pediatrics Associate Dean for Child Health Research University of Colorado School of Medicine Denver, Colorado; Chief Research Officer and Director Children's Hospital Colorado Research Institute Aurora, Colorado

Autoimmune Hepatitis Drug- and Toxin-Induced Liver Injury Acute Hepatic Failure Fulminant Hepatic Failure Cystic Diseases of the Biliary Tract and Liver Diseases of the Gallbladder Portal Hypertension and Varices Kristen R. Suhrie MD Assistant Professor Department of Pediatrics University of Cincinnati College of Medicine Neonatologist, Perinatal Institute Division of Neonatology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

High-Risk Pregnancies The Fetus Kathleen E. Sullivan MD, PhD Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Chief, Division of Allergy and Immunology Frank R. Wallace Endowed Chair in Infectious Diseases Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Evaluation of Suspected Immunodeficiency The T-, B-, and NK-Cell Systems Primary Defects of Antibody Production Treatment of B-Cell Defects Primary Defects of Cellular Immunity

Immunodeficiencies Affecting Multiple Cell Types Moira Szilagyi MD, PhD Professor of Pediatrics David Geffen School of Medicine at UCLA Section Chief, Developmental Studies UCLA Mattel Children's Hospital Los Angeles, California

Foster and Kinship Care Sammy M. Tabbah MD Assistant Professor of Obstetrics and Gynecology University of Cincinnati College of Medicine Maternal-Fetal Medicine Specialist, Cincinnati Fetal Center Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

High-Risk Pregnancies The Fetus Robert R. Tanz MD Professor of Pediatrics Division of Academic General Pediatrics and Primary Care Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Acute Pharyngitis Cristina Tarango MD Associate Professor of Pediatrics University of Cincinnati College of Medicine Medical Director, Hemophilia Treatment Center Clinical Director, Hematology Program Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Hemorrhage in the Newborn Infant Nonimmune Hydrops Nidale Tarek MD Assistant Professor of Pediatrics Department of Pediatrics and Adolescent Medicine American University of Beirut Beirut, Lebanon

Retinoblastoma Neoplasms of the Liver Desmoplastic Small Round Cell Tumor Robert C. Tasker MBBS, MD Professor of Neurology Professor of Anesthesia Harvard Medical School Senior Associate, Critical Care Medicine Director, Pediatric NeuroCritical Care Program Boston Children's Hospital Boston, Massachusetts

Outcomes and Risk Adjustment of Pediatric Emergency Medical Services Dmitry Tchapyjnikov MD Assistant Professor of Pediatrics and Neurology Duke University Medical Center Durham, North Carolina

Seizures in Childhood Brenda L. Tesini MD Assistant Professor of Medicine and Pediatrics University of Rochester Medical Center Division of Pediatric Infectious Diseases Golisano Children's Hospital

Rochester, New York

Roseola (Human Herpesviruses 6 and 7) Jillian L. Theobald MD, PhD Assistant Professor of Emergency Medicine Medical College of Wisconsin Toxicologist, Wisconsin Poison Center Milwaukee, Wisconsin

Poisoning Beth K. Thielen MD, PhD Fellow, Infectious Diseases and International Medicine Department of Medicine Fellow, Pediatric Infectious Diseases and ImmunologyDepartment of PediatricsUniversity of Minnesota Medical School Minneapolis, Minnesota

Principles of Antiparasitic Therapy Anita A. Thomas MD, MPH Assistant Professor Department of Pediatrics University of Washington School of Medicine Attending Physician Division of Emergency Medicine Seattle Children's Hospital Seattle, Washington

Drowning and Submersion Injury Cameron W. Thomas MD, MS Assistant Professor of Pediatrics and Neurology University of Cincinnati College of Medicine Fetal and Neonatal Neurology Specialist, Division of Neurology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Nervous System Disorders Courtney D. Thornburg MD, MS Professor of Clinical Pediatrics University of California San Diego School of Medicine La Jolla, California; Medical Director, Hemophilia and Thrombosis Treatment Center Rady Children's Hospital, San Diego San Diego, California

The Anemias Congenital Hypoplastic Anemia (Diamond-Blackfan Anemia) Pearson Syndrome Acquired Pure Red Blood Cell Anemia Anemia of Chronic Disease and Renal Disease Congenital Dyserythropoietic Anemias Physiologic Anemia of Infancy Megaloblastic Anemias Joel S. Tieder MD, MPH Associate Professor of Pediatrics Seattle Children's Hospital University of Washington School of Medicine Division of Hospital Medicine Seattle Children's Hospital Seattle, Washington

Brief Resolved Unexplained Events and Other Acute Events in Infants Cynthia J. Tifft MD, PhD Director, Pediatric Undiagnosed Diseases Program Senior Staff Clinician

Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

Genetic Approaches to Rare and Undiagnosed Diseases James K. Todd MD Professor Emeritus of Pediatrics Jules Amer Chair in Community Pediatrics University of Colorado School of Medicine Section Head, Epidemiology (Pediatrics) Director, Epidemiology, Clinical Outcomes, and Clinical Microbiology Children's Hospital Colorado Denver, Colorado

Staphylococcus Victor R. Tolentino Jr, JD, MPH, NP Healthcare Consultant Jackson Heights, New York

Principles Applicable to the Developing World Camilo Toro MD Senior Staff Clinician Director, Adult Undiagnosed Diseases Program National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

Genetic Approaches to Rare and Undiagnosed Diseases Richard L. Tower II, MD, MS Assistant Professor Department of Pediatrics

Division of Pediatric Hematology/Oncology Medical College of Wisconsin Children's Hospital of Wisconsin Milwaukee, Wisconsin

Anatomy and Function of the Lymphatic System Abnormalities of Lymphatic Vessels Lymphadenopathy Joseph M. Trapasso MD Resident Physician Department of Pediatrics University of Texas Medical Branch University of Texas Children's Hospital Galveston, Texas

N-Acetylaspartic Acid (Canavan Disease) Riccardo Troncone MD Professor and Director Department of Pediatrics University of Naples Federico II Napoli, Italy

Celiac Disease Elaine Tsao MD Assistant Professor Department of Rehabilitation Medicine University of Washington School of Medicine Seattle Children's Hospital Seattle, Washington

Ambulation Assistance David G. Tubergen MD Medical Director, Host Program MD Anderson Physicians Network

Houston, Texas

The Leukemias Lisa K. Tuchman MD, MPH Associate Professor of Pediatrics Chief, Division of Adolescent and Young Adult Medicine Center for Translational Science, Children's Research Institute Children's National Health System Washington, DC

Transitioning to Adult Care Margaret A. Turk MD Professor Departments of Physical Medicine and Rehabilitation and Pediatrics State University of New York SUNY Upstate Medical University Syracuse, New York

Health and Wellness for Children With Disabilities David A. Turner MD Associate Professor Department of Pediatrics Duke University School of Medicine Director, Pediatric Critical Care Fellowship Program Medical Director, Pediatric Intensive Care Unit Duke University Medical Center Durham, North Carolina

Shock Christina Ullrich MD, PhD Assistant Professor in Pediatrics Department of Psychosocial Oncology and Palliative Care Harvard Medical School Boston Children's Hospital Dana-Farber Cancer Institute

Boston, Massachusetts

Pediatric Palliative Care Nicole Ullrich MD, PhD Associate Professor of Neurology Harvard Medical School Director, Neurologic Neuro-Oncology Associate Director, Clinical Trials Neurofibromatosis Program Boston Children's Hospital Boston, Massachusetts

Neurocutaneous Syndromes Krishna K. Upadhya MD, MPH Assistant Professor Division of Adolescent and Young Adult Medicine Children's National Health System Washington, DC

Menstrual Problems David K. Urion MD Associate Professor and Charles F. Barlow Chair of Neurology Harvard University Medical School Director, Behavioral Neurology Clinics and Programs Boston Children's Hospital Boston, Massachusetts

Attention-Deficit/Hyperactivity Disorder Taher Valika MD Clinical Instructor of Otolaryngology – Head and Neck Surgery Northwestern University Feinberg School of Medicine Attending Physician, Otorhinolaryngology – Head and Neck Surgery Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Laryngotracheal Stenosis and Subglottic Stenosis George F. Van Hare MD Professor of Pediatrics Washington University School of Medicine in St Louis Division of Pediatric Cardiology St Louis Children's Hospital St. Louis, Missouri

Syncope Disturbances of Rate and Rhythm of the Heart Sudden Death Heather A. Van Mater MD, MS Associate Professor of Pediatrics Duke University School of Medicine Division of Pediatric Rheumatology Duke University Health System Durham, North Carolina

Scleroderma and Raynaud Phenomenon Charles D. Varnell Jr, MD, MS Instructor of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Renal Transplantation Ana M. Vaughan MD, MPH, FAAP Assistant in Medicine Division of Infectious Diseases Associate Hospital Epidemiologist Boston Children's Hospital Instructor in Pediatrics Harvard Medical School

Boston, Massachusetts

Childcare and Communicable Diseases Timothy J. Vece MD Associate Professor of Pediatrics University of North Carolina School of Medicine Medical Director, Airway Center North Carolina Children's Hospital Chapel Hill, North Carolina

Granulomatous Lung Disease Eosinophilic Lung Disease Interstitial Lung Disease Aarthi P. Vemana MD Pediatric Sleep Physician Fairfax Neonatal Associates Fairfax, Virginia

Pleurisy, Pleural Effusions, and Empyema Charles P. Venditti MD, PhD Head, Organic Acid Research Section Senior Investigator, National Human Genome Research Institute National Institutes of Health Bethesda, Maryland

An Approach to Inborn Errors of Metabolism Sarah Vepraskas MD Assistant Professor of Pediatrics Section of Hospital Medicine Medical College of Wisconsin Milwaukee, Wisconsin

Sudden Unexpected Postnatal Collapse

James W. Verbsky MD, PhD Associate Professor of Pediatrics (Rheumatology) and Microbiology and Immunology Medical Director, Clinical Immunology Research Laboratory Medical Director, Clinical and Translational Research Medical College of Wisconsin Milwaukee, Wisconsin

Hereditary Periodic Fever Syndromes and Other Systemic Autoinflammatory Diseases Jennifer A. Vermilion MD Instructor in Neurology and Pediatrics University of Rochester Medical Center Rochester, New York

Chorea, Athetosis, Tremor Brian P. Vickery MD Associate Professor of Pediatrics Emory University School of Medicine Director, Food Allergy Center at Emory and Children's Healthcare of Atlanta Atlanta, Georgia

Eosinophils Bernadette E. Vitola MD, MPH Associate Professor of Pediatrics Medical College of Wisconsin Children's Hospital of Wisconsin Milwaukee, Wisconsin

Liver Disease Associated with Systemic Disorders Judith A. Voynow MD Professor of Pediatrics Virginia Commonwealth University School of Medicine Edwin L. Kendig Jr. Professor of Pediatric Pulmonology

Children's Hospital of Richmond at VCU Richmond, Virginia

Cystic Fibrosis Jonathan B. Wagner DO Assistant Professor of Pediatrics University of Missouri–Kansas City School of Medicine Division of Pediatric Cardiology Children's Mercy Hospitals and Clinics Kansas City, Missouri

Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics Steven G. Waguespack MD, FACE Professor Department of Endocrine Neoplasia and Hormonal Disorders University of Texas MD Anderson Cancer Center Houston, Texas

Thyroid Tumors Adrenal Tumors David M. Walker MD Chief, Pediatric Emergency Medicine Department of Pediatrics Joseph M. Sanarzi Children's Hospital Hackensack University Medical Center Hackensack, New Jersey

Principles Applicable to the Developing World Kelly J. Walkovich MD Clinical Associate Professor of Pediatrics and Communicable Diseases Division of Pediatric Hematology/Oncology University of Michigan Medical School Ann Arbor, Michigan

Leukopenia Leukocytosis Heather J. Walter MD, MPH Professor of Psychiatry and Pediatrics Boston University School of Medicine Senior Attending Psychiatrist Boston Children's Hospital Senior Lecturer on Psychiatry Harvard Medical School Boston, Massachusetts

Psychosocial Assessment and Interviewing Psychopharmacology Psychotherapy and Psychiatric Hospitalization Somatic Symptom and Related Disorders Rumination and Pica Motor Disorders and Habits Anxiety Disorders Mood Disorders Suicide and Attempted Suicide Disruptive, Impulse-Control, and Conduct Disorders Tantrums and Breath-Holding Spells Lying, Stealing, and Truancy Aggression Self-Injurious Behavior Childhood Psychoses Jennifer A. Wambach MD Assistant Professor of Pediatrics Washington University School of Medicine in St. Louis Division of Newborn Medicine

St. Louis Children's Hospital St. Louis, Missouri

Inherited Disorders of Surfactant Metabolism Pulmonary Alveolar Proteinosis Julie Wang MD Professor of Pediatrics Jaffe Food Allergy Institute Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Insect Allergy Anaphylaxis Michael F. Wangler MD Assistant Professor of Molecular and Human Genetics Baylor College of Medicine Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital Houston, Texas

Disorders of Very-Long-Chain Fatty Acids and Other Peroxisomal Functions Russell E. Ware MD, PhD Professor of Pediatrics University of Cincinnati College of Medicine Director, Division of Hematology Co-Director, Cancer and Blood Diseases Institute Director, Global Health Center Marjory J. Johnson Chair of Hematology Translational Research Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Hemolytic Disease of the Newborn Neonatal Polycythemia

Hemorrhage in the Newborn Infant Nonimmune Hydrops Stephanie M. Ware MD, PhD, FACMG Professor of Pediatrics and Medical and Molecular Genetics Vice Chair of Clinical Affairs in Medical and Molecular Genetics Program Leader in Cardiovascular Genetics Herman B Wells Center for Pediatric Research Indiana University School of Medicine Indianapolis, Indiana

Diseases of the Myocardium Diseases of the Pericardium Tumors of the Heart Matthew C. Washam MD, MPH Assistant Professor of Pediatrics The Ohio State University Nationwide Children's Hospital Columbus, Ohio

Histoplasmosis (Histoplasma capsulatum) Ari J. Wassner MD Assistant Professor of Pediatrics Harvard Medical School Director, Thyroid Program Boston Children's Hospital Boston, Massachusetts

Thyroid Development and Physiology Disorders of Thyroxine-Binding Globulin Hypothyroidism Thyroiditis Goiter

Thyrotoxicosis Carcinoma of the Thyroid Autoimmune Polyglandular Syndromes Multiple Endocrine Neoplasia Syndrome Rachel Wattier MD, MHS Assistant Professor of Pediatrics University of California San Francisco School of Medicine San Francisco, California

Mucormycosis David R. Weber MD, MSCE Assistant Professor of Pediatrics University of Rochester School of Medicine and Dentistry Division of Endocrinology and Diabetes Pediatric Bone Health Program Golisano Children's Hospital Rochester, New York

Diabetes Mellitus Debra E. Weese-Mayer MD Beatrice Cummings Mayer Professor of Pediatrics and Pediatric Autonomic Medicine Northwestern University Feinberg School of Medicine Chief, Division of Pediatric Autonomic Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Congenital Central Hypoventilation Syndrome Jason B. Weinberg MD

Associate Professor of Pediatrics Associate Professor of Microbiology and Immunology University of Michigan Medical School Division of Pediatric Infectious Diseases C. S. Mott Children's Hospital Ann Arbor, Michigan

Epstein-Barr Virus Adenoviruses Jason P. Weinman MD Associate Professor of Radiology University of Colorado School of Medicine Aurora, Colorado

Fibrotic Lung Disease Kathryn L. Weise MD, MA Program Director, Cleveland Fellowship in Advanced Bioethics Department of Bioethics The Cleveland Clinic Foundation Cleveland, Ohio

Ethics in Pediatric Care Anna K. Weiss MD, MSEd Assistant Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Director of Pediatric Resident Education Division of Emergency Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Triage of the Acutely Ill Child Pamela F. Weiss MD, MSCE Associate Professor of Pediatrics and Epidemiology University of Pennsylvania Perelman School of Medicine

Division of Rheumatology Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Ankylosing Spondylitis and Other Spondylarthritides Reactive and Postinfectious Arthritis Carol Weitzman MD Professor of Pediatrics Director, Developmental-Behavioral Pediatrics Program Yale School of Medicine New Haven, Connecticut

Fetal Alcohol Exposure Morgan P. Welebir MD Department of Obstetrics and Gynecology Providence Saint Joseph Medical Center Burbank, California

Vaginal Bleeding in the Prepubertal Child Lawrence Wells MD Associate Professor Department of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Growth and Development Evaluation of the Child Torsional and Angular Deformities The Hip Common Fractures Jessica W. Wen MD

Associate Professor of Clinical Pediatrics University of Pennsylvania Perelman School of Medicine Children's Hospital of Philadelphia Philadelphia, Pennsylvania

Ascites Peritonitis Danielle Wendel MD Assistant Professor Division of Gastroenterology and Hepatology Department of Pediatrics University of Washington School of Medicine Seattle Children's Hospital Seattle, Washington

Tumors of the Digestive Tract Steven L. Werlin MD Professor Emeritus of Pediatrics The Medical College of Wisconsin Milwaukee, Wisconsin

Embryology, Anatomy, and Physiology of the Pancreas Pancreatic Function Tests Disorders of the Exocrine Pancreas Treatment of Pancreatic Insufficiency Pancreatitis Pseudocyst of the Pancreas Pancreatic Tumors Michael R. Wessels MD John F. Enders Professor of Pediatrics Professor of Medicine (Microbiology)

Harvard Medical School Division of Infectious Diseases Boston Children's Hospital Boston, Massachusetts

Group B Streptococcus Ralph F. Wetmore MD Professor Department of Otorhinolaryngology–Head and Neck Surgery University of Pennsylvania Perelman School of Medicine E. Mortimer Newlin Professor and Chief Division of Pediatric Otolaryngology Children's Hospital of Pennsylvania Philadelphia, Pennsylvania

Tonsils and Adenoids Scott L. Wexelblatt MD Associate Professor Department of Pediatrics University of Cincinnati College of Medicine Medical Director Regional Newborn Services Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

Neonatal Abstinence (Withdrawal) Isaiah D. Wexler MD, PhD Associate Professor Department of Pediatrics Hadassah University Medical Center Jerusalem, Israel

Effects of War on Children A. Clinton White Jr, MD Professor of Medicine Division of Infectious Diseases

The University of Texas Medical Branch at Galveston Galveston, Texas

Adult Tapeworm Infections Cysticercosis Echinococcosis (Echinococcus granulosus and Echinococcus multilocularis) Perrin C. White MD Professor of Pediatrics Audre Newman Rapoport Distinguished Chair in Pediatric Endocrinology Chief, Division of Pediatric Endocrinology University of Texas Southwestern Medical Center Dallas, Texas

Physiology of the Adrenal Gland Adrenocortical Insufficiency Congenital Adrenal Hyperplasia and Related Disorders Cushing Syndrome Primary Aldosteronism Adrenocortical Tumors and Masses Virilizing and Feminizing Adrenal Tumors Cushing Syndrome Primary Aldosteronism Pheochromocytoma John V. Williams MD Henry L. Hillman Professor of Pediatrics Professor of Microbiology and Molecular Genetics University of Pittsburgh School of Medicine Chief, Division of Pediatric Infectious Diseases UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania

Adenoviruses Rhinoviruses The Common Cold Rodney E. Willoughby Jr, MD Professor of Pediatrics Medical College of Wisconsin Division of Pediatric Infectious Diseases Children's Hospital of Wisconsin Milwaukee, Wisconsin

Rabies Michael Wilschanski MBBS Professor of Pediatrics The Hebrew University–Hadassah School of Medicine Director, Pediatric Gastroenterology Unit Hadassah University Hospitals Jerusalem, Israel

Embryology, Anatomy, and Physiology of the Pancreas Pancreatic Function Tests Disorders of the Exocrine Pancreas Treatment of Pancreatic Insufficiency Pancreatitis Pseudocyst of the Pancreas Pancreatic Tumors Karen M. Wilson MD, MPH Professor of Pediatrics Debra and Leon Black Division Chief of General Pediatrics Vice-Chair for Clinical and Translational Research

Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York Pamela Wilson MD Associate Professor Department of Physical Medicine and Rehabilitation University of Colorado School of Medicine Children's Hospital Colorado Denver, Colorado

Meningomyelocele (Spina Bifida) Jennifer J. Winell MD Clinical Assistant Professor of Orthopaedic Surgery University of Pennsylvania Perelman School of Medicine Attending Orthopaedic Surgeon Children's Hospital of Philadelphia Philadelphia, Pennsylvania

The Foot and Toes Glenna B. Winnie MD Director, Pediatric and Adolescent Sleep Center Fairfax Neonatal Associates, PC Fairfax, Virginia

Emphysema and Overinflation α1-Antitrypsin Deficiency and Emphysema Pleurisy, Pleural Effusions, and Empyema Pneumothorax Pneumomediastinum Hydrothorax Hemothorax Chylothorax Lawrence Wissow MD, MPH

James P. Connaughton Professor of Community Psychiatry Division of Child and Adolescent Psychiatry Johns Hopkins School of Medicine Baltimore, Maryland

Strategies for Health Behavior Change Peter Witters MD Professor of Pediatrics Metabolic Center University Hospitals Leuven Leuven, Belgium

Congenital Disorders of Glycosylation Joshua Wolf MBBS Assistant Member, St. Jude Faculty St. Jude Children's Research Hospital Memphis, Tennessee

Infection Associated with Medical Devices Peter M. Wolfgram MD Assistant Professor Medical College of Wisconsin Division of Endocrinology Children's Hospital of Wisconsin Milwaukee, Wisconsin

Delayed or Absent Puberty Joanne Wolfe MD, MPH Professor of Pediatrics Harvard Medical School Chief, Division of Pediatric Palliative Care Dana-Farber Cancer Institute Director, Pediatric Palliative Care Boston Children's Hospital Boston, Massachusetts

Pediatric Palliative Care Brandon T. Woods MD Fellow, Critical Care Medicine Department of Pediatrics University of Washington School of Medicine Seattle, Washington

Pulmonary Edema Benjamin L. Wright MD Assistant Professor Department of Allergy, Asthma, and Clinical Immunology Mayo Clinic Scottsdale, Arizona; Phoenix Children's Hospital Phoenix, Arizona

Eosinophils Joseph L. Wright MD, MPH Adjunct Research Professor Department of Family Science University of Maryland School of Public Health Adjunct Professor of Emergency Medicine and Health Policy George Washington University Washington, DC

Emergency Medical Services for Children Terry W. Wright PhD Associate Professor of Pediatrics (Infectious Diseases) University of Rochester Medical Center School of Medicine and Dentistry Rochester, New York

Pneumocystis jirovecii Eveline Y. Wu MD

Assistant Professor Department of Pediatrics Division of Allergy, Immunology, and Rheumatology University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Juvenile Idiopathic Arthritis Sarcoidosis Pablo Yagupsky MD Professor of Pediatrics and Clinical Microbiology (Emeritus) Ben-Gurion University of the Negev Department of Pediatrics Soroka Medical Center Beer-Sheva, Israel

Kingella kingae E. Ann Yeh MD, MA Associate Professor of Pediatrics (Neurology) University of Toronto Faculty of Medicine Director, MS and Demyelinating Disorders ProgramHospital for Sick Children Toronto, Ontario, Canada

Spinal Cord Lesions Associated with Vascular Processes Anusha K. Yeshokumar MD Assistant Professor Departments of Neurology and Pediatrics Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai New York, New York

Central Nervous System Vasculitis Wafik Zaky MD Professor Department of Pediatrics Patient Care

The University of Texas MD Anderson Cancer Center Houston, Texas

Brain Tumors in Childhood Lauren B. Zapata PhD Epidemiologist, Division of Reproductive Health Centers for Disease Control and Prevention Atlanta, Georgia

Contraception Lonnie K. Zeltzer MD Distinguished Research Professor Departments of Anesthesiology, Psychiatry, and Biobehavioral Science David Geffen School of Medicine at UCLA Los Angeles, California

Pediatric Pain Management Amy Zhou BA Clinical Research Coordinator Center for Autonomic Medicine in Pediatrics Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Illinois

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Congenital Central Hypoventilation Syndrome Barry S. Zuckerman MD Professor of Pediatrics and Chair Emeritus Boston University School of Medicine Boston Medical Center Boston, Massachusetts

Impact of Violence on Children

† Deceased

Preface Whoever saves one life it is considered as if they saved an entire world. — Babylonian Talmud The 21st edition of Nelson Textbook of Pediatrics continues its tradition of being an essential resource for general pediatric providers and pediatric subspecialists as they diagnose and treat infants, children, and adolescents throughout the world. The 21st edition has been thoroughly revised, updated, and edited to keep up with the huge advances in clinical care derived from basic, clinical, and population-based research. The promise that translational medicine will improve the lives of children has become a daily reality for most but not all children. Knowledge of human development, behavior, and diseases from the molecular to sociologic levels has led to greater understanding of health and illness in children and substantial improvements in health quality for those who have access to health care. These exciting scientific advances also provide hope to effectively address prevention and treatment of new and emerging diseases threatening children and their families. The field of pediatrics encompasses advocacy for all children throughout the world and must address societal inequalities of important resources required for normal development, as well as protection from natural and man-made disasters. Unfortunately, many children throughout the world have not benefited from the significant advances in the prevention and treatment of health-related problems. For our increasing knowledge to benefit all children and youth, medical advances and good clinical practice must always be coupled with effective advocacy to overcome unconscious bias, lack of political will, and misplaced priorities. This new edition of Nelson Textbook of Pediatrics attempts to provide the essential information that practitioners, house staff, medical students, and all other care providers involved in pediatric health care throughout the world need to understand to effectively address the enormous range of biologic, psychologic, and social problems that our children and youth face. In addition,

pediatric subspecialists will benefit from the details of coexisting disorders often seen in their patients. Our goal is to be comprehensive yet concise and reader friendly, embracing both new advances in clinical science and the time-honored art of pediatric practice. The 21st edition is reorganized and revised from the previous edition. There are many additions of new diseases and new chapters, as well as substantial expansion or significant modification of others. In addition, many more tables, photographs, imaging studies, and illustrative figures, as well as up-to-date references, have been added. This new edition has greatly benefited by the addition of four new associate editors with an extremely broad base of clinic experiences: Dr. Nathan Blum, Chief, Division of Developmental and Behavioral Pediatrics at the Children's Hospital of Philadelphia; Dr. Samir S. Shah, Director, Division of Hospital Medicine and Chief Metrics Officer, Cincinnati Children's Hospital Medical Center; Dr. Robert Tasker, Director, Pediatric NeuroCritical Care Medicine, Boston Children's Hospital; and Dr. Karen Wilson, Division Chief of General Pediatrics, Vice-Chair for Clinical and Translational Research, Kravis Children's Hospital at the Icahn School of Medicine at Mount Sinai, have all contributed to the planning and editing of the 21st edition. Although, to an ill child and their family and physician, even the rarest disorder is of central importance, all health problems cannot possibly be covered with the same degree of detail in one general textbook of pediatrics. Thus, leading articles and subspecialty texts are referenced and should be consulted when more information is desired. In addition, as new recommendations or policies are developed, they will be updated on our website. The outstanding value of the 21st edition of the textbook is due to its many expert and authoritative contributors. We are all indebted to these dedicated authors for their hard work, knowledge, thoughtfulness, and good judgment. Our sincere appreciation also goes to Jennifer Shreiner and Sarah Barth at Elsevier and to Carolyn Redman in the Pediatric Department of the Medical College of Wisconsin. We have all worked hard to produce an edition that will be helpful to those who provide care for children and youth and to those desiring to know more about children's health worldwide. In this edition we have had informal assistance from many faculty and house staff of the department of pediatrics at the Medical College of Wisconsin, University of Pennsylvania Perelman School of Medicine, University of Cincinnati College of Medicine, Harvard Medical School, and the Kravis

Children's Hospital at the Icahn School of Medicine at Mount Sinai. The help of these individuals and of the many practicing pediatricians from around the world who have taken the time to offer thoughtful feedback and suggestions is always greatly appreciated and helpful. Last and certainly not least, we especially wish to thank our families for their patience and understanding about the great time commitment we as editors have spent reading and editing this edition. Robert M. Kliegman MD Joseph W. St. Geme III, MD Nathan J. Blum MD Samir S. Shah MD, MSCE Robert C. Tasker MBBS, MD Karen M. Wilson MD, MPH

Videos Video 116.1 Fetoscopic open neural tube defect repair 895 Video 330.1 Echinococcus granulosus protoscolex 1898 Video 616.1 Severely limited level of consciousness and movement disorder in patient with anti-NMDAR encephalitis after herpes simplex encephalitis 3182 Video 616.2 Improved level of consciousness in patient with anti-NMDAR encephalitis after immunotherapy 3182 Video 616.3 Intact cognition in patient with antiNMDAR encephalitis after immunotherapy and prolonged follow-up 3182 Video 626.1 Physical examination of mother of newborn baby presenting with arthrogryposis 3278 Video 626.2 Infant with arthrogryposis, respiratory insufficiency, and fractures at birth 3278 Video 630.1 Spinal muscular atrophy type I 3312 Video 630.2 Kugelberg-Welander disease (spinal muscular atrophy type III) 3312 Video 630.3 Hand polyminimyoclonus (tremor),

typical of spinal muscular atrophy type III 3312

Volume 1 OUTLINE Part I The Field of Pediatrics Part II Growth, Development, and Behavior Part III Behavioral and Psychiatric Disorders Part IV Learning and Developmental Disorders Part V Nutrition Part VI Fluid and Electrolyte Disorders Part VII Pediatric Drug Therapy Part VIII Emergency Medicine and Critical Care Part IX Human Genetics Part X Metabolic Disorders Part XI The Fetus and the Neonatal Infant Part XII Adolescent Medicine Part XIII Immunology Part XIV Allergic Disorders Part XV Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Part XVI Infectious Diseases

PA R T I

The Field of Pediatrics OUTLINE Chapter 1 Overview of Pediatrics Chapter 2 Child Health Disparities Chapter 3 Global Child Health Chapter 4 Quality and Value in Healthcare for Children Chapter 5 Safety in Healthcare for Children Chapter 6 Ethics in Pediatric Care Chapter 7 Pediatric Palliative Care Chapter 8 Domestic and International Adoption Chapter 9 Foster and Kinship Care Chapter 10 Medical Evaluation of the Foreign-Born Child Chapter 11 Cultural Issues in Pediatric Care Chapter 12 Maximizing Children's Health Screening, Anticipatory Guidance, and Counseling Chapter 13 Injury Control Chapter 14 Impact of Violence on Children Chapter 15 Child Trafficking for Sex and Labor Chapter 16 Abused and Neglected Children Chapter 17 Strategies for Health Behavior Change

CHAPTER 1

Overview of Pediatrics Lee M. Pachter

Pediatrics is the only discipline dedicated to all aspects of the care and wellbeing of infants, children, and adolescents, including their health—their physical, mental, social, and psychological growth and development—and their ability to achieve full potential as adults. Pediatricians must be concerned not only with specific organ systems, genetics, and biologic processes, but also with environmental, psychosocial, cultural, and political influences, all of which may have major impacts on the health and well-being of children and their families. Children cannot advocate wholly for themselves. As the professionals whose purpose is to advance the well-being of children, pediatricians must be advocates for the individual child and for all children, irrespective of culture, religion, gender, sexual orientation, race, or ethnicity or of local, state, or national boundaries. The more politically, economically, or socially disenfranchised a population is, the greater the need for advocacy for its children and for those who support children. Youth are often among the most vulnerable persons in society, and thus their needs require special attention. As segmentation between nations blur through advances in media, transportation, technology, communication, and economics, a global , rather than a national or local, perspective for the field of pediatrics becomes both a reality and a necessity. The interconnectedness of health issues across the world has achieved widespread recognition in the wake of the Zika, Ebola, SARS, and AIDS epidemics; war and bioterrorism; the tsunami of 2004; the earthquake in Haiti in 2010; the displacement of families during the Syrian refugee crisis in 2016–2018; and the growing severity of drought, hurricanes, and cyclones brought about by climate change. More than a century ago, pediatrics emerged as a medical specialty in response to increasing awareness that the health problems of children differ from

those of adults, and that a child's response to disease and stress varies with age and development. In 1959 the United Nations issued the Declaration of the Rights of the Child , articulating the universal presumption that children everywhere have fundamental needs and rights. Today, an affirmation of those rights and an effort to satisfy those needs are more important than ever.

Vital Statistics About Children's Health Globally From 1990 to 2010, the world population grew at an annual rate of 1.3% per year, down from 1.8% during the prior 20 yr. This rate continues to decline; in 2016 the growth rate was 1.13%. Worldwide, there are 2.34 billion children 18 yr and younger, which accounts for approximately one third (32%) of the world's population of 7.4 billion persons. In 2016 the average birthrate in the world was 18.5 births per 1,000 population, with a high of 44.8/1,000 in Niger to the lowest in Monaco at 6.6/1,000. The most populous countries—China, India, and the United States—have rates of 12.4, 19.3, and 12.5 per 1,000 population, respectively. Despite global interconnectedness, the health of children and youth varies widely between and within regions and nations of the world, depending on several interrelated factors. These include (1) economic conditions; (2) educational, social, and cultural considerations; (3) health and social welfare infrastructure; (4) climate and geography; (5) agricultural resources and practices, which account for nutritional resources; (6) stage of industrialization and urbanization; (7) gene frequencies for certain disorders; (8) the ecology of infectious agents and their hosts; (9) social stability; and (10) political focus and stability. Although genetics, biology, and access to affordable and quality healthcare are important determinants, it has been shown that the social determinants of health—the physical environment, political and economic conditions, social and cultural considerations, and behavioral psychology—play as great a role, if not greater, in health outcomes. To ensure that the needs of children and adults worldwide were not obscured by local needs, in 2000 the international community established 8 Millennium Development Goals (MDGs) to be achieved by 2015. Although all 8 MDGs impact child well-being, MDG 4 was exclusively focused on children: to reduce the under-five mortality rate (U5MR) by two-thirds between 1990 and 2015. It

was estimated that poor nutrition contributed to more than one third of the deaths worldwide in children 3 times the rate of child abuse deaths than counties with the lowest concentration of poverty. Nonetheless, race itself should not be a marker for child abuse or neglect.

Behavioral Health Disparities Attention-Deficit/Hyperactivity Disorder (ADHD) White and black children are more often diagnosed with ADHD (10.7% and 8.4%, respectively) than are Hispanic children (6.3%), according to NHIS data. Other studies have shown that both black and Hispanic children have lower odds of having an ADHD diagnosis than white children. Children reared in homes that are below the federal poverty level are diagnosed more often (11.6%) that those at or above the FPL (8.1%). Children diagnosed with ADHD have different medication practices. Hispanic (43.8%) and black (40.9%) children with ADHD are more likely than white children (25.5%) not to be taking medication. The causes of this disparity are

unknown but may include different patient and parental beliefs and perceptions about medication side effects and different prescribing patterns by clinicians.

Depression and Anxiety Disorders According to the 2011/12 NSCH, there were no parent-reported differences in rates of childhood depression (2-17 yr) among racial/ethnic groups. Children living in poverty, as well as children living in rural areas, had higher rates of parent-reported depression. According to the 2015 Youth Risk Behavior Survey of adolescent in grades 9-12, Hispanic students had higher rates of reporting that they felt sad or hopeless (35.3%) compared to white (28.6%) and black (25.2%) students. This relationship existed for both male and female students. The NSCH data noted that white children ages 2-17 yr had higher rates of anxiety than black or Hispanic children. “Poor” children had higher rates of anxiety than “not poor” children.

Autism Spectrum Disorder (ASD) Compared with white children, black and Hispanic children are less likely to be diagnosed with ASD, and when diagnosed, are typically diagnosed at a later age and with more severe symptoms. This disparity in diagnosis and timing of diagnosis is concerning given that early diagnosis provides access to therapeutic services that are best initiated as early as possible. Reasons for these disparities may include differences in cultural behavioral norms, stigma, differences in parental knowledge of typical and atypical child development, poorer access to quality healthcare and screening services, differences in the quality of provider– patient communication, trust in providers, as well as differential access to specialists.

Behavioral or Conduct Problems According to the 2011/12 NSCH, black children age 2-17 yr have higher rates of oppositional defiant disorder (ODD) or conduct disorder than white and Hispanic children. Children living in poverty have higher rates than those not living in poverty.

Developmental Delay The 2011/12 NSCH found that black and white children age 2-17 yr had higher

rates of developmental delay than Hispanic children (4.5% and 3.8% vs 2.7%, respectively). However, when parents of children age 4 mo to 5 yr were asked if they had concerns about their child's development (highly correlated with risk of developmental, behavioral, or social delays), Hispanic children had higher rates of moderate or high risk for developmental delay (32.5%) than did black (29.7%) or white (21.2%) children. This discrepancy may result from either overestimation of concerns in Hispanic mothers or underdiagnosis of Hispanic children by clinicians. Children living below the poverty level have higher rates of developmental delay as well.

Disparities in Healthcare In almost all areas, minority children have been identified as having worse access to needed healthcare, including receipt of any type of medical care within the past 12 mo, well-child or preventive visits, delay in care, having an unmet need due to healthcare cost, lack of care in a medical home, problems accessing specialist care when needed, lack of preventive dental care, vision screening, mental health counseling, and recommendations for adolescent immunizations (see Table 2.2 ). In addition, many of these healthcare indicators are found to be worse for children living in poverty, as well as those living in a rural area, compared to urban-dwelling children.

Approaches to Eradicating Disparities: Interventions Much of the information regarding health disparities over the past 10-20 yr has focused on the identification of areas where health disparities exist. Additional work has expanded on simple description and acknowledged the multivariable nature of disparities. This has provided a more nuanced understanding of the complex interrelationships among factors such as race/ethnicity, socioeconomic status, social class, generation, acculturation, gender, and residency. An example of a successful intervention that closed the disparity gap is the implementation of the VFC program, which, as noted earlier, significantly decreased the disparity in underimmunization rates noted among racial/ethnic groups and poor/underinsured children. This is an example of a public health

policy approach to intervention. Interventions need to occur at the clinical level as well. The almost universal use of electronic health records (EHR) provides a unique opportunity for collecting clinical and demographic data that can be helpful in identify disparities and monitor the success of interventions. All EHR platforms should use a standardized approach to gathering information on patient race/ethnicity, SES, primary language preferences, and health literacy. The Institute of Medicine's 2009 report Race, Ethnicity, and Language Data: Standardization for Health Care Quality Improvement provides best practices information about capturing these data in the health record. The advancing science of clinical quality improvement can also provide a framework for identifying clinical strategies to reduce disparities in care. Use of PDSA (Plan-Do-Study-Act) cycles targeting specific clinical issues where health disparities exist can result in practice transformation and help reduce differential outcomes. Another practice-level intervention that has the potential to reduce disparities in care and outcomes is the medical home model, providing care that is accessible, family centered, continuous, comprehensive, compassionate, coordinated, and culturally effective. The use of care coordinators and community-based health navigators is an effective tool in helping to break down the multiple social and health system barriers that contribute to disparities. Population health strategies have the advantage of addressing the determinants of disparities at both the clinic and the community levels. Techniques such as “hotspotting,” “cold-casing” (finding patients and families lost to follow up and not receiving care), and “geocoding,” combined with periodic community health needs assessments, identify the structural, systemic, environmental, and social factors that contribute to disparities and help guide interventions that are tailored to the local setting. When developing strategies to address disparities, it is imperative to include patients and community members from the beginning of any process aimed at identification and intervention. Many potential interventions seem appropriate and demonstrate efficacy under ideal circumstances. However, if the intervention does not address the concerns of the end users—patients and communities—or fit the social or cultural context, it will likely be ineffective in the “real world.” Only by involving the community from the beginning, including defining the issues and problems, can the likelihood of success be optimized. Health disparities are a consequence of the social stratification mechanisms

inherent in many modern societies. Health disparities mirror other societal disparities in education, employment opportunities, and living conditions. While society grapples with the broader issues contributing to disparities, healthcare and public health can work to understand the multiple causes of these disparities and develop interventions that address the structural, clinical, and social root causes of these inequities.

2.1

Racism and Child Health Mary T. Bassett, Zinzi D. Bailey, Aletha Maybank

Keywords adverse childhood experiences cultural humility cultural safety doll experiment equity implicit bias infant mortality rate institutional racism internalized racism interpersonal racism microaggression racial disparities residential segregation social determinants stereotype threat structural competency structural racism

Racism as Social Determinant An emerging body of evidence supports the role of racism in a range of adverse physical, behavioral, developmental, and mental health outcomes. Racial/ethnic patterning of health in the United States is long-standing, apparent from the first collection of vital statistics in the colonial period. However, the extensive data that document racial disparities have not settled the question of why groups of people, particularly of African and Native American Indian ancestry, face increased odds of shorter lives and poorer health (Table 2.3 ). The role of societal factors, not only factors related to the individual, is increasingly recognized in determining population health, but often omits racism among social determinants of health. This oversight occurs in the face of a long history of racial and ethnic subjugation in the United States that has been justified both explicitly and implicitly by racism. From the early 18th century, colonial America established racial categories that enshrined the superiority of whites, conferring rights specifically on white men, while denying these rights to others. Similar, perhaps less explicit, discrimination has continued through the centuries and remains a primary contributor to racial inequities in children's health. Table 2.3

New Social and Health Inequities in the United States

Wealth: median household assets (2011) Poverty: proportion living below poverty level, all ages (2014); children 18 yr) patients whether they have completed an advance directive and, if not, inform them of their right to do so. Few states support creation of broad advance directives for minors because advance directives are traditionally created for persons with legal decision-making capacity. Some have moved in this direction, however, because it is recognized that minors may be capable of participating in decision-making, especially if they have experienced chronic disease. Most states have approved the implementation of prehospital or portable DNAR orders , through which adults may indicate their desire not to be resuscitated by emergency personnel. On a state-by-state basis, portable orders regarding resuscitation status may also apply to children. If DNAR orders exist for an infant or a child, it is important to communicate effectively about their intent among all potential caregivers, because nonmedical stakeholders such as teachers or sitters may not want to be in the position of interpreting or honoring them. Some institutions have established local policies and procedures by which an appropriately executed, outpatient DNAR order can be honored on a child's arrival in the emergency department. Key features may include a standardized document format, review by an attending physician, ongoing education, and involvement of a pediatric palliative medicine service. In cases involving prenatal diagnosis of a lethal or significantly burdensome anomaly, parents may choose to carry their fetus/unborn child to term in order to cherish a short time with the infant after birth, but they do not feel that resuscitation or certain other aggressive measures would support their wellconsidered goals of care. In this setting, a birth plan explaining the reasons for each choice can be developed by the parents and medical staff before delivery and shared with involved medical staff. This approach gives staff a chance to find other caregivers if they are uncomfortable with the approach, without abandoning the care of the child. If, after evaluation at birth, the infant's condition is as had been expected, honoring the requested plan is ethically

supportable and should be done in a way that optimizes comfort of the infant and family. Many states use Physician Orders for Life-Sustaining Treatment or Medical Orders for Life-Sustaining Treatment approaches to communicating a patient or surrogates wishes regarding advance care planning. Other tools, such as Five Wishes , have been adapted for use by adolescent patients to elicit values and desires. It is important for pediatricians to learn which pathways for communicating goals of care are available in their own states.

Artificial Hydration and Nutrition Issues surrounding withholding or withdrawing artificial hydration and nutrition are controversial, and interpretations are affected by parental, religious, and medical beliefs. Any adult or child who is fully dependent on the care of others will die as a result of not receiving hydration and nutrition. Case law has supported the withholding of artificially administered nutrition and hydration in the setting of adult vegetative or permanently unconscious patients who can be shown to have previously expressed a wish not to be maintained in such a state. This requires a valid advance directive, or for a surrogate decision maker to speak on behalf of the patient's known wishes. Because infants and many children have not reached a developmental stage in which such discussions would have been possible, decisions about stopping artificially administered nutrition and hydration as a limitation of treatment are more problematic. These decisions should be based on what families and caregivers decide best support comfort. In the child who is imminently dying, unaware of hunger, does not tolerate enteral feedings, and in whom family and staff agree that IV nutrition and hydration only prolong the dying process, it may be ethically supportable to withhold or withdraw these treatments based on a benefit-burden analysis.

The Doctrine of Double Effect Treatment decisions at the end of life may include limitations of certain LSMT or may involve the use of analgesic or sedative medications that some fear may shorten life, thereby causing death. The doctrine of double effect (DDE ) holds that an action with both good and bad effects is morally justifiable if the good effect is the only one intended, and the bad effect is foreseen and accepted, but not desired. In pediatrics, DDE is most commonly applied in end-of-life cases, when upward titration of medication (opiates) necessary to relieve pain, anxiety,

or air hunger can be expected to result in a degree of respiratory depression. In such cases, meeting a provider's obligation to relieve suffering is the intended effect, and this obligation to the patient outweighs the acknowledged but unavoidable side effect. Choosing medications that adequately relieve symptoms with minimal adverse effects would be ethically preferable, but the obligation to provide comfort at the end of life outweighs the foreseeable occurrence of unavoidable side effects. Hastening death as a primary intention is not considered to be morally acceptable. Providing pain medication guided by the DDE should not be confused with active euthanasia. The distinction is clear:

◆ In active euthanasia , causing death is chosen as a means of relieving the symptoms that cause suffering. ◆ Under DDE, adequate management of pain, anxiety, or air hunger is recognized as an obligation to dying patients, and is provided by careful titration of medications in response to symptoms. If death occurs sooner as a result, this is accepted. In both cases the patient dies, and in both cases suffering ends, but immediate death is the intended consequence only in the case of euthanasia. Codes of ethics and legislation in many states support the obligation to provide pain and symptom relief at the end of life, even if this requires increasing doses of medication.

Neonatal Ethics As neonatal care has evolved, the limits of viability of extremely premature infants are continuing to change. This introduces new elements of uncertainty to decision-making, often in emotionally fraught circumstances such as a precipitous premature delivery. In cases of uncertain prognosis, the American Academy of Pediatrics (AAP) supports parental desires as driving decisionmaking, while encouraging providers to recognize when treatments are inappropriate, and using a careful shared decision-making approach to

developing plans of care. The federal Child Abuse Prevention and Treatment Act of 1984 (CAPTA), which became known as “Baby Doe Regulations,” required state child protective services agencies to develop and implement mechanisms to report to a specific government agency treatment that providers believed was withheld from infants on the basis of disability. Exceptions were (1) an infant is chronically and irreversibly comatose, (2) if providing a treatment would merely prolong dying, would not be effective in ameliorating or correcting all the infant's lifethreatening conditions, or would be futile in terms of the infant's survival, and (3) if the treatment would be virtually futile and inhumane. This legislation pertains only to infants and is intended to prevent discrimination on the basis of disability alone. One consequence of the legislation was a shift from potential undertreatment to widespread overtreatment (LSMT that does not serve the interests of the child) of severely disabled newborns. As parental involvement in decisions-making is again taking a more central role, and as palliative care approaches in infants have become more available and skilled, balanced approaches to valuing lives of disabled infants should be considered. Understanding institutional, regional, state, and national regulations related to care of infants is important in order to practice within regulatory frameworks while respecting family values and pursuing the interests of the patient. Active euthanasia of severely suffering disabled newborns has been legalized in The Netherlands and Belgium, using protocols designed to minimize risk of abuse and maximize transparency. It is currently illegal in the United States, and although controversy surrounds the subject, the predominant view is that active euthanasia is not ethically acceptable in the care of infants and children, instead favoring palliative treatment and potential limitation of escalation.

Declaring Death and Organ Donation Donation of solid organs necessary to support life can occur after a patient is declared dead based on either irreversible cessation of neurologic function of the brain and brainstem (death by neurologic criteria, or brain death ) or a predetermined period of cardiac asystole called circulatory death . To avoid a potential conflict of interest by surgeons or others caring for a potential organ recipient, the request for organ donation should be separated from the clinical discussion of either brain death or withdrawal of LSMT. Although clinicians may be the first providers to enter discussion about death and organ donation

with family members during conversations about outcomes and options, detailed discussion of organ donation should be done by other individuals who are specifically trained for this purpose. This decoupling of clinical decision-making from a request for organ donation by trained individuals, perhaps by providing families with expert information without a perceived conflict of interest, has been associated with improved donation rates.

Death by Neurologic Criteria Death by neurologic criteria (DBNC ), commonly referred to as “brain death,” may be difficult for families to understand when the child appears to be breathing (although on a ventilator), pink, and warm to the touch, and when language such as “life support” is used at the bedside by staff. Studies also document clinician misunderstanding of the diagnosis of DBNC. For these reasons, strict criteria adhering to nationally accepted guidelines must be used to determine when irreversible cessation of brain and brainstem function has occurred and adequately document these findings (see Chapter 85 ). The states of New York and New Jersey allow families to object on “religious grounds” to the declaration of DBNC. In this situation the clinical determination of DBNC sets the stage for a discussion of forgoing LSMT, rather than the death of the patient. A unilateral decision not to initiate new or escalate existing interventions is ethically supportable under these circumstances, given the documented death of the patient. Even though it would seem to follow that a similar unilateral decision to withdraw existing interventions would also be supportable, this act is not in accordance with the intent of the state laws. Institutional procedures for conflict resolution, including involvement of the courts if necessary, should be followed.

Circulatory Death Protocols allowing for organ donation after determination of circulatory death (DDCD) rather than after DBNC have been developed. DDCD can occur under either controlled (after planned withdrawal of LSMT) or uncontrolled (after failed CPR) circumstances, but in both cases require rapid removal of organs in order for subsequent transplantation to be successful. An increasing number of programs are pursuing DDCD protocols after federal legislation began requiring accredited hospitals to address the issue in hopes of decreasing

organ shortages. Hospitals can make policy that either allows or disallows the process. In adults, consent for donation by either means can be obtained from patients or surrogates; for children, parents or guardians would make the decision to donate. Ethical concerns about DDCD protocols focus on 2 principles that have served as the basis for organ donation: (1) the dead donor rule limiting the donation of vital organs to those who are irreversibly dead (either by circulatory or neurologic criteria, not both), and (2) the absence of conflict of interest between clinical care and organ procurement. With DDCD protocols, irreversibility has been declared at varying times after asystole occurs (usually 25 min), to avoid spontaneous return of circulation after forgoing CPR. To avoid a potential conflict of interest during the DDCD process, there is a requirement for strict decoupling of end-of-life care after discontinuation of LSMT and presence of the transplant team. Unlike in the setting of DBNC, a patient who is being considered for DDCD remains alive until after asystole has occurred. Careful evaluation by the transplantation team and organ procurement agency is performed before discontinuation of LSMT. Then, in most DDCD protocols, the medical caregivers from the ICU continue to care for the patient until after death by cardiac criteria has been declared, and only then is the surgical transplant team allowed into the room to procure organs. It is ethically imperative to correctly diagnose the state of death, whether by neurologic criteria or prior to organ donation after cardiac death. Doing so avoids the danger of removing life-sustaining organs from a living person. Strict adherence to an ethically sound protocol is the best way to prevent both the perception and the potential reality of mistakes related to the pronunciation of death and organ procurement.

Religious or Cultural Objections to Treatment Differences in religious beliefs or ethic-based cultural norms may lead to conflict between patients, families, and medical caregivers over the approach to medical care. Pediatricians need to remain sensitive to and maintain an attitude of respect for these differences, yet recognize that an independent obligation exists to provide effective medical treatment to the child. An adult with decision-making capacity is recognized as having the right to refuse treatment on religious or

cultural grounds, but children who have not yet developed this capacity are considered a vulnerable population who has a right to treatment. In situations that threaten the life of the child or that may result in substantial harm, legal intervention should be sought if reasonable efforts toward collaborative decisionmaking are ineffective. If a child's life is imminently threatened, medical intervention is ethically justified despite parental objections.

Pediatric Ethics Committees and Ethics Consultation Most hospitals have institutional ethics committees to assist with policy development, education, and case consultation. When these committees serve institutions caring for children, they may be referred to as pediatric ethics committees . Because of the important differences in approach between adult and pediatric ethics, member expertise on this committee should include those with special insight into the unique ethical issues arising in the care of children. Such committees generally provide ethics consultation advice without mandating action or being determinative. For the vast majority of decisions involving the medical treatment of children (including forgoing LSMT), pediatric clinicians and parents are in agreement about the desirability of the proposed intervention. Because of the ethical importance of assent, the views of older children should also be given considerable weight. Pediatric ethics committees typically perform at least 3 different functions: (1) the drafting and review of institutional policy on such issues as DNAR orders and forgoing LSMT; (2) the education of healthcare professionals, patients, and families about ethical issues in healthcare; and (3) case consultation and conflict resolution. Although the process of case consultation may vary, ideally the committee (or consultant) should adopt a collaborative approach that uncovers all the readily available and relevant facts, considers the values of those involved, and balances the relevant interests, while arriving at a recommendation based on a consistent ethical analysis. One helpful approach involves consideration of the 4 following elements: (1) medical indications, (2) patient preferences, (3) quality of life, and (4) contextual features. Another framework based on principles would suggest attention to respect for persons, beneficence/nonmaleficence, and justice. Pediatric ethics committees often play a constructive role when parents and

medical staff cannot agree on the proper course of action. Over the past several decades, these committees have acquired considerable influence and are increasingly recognized by state courts as an important aid in decision-making. The membership, policies, and procedures of a pediatric ethics committee should conform to accepted professional standards.

Newborn Screening The Oxford Dictionary of Public Health defines screening as “the identification of a previously unrecognized disease or disease precursor, using procedures or tests that can be conducted rapidly and economically on large numbers of people with the aim of sorting them into those who may have the condition(s)… and those who are free from evidence of the condition(s).” Several programs, such as newborn screening for inborn errors of metabolism (see Chapter 102 ; e.g., phenylketonuria and hypothyroidism), are rightly counted among the triumphs of contemporary pediatrics. The success of such programs sometimes obscures serious ethical issues that continue to arise in proposals to screen for other conditions for which the benefits, risks, and costs have not been clearly established. Advances in genetics and technology have led to exponential growth in the number of conditions for which screening programs might be considered, with insufficient opportunity to study each proposed testing program (see Chapter 95 ). The introduction of screening efforts should be done in a carefully controlled manner that allows for the evaluation of the costs (financial, medical, and psychological) and benefits of screening, including the effectiveness of followup and treatment protocols. New programs should be considered experimental until the risks and benefits can be carefully evaluated. Screening tests that identify candidates for treatment must have demonstrated sensitivity, specificity, and high predictive value, lest individuals be falsely labeled and subject to possibly toxic treatments or to psychosocial risks. As newborn screening tests are being developed, parents should be given the opportunity to exercise informed parental permission or refusal. However, once a particular screening test has been clearly demonstrated to benefit the individual or public health, a formal, active parental permission process may not be ethically obligatory. A persistent ethical issue is whether screening should be (1) voluntary (“opt in”), (2) routine, with the ability to “opt out” or refuse, or (3) mandatory. A voluntary approach entails an informed decision by parents before screening.

Concern is often expressed that seeking parental permission is ethically misguided for tests of clear benefit, such as phenylketonuria screening, because refusal would constitute neglect. Routine testing with an opt-out approach requires an explicit refusal of screening by parents who object to this intervention. The principal ethical justification for mandatory screening is the claim that society's obligation to promote child welfare through early detection and treatment of selected conditions supersedes any parental right to refuse this simple and low-risk medical intervention. Parental permission is clearly required when there is a research agenda (i.e., for incorporating experimental tests into established screening programs).

Genetics, Genomics, and Precision Medicine Genetics refers to the study of particular genes, and genomics describes the entirety of an individual's genetic material. Genomics has been made possible by technologic advances that allowed the rapid and inexpensive sequencing now used in clinical care. The development of precision medicine is in large part predicated on genomic science and may have a major impact on the practice of pediatrics in the future. Efforts to undertake whole genome sequencing of newborns may yield actionable information to benefit the child, but also carry the risk of stigmatization, false positives, and unwanted information that could lead to anxiety and psychological distress. Genetic testing of young children for late-onset disorders such as the BRCA1 and BRCA2 breast cancer risk genes has also been the subject of some ethical controversy. Knowledge of increased risk status may lead to lifestyle changes that can reduce morbidity and the risk of mortality, or may precipitate adverse emotional and psychological responses and discrimination. Because many adults choose not to be tested for late-onset disorders, one cannot assume that a child would want or will benefit from similar testing. Genetic testing of young children for late-onset disorders is generally inappropriate unless such testing will result in interventions that have been shown to reduce morbidity and mortality when initiated in childhood. Otherwise, such testing should be deferred until the child has the capacity to make an informed and voluntary choice.

Adolescent Healthcare Adolescent Assent and Consent Many adolescents are more like adults than children in their capacity to understand healthcare issues and to relate them to their life goals (see Chapter 132 ). Teenagers may lack legally defined competency, yet they may have developed the capacity meet the elements of informed consent for many aspects of medical care (see Chapter 137 ). There are also public health reasons for allowing adolescents to consent to their own healthcare with regard to reproductive decisions, such as contraception, abortion, and treatment of sexually transmitted infections. Strict requirements for parental permission may deter adolescents from seeking healthcare, with serious implications for their health and other community interests. Counterbalancing these arguments are legitimate parental interests to maintain responsibility and authority for child rearing, including the opportunity to influence the sexual attitudes and practices of their children. Others claim that access to treatment such as contraception, abortion, or needle exchange programs implicitly endorses sexual activity or drug use during adolescence. Pediatricians should not impose their own moral beliefs in these disputes. Rather, they should provide unbiased evidence-based information and nonjudgmental support. One guiding principle should be encouragement of children and adolescents to begin taking responsibility, with guidance, for their own health. This requires some input from parents or guardians but also some privacy during decision-making as adolescents achieve developmentally anticipated separation from parental control.

Chronic Illness The normal process of adolescent development involves gradually separating from parents, establishing self-confidence, asserting individuality, developing strong peer relationships, solidifying an ability to function independently outside the family, and taking on increasing autonomy in healthcare decisions. Most developmentally normal children older than age 14 yr understand the implications of well-explained medical options as well as the average adult, and their input into their own care should be respected. For children living with chronic illness, the ability to make medical decisions for themselves may either occur earlier than for those who have been previously healthy, or may occur later

if, because of illness, they have not been able to achieve normal developmental milestones or psychological maturity. The clinician's role involves assessment of the individual adolescent patient's ability to understand the medical situation, to support the patient's efforts to express wishes regarding medical treatment, to value and encourage parental support and involvement, and to foster cooperation and mutual understanding. This may be difficult in situations in which parents and adolescents disagree about life-sustaining treatments such as organ transplantation or chemotherapy, but many such conflicts may be resolved by exploring the reasons for the disagreement. Overriding an adolescent's wishes should be done very infrequently, and only after careful consideration of the potential consequences of unwanted interventions.

Decisions in Terminally Ill Adolescents Most adolescents share end-of-life decision making with family members, although communication may be challenging because of a growing sense of independence. Open communication and flexibility about treatment preferences may help teens cope with fears and uncertainties. Development of an ageappropriate advance directive may support the patient's emerging autonomy by clarifying the adolescent's wishes, while fostering a collaborative process among the patient, family, and medical caregivers. From the time of diagnosis of a lifethreatening condition through the end-of-life phase, children should be included in a developmentally tailored process of communication and shared decisionmaking that builds a foundation of mutual respect and trust. Some experts believe that most adolescents are not yet fully capable of making a decision to forgo life-sustaining treatment. Careful case-by-case evaluation is required to make this determination, and assistance from developmental psychologists and ethics consultants may be helpful.

Research The central ethical challenge of pediatric research is the need to balance protection of children from research risk against the ethical imperative of conducting studies to better the lives of future children. Research is defined in the federal regulations as “a systematic investigation designed to develop or contribute to generalizable knowledge.” For any research to be performed, the risks should be minimized and reasonable with respect to any anticipated

benefits to the participants and the importance of the resulting knowledge. That some children derive a direct benefit from participation in research must also be considered, making it important to distinguish research with the prospect of direct benefit from nontherapeutic pediatric research. Because children are a vulnerable population, there are restrictions on the research risks to which a child may be exposed, in contrast to the risk level acceptable for research with consenting adults . These restrictions function by limiting the type of research that institutional review boards (IRBs) are permitted to approve and by specifying the conditions under which parents have the moral and legal authority to permit a child to participate in research. Nontherapeutic research in children is the most ethically controversial because it holds no expected direct benefit for the individual. The prohibition against using a person (especially a child) solely as a means to an end has led some to argue that children should never be used in nontherapeutic research. The more widely held opinion is that children may be exposed to a limited degree of risk with IRB approval, parental permission, and assent if the child is capable. The federal regulations allow healthy children to participate in minimal-risk research regardless of the potential benefit to the child. More controversially, the regulations also state that children with a disorder or condition may be exposed to slightly more than minimal risk in nontherapeutic research if the child's experience is similar to everyday life with the condition and the anticipated knowledge is of vital importance for understanding the condition. In pediatric research with the prospect of direct benefit, the risks must be justified by the anticipated benefit to the child, and the balance of anticipated benefit to the risk should be at least as favorable as that presented by available alternatives. The welfare of an individual child must always come before the scientific goals of the research study. U.S. regulations for the protection of human research participants rest on 2 foundations: (1) independent review of the ethics and science of the research by an IRB prior to (2) voluntary and informed consent of the participant. Although it is not amenable to regulation, the integrity of the investigator is probably the most important element contributing to the protection of human research participants. The standard for informed consent in a research setting is higher than for clinical care because the risks and benefits are typically less clear, the investigator has a conflict of interest, and humans have historically been subjected to unauthorized risks when strict requirements for consent were not respected.

Adolescents who are competent may sometimes consent to be research participants. Younger children may participate in a process of assent, but this does not imply that a child's signature on an assent document is necessarily a legal or ethical requirement. Children should be given the opportunity to dissent, particularly for nontherapeutic research, when there cannot be a claim that participation is in the child's interest. In the United States, national regulations require that reasonable efforts be made at least to inform children who are capable of understanding that participation is not part of their care, and therefore they are free to refuse to participate. In the rare case that the research offers a direct benefit to the child that would not otherwise be available, the regulations do not require child assent but only parental permission. In addition to the protection that informed consent or parental permission is intended to provide, virtually all research involving humans in the United States is reviewed by an IRB, as required by federal regulations for institutions receiving federal research funds and for drug research regulated by the U.S. Food and Drug Administration. For research that carries more than a minor increase over minimal risk without prospect of benefit to the child such that a local IRB cannot provide approval, there is a process for federal review of research that “presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.” Ultimately, the U.S. Secretary of Health and Human Services has the authority to approve such research.

Balancing Maternal and Fetal Interests Some situations require balancing of maternal health and well-being with those of the fetus/unborn child to reach an ethically sound decision. For instance, innovative surgical treatment of a prenatally diagnosed anomaly may help the fetus/unborn child survive, but in the process place the mother at risk of injury or of loss of the pregnancy. Alternatively, a pregnant woman may object to cesarean delivery for various reasons despite advice that it may protect the fetus/unborn child during birth. Another important situation involves risk-taking behaviors during pregnancy that are known to injure the developing fetus/unborn child, such as drug or alcohol use. These issues raise conflicts over clinicians’ responsibility to the living, competent decision-maker—the pregnant mother—as opposed to the interests of the fetus/unborn child. In certain cases, U.S. courts have decided that a woman can be required to

undergo cesarean birth against her will when the risk to her health is minimal and the benefit to the otherwise normal, near-term fetus/unborn child is clear, as in a case of placenta previa. Other factors, such as prematurity, have led to the opposite legal conclusion in otherwise similar situations, because the benefit of intervention was less clear. In general, a clinician should not oppose a pregnant woman's refusal of a recommended intervention unless (1) the risk to the pregnant woman is minimal, (2) the intervention is clearly effective, and (3) the harm to the fetus/unborn child without the intervention would be certain, substantial, and irrevocable. Attempts should be made to persuade the pregnant woman to comply with recommendations in the interest of the fetus/unborn child when these 3 conditions exist, using support strategies such as the influence of other trusted caregivers, clergy, and ethics consultation or committee involvement. If these approaches fail and there is time, a clinician may seek judicial intervention as a last resort in the attempt to prevent harm to the fetus/unborn child. Obstetricians and pediatricians may consider reporting women under child abuse or neglect statutes if ingesting alcohol or illicit drugs during pregnancy is believed to place the fetus/unborn child at risk of injury. However, clinicians must consider the likelihood of benefit from reporting, the harm to the child as well as to the mother if criminal charges or custody changes are sought, and the possible effects of reporting on driving pregnant women away from prenatal or postnatal care. The U.S. Supreme Court has held that drug testing of pregnant women without consent was a violation of the Fourth Amendment, which provides protection from unreasonable searches.

Justice and Pediatric Ethics The most serious ethical problem in U.S. healthcare may be inequality in access to healthcare. Children are particularly vulnerable to this disparity, and pediatricians have a moral obligation to advocate for children as a class. Because children do not vote and do not have financial resources at their disposal, they are subject to a greater risk of being uninsured or underinsured. This lack of adequate and affordable healthcare has serious consequences in terms of death, disability, and suffering. The per capita proportion of healthcare funding spent on adults greatly exceeds that spent on children, and Medicare is available to all adults who turn 65 yr old, whereas Medicaid is limited to those beneath a specific income level. Pediatricians should be familiar with policy issues around

the economics of childcare so that they will be better able to advocate for their own patients.

Emerging Issues The ready availability of information on the internet and disease-specific social media support groups have encouraged parents to become more involved in advocating for specific approaches to the healthcare of their children, requiring physicians to remain aware of the quality of these information sources in order to counsel parents on treatment choices. Because the range of aggressive, innovative, or exceedingly expensive therapies has increased, without necessarily providing clear benefit to the patient, pediatricians must exercise care and judgment before agreeing to pursue these interventions. In addition, the growth of social media has presented expectations for clinicians to be quickly responsive, as well as challenges in maintaining privacy of medical information and professional boundaries. This will be an evolving issue, since the use of telemedicine is also gaining traction in certain sectors of healthcare, including the care of children and adolescents. A growing number of parents are refusing to immunize their children because of fear of adverse reaction to vaccine. This raises the ethical problem of the free rider , in which a child may benefit from herd immunity because others have been immunized without contributing to this public good. Outbreaks of preventable infectious disease have been detected in communities where vaccine refusal is prevalent. Pediatricians should manage this issue with ethical sensitivity, educating parents about the safety profile of vaccines and encouraging appropriate immunization. More confrontational approaches are not generally effective or ethically warranted. Another emerging issue is children as stem cell or solid-organ donors. Here the risk/benefit balance should be carefully weighed, but in general, a permissive policy with regard to stem cell donation and a more restrictive approach to solid-organ donation are ethically justified. Lastly, controversial medical and surgical interventions have raised awareness of situations in which families and children may not be in agreement with approaches that were recommended as “standard of care” in the past. Examples include delaying surgical treatment of sexual development disorders to determine the child's gender identity and arresting puberty through hormonal treatment to allow transgender or questioning children or adolescents to make decisions about gender identity before developing enduring secondary sexual

characteristics. Attitudes about emerging technologies and treatments may be influenced by media coverage, special interest groups, and efforts by understandably desperate families to help their children. The clinician attempting to practice ethically must carefully consider all relevant facts in each case and try to focus families and caregivers on a reasonable best interest assessment for the child. The tension between finding optimal policy for groups of children and doing the right thing for an individual child raises formidable ethical challenges in this context. Ethics consultation may be helpful to frame the issues and design ethically supportable approaches to care.

Bibliography American Academy of Pediatrics, Committee on Bioethics and Committee on Hospital Care. Palliative care for children. Pediatrics . 2000;106:351–357 [(Reaffirmed February 2007)]. American Academy of Pediatrics, Committee on Bioethics. Clinical report: forgoing medically provided nutrition and hydration in children. Pediatrics . 2009;124(2):813–822 [(Reaffirmed January 2014)]. American Academy of Pediatrics, Committee on Bioethics. Informed consent in decision-making in pediatric practice. Pediatrics . 2016;138(2):e20161484. American Academy of Pediatrics, Committee on Bioethics. Children as hematopoietic stem cell donors. Pediatrics . 2010;125:2392–2404. American Academy of Pediatrics, Committee on Bioethics. Committee on Genetics; The American College of Medical Genetics; and Genomics, Social, Ethical and Legal Issues Committee. Pediatrics . 2013;131(3):620–622. American Academy of Pediatrics, Committee on Bioethics. Conflicts between religious or spiritual beliefs and pediatric care: informed refusal, exemptions, and public funding. Pediatrics . 2013;132(5):962–965.

American Academy of Pediatrics, Committee on Bioethics. Ethical controversies in organ donation after circulatory death. Pediatrics . 2013;131(5):1021–1026. American Academy of Pediatrics, Committee on Bioethics. Ethics and the care of critically ill infants and children. Pediatrics . 1996;98:149–152. Academy of Pediatrics, Committee on Bioethics Policy Statement. Guidance on forgoing life-sustaining medical treatment. Pediatrics . 2017;140(3):109–117. American Academy of Pediatrics, Committee on Fetus and Newborn. Noninitiation or withdrawal of intensive care for high-risk newborns. Pediatrics . 2007;119(2):401–403. American Academy of Pediatrics. Council on School Health and Committee on Bioethics: policy statement—honoring donot-attempt-resuscitation requests in schools. Pediatrics . 2010;125:1073–1077. Bosslet GT, Pope TM, Rubenfeld GD, et al. An official ATS/AACN/ACCP/ESICM/SCCM policy statement: responding to requests for potentially inappropriate treatments in intensive care units. Am J Respir Crit Care Med . 2015;191(11):1318–1330. Brouwer M, Kaczor C, Battin MP, et al. Should pediatric euthanasia be legalized? Pediatrics . 2017;141(2):e20171343. Costeloe K. Euthanasia in neonates: should it be available? BMJ . 2007;334:912–913. Diekema DS, Botkin JR. Clinical report—forgoing medically provided nutrition and hydration in children. Pediatrics . 2009;124:813–822. Diekema DS. Adolescent refusal of lifesaving treatment: are we asking the right questions? Adolesc Med State Art Rev . 2011;22(2):213–228. Diekema DS. Parental refusals of medical treatment: the harm principle as threshold for state intervention. Theor Med

Bioeth . 2004;25(4):243–264. 2004. Ethical conduct of clinical research involving children. National Academy Press: Washington, DC; 2004. Fallat ME, Hertweck P, Ralston SJ. Surgical and ethical challenges in disorders of sexual development. Adv Pediatr . 2012;59(1):283–302. Goodyear MDE, Eckenwiler LA, Ells C. Fresh thinking about the declaration of Helsinki. BMJ . 2008;337:1067–1068. Goodyear MDE, Krieza-Jeric K, Lemmens T. The declaration of Helsinki. BMJ . 2007;335:624–626. Greer DM, Wang HH, Robinson JD, et al. Variability of brain death policies in the United States. JAMA Neurol . 2016;73(2):213–218. Himelstein BP. Palliative care for infants, children, adolescents, and their families. J Palliat Med . 2006;9(1):163–181. Joffe S, Kodish E. Protecting the rights and interests of pediatric stem cell donors. Pediatr Blood Cancer . 2011;56:517–519. Kimberly MB, Forte AL, Carroll JM, et al. Pediatric do-notattempt-resuscitation orders and public schools: a national assessment of policies and laws. Am J Bioeth . 2005;5(1):59– 65. Kodish E. Ethics and research with children: a case-based approach . Oxford University Press: New York; 2005. Kodish E. Paediatric ethics: a repudiation of the Groningen protocol. Lancet . 2008;371(9616):892–893. Kopelman LM. Are the 21-year-old Baby Doe rules misunderstood or mistaken? Pediatrics . 2005;115(3):797– 802. Lo B. Euthanasia in The Netherlands: what lessons for elsewhere? Lancet . 2012;380:869–870. Mercurio MR. An adolescent's refusal of medical treatment: implications of the Abraham Cheerix case. Pediatrics . 2007;120(6):1357–1358.

Nakagawa TA, et al. Clinical report—guidelines for the determination of brain death in infants and children: an update of the 1987 Task Force Recommendations. Pediatrics . 2011;128(3):e720–e740. Nelson RM, Botkjin JR, Kodish ED, et al. Committee on Bioethics: ethical issues with genetic testing in pediatrics. Pediatrics . 2001;107:1451–1455 [(Reaffirmed May 2009)]. 1985. Nondiscrimination on the basis of handicap; procedures and guidelines relating to health care for handicapped infants— HHS. Final rules. Fed Regist . 1985;50:14879–14892. President's Council on Bioethics. The changing moral focus of newborn screening: an ethical analysis by the President's Council on Bioethics . [Washington, DC] 2008. Quadri-Sheriff M, Hendrix KS, Downs SM, et al. The role of herd immunity in parents’ decision to vaccinate children: a systematic review. Pediatrics . 2012;130(3):522–530. Sisk BA, DuBois J, Kodish E, et al. Navigating decisional discord: the pediatrician's role when child and parents disagree. Pediatrics . 2017;139(6):e20170234. Verhagen E, Sauer PJJ. The Groningen protocol—euthanasia in severely ill newborns. N Engl J Med . 2005;352(10):959–962. Weise KL. What is the “rule of double effect”? Thompson DR, Kummer HB. Critical care ethics: a practice guide from the ACCM Ethics Committee . ed 2. Society of Critical Care Medicine; 2009. Wilkinson D. Beyond resources: denying parental requests for futile treatment. Lancet . 2017;389:1866–1867. World Medical Association. The physician's pledge . https://www.wma.net/policies-post/wma-declaration-ofgeneva/ ; 2017.

CHAPTER 7

Pediatric Palliative Care Christina Ullrich, Janet Duncan, Marsha Joselow, Joanne Wolfe

According to the World Health Organization (WHO), “Palliative care for children is the active total care of the child's body, mind and spirit and also involves giving support to the family. Optimally, this care begins when a lifethreatening illness or condition is diagnosed and continues regardless of whether or not a child receives treatment directed at the underlying illness.” Provision of palliative care applies to children with a wide variety of diagnoses, including cancer, cystic fibrosis, complex or severe cardiac disease, neurodegenerative disorders, severe malformations, and trauma with life-threatening sequelae (Table 7.1 ). Medical and technologic advances have resulted in children living longer, often with significant dependence on expensive technologies. These children have complex chronic conditions across the spectrum of congenital and acquired life-threatening disorders. Children with complex chronic conditions benefit from integration of palliative care strategies. These children, who often survive near-death crises followed by the renewed need for rehabilitative and life-prolonging treatments, are best served by a system that is flexible and responsive to changing needs and blended goals of care.

Table 7.1

Conditions Appropriate for Pediatric Palliative Care Conditions for Which Curative Treatment Is Possible but May Not Succeed Advanced or progressive cancer or cancer with a poor prognosis Complex and severe congenital or acquired heart disease

Conditions for Which There Is Intensive Long-Term Treatment Aimed at Prolonging Life and Maintaining Quality of Life, but Premature Death Is Still Possible Cystic fibrosis Severe immunodeficiency High-risk solid-organ transplant candidates and/or recipients (e.g., lung, multivisceral) Chronic or severe respiratory failure Muscular dystrophy Complex multiple congenital malformation syndromes Primary pulmonary hypertension Severe chromosomal disorders (aneuploidy, deletions, duplications) Progressive Conditions for Which There Is No Curative Option and in Which Treatment Is Almost Exclusively Palliative After Diagnosis Progressive metabolic disorders (Tay-Sachs disease) Batten disease Severe forms of osteogenesis imperfecta Conditions Involving Severe, Nonprogressive Disability, Causing Extreme Vulnerability to Health Complications Severe cerebral palsy with recurrent infection or difficult-to-control symptoms Severe neurologic sequelae of infectious disease Hypoxic or anoxic brain injury Brain malformations (e.g., holoprosencephaly, lissencephaly)

Adapted from The Together for Short Lives [formerly the Association for Children's Palliative Care (ACT)] Life-limiting/Life-threatening Condition Categories. http://www.togetherforshortlives.org.uk/professionals/childrens_palliative_care_essentials/app .

Although often mistakenly understood as equivalent to end-of-life care , the scope and potential benefits of palliative care are applicable throughout the illness trajectory . Palliative care emphasizes optimization of quality of life, communication, and symptom control, goals that may be congruent with maximal treatment aimed at sustaining or prolonging life. The mandate of the pediatrician and other pediatric clinicians to attend to children's physical, mental, and emotional health and development includes the provision of palliative care for those who live with a significant possibility of death before adulthood (Fig. 7.1 ). Such comprehensive physical, psychological, social, and spiritual care requires an interdisciplinary approach.

FIG. 7.1 Typical illness trajectories for children with life-threatening illness. (From Field M, Behrman R, editors: When children die: improving palliative and end-of-life care for children and their families, Washington, DC, 2003, National Academies Press, p 74.)

In the United States the healthcare and reimbursement structure, combined with frequent use of medical technology (e.g., home ventilatory support) or continuous home nursing, historically precluded formal enrollment of children on the hospice benefit when they were otherwise eligible (i.e., had estimated prognosis of ≤6 mo). Section 2302 of the Patient Protection and Affordable Care Act (ACA), the Concurrent Care for Children Requirement (CCCR) , eliminated the requirement that Medicaid patients 2 yr. Apply to upper back in young children. Patch may not be cut. Typically for patients taking at least 60 mg morphine/day or its equivalent. Not appropriate when dosage changes are frequent or for opioid-naïve patients. Fever >40°C results in higher serum concentrations. § Fewer anticholinergic side effects than amitriptyline. May cause constipation, sedation, postural hypotension, and dry mouth. May cause QT interval prolongation (consider ECG). At higher doses, monitor ECG and plasma levels. May cause neuropsychiatric events in children (aggression, emotional lability, hyperkinesia), usually mild but may require discontinuation of gabapentin. May cause dizziness, drowsiness, tremor, nystagmus, ataxia, and swelling.

See previous listing. All opioids may relieve dyspnea. For dyspnea, the starting dose is 30% of the dose that would be administered for pain. § See previous listing

Respiratory secretions

Scopolamine patch

Glycopyrrolate

Hyoscyamine sulfate

Atropine Nausea

Metoclopramide

Ondansetron

Dexamethasone

Lorazepam Dronabinol

up to 2 mg/dose 1.5 mg patch, change q72h (for Excessive drying of secretions can children >8-12 yr old) cause mucus plugging of airways. Good for motion-induced nausea and vomiting. Handling patch and contacting eye may cause anisocoria and blurry vision. May fold patches, but do not cut them. Anticholinergic side effects possible. 0.04-0.1 mg/kg PO q4-8h Powerful antisialagogue. Excessive drying of secretions can cause mucus plugging of airways. Anticholinergic side effects possible. Quaternary ammonium structure limits its ability to cross lipid membranes, such as the blood-brain barrier (in contrast to atropine, scopolamine, and hyoscyamine sulfate), so may exert fewer central anticholinergic effects. 4 gtt PO q4h prn if 27 kg)

Stool softener available as liquid or capsule Tasteless powder may be mixed in beverage of choice. Now available over the counter.

Bowel stimulant; dosing q2h may cause cramping. Bowel stimulant; available as granules

Dulcolax

Muscle spasm

Seizures

3-12 yr: 5-10 mg PO daily >12 yr 5-15 mg PO daily Pediatric Fleets 2.5 oz pediatric enema for Enema children 2-11 yr; adult enema for children ≥12 yr Methylnaltrexone 10-20 kg: 2 mg SC 21-33 kg: 4 mg SC 34-46 kg: 6 mg SC 47.62 kg: 8 mg SC 63-114 kg: 12 mg SC ≥155 kg: 0.15 mg/kg SC Administer 1 dose every other day as needed; max 1 dose/24 hr Diazepam 0.5 mg/kg/dose IV/PO q6h prn Initial dose for children 400 cells/µL, if persistently elevated for 3-6 mo after arrival, should prompt further investigation for tissueinvasive parasites such as Strongyloides (see Chapter 321 ) and Schistosoma (Chapter 326 ) species (if no predeparture praziquantel given). If no documented predeparture treatment was given, 2 stool O&P specimens obtained from separate morning stools should be examined by the concentration method, and an eosinophil count performed. If the child is symptomatic, including evidence of poor physical growth, but no eosinophilia is present, a single stool specimen should also be sent for Giardia lamblia (see Chapter 308.1 ) and Cryptosporidium parvum (Chapter 309 ) antigen detection. All potentially pathogenic parasites found should be treated appropriately. All nonpregnant refugees >2 yr of age coming from sub-Saharan Africa and Southeast Asia should be presumptively treated with predeparture albendazole.

Tuberculosis See also Chapter 242 . Tuberculosis (TB) commonly is encountered in immigrants from all countries because Mycobacterium tuberculosis infects approximately 30% of the world's population. Latent TB infection rates can be up to 60% in some refugee children from North Africa and the Middle East. Prior to 2007, chest radiographs or tuberculin skin tests were generally not administered in children 45 kg: 0.5-4 mg

CV history; BP, P; rebound hypertension; cardiac conduction abnormalities CV history; BP, P; rebound hypertension; cardiac conduction abnormalities

0.1-0.4 mg

CV history; BP, P; rebound hypertension; cardiac conduction

Guanfacine (Intuniv) 24 hr

ADHD (6+)

Inattention 1 mg Hyperactivity Impulsivity

Monotherapy : 25-33.9 kg: 2-3 mg 34-41.4 kg: 2-4 mg 41.5-49.4 kg: 3-5 mg 49.5-58.4 kg: 3-6 mg 58.5-91 kg: 4-7 mg >91 kg: 5-7 mg Adjunctive (with stimulant): 0.05-0.12 mg/kg/day

abnormalities CV history; BP, P; rebound hypertension, cardiac conduction abnormalities

* Doses shown in table may exceed maximum recommended dose for some children. † Capsule contents may be sprinkled on soft food.

FDA, U.S. Food and Drug Administration; CV, cardiovascular; Ht, height; Wt, weight; BP, blood pressure; P, pulse; GI, gastrointestinal.

No major differences in efficacy or tolerability have been found between different classes of stimulants, and no consistent patient profile identifies those who will respond preferentially to one class over another. The most common (generally dose-dependent) side effects of stimulants include headache, stomachache, appetite suppression, weight loss, blood pressure (BP) and heart rate increases, and delayed sleep onset. Less common side effects include irritability (particularly prominent in younger children), aggression, social withdrawal, and hallucinations (visual or tactile). Amphetamine preparations prescribed concurrently with serotonergic antidepressants can be associated with the development of serotonin syndrome. Stimulants have been associated with elevations in mean BP (300 mg/day), BP; mania; contraindicated in patients with seizure and eating disorders Suicidal ideation; BP, P; liver damage; severe skin reactions; abnormal bleeding; mania; SS, DS Suicidal ideation; weight; somnolence; agranulocytosis; QT prolongation; mania; SS, DS Suicidal ideation; BP; abnormal bleeding; mania; SS, DS

Hydroxyzine (Atarax, Vistaril)

Anxiety

Anxiety

50 mg

Age 6: 50100 mg

dependence; paradoxical reactions; suicidal ideation QT prolongation

* Doses shown in table may exceed maximum recommended dose for some children.

OCD, Obsessive-compulsive disorder; BP, blood pressure; P, pulse; ECG, electrocardiogram; SS, serotonin syndrome; DS, discontinuation syndrome.

The selective serotonin reuptake inhibitor (SSRI) fluoxetine outperforms all other antidepressants (both SSRI and non-SSRI) studied and is the only SSRI separating from placebo in studies of depressed preadolescents . SSRIs have a large margin of safety. Side effects to SSRIs generally manifest in the first few weeks of treatment, and many will resolve with time. More common side effects include nausea, irritability, insomnia, appetite changes, weight loss/gain, headaches, dry mouth, dizziness, bruxism, diaphoresis, tremors, akathisia, restlessness, and behavioral activation. Approximately 5% of youth taking SSRIs, particularly children, develop behavioral activation (increased impulsivity, agitation, and irritability) that can be confused with mania, but the activation symptoms typically resolve when the dose is decreased or the medication discontinued. Sexual side effects are common, including decreased libido, anorgasmia, and erectile dysfunction. There is an increased risk of bleeding, especially when used with aspirin or nonsteroidal antiinflammatory drugs (NSAIDs). SSRIs can be associated with abnormal heart rhythms, and citalopram causes dose-dependent QT-interval prolongation, contraindicating doses >40 mg/day. Patients with diabetes may experience hypoglycemia during SSRI treatment and hyperglycemia on discontinuation. Discontinuation symptoms (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania) are common with short-acting SSRIs (sertraline, citalopram, escitalopram), leading to a recommendation for divided doses if these medications are used at higher doses and graduated reduction if discontinued. The serotonin syndrome is characterized by the triad of mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), and neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia,

incoordination). Serotonin syndrome results from excessive agonism of the CNS and peripheral nervous system serotonergic receptors and can be caused by a range of drugs, including SSRIs, valproate, and lithium. Interactions that can cause serotonin syndrome include SSRIs with linezolid (antibiotic with monoamine oxidase inhibitor properties) and with antimigraine preparations, as well as with amphetamine preparations, trazodone, buspirone, and venlafaxine. Serotonin syndrome is generally self-limited and can resolve spontaneously after the serotonergic agents are discontinued. Patients with severe disease require the control of agitation, autonomic instability, and hyperthermia as well as administration of 5-hydroxytryptamine (5-HT2A , serotonin) antagonists (e.g., cyproheptadine). The non-SSRI antidepressants include bupropion, duloxetine, venlafaxine, and mirtazapine (Table 33.4 ). These medications all lack rigorous evidence to support their effectiveness in children and adolescents, and as such should not be considered first-line options. Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI) , appears to have an indirect mixed-agonist effect on dopamine and norepinephrine transmission. No rigorous studies of bupropion for anxiety or depression have been conducted with children or adolescents, although some evidence suggests that bupropion may be effective for smoking cessation and ADHD in youth. Common side effects include irritability, nausea, anorexia, headache, and insomnia. Dose-related seizures (0.1% risk at 300 mg/day and 0.4% risk at 400 mg/day) have occurred with bupropion, so it is contraindicated in those with epilepsy, eating disorders, or at risk for seizures. Duloxetine and venlafaxine are serotonin-norepinephrine reuptake inhibitors (SNRIs) . Duloxetine has FDA approval for treatment of generalized anxiety disorder in children and adolescents, but studies of duloxetine for depression in youth have been negative. There is some evidence in adults that duloxetine can be useful for fibromyalgia and chronic musculoskeletal pain, an effect that has also been observed in children and adolescents. Common side effects of duloxetine include nausea, diarrhea, decreased weight, and dizziness. Increases in heart rate and BP have been noted, and BP should be monitored at each visit and with each dosage change. In addition, there have been reports of hepatic failure, sometimes fatal; duloxetine should be discontinued and not resumed in patients who develop jaundice or other evidence of liver dysfunction. Duloxetine also has been associated with severe skin reactions (erythema multiforme and Stevens-Johnson syndrome). Venlafaxine has only negative trials for the treatment of depression in children

and adolescents, but does have favorable evidence for the treatment of anxiety. Side effects are similar to SSRIs, including hypertension, irritability, insomnia, headaches, anorexia, nervousness, and dizziness, and dropout rates are high in clinical trials of venlafaxine. BP should be monitored at each visit and with each dosage change. Discontinuation symptoms (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures) are more pronounced with venlafaxine than the other non-SSRI antidepressants. In addition, suicidal thinking and agitation may be more common with venlafaxine than with other antidepressants, requiring close monitoring. In light of the substantial adverse effects, venlafaxine likely should be considered to be a third-line medication. Mirtazapine is both a noradrenergic and a specific serotonergic antidepressant. Mirtazapine has only negative trials for the treatment of depression in youth and has no rigorous evidence of effectiveness for any other child or adolescent psychiatric disorder. Mirtazapine is associated with a risk for substantial weight gain and more rarely, hypotension, elevated liver enzymes, agranulocytosis, and QT prolongation. While its sedating properties have led to its adjunctive use for insomnia in adults with depressive/anxiety disorders, there is no evidence for use of mirtazapine in childhood sleep disorders. The tricyclic antidepressants (TCAs) have mixed mechanisms of action; for example, clomipramine is primarily serotonergic, and imipramine is both noradrenergic and serotonergic. With the advent of the SSRIs, the lack of efficacy studies, particularly in depression, and more serious side effects, the use of TCAs in children has declined. Clomipramine is used in the treatment of obsessive-compulsive disorder (Table 33.4 ). Unlike the SSRIs, the TCAs may be helpful in pain disorders. They have a narrow therapeutic index, with overdoses being potentially fatal. Anticholinergic symptoms (e.g., dry mouth, blurred vision, constipation) are the most common side effects. TCAs can have cardiac conduction effects in doses >3.5 mg/kg. BP and ECG monitoring is indicated at doses above this level. Anxiolytic agents, including lorazepam, clonazepam, and hydroxyzine, have been effectively used for the short-term relief of the symptoms of acute anxiety (Table 33.4 ). They are less effective as chronic (>4 mo) anxiolytic medications, particularly when one is used as monotherapy. Chronic use carries a significant risk of physical and psychological dependence.

Antipsychotics Based on their mechanism of action, antipsychotic medications can be divided into first-generation (blocking dopamine D2 receptors) and second-generation (mixed dopaminergic and serotonergic antagonists) agents (Table 33.5 ). Table 33.5

Select Medications for Psychosis, Mania, Irritability, Agitation, Aggression, and Tourette Disorder in Children and Adolescents GENERIC (BRAND)

FDA APPROVED (Pediatric age range in years)

TARGET SYMPTOMS

SECOND-GENERATION ANTIPSYCHOTICS Aripiprazole Bipolar (10Mania (Abilify) 17) Psychosis Available in Schizophrenia Irritability liquid (13-17) Aggression preparation Irritability in Agitation autism (6-17) Vocal/motor Tourette (6tics 17)

Olanzapine (Zyprexa) Available in liquid, dissolvable, and IM preparations

Quetiapine (Seroquel)

DAILY STARTING DOSE

Bipolar, schizophrenia: 2 mg Autism: 2 mg Tourette: 2 mg

Bipolar (1317) Schizophrenia (13-17)

Mania Psychosis Agitation

2.5 mg

Bipolar (1017) Schizophrenia (13-17)

Mania Psychosis Agitation

25 mg bid

DAILY THERAPEUTIC DOSAGE RANGE* Bipolar, schizophrenia: 10-30 mg Autism: 5-15 mg Tourette: 5-20 mg

SELECT MEDICAL MONITORING AND PRECAUTIONS

BMI, BP, P, fasting glucose and lipids, abnormal movements; compulsive behaviors; neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures 2.5-20 mg BMI, BP, P, fasting glucose and lipids, abnormal movements; skin rash (DRESS); neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures Bipolar: 400BMI, BP, P, 600 mg fasting glucose Schizophrenia: and lipids, 400-800 mg abnormal

Risperidone (Risperdal) Available in liquid and dissolvable preparations

Bipolar (1017) Schizophrenia (13-17) Irritability in autism (5-17)

Paliperidone Schizophrenia (Invega) (12-17) Available in liquid and IM preparations

Lurasidone (Latuda)

Schizophrenia (13-17)

Asenapine (Saphris)

Bipolar (10-17)

Mania Psychosis Irritability Aggression Agitation

Bipolar, schizophrenia: 0.5 mg Autism: 40 mg/day) can lead to prolongation of the QTc interval, with increased risk of ventricular tachycardia and ventricular fibrillation, particularly in patients with structural heart disease. Patients with a baseline QTc interval of >440 msec should be particularly considered at risk. The normal QTc value in children is 400 msec (±25-30 msec). A QTc value that exceeds 2 SD (>450-460 msec) is considered too long and may be associated with increased mortality. An increase in the QTc from baseline of >60 msec is also associated with increased mortality. There is increased risk of morbidity and mortality in patients with preexisting cardiac conduction problems. Some of the calcium channel–blocking agents (e.g., verapamil) can slow atrioventricular conduction and can theoretically interact with TCAs. Patients with Wolff-Parkinson-White syndrome who have a short PR interval (6 mo). Specify if: With predominant pain (previously known as “pain disorder” in DSM IV-TR): for individuals whose somatic symptoms predominantly involve pain. Persistent: A persistent course is characterized by severe symptoms, marked impairment, and long duration (>6 mo). Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, p 311.

Table 35.2

DSM-5 Diagnostic Criteria for Conversion Disorder or Functional Neurologic Symptom Disorder A. One or more symptoms of altered voluntary motor or sensory function. B. Clinical findings provide evidence of incompatibility between the symptom and recognized neurologic or medical conditions. C. The symptom is not better explained by another medical or mental disorder. D. The symptom causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation. Specify symptom type: weakness or paralysis, abnormal movements, swallowing symptoms, speech symptom, attacks/seizures, anesthesia/sensory loss, special sensory symptom (e.g., visual, olfactory, hearing), or mixed symptoms.

Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, p 318.

Table 35.3

DSM-5 Diagnostic Criteria for Factitious Disorders Factitious Disorder Imposed on Self A. Falsification of physical or psychological signs or symptoms, or induction of injury or disease, associated with identified deception. B. The individual presents himself or herself to others as ill, impaired, or injured. C. The deceptive behavior is evident even in the absence of obvious external rewards. D. The behavior is not better explained by another mental disorder, such as delusional disorder or another psychotic disorder. Specify if: single episode or recurrent episodes. Factitious Disorder Imposed on Another (Previously “Factitious Disorder by Proxy”) A. Falsification of physical or psychological signs or symptoms, or induction of injury or disease, in another, associated with identified deception. B. The individual presents another individual (victim) to others as ill, impaired, or injured. C. The deceptive behavior is evident even in the absence of obvious external rewards. D. The behavior is not better explained by another mental disorder, such as delusional disorder or another psychotic disorder. Note : The perpetrator, not the victim, receives this diagnosis. Specify if: single episode or recurrent episodes. Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, p 324.

Table 35.4

DSM-5 Diagnostic Criteria for Illness Anxiety Disorder A. Preoccupation with having or acquiring a serious illness. B. Somatic symptoms are not present, or, if present, are only mild in intensity. If another medical condition is present or there is a high risk for developing a medical condition (e.g., strong family history is present), the preoccupation is clearly excessive or disproportionate. C. There is a high level of anxiety about health, and the individual is easily alarmed about personal health status. D. The individual performs excessive health-related behaviors (e.g., repeatedly checks his or her body for signs of illness) or exhibits maladaptive avoidance (e.g., avoids doctor appointments and hospitals). E. Illness preoccupation has been present for at least 6 mo, but the specific illness that is feared may change over that time. F. The illness-related preoccupation is not better explained by another mental disorder. Specify whether: care-seeking type or care-avoidant type. Adapted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, p 315.

Table 35.5

DSM-5 Diagnostic Criteria for Other Specified/Unspecified Somatic Symptom and Related Disorders Other Specified This category applies to presentations in which symptoms characteristic of a somatic symptom and related disorder that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning predominate but do not meet full criteria for any of the

disorders in the somatic symptom and related disorders diagnostic class. Examples of presentations that can be specified using the “other specified” designation include the following: 1. Brief somatic symptom disorder: duration of symptoms is 1 yr since first tic onset. C. Onset is before age 18 yr. D. The disturbance is not attributable to the physiologic effects of a substance (e.g., cocaine) or another medical condition (e.g., Huntington disease,

postviral encephalitis). E. Criteria have never been met for Tourette disorder. Specify if: With motor tics only With vocal tics only

Provisional Tic Disorder A. Single or multiple motor and/or vocal tics. B. The tics have been present for 6 : 1 among 20-24 yr olds. In 2015 among 10-19 yr olds, the highest suicide rates, 21.8 and 16.6 per 100,000, were among Native American males and females, respectively, followed by white males (10.6/100,000). The groups with the lowest rates were Asian/Pacific Islander females, Hispanic females, and black females (2.4, 2.3, and 1.9/100,000, respectively). Firearms are the most common method used to complete suicide in the United States, accounting for 50% of all suicide deaths in 2015 (Fig. 40.2 ). The next most prevalent methods are suffocation (27%) and poisoning (15%). Firearms are the most lethal method of suicide completion; the death rate with respect to firearms is approximately 80–90%, whereas the death rate is only 1.5–4% for overdoses. Among males, firearms are the most frequently used method of suicide (55%); among females, poisoning is the most common method (34%). From 1999 through 2014, the age-adjusted suicide rate in the United States increased 24%, from 10.5 to 13.0/100,000, with the pace of increase greater after 2006. Rates increased for both males and females and for all ages 10-74; the percent increase among females was greatest for those age 10-14, and for males, those age 45-64.

Risk Factors In addition to age, race/ethnicity, and a history of a previous suicide attempt, multiple risk factors predispose youths to suicide (see Fig. 40.1 ).

Preexisting Mental Disorder Approximately 90% of youths who complete suicide have a preexisting psychiatric illness, most often major depression. Among females, chronic anxiety, especially panic disorder, also is associated with suicide attempts and completion. Among males, conduct disorder and substance use convey increased risk. Comorbidity of a substance use disorder, a depressive disorder, and conduct

disorder are linked to suicide by firearm. Schizophrenia spectrum disorders are linked to suicide attempts and completions.

Cognitive Distortions Negative self-attributions can contribute to the hopelessness typically associated with suicidality; hopelessness may contribute to approximately 55% of the explained variance in continued suicidal ideation. Many youth who are suicidal hold negative views of their own competence, have poor self-esteem, engage in catastrophic thinking, and have difficulty identifying sources of support or reasons to live. Many young people lack the coping strategies necessary to manage strong emotions and instead tend to catastrophize and engage in all-ornothing thinking.

Biologic Factors Postmortem studies show observable differences between the brains of individuals who have completed suicide and those who died from other causes. The brain systems that may be related to suicide completion are the serotonergic system, adrenergic system, and the hypothalamic-pituitary axis. Family history of mental disorders also is linked to completed suicide.

Social, Environmental, and Cultural Factors Of youths who attempt suicide, 65% can name a precipitating event for their action. Most adolescent suicide attempts are precipitated by stressful life events (e.g., academic or social problems; being bullied; trouble with the law; questioning one's sexual orientation or gender identify; newly diagnosed medical condition; recent or anticipated loss). Suicide attempts may also be precipitated by exposure to news of another person's suicide or by reading about or viewing a suicide portrayed in a romantic light in the media. Media coverage of suicide is linked to fluctuating incidence rates of suicides, particularly among adolescents. Glorification or sensationalization of suicide in the media has found to be associated with an increase in suicides. When media coverage includes a detailed description of specific means used, the use of that particular method may increase in the overall population.

For some immigrants, suicidal ideation can be associated with high levels of acculturative stress, especially in the context of family separation and limited access to supportive resources. Physical and sexual abuse can also increase one's risk of suicide, with 15–20% of female suicide attempters having had a history of abuse. The general association between family conflict and suicide attempts is strongest in children and early adolescents. Family psychopathology and a family history of suicidal behavior also convey excess risk. The lack of supportive social relations with peers, parents, and school personnel interacts in increasing the risk of suicide among youth.

Protective Factors Protective factors can provide a counterbalance for those contemplating suicide. These may include a sense of family responsibility, life satisfaction, future orientation, social support, coping and problem-solving skills, religious faith, intact reality testing, and solid therapeutic relationships (e.g., pediatrician, teacher, therapist).

Assessment and Intervention The U.S. Preventive Services Task Force has concluded that there is insufficient evidence to recommend universal suicide screening in the primary care setting for children and adolescents. Pediatric practitioners should consider suicide potential and the need for mental health assessment in the context of concerning information elicited in child/parent psychosocial histories (e.g., HEADSS Psychosocial Risk Assessment; see Chapter 32 , Table 32.2 ), general screening measure scores out of the normal range (e.g., Pediatric Symptom Checklist Internalizing Sub-Scale; see Chapter 28 ), or self-reported statements or behaviors from patients and parents. All suicidal ideation and attempts should be taken seriously and require a thorough assessment by a child-trained mental health clinician to evaluate the youth's current state of mind, underlying psychiatric conditions, and ongoing risk of harm. Emergency mental health assessment is needed for immediate threat to self (i.e., suicidal intent and plan); urgent mental health assessment (48-72 hr) is needed for severe psychiatric symptoms, significant change in overall functioning, and suicidal ideation without intent or plan. Routine mental health assessment is appropriate for mild to moderate psychiatric symptoms without

suicidal ideation. Pediatric practitioners should expect the mental health clinician to evaluate the presence and degree of suicidality and underlying risk factors. The reliability and validity of child interviewing are affected by children's level of cognitive development as well as their understanding of the relationship between their emotions and behavior. Confirmation of the youth's suicidal behavior can be obtained from information gathered by interviewing others who know the child or adolescent. A discrepancy between patient and parent reports is not unusual, with both children and adolescents being more likely to disclose suicidal ideation and suicidal actions than their parents. In the mental health assessment, suicidal ideation can be assessed by explicit questions posed in a nonjudgmental, noncondescending, matter-of-fact approach. The Ask Suicide-Screening Questionnaire (ASQ) is a validated 4-item measure shown in the ED setting to have high sensitivity and negative predictive value in identifying youth at risk for suicide ideation and behavior: (1) “In the past few weeks, have you felt that you or your family would be better off if you were dead?” (2) “In the past few weeks, have you wished you were dead?” (3) “In the past few weeks, have you been having thoughts about killing yourself?” and (4) “Have you ever tried to kill yourself?” If a “yes” response is given to any of these 4 questions, the patient is asked, (5) “Are you having thoughts of killing yourself right now?” Another common screening test is the Columbia Suicide Severity Rating Scale (C-SSRS) Screener (Table 40.1 ).

Table 40.1

Columbia Suicide Severity Rating Scale Screener 1. Have you wished you were dead or wished you could go to sleep and not wake up? 2. Have you actually had any thoughts about killing yourself? If “Yes” to 2, answer questions 3, 4, 5, and 6. If “No” to 2, go directly to question 6. 3. Have you thought about how you might do this? 4. Have you had any intention of acting on these thoughts of killing yourself, as opposed to you having the thoughts but you definitely would not act on them? 5. Have you started to work out or worked out the details of how to kill

yourself? Do you intend to carry out this plan? 6. Have you done anything, started to do anything, or prepared to do anything to end your life? Response Protocol to Screening (based on last item answered “Yes”) Item 1— Mental Health Referral at discharge Item 2— Mental Health Referral at discharge Item 3— Care Team Consultation (Psychiatric Nurse) and Patient Safety Monitor/Procedures Item 4— Psychiatric Consultation and Patient Safety Monitor/Procedures Item 5— Psychiatric Consultation and Patient Safety Monitor/Procedures Item 6— If over 3 months ago, Mental Health Referral at discharge If 3 months ago or less, Psychiatric Consultation and Patient Safety Monitor From Posner K. Columbia Lighthouse Project. The Columbia-Suicide Severity Rating Scale (C-SSRS) Screener–Recent. http://www.cssrs.columbia.edu/scales_practice_cssrs.html . The assessment of a suicidal attempt should include a detailed exploration of the hours immediately preceding the attempt to identify precipitants as well as the circumstances of the attempt itself, to understand fully the patient's intent and potential lethality. The calculation of the level of suicide concern is complex, requiring a determination across a spectrum of risk. At the low end of the risk spectrum are youth with thoughts of death or wanting to die, but without suicidal thoughts, intent, or plan. Those with highly specific suicide plans, preparatory acts or suicide rehearsals, and clearly articulated intent are at the high end. A suicidal history, presently impaired judgment (as seen in altered mental states including depression, mania, anxiety, intoxication, substance abuse, psychosis, trauma-reactive, hopelessness, rage, humiliation, impulsivity), as well as poor social support, further exacerbates the heightened risk. Among adolescents who consider self-harm, those who carry out (enactors ) self-injury are more likely to have family or friends (or think that their peers) engaged in self-harm, and are more impulsive than those who only have thoughts of self-harm (ideators ). For youth who are an imminent danger to themselves (i.e, have active [“I want

to die”] or implied [“I can't see any reason to go on living”] suicidal intent), inpatient level of psychiatric care is necessary to ensure safety, clarify diagnoses, and comprehensively plan treatment. These patients can be hospitalized voluntarily or involuntarily. It is helpful for the pediatric practitioner to have an office protocol to follow in these situations. This protocol should take into consideration state laws regarding involuntary hospitalization, transportation options, nearest emergency assessment site, necessary forms for hospitalization, and available emergency mental health consultants. For those youth suitable for treatment in the outpatient setting (e.g., suicidal ideation without intent, intact mental status, few or no other risk factors for suicidality, willing and able to participate in outpatient treatment; has caregivers able to provide emotional support, supervision, safeguarding, and adherence to follow-up), an appointment should be scheduled within a few days with a mental health clinician. Ideally, this appointment should be scheduled before leaving the assessment venue, because almost 50% of those who attempt suicide fail to follow through with the mental health referral. A procedure should be in place to contact the family if the family fails to complete the referral. Through follow-up office visits, pediatric practitioners can help support and facilitate the implementation of psychotherapies (e.g., cognitive-behavioral therapy, dialectical behavioral therapy, mentalization-based treatment, family therapy) that target the specific psychiatric disorders and the emotional dysphoria or behavioral dysregulation that accompany suicidal ideation or behavior. In conjunction with a child and adolescent child psychiatrist, psychotropic medications may be used as indicated to treat underlying psychiatric disorders. Pediatric practitioners also can encourage social connectedness to peers and to community organizations (e.g., school or church), as well as promote help-seeking (e.g., talking to a trusted adult when distressed) and wellness (e.g., sleep, exercise, relaxation, nutrition) behaviors. In the event of a completed suicide, pediatricians can offer support to the family, particularly by monitoring for adverse bereavement responses in siblings and parents.

Prevention The aforementioned risk factors associated with suicide are relatively common and individually not strong predictors of suicide. The assessment is complicated by patients who may attempt to conceal their suicide thoughts and by those who express suicidal thoughts without serious intent. Suicide screening has been

challenging because most screening instruments have variable sensitivity and specificity. In addition, the burden of follow-up mental health evaluations for those who screen positive has been daunting. Although primary care–feasible screening tools may be help to identify some adults at increased risk for suicide, they have, to date, demonstrated limited ability to detect suicide risk in adolescents. Prevention strategies in the pediatric medical home include training staff to recognize and respond to the warning signs of suicide (Table 40.2 ), screening for and treating depression, educating patients/parents about warning signs for suicide, and restricting access to modes of lethal self-harm. Young people have increased rates of suicide attempts and completions if they live in homes where firearms are present and available. When recommended by their primary care providers, most parents restrict access of their children to guns and medications. Pediatric practitioners should consider counseling parents to remove firearms from the home entirely or securely lock guns and ammunition in separate locations. Anecdotal evidence suggests youths frequently know where guns and keys to gun cabinets are kept, even though parents may think they do not. The same recommendation applies to restricting access to potentially lethal prescription and nonprescription medications (e.g., containers of >25 acetaminophen tablets) and alcohol. These approaches emphasize the importance of restriction of access to means for suicide to prevent self-harm.

Table 40.2

Warning Signs of Suicide Seek help as soon as possible by contacting a mental health professional or by calling the National Suicide Prevention Lifeline at 1-800-273-TALK if you or someone you know exhibits any of the following signs: • Threatening to hurt or kill oneself or talking about wanting to hurt or kill oneself. • Looking for ways to kill oneself by seeking access to firearms, available pills, or other means. • Talking or writing about death, dying, or suicide when these actions are out of the ordinary for the person. • Feeling hopeless. • Feeling rage or uncontrolled anger or seeking revenge.

• Acting reckless or engaging in risky activities, seemingly without thinking. • Feeling trapped, “like there's no way out.” • Increasing alcohol or drug use. • Withdrawing from friends, family, and society. • Feeling anxious, agitated, or unable to sleep, or sleeping all the time. • Experiencing dramatic mood changes. • Seeing no reason for living, or having no sense of purpose in life. Developed by the US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA). https://www.nimh.nih.gov/health/topics/suicide-prevention/suicide-preventionstudies/warning-signs-of-suicide.shtml . Screening for suicide in schools is also fraught with problems related to low specificity of the screening instrument and paucity of referral sites, as well as poor acceptability among school administrators. Gatekeeper (e.g., student support personnel) training appears effective in improving skills among school personnel and is highly acceptable to administrators but has not been shown to prevent suicide. School curricula (e.g., Signs of Suicide ) have shown some preventive potential by teaching students to recognize the signs of depression and suicide in themselves and others and providing them with specific action steps necessary for responding to these signs. Peer helpers have not generally been shown to be efficacious.

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CHAPTER 41

Eating Disorders Richard E. Kreipe, Taylor B. Starr

Eating disorders (EDs) are characterized by body dissatisfaction related to overvaluation of a thin body ideal, associated with dysfunctional patterns of cognition and weight control behaviors that result in significant biologic, psychological, and social complications. Although usually affecting white, adolescent females, EDs also affect males and cross all racial, ethnic, and cultural boundaries. Early intervention in EDs improves outcome.

Definitions Anorexia nervosa (AN) involves significant overestimation of body size and shape, with a relentless pursuit of thinness that, in the restrictive subtype, typically combines excessive dieting and compulsive exercising. In the bingepurge subtype, patients might intermittently overeat and then attempt to rid themselves of calories by vomiting or taking laxatives, still with a strong drive for thinness (Table 41.1 ).

Table 41.1

DSM-5 Diagnostic Criteria for Anorexia Nervosa A. Restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health. Significantly low weight is defined as a weight that is less than minimally normal or, for children and adolescents, less than that minimally expected.

B. Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even though at a significantly low weight. C. Disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight. Specify whether: Restricting type (ICD-10-CM code F50.01): During the last 3 mo, the individual has not engaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas). This subtype describes presentations in which weight loss is accomplished primarily through dieting, fasting, and/or excessive exercise. Binge-eating/purging type (ICD-10-CM code F50.02): During the last 3 mo, the individual has engaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas). Specify if: In partial remission : After full criteria for anorexia nervosa were previously met, Criterion A (low body weight) has not been met for a sustained period, but either Criterion B (intense fear of gaining weight or becoming fat or behavior that interferes with weight gain) or Criterion C (disturbances in selfperception of weight and shape) is still met. In full remission : After full criteria for anorexia nervosa were previously met, none of the criteria has been met for a sustained period of time. Specify current severity: The minimum level of severity is based, for adults, on current body mass index (BMI) (see below) or, for children and adolescents, on BMI percentile. The ranges below are derived from World Health Organization categories for thinness in adults; for children and adolescents, corresponding BMI percentiles should be used. The level of severity may be increased to reflect clinical symptoms, the degree of functional disability, and the need for supervision.

Mild : BMI ≥ 17 kg/m2 Moderate : BMI 16-16.99 kg/m2 Severe : BMI 15-15.99 kg/m2 Extreme : BMI < 15 kg/m2 From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, pp 338–339. Bulimia nervosa (BN) is characterized by episodes of eating large amounts of food in a brief period, followed by compensatory vomiting, laxative use, exercise, or fasting to rid the body of the effects of overeating in an effort to avoid obesity (Table 41.2 ).

Table 41.2

DSM-5 Diagnostic Criteria for Bulimia Nervosa A. Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following: 1. Eating, in a discrete period of time (e.g., within any 2 hr period), an amount of food that is definitely larger than what most individuals would eat in a similar period of time under similar circumstances. 2. A sense of lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating). B. Recurrent inappropriate compensatory behaviors in order to prevent weight gain, such as self-induced vomiting; misuse of laxatives, diuretics, or other medications; fasting; or excessive exercise. C. The binge eating and inappropriate compensatory behaviors both occur, on average, at least once a week for 3 mo. D. Self-evaluation is unduly influenced by body shape and weight. E. The disturbance does not occur exclusively during episodes of anorexia nervosa.

Specify if: In partial remission : After full criteria for bulimia nervosa were previously met, some, but not all, of the criteria have been met for a sustained period of time. In full remission : After full criteria for bulimia nervosa were previously met, none of the criteria has been met for a sustained period of time. Specify current severity: The minimum level of severity is based on the frequency of inappropriate compensatory behaviors (see below). The level of severity may be increased to reflect other symptoms and the degree of functional disability. Mild : An average of 1-3 episodes of inappropriate compensatory behaviors per week. Moderate : An average of 4-7 episodes of inappropriate compensatory behaviors per week. Severe : An average of 8-13 episodes of inappropriate compensatory behaviors per week. Extreme : An average of 14 or more episodes of inappropriate compensatory behaviors per week. From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, p 345. Children and adolescents with EDs may not fulfill criteria for AN or BN in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and may fall into a subcategory of atypical anorexia nervosa, or a more appropriately defined category of avoidant/ restrictive food intake disorder (ARFID). In these conditions, food intake is restricted or avoided because of adverse feeding or eating experiences or the sensory qualities of food, resulting in significant unintended weight loss or nutritional deficiencies and problems with social interactions (Table 41.3 ).

Table 41.3

DSM-5 Diagnostic Criteria for Avoidant/Restrictive Food Intake Disorder

A. An eating or feeding disturbance (e.g., apparent lack of interest in eating or food; avoidance based on the sensory characteristics of food; concern about aversive consequences of eating) as manifested by persistent failure to meet appropriate nutritional and/or energy needs associated with one (or more) of the following: 1. Significant weight loss (or failure to achieve expected weight gain or faltering growth in children). 2. Significant nutritional deficiency. 3. Dependence on enteral feeding or oral nutritional supplements. 4. Marked interference with psychosocial functioning. B. The disturbance is not better explained by lack of available food or by an associated culturally sanctioned practice. C. The eating disturbance does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one's body weight or shape is experienced. D. The eating disturbance is not attributable to a concurrent medical condition or not better explained by another mental disorder. When the eating disturbance occurs in the context of another condition or disorder, the severity of the eating disturbance exceeds that routinely associated with the condition or disorder and warrants additional clinical attention. Specify if: In remission : After full criteria for avoidant/restrictive food intake disorder were previously met, the criteria have not been met for a sustained period of time. From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, p 334. Binge eating disorder (BED) , in which binge eating is not followed regularly by any compensatory behaviors (vomiting, laxatives), is a stand-alone category in DSM-5 but shares many features with obesity (see Chapter 60 ). Eating disorder–not otherwise specified (ED-NOS) , often called “disordered eating,” can worsen into full syndrome EDs.

Epidemiology The classic presentation of AN is an early to middle adolescent female of aboveaverage intelligence and socioeconomic status who is a conflict-avoidant, riskaversive perfectionist and is struggling with disturbances of anxiety and/or mood. BN tends to emerge in later adolescence, sometimes evolving from AN, and is typified by impulsivity and features of borderline personality disorder associated with depression and mood swings. The 0.5–1% and 3–5% incidence rates among younger and older adolescent females for AN and BN, respectively, probably reflect ascertainment bias in sampling and underdiagnosis in cases not fitting the common profile. The same may be true of the significant gender disparity, in which female patients account for approximately 85% of patients with diagnosed EDs. In some adolescent female populations, ≥10% have EDNOS. No single factor causes the development of an ED; sociocultural studies indicate a complex interplay of culture, ethnicity, gender, peers, and family. The gender dimorphism is presumably related to females having a stronger relationship between body image and self-evaluation, as well as the influence of the Western culture's thin body ideal. Race and ethnicity appear to moderate the association between risk factors and disordered eating, with African American and Caribbean females reporting lower body dissatisfaction and less dieting than Hispanic and non-Hispanic white females. Because peer acceptance is central to healthy adolescent growth and development, especially in early adolescence, when AN tends to have its initial prevalence peak, the potential influence of peers on EDs is significant, as are the relationships among peers, body image, and eating. Teasing by peers or by family members (especially males) may be a contributing factor for overweight females. Family influence in the development of EDs is even more complex because of the interplay of environmental and genetic factors; shared elements of the family environment and immutable genetic factors account for approximately equal amounts of the variance in disordered eating. There are associations between parents' and children's eating behaviors; dieting and physical activity levels suggest parental reinforcement of body-related societal messages. The influence of inherited genetic factors on the emergence of EDs during adolescence is also significant, but not directly. Rather, the risk for developing an ED appears to be mediated through a genetic predisposition to anxiety (see Chapter 38 ), depression (see Chapter 39 ), or obsessive-compulsive traits that may be

modulated through the internal milieu of puberty. There is no evidence to support the outdated notion that parents or family dynamics cause an ED. Rather, the family dynamics may represent responses to having a family member with a potentially life-threatening condition. The supportive influence on recovery of parents as nurturing caregivers cannot be overestimated.

Pathology and Pathogenesis The emergence of EDs coinciding with the processes of adolescence (e.g., puberty, identity, autonomy, cognition) indicates the central role of development. A history of sexual trauma is not significantly more common in EDs than in the population at large, but when present makes recovery more difficult and is more common in BN. EDs may be viewed as a final common pathway, with a number of predisposing factors that increase the risk of developing an ED, precipitating factors often related to developmental processes of adolescence triggering the emergence of the ED, and perpetuating factors that cause an ED to persist. EDs often begin with dieting but gradually progress to unhealthy habits that lessen the negative impact of associated psychosocial problems to which the affected person is vulnerable because of premorbid biologic and psychological characteristics, family interactions, and social climate. When persistent, the biologic effects of starvation and malnutrition (e.g., true loss of appetite, hypothermia, gastric atony, amenorrhea, sleep disturbance, fatigue, weakness, depression), combined with the psychological rewards of increased sense of mastery and reduced emotional reactivity, actually maintain and reward pathologic ED behaviors. This positive reinforcement of behaviors and consequences, generally viewed by parents and others as negative, helps to explain why persons with an ED characteristically deny that a problem exists and resist treatment. Although noxious, purging can be reinforcing because of a reduction in anxiety triggered by overeating; purging also can result in short-term, but reinforcing, improvement in mood related to changes in neurotransmitters. In addition to an imbalance in neurotransmitters, most notably serotonin and dopamine, alterations in functional anatomy also support the concept of EDs as brain disorders. The cause-and-effect relationship in central nervous system (CNS) alterations in EDs is not clear, nor is their reversibility.

Clinical Manifestations Except for ARFID, in which weight loss is unintentional, a central feature of EDs is the overestimation of body size, shape, or parts (e.g., abdomen, thighs) leading to intentional weight control practices to reduce weight (AN) or prevent weight gain (BN). Associated practices include severe restriction of caloric intake and behaviors intended to reduce the effect of calories ingested, such as compulsive exercising or purging by inducing vomiting or taking laxatives. Eating and weight loss habits commonly found in EDs can result in a wide range of energy intake and output, the balance of which leads to a wide range in weight, from extreme loss of weight in AN to fluctuation around a normal to moderately high weight in BN. Reported eating and weight control habits thus inform the initial primary care approach (Table 41.4 ). Table 41.4

Eating and Weight Control Habits Commonly Found in Children and Adolescents With an Eating Disorder (ED) HABIT Overall intake

Food

CLINICAL COMMENTS REGARDING ED HABITS Anorexia Nervosa Bulimia Nervosa Anorexia Nervosa Bulimia Nervosa Inadequate energy Variable, but Consistent inadequate caloric Inconsistent balance (calories), although calories normal to intake leading to wasting of of intake, exercise volume of food and high; intake in the body is an essential feature and vomiting, but beverages may be high binges is often of diagnosis severe caloric because of very low “forbidden” food or restriction is shortcaloric density of intake drink that differs lived as a result of “diet” and from intake at nonfat choices meals Counts and limits Aware of Obsessive-compulsive Choices less calories, especially calories and attention to nutritional data on structured, with more from fat; emphasis fat, but less food labels and may have frequent diets on “healthy food regimented in “logical” reasons for food choices” with avoidance than choices in highly regimented reduced caloric AN pattern, such as sports density Frequent participation or family history Monotonous, dieting of lipid disorder limited “good” food interspersed choices, often with leading to overeating, vegetarian or vegan often triggered diet by depression, Strong feelings of isolation, or guilt after eating anger more than planned PROMINENT FEATURE

leads to exercise and renewed dieting Beverages Water or other low- or no-calorie drinks; nonfat milk Meals Consistent schedule and structure to meal plan Reduced or eliminated caloric content, often starting with breakfast, then lunch, then dinner Volume can increase with fresh fruits, vegetables, and salads as primary food sources Snacks Reduced or eliminated from meal plan Dieting

Binge eating

Exercise

Vomiting

Initial habit that becomes progressively restrictive, although often appearing superficially “healthy” Beliefs and “rules” about the patient's idiosyncratic nutritional requirements and response to foods are strongly held None in restrictive subtype, but an essential feature in binge-purge subtype

Characteristically obsessivecompulsive, ritualistic, and progressive May excel in dance, long-distance running Characteristic of binge-purge subtype May chew, then spit out, rather than

Variable, diet soda common; may drink alcohol to excess Meals less regimented and planned than in AN; more likely impulsive and unregulated, often eliminated following a bingepurge episode

Fluids often restricted to avoid Fluids ingested to aid weight gain vomiting or replace losses Rigid adherence to “rules” Elimination of a meal governing eating leads to following a bingesense of control, confidence, purge only reinforces and mastery the drive for binge later in the day

Often avoided in meal plans, but then impulsively eaten Initial dieting gives way to chaotic eating, often interpreted by the patient as evidence of being “weak” or “lazy”

Snack foods removed early because “unhealthy”

Snack “comfort foods” can trigger a binge Distinguishing between Dieting tends to be healthy meal planning with impulsive and shortreduced calories and dieting in lived, with “diets” ED may be difficult often resulting in unintended weight gain

Essential feature, often secretive Shame and guilt prominent afterward Less predictable May be athletic, or may avoid exercise entirely

Often “subjective” (more than Relieves emotional planned but not large) distress, may be planned

Most common habit intended to reduce effects of

Physiologic and emotional instability prominent

May be difficult to distinguish Males often use active thin vs ED exercise as means of “purging”

Strongly “addictive” and self-punishing, but does not eliminate calories

swallow, food as a variant

Laxatives If used, generally to relieve constipation in restrictive subtype, but as a cathartic in bingepurge subtype

Diet pills

overeating Can occur after meal as well as a binge Second most Physiologic and emotional common habit used instability prominent to reduce or avoid weight gain, often used in increasing doses for cathartic effect

Very rare, if used; more Used to either common in binge-purge reduce appetite or subtype increase metabolism

Use of diet pills implies inability to control eating

ingested—many still absorbed

Strongly “addictive,” self-punishing, but ineffective means to reduce weight (calories are absorbed in small intestine, but laxatives work in colon) Control over eating may be sought by any means

AN, Anorexia nervosa; BN, bulimia nervosa.

Although weight control patterns guide the initial pediatric approach, an assessment of common symptoms and findings on physical examination is essential to identify targets for intervention. When reported symptoms of excessive weight loss (feeling tired and cold; lacking energy; orthostasis; difficulty concentrating) are explicitly linked by the clinician to their associated physical signs (hypothermia with acrocyanosis and slow capillary refill; loss of muscle mass; bradycardia with orthostasis), it becomes more difficult for the patient to deny that a problem exists. Furthermore, awareness that bothersome symptoms can be eliminated by healthier eating and activity patterns can increase a patient's motivation to engage in treatment. Tables 41.5 and 41.6 detail common symptoms and signs that should be addressed in a pediatric assessment of a suspected ED. Table 41.5

Symptoms Commonly Reported by Patients With an Eating Disorder (ED) DIAGNOSIS SYMPTOMS Body image

Anorexia Nervosa Feels fat, even with extreme emaciation, often with specific body distortions (e.g., stomach, thighs); strong drive for thinness, with selfefficacy closely tied to appraisal of body shape, size, and/or weight

CLINICAL COMMENTS REGARDING ED Bulimia Nervosa SYMPTOMS Variable body image Challenging patient's body distortion and image is both ineffective and dissatisfaction, but countertherapeutic clinically drive for thinness is Accepting patient's expressed less than desire to body image but noting its avoid gaining weight discrepancy with symptoms and signs reinforces concept

Metabolism

Hypometabolic symptoms include feeling cold, tired, and weak and lacking energy May be both bothersome and reinforcing

Skin

Dry skin, delayed healing, easy bruising, gooseflesh Orange-yellow skin on hands

Hair

Lanugo-type hair growth on face and upper body Slow growth and increased loss of scalp hair

Eyes

No characteristic symptom

Teeth

No characteristic symptom

Salivary glands No characteristic symptom

Heart

Dizziness, fainting in restrictive subtype Palpitations more common in binge-purge subtype

Abdomen

Early fullness and discomfort with eating

that patient can “feel” fat but also “be” too thin and unhealthy Variable, depending Symptoms are evidence of on balance of intake body's “shutting down” in an and output and attempt to conserve calories hydration with an inadequate diet Emphasizing reversibility of symptoms with healthy eating and weight gain can motivate patients to cooperate with treatment No characteristic Skin lacks good blood flow symptom; selfand ability to heal in low injurious behavior weight may be seen Carotenemia with large intake of β-carotene foods; reversible No characteristic Body hair growth conserves symptom energy Scalp hair loss can worsen during refeeding “telogen effluvium” (resting hair is replaced by growing hair) Reversible with continued healthy eating Subconjunctival Caused by increased intrathoracic hemorrhage pressure during vomiting Erosion of Intraoral stomach acid resulting dental enamel from vomiting etches dental erosion enamel, exposing softer dental Decay, fracture, elements and loss of teeth Enlargement (no to Caused by chronic binge eating mild tenderness) and induced vomiting, with parotid enlargement more prominent than submandibular; reversible Dizziness, fainting, Dizziness and fainting due to palpitations postural orthostatic tachycardia and dysregulation at hypothalamic and cardiac level with weight loss, as a result of hypovolemia with binge-purge Palpitations and arrhythmias often caused by electrolyte disturbance Symptoms reverse with weight gain and/or cessation of binge-purge Discomfort after a binge

Weight loss is associated with reduced volume and

Constipation Perceives contour as “fat,” often preferring well-defined abdominal musculature

Extremities and Cold, blue hands and feet musculoskeletal

Nervous system No characteristic symptom Mental status

Depression, anxiety, obsessivecompulsive symptoms, alone or in combination

Cramps and diarrhea with laxative abuse

No characteristic symptoms Self-cutting or burning on wrists or arms No characteristic symptom Depression; PTSD; borderline personality disorder traits

tone of GI tract musculature, especially the stomach Laxatives may be used to relieve constipation or as a cathartic Symptom reduction with healthy eating can take weeks to occur Energy-conserving low body temperature with slow blood flow most notable peripherally Quickly reversed with healthy eating Neurologic symptoms suggest diagnosis other than ED Underlying mood disturbances can worsen with dysfunctional weight control practices and can improve with healthy eating AN patients might report emotional “numbness” with starvation preferable to emotionality associated with healthy eating

AN, Anorexia nervosa; BN, bulimia nervosa; ED, eating disorder; GI, gastrointestinal; PTSD, posttraumatic stress disorder.

Table 41.6

Signs Commonly Found in Patients With Eating Disorder (ED) Relative to Prominent Feature of Weight Control PHYSICAL SIGN General appearance

Weight

PROMINENT FEATURE

CLINICAL COMMENTS Binge RELATED TO ED SIGNS Eating/Purging Thin to cachectic, depending on Thin to overweight, Examine in hospital gown balance of intake and output depending on the Weight loss more rapid with Might wear bulky clothing to balance of intake reduced intake and excessive hide thinness and might resist and output through exercise being examined various means Binge eating can result in large weight gain, regardless of purging behavior Appearance depends on balance of intake and output and overall weight control habits Low and falling (if previously Highly Weigh in hospital gown with overweight, may be normal or high); variable, no underwear, after voiding may be falsely elevated if patient depending on (measure urine SG)

Restrictive Intake

drinks fluids or adds weights to body before being weighed

Metabolism

Hypothermia: temp submandibular relatively nontender involvement with frequent and chronic binge eating and induced vomiting Absent gag reflex Extinction of gag response with repeated pharyngeal stimulation Hypovolemia if Changes in AN resulting from dehydrated central hypothalamic and intrinsic cardiac function Orthostatic changes less prominent if athletic, more prominent if associated with purging Increased bowel Presence of organomegaly sounds if recent requires investigation to laxative use determine cause Constipation prominent with weight loss

Extremities and musculoskeletal system

Cold, acrocyanosis, slow capillary refill Edema of feet Loss of muscle, subcutaneous, and fat tissue

Nervous system No characteristic sign Mental status

Anxiety about body image, irritability, depressed mood, oppositional to change

No characteristic sign, but may have rebound edema after stopping chronic laxative use

Signs of hypometabolism (cold) and cardiovascular dysfunction (slow capillary refill and acrocyanosis) in hands and feet Edema, caused by capillary fragility more than hypoproteinemia in AN, can worsen in early phase of refeeding No characteristic Water loading before weigh-ins sign can cause acute hyponatremia Depression, Mental status often improves with evidence of PTSD, healthier eating and weight; SSRIs more likely suicidal only shown to be effective for BN than AN

AN, Anorexia nervosa; BN, bulimia nervosa; PTSD, posttraumatic stress disorder; SG, specific gravity; SSRIs, selective serotonin reuptake inhibitors.

Differential Diagnosis In addition to identifying symptoms and signs that deserve targeted intervention for patients who have an ED, a comprehensive history and physical examination are required to rule out other conditions in the differential diagnosis. Weight loss can occur in any condition with increased catabolism (e.g., hyperthyroidism, malignancy, occult chronic infection) or malabsorption (e.g., inflammatory bowel disease, celiac disease) or in other disorders (Addison disease, type 1 diabetes mellitus, stimulant abuse), but these illnesses are generally associated with other findings and are not usually associated with decreased caloric intake. Patients with inflammatory bowel disease can reduce intake to minimize abdominal cramping; eating can cause abdominal discomfort and early satiety in AN because of gastric atony associated with significant weight loss, not malabsorption. Likewise, signs of weight loss in AN might include hypothermia, acrocyanosis with slow capillary refill, and neutropenia similar to some features of sepsis, but the overall picture in EDs is one of relative cardiovascular stability compared with sepsis. Endocrinopathies are also in the differential of EDs. With BN, voracious appetite in the face of weight loss might suggest diabetes mellitus, but blood glucose levels are normal or low in EDs. Adrenal insufficiency mimics many physical symptoms and signs found in restrictive AN but is associated with elevated potassium levels and hyperpigmentation. Thyroid disorders may be considered, because of changes in weight, but the overall presentation of AN includes symptoms of both underactive and overactive

thyroid, such as hypothermia, bradycardia, and constipation, as well as weight loss and excessive physical activity, respectively. In the CNS, craniopharyngiomas and Rathke pouch tumors can mimic some of the findings of AN, such as weight loss and growth failure, and even some body image disturbances, but the latter are less fixed than in typical EDs and are associated with other findings, including evidence of increased intracranial pressure. Mitochondrial neurogastrointestinal encephalomyopathy , caused by a mutation in the TYMP gene, presents with gastrointestinal dysmotility, cachexia, ptosis, peripheral neuropathy, ophthalmoplegia, and leukoencephalopathy. Symptoms begin during the 2nd decade of life and are often initially diagnosed as AN. Early satiety, vomiting, cramps, constipation, and pseudoobstruction result in weight loss often before the neurologic features are noticed (see Chapter 616.2 ). Acute or chronic oromotor dysfunction and obsessive-compulsive disorder may mimic an eating disorder. Fear of choking may lead to avoidance-restrictive food intake disorder . Any patient with an atypical presentation of an ED, based on age, sex, or other factors not typical for AN or BN, deserves a scrupulous search for an alternative explanation. In ARFID, disturbance in the neurosensory processes associated with eating, not weight loss, is the central concern and must be recognized for appropriate treatment. Patients can have both an underlying illness and an ED. The core features of dysfunctional eating habits—body image disturbance and change in weight—can coexist with conditions such as diabetes mellitus, where patients might manipulate their insulin dosing to lose weight.

Laboratory Findings Because the diagnosis of an ED is made clinically, there is no confirmatory laboratory test. Laboratory abnormalities, when found, are the result of malnutrition, weight control habits, or medical complications; studies should be chosen based on history and physical examination. A routine screening battery typically includes complete blood count, erythrocyte sedimentation rate (should be normal), and biochemical profile. Common abnormalities in ED include low white blood cell count with normal hemoglobin and differential; hypokalemic, hypochloremic metabolic alkalosis from severe vomiting; mildly elevated liver enzymes, cholesterol, and cortisol levels; low gonadotropins and blood glucose with marked weight loss; and generally normal total protein, albumin, and renal function. An electrocardiogram may be useful when profound bradycardia or

arrhythmia is detected; the ECG usually has low voltage, with nonspecific ST or T-wave changes. Although prolonged QTc has been reported, prospective studies have not found an increased risk for this. Nonetheless, when a prolonged QTc is present in a patient with ED, it may increase the risk for ventricular dysrhythmias.

Complications No organ is spared the harmful effects of dysfunctional weight control habits, but the most concerning targets of medical complications are the heart, brain, gonads, and bones. Some cardiac findings in EDs (e.g., sinus bradycardia, hypotension) are physiologic adaptations to starvation that conserve calories and reduce afterload. Cold, blue hands and feet with slow capillary refill that can result in tissue perfusion insufficient to meet demands also represent energyconserving responses associated with inadequate intake. All these acute changes are reversible with restoration of nutrition and weight. Significant orthostatic pulse changes, ventricular dysrhythmias, or reduced myocardial contractility reflect myocardial impairment that can be lethal. In addition, with extremely low weight, refeeding syndrome (a result of the rapid drop in serum phosphorus, magnesium, and potassium with excessive reintroduction of calories, especially carbohydrates), is associated with acute tachycardia and heart failure and neurologic symptoms. With long-term malnutrition, the myocardium appears to be more prone to tachyarrhythmias, the second most common cause of death in these patients after suicide. In BN, dysrhythmias can also be related to electrolyte imbalance. Clinically, the primary CNS area affected acutely in EDs, especially with weight loss, is the hypothalamus. Hypothalamic dysfunction is reflected in problems with thermoregulation (warming and cooling), satiety, sleep, autonomic cardioregulatory imbalance (orthostasis), and endocrine function (reduced gonadal and excessive adrenal cortex stimulation), all of which are reversible. Anatomic studies of the brain in ED have focused on AN, with the most common finding being increased ventricular and sulcal volumes that normalize with weight restoration. Persistent gray matter deficits following recovery, related to the degree of weight loss, have been reported. Elevated medial temporal lobe cerebral blood flow on positron emission tomography, similar to that found in psychotic patients, suggests that these changes may be related to body image distortion. Also, visualizing high-calorie foods is

associated with exaggerated responses in the visual association cortex that are similar to those seen in patients with specific phobias. Patients with AN might have an imbalance between serotonin and dopamine pathways related to neurocircuits in which dietary restraint reduces anxiety. Reduced gonadal function occurs in male and female patients; it is clinically manifested in AN as amenorrhea in female patients and erectile dysfunction in males. It is related to understimulation from the hypothalamus as well as cortical suppression related to physical and emotional stress. Amenorrhea precedes significant dieting and weight loss in up to 30% of females with AN, and most adolescents with EDs perceive the absence of menses positively. The primary health concern is the negative effect of decreased ovarian function and estrogen on bones . Decreased bone mineral density (BMD) with osteopenia or the more severe osteoporosis is a significant complication of EDs (more pronounced in AN than BN). Data do not support the use of sex hormone replacement therapy because this alone does not improve other causes of low BMD (low body weight, lean body mass, low insulin-like growth factor-1, high cortisol).

Treatment Principles Guiding Primary Care Treatment The approach in primary care should facilitate the acceptance by the ED patient (and parents) of the diagnosis and initial treatment recommendations. A nurturant-authoritative approach using the biopsychosocial model is useful. A pediatrician who explicitly acknowledges that the patient may disagree with the diagnosis and treatment recommendations and may be ambivalent about changing eating habits, while also acknowledging that recovery requires strength, courage, willpower, and determination, demonstrates nurturance . Parents also find it easier to be nurturing once they learn that the development of an ED is neither a willful decision by the patient nor a reflection of poor parenting. Framing the ED as a “coping mechanism” for a complex variety of issues with both positive and negative aspects avoids blame or guilt and can prepare the family for professional help that will focus on strengths and restoring health, rather than on the deficits in the adolescent or the family. The authoritative aspect of a physician's role comes from expertise in health, growth, and physical development. A goal of primary care treatment should be attaining and maintaining health—not merely weight gain—although weight

gain is a means to the goal of wellness. Providers who frame themselves as consultants to the patient with authoritative knowledge about health can avoid a countertherapeutic authoritarian stance. Primary care health-focused activities include monitoring the patient's physical status, setting limits on behaviors that threaten the patient's health, involving specialists with expertise in EDs on the treatment team, and continuing to provide primary care for health maintenance, acute illness, or injury. The biopsychosocial model uses a broad ecologic framework, starting with the biologic impairments of physical health related to dysfunctional weight control practices, evidenced by symptoms and signs. Explicitly linking ED behaviors to symptoms and signs can increase motivation to change. In addition, there are usually unresolved psychosocial conflicts in both the intrapersonal (self-esteem, self-efficacy) and the interpersonal (family, peers, school) domains. Weight control practices initiated as coping mechanisms become reinforced because of positive feedback. That is, external rewards (e.g., compliments about improved physical appearance) and internal rewards (e.g., perceived mastery over what is eaten or what is done to minimize the effects of overeating through exercise or purging) are more powerful to maintain behavior than negative feedback (e.g., conflict with parents, peers, and others about eating) is to change it. Thus, when definitive treatment is initiated, more productive alternative means of coping must be developed.

Nutrition and Physical Activity The primary care provider generally begins the process of prescribing nutrition, although a dietitian should be involved eventually in the meal planning and nutritional education of patients with AN or BN. Framing food as fuel for the body and the source of energy for daily activities emphasizes the health goal of increasing the patient's energy level, endurance, and strength. For patients with AN and low weight, the nutrition prescription should work toward gradually increasing weight at the rate of about 0.5-1 lb/wk, by increasing energy intake by 100-200 kcal increments every few days, toward a target of approximately 90% of average body weight for sex, height, and age. Weight gain will not occur until intake exceeds output, and eventual intake for continued weight gain can exceed 4,000 kcal/day, especially for patients who are anxious and have high levels of thermogenesis from nonexercise activity. Stabilizing intake is the goal for patients with BN, with a gradual introduction of “forbidden” foods while also

limiting foods that might trigger a binge. When initiating treatment of an ED in a primary care setting, the clinician should be aware of common cognitive patterns. Patients with AN typically have all-or-none thinking (related to perfectionism) with a tendency to overgeneralize and jump to catastrophic conclusions, while assuming that their body is governed by rules that do not apply to others. These tendencies lead to the dichotomization of foods into good or bad categories, having a day ruined because of one unexpected event, or choosing foods based on rigid self-imposed restrictions. These thoughts may be related to neurocircuitry and neurotransmitter abnormalities associated with executive function and rewards. Weight loss in the absence of body shape, size, or weight concerns should raise suspicion about ARFID, because the emotional distress associated with “forced” eating is not associated with gaining weight, but with the neurosensory experience of eating. A standard nutritional balance of 15–20% calories from protein, 50–55% from carbohydrate, and 25–30% from fat is appropriate. The fat content may need to be lowered to 15–20% early in the treatment of AN because of continued fat phobia. With the risk of low BMD in patients with AN, calcium and vitamin D supplements are often needed to attain the recommended 1,300 mg/day intake of calcium. Refeeding can be accomplished with frequent small meals and snacks consisting of a variety of foods and beverages (with minimal diet or fat-free products), rather than fewer high-volume high-calorie meals. Some patients find it easier to take in part of the additional nutrition as canned supplements (medicine) rather than food. Regardless of the source of energy intake, the risk for refeeding syndrome (see Complications earlier) increases with the degree of weight loss and the rapidity of caloric increases. Therefore, if the weight has fallen below 80% of expected weight for height, refeeding should proceed carefully (not necessarily slowly) and possibly in the hospital (Table 41.7 ).

Table 41.7

Potential Indications for Inpatient Medical Hospitalization of Patients With Anorexia Nervosa Physical and Laboratory Heart rate 25 beats/min increase Hypokalemia Hypophosphatemia Hypoglycemia Dehydration Body temperature 2 standard deviations below the mean (a standard score of 1 setting

Criteria are met for >1 setting

ADHD, Attention-deficit/hyperactivity disorder; HKD, hyperkinetic disorder; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ; ICD-10, International Classification of Diseases, Tenth Edition . From Biederman J, Faraone S: Attention-deficit hyperactivity disorder, Lancet 366:237–248, 2005.

Table 49.3

Differential Diagnosis of AttentionDeficit/Hyperactivity Disorder (ADHD) Psychosocial Factors Response to physical or sexual abuse Response to inappropriate parenting practices Response to parental psychopathology Response to acculturation Response to inappropriate classroom setting

Diagnoses Associated With ADHD Behaviors Fragile X syndrome Fetal alcohol syndrome Pervasive developmental disorders Obsessive-compulsive disorder Gilles de la Tourette syndrome Attachment disorder with mixed emotions and conduct

Medical and Neurologic Conditions Thyroid disorders (including general resistance to thyroid hormone) Heavy metal poisoning (including lead) Adverse effects of medications Effects of abused substances Sensory deficits (hearing and vision) Auditory and visual processing disorders Neurodegenerative disorder, especially leukodystrophies

Posttraumatic head injury Postencephalitic disorder Note: Coexisting conditions with possible ADHD presentation include oppositional defiant disorder, anxiety disorders, conduct disorder, depressive disorders, learning disorders, and language disorders. Presence of one or more of the symptoms of these disorders can fall within the spectrum of normal behavior, whereas a range of these symptoms may be problematic but fall short of meeting the full criteria for the disorder. From Reiff MI, Stein MT: Attention-deficit/hyperactivity disorder evaluation and diagnosis: a practical approach in office practice, Pediatr Clin North Am 50:1019–1048, 2003. Adapted from Reiff MI: Attention-deficit/hyperactivity disorders. In Bergman AB, editor: 20 Common problems in pediatrics, New York, 2001, McGraw-Hill, p 273.

FIG. 49.2 Possible developmental impacts of attention-deficit/hyperactivity disorder. (From Verkuijl N, Perkins M, Fazel M: Childhood attentiondeficit/hyperactivity disorder, BMJ 350:h2168, 2015, Fig 1, p 145.)

FIG. 49.3 Pathways to premature death in persons with attentiondeficit/hyperactivity disorder (ADHD). (From Faraone SV: Attention deficit hyperactivity disorder and premature death, Lancet 385:2132–2133, 2015.)

Etiology No single factor determines the expression of ADHD; ADHD may be a final common pathway for a variety of complex brain developmental processes. Mothers of children with ADHD are more likely to experience birth complications, such as toxemia, lengthy labor, and complicated delivery. Maternal drug use has also been identified as a risk factor in the development of ADHD. Maternal smoking, alcohol use during pregnancy, and prenatal or postnatal exposure to lead are frequently linked to the attentional difficulties associated with development of ADHD, but less clearly to hyperactivity. Food coloring and preservatives have inconsistently been associated with increased hyperactivity in children with ADHD. There is a strong genetic component to ADHD. Genetic studies have primarily implicated 2 candidate genes, the dopamine transporter gene (DAT1) and a

particular form of the dopamine 4 receptor gene (DRD4), in the development of ADHD. Additional genes that might contribute to ADHD include DOCK2, associated with a pericentric inversion 46N inv(3)(p14:q21) involved in cytokine regulation; a sodium-hydrogen exchange gene; and DRD5, SLC6A3, DBH, SNAP25, SLC6A4, and HTR1B. Structural and functional abnormalities of the brain have been identified in children with ADHD. These include dysregulation of the frontal subcortical circuits, small cortical volumes in this region, widespread small-volume reduction throughout the brain, and abnormalities of the cerebellum, particularly midline/vermian elements (see Pathogenesis ). Brain injury also increases the risk of ADHD. For example, 20% of children with severe traumatic brain injury are reported to have subsequent onset of substantial symptoms of impulsivity and inattention. However, ADHD may also increase the risk of traumatic brain injury. Psychosocial family stressors can also contribute to or exacerbate the symptoms of ADHD, including poverty, exposure to violence, and undernutrition or malnutrition.

Epidemiology Studies of the prevalence of ADHD worldwide have generally reported that 5– 10% of school-age children are affected, although rates vary considerably by country, perhaps in part because of differing sampling and testing techniques. Rates may be higher if symptoms (inattention, impulsivity, hyperactivity) are considered in the absence of functional impairment. The prevalence rate in adolescent samples is 2–6%. Approximately 2% of adults meet criteria for ADHD. ADHD is often underdiagnosed in children and adolescents. Youth with ADHD are often undertreated with respect to what is known about the needed and appropriate doses of medications. Many children with ADHD also present with comorbid neuropsychiatric diagnoses, including oppositional defiant disorder, conduct disorder, learning disabilities, and anxiety disorders. The incidence of ADHD appears increased in children with neurologic disorders such as the epilepsies, neurofibromatosis, and tuberous sclerosis (see Table 49.3 ).

Pathogenesis

Brain MRI studies in children with ADHD indicate a reduction or even loss of the normal hemispheric asymmetry in the brain, as well as smaller brain volumes of specific structures, such as the prefrontal cortex and basal ganglia. Children with ADHD have approximately a 5–10% reduction in the volume of these brain structures. MRI findings suggest low blood flow to the striatum. Functional MRI data suggest deficits in dispersed functional networks for selective and sustained attention in ADHD that include the striatum, prefrontal regions, parietal lobe, and temporal lobe. The prefrontal cortex and basal ganglia are rich in dopamine receptors. This knowledge, plus data about the dopaminergic mechanisms of action of medication treatment for ADHD, has led to the dopamine hypothesis, which postulates that disturbances in the dopamine system may be related to the onset of ADHD. Fluorodopa positron emission tomography (PET) scans also support the dopamine hypothesis through the identification of low levels of dopamine activity in adults with ADHD.

Clinical Manifestations Development of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria leading to the diagnosis of ADHD has occurred mainly in field trials with children 5-12 yr of age (see Table 49.1 and Fig. 49.1 ). The DSM-5 notably expanded the accepted age of onset for symptoms of ADHD, and studies utilizing these broader criteria demonstrate a good correlation with data from DSM-IV criteria–based studies. The current DSM-5 criteria state that the behavior must be developmentally inappropriate (substantially different from that of other children of the same age and developmental level), must begin before age 12 yr, must be present for at least 6 mo, must be present in 2 or more settings and reported as such by independent observers, and must not be secondary to another disorder. DSM-5 identifies three presentations of ADHD. The inattentive presentation is more common in females and is associated with relatively high rates of internalizing symptoms (anxiety and low mood). The other two presentations, hyperactive-impulsive and combined , are more often diagnosed in males (see Fig. 49.1 ). Clinical manifestations of ADHD may change with age (see Fig. 49.2 ). The symptoms may vary from motor restlessness and aggressive and disruptive behavior, which are common in preschool children, to disorganized, distractible, and inattentive symptoms, which are more typical in older adolescents and adults. ADHD is often difficult to diagnose in preschoolers because

distractibility and inattention are often considered developmental norms during this period.

Diagnosis and Differential Diagnosis A diagnosis of ADHD is made primarily in clinical settings after a thorough evaluation, including a careful history and clinical interview to rule in or to identify other causes or contributing factors; completion of behavior rating scales by different observers from at least 2 settings (e.g., teacher and parent); a physical examination; and any necessary or indicated laboratory tests that arise from conditions suspected based on history and/or physical examination. It is important to systematically gather and evaluate information from a variety of sources, including the child, parents, teachers, physicians, and when appropriate, other caretakers, over the course of both diagnosis and subsequent management.

Clinical Interview and History The clinical interview allows a comprehensive understanding of whether the symptoms meet the diagnostic criteria for ADHD. During the interview, the clinician should gather information pertaining to the history of the presenting problems, the child's overall health and development, and the social and family history. The interview should emphasize factors that might affect the development or integrity of the central nervous system or reveal chronic illness, sensory impairments, sleep disorders, or medication use that might affect the child's functioning. Disruptive social factors, such as family discord, situational stress, and abuse or neglect, can result in hyperactive or anxious behaviors. A family history of first-degree relatives with ADHD, mood or anxiety disorders, learning disability, antisocial disorder, or alcohol or substance abuse might indicate an increased risk of ADHD and comorbid conditions.

Behavior Rating Scales Behavior rating scales are useful in establishing the magnitude and pervasiveness of the symptoms, but are not sufficient alone to make a diagnosis of ADHD. A variety of well-established behavior rating scales have obtained good results in discriminating between children with ADHD and controls. These measures include, but are not limited to, the Vanderbilt ADHD Diagnostic

Rating Scale, the Conner Rating Scales (parent and teacher), ADHD Rating Scale 5, the Swanson, Nolan, and Pelham Checklist (SNAP), and the ADD-H: Comprehensive Teacher Rating Scale (ACTeRS). Other broad-band checklists, such as the Achenbach Child Behavior Checklist (CBCL) or Behavioral Assessment Scale for Children (BASC), are useful, particularly when the child may be experiencing coexisting problems in other areas (anxiety, depression, conduct problems). Some, such as the BASC, include a validation scale to help determine the reliability of a given observer's assessment of the child.

Physical Examination and Laboratory Findings No laboratory tests are available to identify ADHD in children. The presence of hypertension, ataxia, or symptoms of a sleep or thyroid disorder should prompt further neurologic or endocrine diagnostic evaluation. Impaired fine motor movement and poor coordination and other subtle neurologic motor signs (difficulties with finger tapping, alternating movements, finger-to-nose, skipping, tracing a maze, cutting paper) are common but not sufficiently specific to contribute to a diagnosis of ADHD. The clinician should also identify any possible vision or hearing problems. The clinician should consider testing for elevated lead levels in children who present with some or all of the diagnostic criteria, if these children are exposed to environmental factors that might put them at risk (substandard housing, old paint, proximity to highway with deposition of lead in topsoil from automobile exhaust years ago). Behavior in the structured laboratory setting might not reflect the child's typical behavior in the home or school environment. Thus, computerized attentional tasks and electroencephalographic assessments are not needed to make the diagnosis, and compared to the clinical gold standard, these are subject to false-positive and false-negative errors. Similarly, observed behavior in a physician's office is not sufficient to confirm or rule-out the diagnosis of ADHD.

Differential Diagnosis Chronic illnesses, such as migraine headaches, absence seizures, asthma/allergies, hematologic disorders, diabetes, and childhood cancer, affect up to 20% of U.S. children and can impair children's attention and school performance, because of either the disease itself or the medications used to treat or control the underlying illness (medications for asthma, corticosteroids,

anticonvulsants, antihistamines) (see Table 49.3 ). In older children and adolescents, substance abuse can result in declining school performance and inattentive behavior (see Chapter 140 ). Sleep disorders , including those secondary to chronic upper airway obstruction from enlarged tonsils and adenoids, often result in behavioral and emotional symptoms that can resemble or exacerbate ADHD (see Chapter 31 ). Periodic leg movements of sleep/restless leg syndrome has been associated with attentional symptoms, and inquiry regarding this should be made during the history. Behavioral and emotional disorders can cause disrupted sleep patterns as well. Depression and anxiety disorders can cause many of the same symptoms as ADHD (inattention, restlessness, inability to focus and concentrate on work, poor organization, forgetfulness) but can also be comorbid conditions (see Chapters 38 and 39 ). Obsessive-compulsive disorder can mimic ADHD, particularly when recurrent and persistent thoughts, impulses, or images are intrusive and interfere with normal daily activities. Adjustment disorders secondary to major life stresses (death of a close family member, parents' divorce, family violence, parents' substance abuse, a move, shared social trauma such as bombings or other attacks) or parent–child relationship disorders involving conflicts over discipline, overt child abuse and/or neglect, or overprotection can result in symptoms similar to those of ADHD. Although ADHD is believed to result from primary impairment of attention, impulse control, and motor activity, there is a high prevalence of comorbidity with other neuropsychiatric disorders (see Table 49.3 ). Of children with ADHD, 15–25% have learning disabilities, 30–35% have developmental language disorders, 15–20% have diagnosed mood disorders, and 20–25% have coexisting anxiety disorders. Children with ADHD can also have concurrent diagnoses of sleep disorders, memory impairment, and decreased motor skills.

Treatment Psychosocial Treatments Once the diagnosis of ADHD has been established, the parents and child should be educated with regard to the ways ADHD can affect learning, behavior, selfesteem, social skills, and family function. The clinician should set goals for the family to improve the child's interpersonal relationships, develop study skills,

and decrease disruptive behaviors. Parent support groups with appropriate professional consultation to such groups can be very helpful.

Behaviorally Oriented Treatments Treatments geared toward behavioral management often occur in the time frame of 8-12 sessions. The goal of such treatment is for the clinician to identify targeted behaviors that cause impairment in the child's life (disruptive behavior, difficulty in completing homework, failure to obey home or school rules) and for the child to work on progressively improving his or her skill in these areas. The clinician should guide the parents and teachers in setting appropriate expectations, consistently implementing rewards to encourage desired behaviors and consequences to discourage undesired behaviors. In short-term comparison trials, stimulants have been more effective than behavioral treatments used alone in improving core ADHD symptoms for most children. Behavioral interventions are modestly successful at improving core ADHD symptoms and are considered the first-line treatment in preschool-age children with ADHD. In addition, behavioral treatment may be particularly useful for children with comorbid anxiety, complex comorbidities, family stressors, and when combined with medication.

Medications The most widely used medications for the treatment of ADHD are the presynaptic dopaminergic agonists, commonly called psychostimulant medications, including methylphenidate, dexmethylphenidate, amphetamine, and various amphetamine and dextroamphetamine preparations. Longer-acting, once-daily forms of each of the major types of stimulant medications are available and facilitate compliance with treatment and coverage over a longer period (see Table 49.3 ). When starting a stimulant, the clinician can select either a methylphenidate-based or an amphetamine-based compound. If a full range of methylphenidate dosages is used, approximately 25% of patients have an optimal response on a low dose (50% of children with oral language disorders reportedly have IWE. The relationship between attention-deficit/hyperactivity disorder (ADHD) and learning disorders in general is well established, including IWE estimates in the 60% range for the combined and inattentive presentations of ADHD. Because of the importance of working memory and other executive functions in the writing process, any child with weakness in these areas will likely find the writing process difficult (see Chapter 48 ).

Skill Deficits Associated With Impaired Writing Written language, much like reading, occurs along a developmental trajectory that can be seamless as children master skills critical to the next step in the process. Mastery of motor control that allows a child to produce letters and letter sequences frees up cognitive energy to devote to spelling words and eventually stringing words into sentences, paragraphs, and complex composition. Early in the development of each individual skill, considerable cognitive effort is required, although ideally the lower-level skills of motor production, spelling,

punctuation, and capitalization (referred to as writing mechanics or writing conventions ) will gradually become automatic and require progressively less mental effort. This effort can then be devoted to higher-level skills, such as planning, organization, application of knowledge, and use of varied vocabulary. For children with writing deficits, breakdowns can occur at one, some, or every stage.

Transcription Among preschool and primary grade children, there is a wide range of what is considered “developmentally typical” as it relates to letter production and spelling. However, evidence indicates that poor writers in later grades are slow to produce letters and write their name in preschool and kindergarten. Weak early spelling and reading skills (letter identification and phonologic awareness; see Chapter 50 ) and weak oral language have also been found to predict weak writing skills in later elementary grades. Children struggling to master early transcription skills tend to write slowly, or when writing at reasonable speed, the legibility of their writing degrades. Output in quantity and variety is limited, and vocabulary use in poor spellers is often restricted to words they can spell. As children progress into upper elementary school and beyond, a new set of challenges arise. They are now expected to have mastered lower-level transcription skills, and the focus turns to the application of these skills to more complex text generation. In addition to transcription, this next step requires the integration of additional cognitive skills that have yet to be tapped by young learners.

Oral Language Language, although not speech, has been found to be related to writing skills. Writing difficulties are associated with deficits in both expression and comprehension of oral language. Writing characteristics of children with specific language impairment (SLI) can differ from their unimpaired peers early in the school experience, and persist through high school (see Chapter 52 ). In preschool and kindergarten, as a group, children with language disorders show poorer letter production and ability to print their name. Poor spelling and weak vocabulary also contribute to the poor writing skills. Beyond primary grades, the written narratives of SLI children tend to be evaluated as “lower quality with

poor organization” and weaker use of varied vocabulary. Pragmatic language and higher-level language deficits also negatively impact writing skills. Pragmatic language refers to the social use of language, including, though not limited to greeting and making requests; adjustments to language used to meet the need of the situation or listener; and following conversation rules verbally and nonverbally. Higher-level language goes beyond basic vocabulary, word form, and grammatical skills and includes making inferences, understanding and appropriately using figurative language, and making cause-and-effect judgments. Weaknesses in these areas, with or without intact foundational language, can present challenges for students in all academic areas that require writing. For example, whether producing an analytic or narrative piece, the writer must understand the extent of the reader's background knowledge and in turn what information to include and omit, make an argument for a cause-and-effect relationship, and use content-specific vocabulary or vocabulary rich in imagery and nonliteral interpretation.

Executive Functions Writing is a complicated process and, when done well, requires the effective integration of multiple processes. Executive functions (EFs) are a set of skills that include planning, problem solving, monitoring and making adjustments as needed (see Chapter 48 ). Three recursive processes have consistently been reported as involved in the writing process: translation of thought into written output, planning, and reviewing. Coming up with ideas, while challenging for many, is simply the first step when writing a narrative (story). Once an idea has emerged, the concept must be developed to include a plot, characters, and story line and then coordinated into a coherent whole that is well organized and flows from beginning to end. Even if one develops ideas and begins to write them down, persistence is required to complete the task, which requires selfregulation. Effective writers rely heavily on EFs, and children with IWE struggle with this set of skills. Poor writers seldom engage in the necessary planning and struggle to self-monitor and revise effectively.

Working Memory Working memory (WM) refers to the ability to hold, manipulate, and store information for short periods. The more space available, the more memory can

be devoted to problem solving and thinking tasks. Nevertheless, there is limited space in which information can be held, and the more effort devoted to one task, the less space is available to devote to other tasks. WM has consistently been shown to play an important role in the writing process, because weak WM limits the space available. Further, when writing skills that are expected to be automatic continue to require effort, precious memory is required, taking away what would otherwise be available for higher-level language. The Simple View of Writing is an approach that integrates each of the 4 ideas just outlined to describe the writing process (Fig. 51.1 ). At the base of the triangle are transcription and executive functions, which support, within WM, the ability to produce text. Breakdowns in any of these areas can lead to poor writing, and identifying where the deficit(s) are occurring is essential when deciding to treat the writing problem. For example, children with weak graphomotor skills (e.g., dysgraphia) must devote considerable effort to the accurate production of written language, thereby increasing WM use devoted to lower-level transcription and limiting memory that can be used for developing discourse. The result might be painfully slow production of a legible story, or a passage that is largely illegible. If, on the other hand, a child's penmanship and spelling have developed well, but their ability to persist with challenging tasks or to organize their thoughts and develop a coordinated plan for their paper is limited, one might see very little information written on the paper despite considerable time devoted to the task. Lastly, even when skills residing at the base of this triangle are in place, students with a language disorder will likely produce text that is more consistent with their language functioning than their chronological grade or age (Fig. 51.1 ).

FIG. 51.1 Simple view of writing. (From Berninger VW: Preventing written expression disabilities through early and continuing assessment and intervention for handwriting and/or spelling problems: research into practice. In Swanson HL, Harris KR, Graham S, editors: Handbook of learning disabilities, New York, 2003, The Guilford Press.)

Treatment Poor writing skills can improve with effective treatment. Weak graphomotor skills may not necessarily require intervention from an occupational therapist (OT), although Handwriting Without Tears is a curriculum frequently used by OTs when working with children with poor penmanship. An empirically supported writing program has been developed by Berninger, but it is not widely used inside or outside school systems (PAL Research-Based Reading and Writing Lessons). For children with dysgraphia, lower-level transcription skills should be emphasized to the point of becoming automatic. The connection between transcription skills and composition should be included in the instructional process; that is, children need to see how their work at letter production is related to broader components of writing. Further, because of WM constraints that frequently impact the instructional process for students with learning disorders, all components of writing should be taught within the same lesson. Explicit instruction of writing strategies combined with implementation and coaching in self-regulation will likely produce the greatest gains for students with writing deficits. Emphasis will vary depending on the deficit specific to the child. A well-researched and well-supported intervention for poor writers is self-

regulated strategy development (SRSD) . The 6 stages in this model include developing and activating a child's background knowledge; introducing and discussing the strategy that is being taught; modeling the strategy for the student; assisting the child in memorization of the strategy; supporting the child's use of the strategy during implementation; and independent use of the strategy. SRSD can be applied across various writing situations and is supported until the student has developed mastery. The model can emphasize or deemphasize the areas most needed by the child.

Educational Resources Children with identified learning disorders can potentially qualify for formal education programming through special education or a section 504 plan. Special education is guided on a federal level by the Individual with Disabilities Education Act (IDEA) and includes development of an individual education plan (see Chapter 48 ). A 504 plan provides accommodations to help children succeed in the regular classroom. Accommodations that might be provided to a child with IWE, through an IEP or a 504 plan, include dictation to a scribe when confronted with lengthy writing tasks, additional time to complete exams that require writing, and use of technology such as keyboarding, speech-to-text software, and writing devices that record teacher instruction. When recommending that parents pursue assistive technology for their child as a potential accommodation, the physician should emphasize the importance of instruction to mastery of the device being used. Learning to use technology effectively requires considerable time and is initially likely to require additional effort, which can result in frustration and avoidance.

Bibliography Andrews JE, Lombardino LJ. Strategies for teaching handwriting to children with writing disabilities. Perspect Lang Learn Educ . 2014;21:114–126. Berninger VW. Preventing written expression disabilities through early and continuing assessment and intervention for handwriting and/or spelling problems: research into practice. Swanson HL, Harris KR, Graham S. Handbook of learning

disabilities . The Guilford Press: New York; 2003:35–363. Berninger VW. Process assessment of the learner (PAL): research-based reading and writing lessons . Psychological Corporation: San Antonio, TX; 2003. Berninger VW. Interdisciplinary frameworks for schools: best professional practices for serving the needs of all students . American Psychological Association: Washington, DC; 2015. Berninger VW, May MO. Evidence-based diagnosis and treatment for specific learning disabilities involving impairments in written and/or oral language. J Learn Disabil . 2011;44(2):167–183. Dockrell JE. Developmental variations in the production of written text: challenges for students who struggle with writing. Stone CA, Silliman ER, Ehren BJ, Wallach GP. Handbook of language and literacy . ed 2. The Guilford Press: New York; 2014:505–523. Dockrell JE, Lindsay G, Connelly V. The impact of specific language impairment on adolescents' written text. Except Child . 2009;75(4):427–446. Graham S, Harris KR. Writing better: effective strategies for teaching students with learning difficulties . Paul H Brookes Publishing: Baltimore; 2005. Katusic SK, Colligan RC, Weaver AL, Barbaresi WJ. The forgotten learning disability: epidemiology of writtenlanguage disorder in a population-based birth cohort (19761982), Rochester, Minnesota. Pediatrics . 2009;123(5):1306– 1313. Paul R, Norbury C. Language disorders from infancy through adolescence: listening, speaking, reading, writing, and communicating . Elsevier: St Louis; 2012. Silliman ER, Berninger VW. Cross-disciplinary dialogue about the nature of oral and written language problems in the context of developmental, academic, and phenotypic profiles.

Top Lang Disord . 2011;31:6–23. Stoeckel RE, Colligan RC, Barbaresi WJ, et al. Early speechlanguage impairment and risk for written language disorder: a population-based study. J Dev Behav Pediatr . 2013;34(1):38–44. Sun L, Wallach GP. Language disorders are learning disabilities: challenges on the divergent and diverse paths to language learning disability. Top Lang Disord . 2014;34:25–38. Williams GJ, Larkin RF, Blaggan S. Written language skills in children with specific language impairment. Int J Lang Commun Disord . 2013;48(2):160–171.

CHAPTER 52

Language Development and Communication Disorders Mark D. Simms

Most children learn to communicate in their native language without specific instruction or intervention other than exposure to a language-rich environment. Normal development of speech and language is predicated on the infant's ability to hear, see, comprehend, remember, and socially interact with others. The infant must also possess sufficient motor skills to imitate oral motor movements.

Normal Language Development Language can be subdivided into several essential components. Communication consists of a wide range of behaviors and skills. At the level of basic verbal ability, phonology refers to the correct use of speech sounds to form words, semantics refers to the correct use of words, and syntax refers to the appropriate use of grammar to make sentences. At a more abstract level, verbal skills include the ability to link thoughts together coherently and to maintain a topic of conversation. Pragmatic abilities include verbal and nonverbal skills that facilitate the exchange of ideas, including the appropriate choice of language for the situation and circumstance and the appropriate use of body language (i.e., posture, eye contact, gestures). Social pragmatic and behavioral skills also play an important role in effective interactions with communication partners (i.e., engaging, responding, and maintaining reciprocal exchanges). It is customary to divide language skills into receptive (hearing and understanding) and expressive (talking) abilities. Language development usually follows a fairly predictable pattern and parallels general intellectual development (Table 52.1 ).

Table 52.1

Normal Language Milestones: Birth to 5 Years HEARING AND UNDERSTANDING BIRTH TO 3 MONTHS Startles to loud sounds Quiets or smiles when spoken to Seems to recognize your voice and quiets if crying Increases or decreases sucking behavior in response to sound 4-6 MONTHS Moves eyes in direction of sounds Responds to changes in tone of your voice Notices toys that make sounds Pays attention to music 7 MONTHS TO 1 YEAR Enjoys games such as peek-a-boo and pat-a-cake Turns and looks in direction of sounds Listens when spoken to Recognizes words for common items, such as cup, shoe, and juice Begins to respond to requests (Come here; Want more?) 1-2 YEARS Points to a few body parts when asked Follows simple commands and understands simple questions (Roll the ball; Kiss the baby; Where's your shoe?) Listens to simple stories, songs, and rhymes Points to pictures in a book when named 2-3 YEARS Understands differences in meaning (e.g., go–stop, in–on, big–little, up–down) Follows 2-step requests (Get the book and put it on the table.)

3-4 YEARS Hears you when you call from another room Hears television or radio at the same loudness level as other family members Understands simple who, what, where, why questions

4-5 YEARS Pays attention to a short story and answers simple questions about it Hears and understands most of what is said at home and in

TALKING Makes pleasure sounds (cooing, gooing) Cries differently for different needs Smiles when sees you

Babbling sounds more speech-like, with many different sounds, including p, b, and m Vocalizes excitement and displeasure Makes gurgling sounds when left alone and when playing with you Babbling has both long and short groups of sounds, such as tata upup bibibibi. Uses speech or noncrying sounds to get and keep attention Imitates different speech sounds Has 1 or 2 words (bye-bye, dada, mama), although they might not be clear Says more words every month Uses some 1-2 word questions (Where kitty? Go bye-bye? What's that?) Puts 2 words together (more cookie, no juice, mommy book) Uses many different consonant sounds at the beginning of words Has a word for almost everything Uses 2-3 word “sentences” to talk about and ask for things Speech is understood by familiar listeners most of the time Often asks for or directs attention to objects by naming them Talks about activities at school or at friends' homes Usually understood by people outside the family Uses a lot of sentences that have ≥4 words Usually talks easily without repeating syllables or words Voice sounds as clear as other children's Uses sentences that include details (I like to read my books)

school

Tells stories that stick to a topic Communicates easily with other children and adults Says most sounds correctly except a few, such as l, s, r, v, z, ch, sh, and th Uses the same grammar as the rest of the family

Adapted from American Speech-Language-Hearing Association, 2005. http://www.asha.org/public/speech/development/chart.htm .

Receptive Language Development The peripheral auditory system is mature by 26 wk gestation, and the fetus responds to and discriminates speech sounds. Anatomic asymmetry in the planum temporale , the structural brain region specialized for language processing, is present by 31 wk gestation. At birth, the full-term newborn appears to have functionally organized neural networks that are sensitive to different properties of language input. The normal newborn demonstrates preferential response to human voices over inanimate sound and recognizes the mother's voice, reacting stronger to it than to a stranger's voice. Even more remarkable is the ability of the newborn to discriminate sentences in their “native” (mother's) language from sentences in a “foreign” language. In research settings, infants of monolingual mothers showed a preference for only that language, whereas infants of bilingual mothers showed a preference for both exposed languages over any other language. Between 4 and 6 mo, infants visually search for the source of sounds, again showing a preference for the human voice over other environmental sounds. By 6 mo, infants can passively follow the adult's line of visual regard, resulting in a “joint reference” to the same objects and events in the environment. The ability to share the same experience is critical to the development of further language, social, and cognitive skills as the infant “maps” specific meanings onto his or her experiences. By 8-9 mo, the infant can actively show, give, and point to objects. Comprehension of words often becomes apparent by 9 mo, when the infant selectively responds to his or her name and appears to comprehend the word “no.” Social games, such as “peek-a-boo,” “so big,” and waving “bye-bye” can be elicited by simply mentioning the words. At 12 mo, many children can follow a simple, 1-step request without a gesture (e.g., “Give it to me”). Between 1 and 2 yr, comprehension of language accelerates rapidly. Toddlers can point to body parts on command, identify pictures in books when named,

and respond to simple questions (e.g., “Where's your shoe?”). The 2 yr old is able to follow a 2-step command, employing unrelated tasks (e.g., “Take off your shoes, then go sit at the table”), and can point to objects described by their use (e.g., “Give me the one we drink from”). By 3 yr, children typically understand simple “wh-” question forms (e.g., who, what, where, why). By 4 yr, most children can follow adult conversation. They can listen to a short story and answer simple questions about it. A 5 yr old typically has a receptive vocabulary of more than 2000 words and can follow 3- and 4-step commands.

Expressive Language Development Cooing noises are established by 4-6 wk of age. Over the 1st 3 mo of life, parents may distinguish their infant's different vocal sounds for pleasure, pain, fussing, tiredness, and so on. Many 3 mo old infants vocalize in a reciprocal fashion with an adult to maintain a social interaction (“vocal tennis”). By 4 mo, infants begin to make bilabial (“raspberry”) sounds, and by 5 mo, monosyllables and laughing are noticeable. Between 6 and 8 mo, polysyllabic babbling (“lalala” or “mamama”) is heard, and the infant might begin to communicate with gestures. Between 8 and 10 mo, babbling makes a phonologic shift toward the particular sound patterns of the child's native language (i.e., they produce more native sounds than nonnative sounds). At 9-10 mo, babbling becomes truncated into specific words (e.g., “mama,” “dada”) for their parents. Over the next several months, infants learn 1 or 2 words for common objects and begin to imitate words presented by an adult. These words might appear to come and go from the child's repertoire until a stable group of 10 or more words is established. The rate of acquisition of new words is approximately 1 new word per week at 12 mo, but it accelerates to approximately 1 new word per day by 2 yr. The first words to appear are used primarily to label objects (nouns) or to ask for objects and people (requests). By 18-20 mo, toddlers should use a minimum of 20 words and produce jargon (strings of word-like sounds) with language-like inflection patterns (rising and falling speech patterns). This jargon usually contains some embedded true words. Spontaneous 2-word phrases (pivotal speech), consisting of the flexible juxtaposition of words with clear intention (e.g., “Want juice!” or “Me down!”), is characteristic of 2 yr olds and reflects the emergence of grammatical ability (syntax). Two-word, combinational phrases do not usually emerge until children have acquired 50-100 words in their lexicon. Thereafter, the acquisition of new words

accelerates rapidly. As knowledge of grammar increases, there is a proportional increase in verbs, adjectives, and other words that serve to define the relation between objects and people (predicates). By 3 yr, sentence length increases, and the child uses pronouns and simple present-tense verb forms. These 3-5 word sentences typically have a subject and verb but lack conjunctions, articles, and complex verb forms. The Sesame Street character Cookie Monster (“Me want cookie!”) typifies the “telegraphic” nature of the 3 yr old's sentences. By 4-5 yr, children should be able to carry on conversations using adult-like grammatical forms and use sentences that provide details (e.g., “I like to read my books”).

Variations of Normal Language milestones have been found to be largely universal across languages and cultures, with some variations depending on the complexity of the grammatical structure of individual languages. In Italian (where verbs often occupy a prominent position at the beginning or end of sentences), 14 mo olds produce a greater proportion of verbs compared with English speaking infants. Within a given language, development usually follows a predictable pattern, paralleling general cognitive development. Although the sequences are predictable, the exact timing of achievement is not. There are marked variations among normal children in the rate of development of babbling, comprehension of words, production of single words, and use of combinational forms within the first 2-3 yr of life. Two basic patterns of language learning have been identified, analytic and holistic. The analytic pattern is the most common and reflects the mastery of increasingly larger units of language form. The child's analytic skills proceed from simple to more complex and lengthy forms. Children who follow a holistic or gestalt learning pattern might start by using relatively large chunks of speech in familiar contexts. They might memorize familiar phrases or dialog from movies or stories and repeat them in an overgeneralized fashion. Their sentences often have a formulaic pattern, reflecting inadequate mastery of the use of grammar to flexibly and spontaneously combine words appropriately in the child's own unique utterance. Over time, these children gradually break down the meanings of phrases and sentences into their component parts, and they learn to analyze the linguistic units of these memorized forms. As this occurs, more original speech productions emerge, and the child is able to assemble thoughts in a more flexible manner. Both analytic and holistic learning processes are

necessary for normal language development to occur.

Language and Communication Disorders Epidemiology Disorders of speech and language are very common in preschool-age children. Almost 20% of 2 yr olds are thought to have delayed onset of language. By age 5 yr, approximately 6% of children are identified as having a speech impairment, 5% as having both speech and language impairment, and 8% as having language impairment. Boys are nearly twice as likely to have an identified speech or language impairment as girls.

Etiology Normal language ability is a complex function that is widely distributed across the brain through interconnected neural networks that are synchronized for specific activities. Although clinical similarities exist between acquired aphasia in adults and childhood language disorders, unilateral focal lesions acquired in early life do not seem to have the same effects in children as in adults. Risk factors for neurologic injury are absent in the vast majority of children with language impairment. Genetic factors appear to play a major role in influencing how children learn to talk. Language disorders cluster in families. A careful family history may identify current or past speech or language problems in up to 30% of first-degree relatives of proband children. Although children exposed to parents with language difficulty might be expected to experience poor language stimulation and inappropriate language modeling, studies of twins have shown the concordance rate for low language test score and/or a history of speech therapy to be approximately 50% in dizygotic pairs, rising to over 90% in monozygotic pairs. Despite strong evidence that language disorders have a genetic basis, consistent genetic mutations have not been identified. Instead, multiple genetic regions and epigenetic changes may result in heterogeneous genetic pathways causing language disorders. Some of these genetic pathways disrupt the timing of early prenatal neurodevelopmental events affecting migration of nerve cells from the germinal matrix to the cerebral cortex. Several single nucleotide polymorphisms (SNPs) involving noncoding regulatory genes, including

CNTNAP2 (contactin-associated-protein-like-2) and KIAA0319 , are strongly associated with early language acquisition and are also believed to affect early neuronal structural development. In addition, other environmental, hormonal, and nutritional factors may exert epigenetic influences by dysregulating gene expression and resulting in aberrant sequencing of the onset, growth, and timing of language development .

Pathogenesis Language disorders are associated with a fundamental deficit in the brain's capacity to process complex information rapidly. Simultaneous evaluation of words (semantics), sentences (syntax), prosody (tone of voice), and social cues can overtax the child's ability to comprehend and respond appropriately in a verbal setting. Limitations in the amount of information that can be stored in verbal working memory can further limit the rate at which language information is processed. Electrophysiologic studies show abnormal latency in the early phase of auditory processing in children with language disorders. Neuroimaging studies identify an array of anatomic abnormalities in regions of the brain that are central to language processing. MRI scans in children with specific language impairment (SLI) may reveal white matter lesions and volume loss, ventricular enlargement, focal gray matter heterotopia within the right and left parietotemporal white matter, abnormal morphology of the inferior frontal gyrus, atypical patterns of asymmetry of language cortex, or increased thickness of the corpus callosum in a minority of affected children. Postmortem studies of children with language disorders found evidence of atypical symmetry in the plana temporale and cortical dysplasia in the region of the sylvian fissure. In support of a genetic mechanism affecting cerebral development, a high rate of atypical perisylvian asymmetries has also been documented in the parents of children with SLI.

Clinical Manifestations Primary disorders of speech and language development are often found in the absence of more generalized cognitive or motor dysfunction. However, disorders of communication are also the most common comorbidities in persons with generalized cognitive disorders (intellectual disability or autism), structural anomalies of the organs of speech (e.g., velopharyngeal insufficiency from cleft

palate), and neuromotor conditions affecting oral motor coordination (e.g., dysarthria from cerebral palsy or other neuromuscular disorders).

Classification Each professional discipline has adopted a somewhat different classification system, based on cluster patterns of symptoms. The American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) organized communication disorders into: (1) language disorder (which combines expressive and mixed receptive-expressive language disorders), speech sound disorder (phonologic disorder), and childhood-onset fluency disorder (stuttering); and (2) social (pragmatic) communication disorder, which is characterized by persistent difficulties in the social uses of verbal and nonverbal communication (Table 52.2 ). In clinical practice, childhood speech and language disorders occur as a number of distinct entities.

Table 52.2

DSM-5 Diagnostic Criteria for Communication Disorders Language Disorder A Persistent difficulties in the acquisition and use of language across modalities (i.e., spoken, written, sign language, or other) due to deficits in comprehension or production that include the following: 1. Reduced vocabulary (word knowledge and use). 2. Limited sentence structure (ability to put words and word endings together to form sentences based on the rules of grammar and morphology). 3. Impairments in discourse (ability to use vocabulary and connect sentences to explain or describe a topic or series of events or have a conversation). B. Language abilities are substantially and quantifiably below those expected for age, resulting in functional limitations in effective communication, social participation, academic achievement, or occupational performance, individually or in any combination. C. Onset of symptoms is in the early developmental period. D. The difficulties are not attributable to hearing or other sensory impairment,

motor dysfunction, or another medical or neurologic condition and are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Speech Sound Disorder A. Persistent difficulty with speech sound production that interferes with speech intelligibility or prevents verbal communication of messages. B. The disturbance causes limitations in effective communication that interfere with social participation, academic achievement, or occupational performance, individually or in any combination. C. Onset of symptoms is in the early developmental period. D. The difficulties are not attributable to congenital or acquired conditions, such as cerebral palsy, cleft palate, deafness or hearing loss, traumatic brain injury, or other medical or neurologic conditions. Social (Pragmatic) Communication Disorder A. Persistent difficulties in the social use of verbal and nonverbal communication as manifested by all of the following: 1. Deficits in using communication for social purposes, such as greeting and sharing information, in a manner that is appropriate for the social context. 2. Impairment of the ability to change communication to match context or the needs of the listener, such as speaking differently in a classroom than on a playground, talking differently to a child than to an adult, and avoiding use of overly formal language. 3. Difficulties following rules for conversation and storytelling, such as taking turns in conversation, rephrasing when misunderstood, and knowing how to use verbal and nonverbal signals to regulate interaction. 4. Difficulties understanding what is not explicitly stated (e.g., making inferences) and nonliteral or ambiguous meanings of language (e.g., idioms, humor, metaphors, multiple meanings that depend on the context for interpretation). B. The deficits result in functional limitations in effective communication,

social participation, social relationships, academic achievement, or occupational performance, individually or in combination. C. The onset of the symptoms is in the early developmental period (but deficits may not become fully manifest until social communication demands exceed limited capacities). D. The symptoms are not attributable to another medical or neurologic condition or to low abilities in the domains of word structure and grammar, and are not better explained by autism spectrum disorder, intellectual disability (intellectual developmental disorder), global developmental delay, or another mental disorder. From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association, pp 42, 44, 47–48.

Language Disorder or Specific Language Impairment The condition DSM-5 refers to as language disorder is also referred to as specific language impairment (SLI) , developmental dysphasia , or developmental language disorder . SLI is characterized by a significant discrepancy between the child's overall cognitive level (typically nonverbal measures of intelligence) and functional language level. These children also follow an atypical pattern of language acquisition and use. Closer examination of the child's skills might reveal deficits in understanding and use of word meaning (semantics) and grammar (syntax). Often, children are delayed in starting to talk. Most significantly, they usually have difficulty understanding spoken language. The problem may stem from insufficient understanding of single words or from the inability to deconstruct and analyze the meaning of sentences. Many affected children show a holistic pattern of language development, repeating memorized phrases or dialog from movies or stories (echolalia). In contrast to their difficulty with spoken language, children with SLI appear to learn visually and demonstrate their ability on nonverbal tests of intelligence. After children with SLI become fluent talkers, they are generally less proficient at producing oral narratives than their peers. Their stories tend to be shorter and include fewer propositions, main story ideas, or story grammar elements. Older children include fewer mental state descriptions (e.g., references to what their characters think and how they feel). Their narratives contain fewer cohesive devices, and the story line may be difficult to follow.

Many children with SLI show difficulties with social interaction, particularly with same-age peers. Social interaction is mediated by oral communication, and a child deficient in communication is at a distinct disadvantage in the social arena. Children with SLI tend to be more dependent on older children or adults, who can adapt their communication to match the child's level of function. Generally, social interaction skills are more closely correlated with language level than with nonverbal cognitive level. Using this as a guide, one usually sees a developmental progression of increasingly more sophisticated social interaction as the child's language abilities improve. In this context, social ineptitude is not necessarily a sign of asocial distancing (e.g., autism) but rather a delay in the ability to negotiate social interactions.

Higher-Level Language Disorder As children mature, the ability to communicate effectively with others depends on mastery of a range of skills that go beyond basic understanding of words and rules of grammar. Higher-level language skills include the development of advanced vocabulary, the understanding of word relationships, reasoning skills (including drawing correct inferences and conclusions), the ability to understand things from another person's perspective, and the ability to paraphrase and rephrase with ease. In addition, higher-order language abilities include pragmatic skills that serve as the foundation for social interactions. These skills include knowledge and understanding of one's conversational partner, knowledge of the social context in which the conversation is taking place, and general knowledge of the world. Social and linguistic aspects of communication are often difficult to separate, and persons who have trouble interpreting these relatively abstract aspects of communication typically experience difficulty forming and maintaining relationships. DSM-5 identified social (pragmatic) communication disorder (SPCD) as a category of communication disorder (Table 52.2 ). Symptoms of pragmatic difficulty include extreme literalness and inappropriate verbal and social interactions. Proper use and understanding of humor, slang, and sarcasm depend on correct interpretation of the meaning and the context of language and the ability to draw proper inferences. Failure to provide a sufficient referential base to one's conversational partner—to take the perspective of another person— results in the appearance of talking or behaving randomly or incoherently. SPCD often occurs in the context of another language disorder and has been recognized as a symptom of a wide range of disorders, including right-hemisphere damage

to the brain, Williams syndrome, and nonverbal learning disabilities. SPCD can also occur independently of other disorders. Children with autism spectrum disorder (ASD) often have symptoms of SPCD, but SPCD is not diagnosed in these children because the symptoms are a component of ASD. In school settings, children with SPCD may be socially ostracized and bullied.

Intellectual Disability Most children with a mild degree of intellectual disability learn to talk at a slower-than-normal rate; they follow a normal sequence of language acquisition and eventually master basic communication skills. Difficulties may be encountered with higher-level language concepts and use. Persons with moderate to severe degrees of intellectual disability can have great difficulty in acquiring basic communication skills. About half of persons with an intelligence quotient (IQ) of 4 wk, and if the dysfluencies are impacting the child's social, behavioral, and emotional functioning, referral is warranted. Although there is no cure for stuttering, behavioral therapies are available that are developed and implemented by SLPs. Treatment emphasizes managing stuttering while speaking by regulating rate of speech and breathing and helping the child gradually progress from the fluent production of syllables to more complex sentences. Approaches to treatment may include parents directly in the process, although even if not active participants, parents play an important role in the child coping with stuttering. Treatment in preschool-age children has been shown to improve stuttering. Management of stuttering is also emphasized in older children. For school-age children, treatment includes improving not only fluency but also concomitants of the condition. This includes recognizing and accepting stuttering and appreciating others' reaction to the child when stuttering, managing secondary behaviors, and addressing avoidance behaviors. The broad focus allows for minimizing the adverse effects of the condition. To date, no evidence supports the use of a pharmacologic agent to treat stuttering in children and adolescents. Preschool children with normal developmental dysfluency can be observed with parental education and reassurance. Parents should not reprimand the child or create undue anxiety. Preschool or older children with stuttering should be referred to a speech pathologist. Therapy is most effective if started during the preschool period. In addition to the risks noted in Table 52.5 , indications for referral include 3 or more dysfluencies per 100 syllables (b-b-but; th-th-the; you, you, you), avoidances or escapes (pauses, head nod, blinking), discomfort or anxiety while speaking, and suspicion of an associated neurologic or psychotic disorder. Most preschool children respond to interventions taught by speech pathologists and to behavioral feedback by parents. Parents should not yell at the child, but should calmly praise periods of fluency (“That was smooth”) or nonjudgmentally note episodes of stuttering (“That was a bit bumpy”). The child can be involved with self-correction and respond to requests (“Can you say that again?”) made by a calm parent. Such treatment greatly improves dysfluency, but it may never be eliminated.

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CHAPTER 53

Developmental Delay and Intellectual Disability Bruce K. Shapiro, Meghan E. O'Neill

Intellectual disability (ID) refers to a group of disorders that have in common deficits of adaptive and intellectual function and an age of onset before maturity is reached.

Definition Contemporary conceptualizations of ID emphasize functioning and social interaction rather than test scores. The definitions of ID by the World Health Organization (WHO) International Classification of Diseases, Tenth Edition (ICD-10), the U.S. Individuals with Disabilities Education Act (IDEA), the American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the American Association on Intellectual and Developmental Disabilities (AAIDD) all include significant impairment in general intellectual function (reasoning, learning, problem solving), social skills, and adaptive behavior. This focus on conceptual, social, and practical skills enables the development of individual treatment plans designed to enhance functioning. Consistent across these definitions is onset of symptoms before age 18 yr or adulthood. Significant impairment in general intellectual function refers to performance on an individually administered test of intelligence that is approximately 2 standard deviations (SD) below the mean. Generally these tests provide a standard score that has a mean of 100 and SD of 15, so that intelligence quotient (IQ) scores 50 rare genetic disorders in most states), newborn hearing screening, and preschool lead poisoning prevention programs are examples. Additionally, screening for comorbid conditions can help to limit the extent of disability and maximize level of functioning in certain populations. Annual thyroid, vision, and hearing screening in a child with Down syndrome is an example of presymptomatic testing in a disorder associated with ID.

Treatment Although the core symptoms of ID itself are generally not treatable, many associated impairments are amenable to intervention and therefore benefit from early identification. Most children with an ID do not have a behavioral or emotional disorder as an associated impairment, but challenging behaviors (aggression, self-injury, oppositional defiant behavior) and mental illness (mood

and anxiety disorders) occur with greater frequency in this population than among children with typical intelligence. These behavioral and emotional disorders are the primary cause for out-of-home placements, increased family stress, reduced employment prospects, and decreased opportunities for social integration. Some behavioral and emotional disorders are difficult to diagnose in children with more severe ID because of the child's limited abilities to understand, communicate, interpret, or generalize. Other disorders are masked by the ID. The detection of ADHD (see Chapter 49 ) in the presence of moderate to severe ID may be difficult, as may be discerning a thought disorder (psychosis) in someone with autism and ID. Although mental illness is generally of biologic origin and responds to medication, behavioral disorders can result from a mismatch between the child's abilities and the demands of the situation, organic problems, and family difficulties. These behaviors may represent attempts by the child to communicate, gain attention, or avoid frustration. In assessing the challenging behavior, one must also consider whether it is inappropriate for the child's mental age, rather than the chronological age. When intervention is needed, an environmental change, such as a more appropriate classroom setting, may improve certain behavior problems. Behavior management techniques are useful; psychopharmacologic agents may be appropriate in certain situations. No medication has been found that improves the core symptoms of ID. However, several agents are being tested in specific disorders with known biologic mechanisms (e.g., mGluR5 inhibitors in fragile X syndrome, mTOR inhibitors in tuberous sclerosis), with the hope for future pharmacologic options that could alter the natural course of cognitive impairment seen in patients with these disorders. Currently, medication is most useful in the treatment of associated behavioral and psychiatric disorders. Psychopharmacology is generally directed at specific symptom complexes, including ADHD (stimulant medication), self-injurious behavior and aggression (antipsychotics), and anxiety, obsessive-compulsive disorder, and depression (selective serotonin reuptake inhibitors). Even if a medication proves successful, its use should be reevaluated at least yearly to assess the need for continued treatment.

Supportive Care and Management Each child with ID needs a medical home with a pediatrician who is readily accessible to the family to answer questions, help coordinate care, and discuss

concerns. Pediatricians can have effects on patients and their families that are still felt decades later. The role of the pediatrician includes involvement in prevention efforts, early diagnosis, identification of associated deficits, referral for appropriate diagnostic and therapeutic services, interdisciplinary management, provision of primary care, and advocacy for the child and family. The management strategies for children with an ID should be multimodal, with efforts directed at all aspects of the child's life: health, education, social and recreational activities, behavior problems, and associated impairments. Support for parents and siblings should also be provided.

Primary Care For children with an ID, primary care has the following important components:

◆ Provision of the same primary care received by all other children of similar chronological age. ◆ Anticipatory guidance relevant to the child's level of function: feeding, toileting, school, accident prevention, sexuality education. ◆ Assessment of issues that are relevant to that child's disorder, such as dental examination in children who exhibit bruxism, thyroid function in children with Down syndrome, and cardiac function in Williams syndrome (see Chapter 454.5 ). The AAP has published a series of guidelines for children with specific genetic disorders associated with ID (Down syndrome, fragile X syndrome, and Williams syndrome). Goals should be considered and programs adjusted as needed during the primary care visit. Decisions should also be made about what additional information is required for future planning or to explain why the child is not meeting expectations. Other evaluations, such as formal psychologic or educational testing, may need to be scheduled.

Interdisciplinary Management The pediatrician has the responsibility for consulting with other disciplines to make the diagnosis of ID and coordinate treatment services. Consultant services may include psychology, speech-language pathology, physical therapy, occupational therapy, audiology, nutrition, nursing, and social work, as well as medical specialties such as neurodevelopmental disabilities, neurology, genetics, physical medicine and rehabilitation, psychiatry, developmental-behavioral pediatricians, and surgical specialties. Contact with early intervention and school personnel is equally important to help prepare and assess the adequacy of the child's individual family service plan or individual educational plan. The family should be an integral part of the planning and direction of this process. Care should be family centered and culturally sensitive; for older children, their participation in planning and decision-making should be promoted to whatever extent possible.

Periodic Reevaluation The child's abilities and the family's needs change over time. As the child grows, more information must be provided to the child and family, goals must be reassessed, and programming needs should be adjusted. A periodic review should include information about the child's health status as well as the child's functioning at home, at school, and in other community settings. Other information, such as formal psychologic or educational testing, may be helpful. Reevaluation should be undertaken at routine intervals (every 6-12 mo during early childhood), at any time the child is not meeting expectations, or when the child is moving from one service delivery system to another. This is especially true during the transition to adulthood, beginning at age 16, as mandated by the IDEA Amendments of 2004, and lasting through age 21, when care should be transitioned to adult-based systems and providers.

Federal and Education Services Education is the single most important discipline involved in the treatment of children with an ID. The educational program must be relevant to the child's needs and address the child's individual strengths and weaknesses. The child's developmental level, requirements for support, and goals for independence provide a basis for establishing an individualized education program (IEP) for

school-age children, as mandated by federal legislation. Beyond education services, families of children with ID are often in great need of federal or state-provided social services. All states offer developmental disabilities programs that provide home and community-based services to eligible children and adults, potentially including in-home supports, care coordination services, residential living arrangements, and additional therapeutic options. A variety of Medicaid waiver programs are also offered for children with disabilities within each state. Children with ID who live in low socioeconomic status households should qualify to receive supplemental security income (SSI). Of note, in 2012, an estimated >40% of children with ID did not receive SSI benefits for which they would have been eligible, indicating an untapped potential resource for many families.

Leisure and Recreational Activities The child's social and recreational needs should be addressed. Although young children with ID are generally included in play activities with children who have typical development, adolescents with ID often do not have opportunities for appropriate social interactions. Community participation among adults with ID is much lower than that of the typical population, stressing the importance of promoting involvement in social activities such as dances, trips, dating, extracurricular sports, and other social-recreational events at an early age. Participation in sports should be encouraged (even if the child is not competitive) because it offers many benefits, including weight management, development of physical coordination, maintenance of cardiovascular fitness, and improvement of self-image.

Family Counseling Many families adapt well to having a child with ID, but some have emotional or social difficulties. The risks of parental depression and child abuse and neglect are higher in this group of children than in the general population. The factors associated with good family coping and parenting skills include stability of the marriage, good parental self-esteem, limited number of siblings, higher socioeconomic status, lower degree of disability or associated impairments (especially behavioral), parents' appropriate expectations and acceptance of the diagnosis, supportive extended family members, and availability of community

programs and respite care services. In families in whom the emotional burden of having a child with ID is great, family counseling, parent support groups, respite care, and home health services should be an integral part of the treatment plan.

Transition to Adulthood Transition to adulthood in adolescents with intellectual disabilities can present a stressful and chaotic time for both the individual and the family, just as it does among young adults of typical intelligence. A successful transition strongly correlates to later improved quality of life but requires significant advanced planning. In moving from child to adult care, families tend to find that policies, systems, and services are more fragmented, less readily available, and more difficult to navigate. Several domains of transition must be addressed, such as education and employment, health and living, finances and independence, and social and community life. Specific issues to manage include transitioning to an adult healthcare provider, determining the need for decision-making assistance (e.g., guardianship, medical power of attorney), securing government benefits after aging out of youth-based programs (e.g., SSI, medical assistance), agreeing on the optimal housing situation, applying for state disability assistance programs, and addressing caretaker estate planning as it applies to the individual with ID (e.g., special needs trusts). Following graduation from high school, options for continued education or entry into the workforce should be thoroughly considered, with the greater goal of ultimate community-based employment. Although employment is a critical element of life adaptation for persons with ID, only 15% are estimated to have jobs, with significant gaps in pay and compensation compared to workers without disability. Early planning and expansion of opportunities can help to reduce barriers to employment. Post–secondary education possibilities might involve community college or vocational training. Employment selection should be “customized” to the individual's interests and abilities. Options may include participation in competitive employment, supported employment, high school– to–work transition programs, job-coaching programs, and consumer-directed voucher programs.

Prognosis In children with severe ID, the prognosis is often evident by early childhood.

Mild ID might not always be a lifelong disorder. Children might meet criteria for GDD at an early age, but later the disability can evolve into a more specific developmental disorder (communication disorder, autism, specific learning disability, or borderline normal intelligence). Others with a diagnosis of mild ID during their school years may develop sufficient adaptive behavior skills that they no longer fit the diagnosis as adolescents or young adults, or the effects of maturation and plasticity may result in children moving from one diagnostic category to another (from moderate to mild ID). Conversely, some children who have a diagnosis of a specific learning disability or communication disorder might not maintain their rate of cognitive growth and may fall into the range of ID over time. The apparent higher prevalence of ID in low- and middle-income countries is of concern given the limitations in available resources. Community-based rehabilitation (CBR) is an effort promoted by WHO over the past 4 decades as a means of making use of existing community resources for persons with disabilities in low-income countries with the goal of increasing inclusion and participation within the community. CBR is now being implemented in >90 countries, although the efficacy of such programs has not been established. The long-term outcome of persons with ID depends on the underlying cause, degree of cognitive and adaptive deficits, presence of associated medical and developmental impairments, capabilities of the families, and school and community supports, services, and training provided to the child and family (Table 53.7 ). As adults, many persons with mild ID are capable of gaining economic and social independence with functional literacy, but they may need periodic supervision (especially when under social or economic stress). Most live successfully in the community, either independently or in supervised settings. Table 53.7 Severity of Intellectual Disability and Adult-Age Functioning MENTAL LEVEL AGE AS ADULT ADAPTATION ADULT Mild 9-11 yr Reads at 4th-5th grade level; simple multiplication and division; writes simple letter, lists; completes job application; basic independent job skills (arrive on time, stay at task, interact with coworkers); uses public transportation, might qualify for driver's license; keeps house, cooks using recipes Moderate 6-8 yr Sight-word reading; copies information (e.g., address from card to job application);

Severe

3-5 yr

Profound 2.5 SD above the mean MeCP2 deletion/duplication testing in males with significant developmental regression, drooling, respiratory infections, and hypotonia Karyotype if unable to obtain CMA or if balanced translocation suspected Additional Targeted Diagnostic Testing EEG in children with seizures, staring spells, or developmental regression Brain MRI in children with microcephaly, focal neurologic findings, or developmental regression Metabolic testing in children with developmental regression, hypotonia, seizures, food intolerance, hearing loss, ataxia, or course facial features Data from Schaefer GB, Mendelsohn NJ: Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions, Genet Med 15(5):399–407, 2013. There are currently several specialty-specific clinical guidelines for genetic evaluation of children diagnosed with ASD. Genetic testing is shown to impact clinical decision-making, but no studies have evaluated the impact of genetic testing on the outcome for the child. The American College of Medical Genetics recommends a tiered approach to genetic testing.

First Tier All children with ASD should have a chromosomal microarray (CMA) . CMA will be positive in 10–15% of individuals with ASD. The rate is increased to almost 30% in individuals who have complex presentations, such as associated microcephaly, dysmorphic features, congenital anomalies, or seizures. CMA technology will identify copy number variants but not DNA sequencing errors, balanced translocations, or abnormalities in trinucleotide repeat length. Fragile X DNA testing is therefore recommended for all boys with ASD. Fragile X testing should also be considered in girls with physical features suggestive of fragile X syndrome or with a family history of fragile X, X-linked pattern of intellectual disability, tremor/ataxia, or premature ovarian failure.

Second Tier Girls with ASD should have testing for mutation in the MeCP2 gene if CMA is normal. Boys who have hypotonia, drooling, and frequent respiratory infections should have MeCP2 deletion/duplication testing. All individuals with ASD and a head circumference greater than 2.5 standard deviations (SD) above the mean should have testing for mutation in the PTEN gene because there is a risk for hamartoma tumor disorders (Cowden, Proteus-like, Bannayan-Riley-Ruvakaba syndromes) in these individuals. Cytogenetic testing (karyotype) has a lower yield than CMA. Karyotype is recommended if microarray is not available and in children with suspected balanced translocation, such as history of multiple prior miscarriages. Further medical diagnostic testing is indicated by the child's history and presentation. Brain imaging is indicated in cases of microcephaly, significant developmental regression, or focal findings on neurologic examination. Because of the high rate (up to 25%) of macrocephaly in ASD, imaging is not indicated for macrocephaly alone. MRI is not recommended for minor language regression (loss of a few words) during the 2nd year of life that is often described in toddlers with ASD. Children with concern for seizures, spells, or developmental regression should have an electroencephalogram (EEG). Metabolic screening is indicated for children with signs of a metabolic or mitochondrial disorder, such as developmental regression, weakness, fatigue, lethargy, cyclic vomiting, or seizures (see Chapters 53 and 102 ).

Treatment and Management Educational The primary treatment for ASD is done outside the medical setting and includes developmental and educational programming. Numerous resources have been developed that can help families in the complex process of treatment planning (Table 54.7 ). Intensive behavioral therapies have the strongest evidence to date. Earlier age at initiation of treatment and higher intensity of treatment are associated with better outcomes. Programming must be individualized, and no approach is successful for all children. In addition, research treatments are often conducted with a high level of intensity and fidelity that are difficult to scale up or reproduce in community settings. Higher cognitive, play, and joint attention skills and lower symptom severity at baseline are predictors for better outcomes in core symptoms, intellectual function, and language function.

Table 54.7

Autism Resources for Families

Autism Speaks First 100 Days kit https://www.autismspeaks.org/family-services/tool-kits/100-daykit Autism Speaks Toolkits–dental, transition, guardianship https://www.autismspeaks.org/family-services/tool-kits AACAP Autism Spectrum Disorder Parent's Medication Guide https://www.aacap.org/App_Themes/AACAP/Docs/resource_centers/autism/Au Sexuality information for individuals with developmental disability http://vkc.mc.vanderbilt.edu/healthybodies/ Behavioral approaches based on the principles of applied behavioral analysis (ABA) involve direct incremental teaching of skills within a traditional behavioral framework using reinforcement of desired behavior, careful data collection, and analysis and adjustment of the treatment program based on review of data. Comprehensive models integrating behavioral and developmental approaches that build on key foundational skills, such as joint attention, shared enjoyment, and reciprocal communication, show strong evidence of efficacy for young children, particularly toddlers, with ASD.

Examples include the Early Start Denver Model (ESDM), Joint Attention Symbolic Play Engagement and Regulation (JASPER), and Social Communication/Emotional Regulation/Transactional Support (SCERTS). Parent training models also show promise for younger children. Educational approaches such as the Treatment and Education of Autistic and Communication Handicapped Children (TEACCH) incorporate structured teaching, visual supports, and adjustment of the environment to the individual needs of students with ASD, such as difficulty with communication, understanding time, and need for routine. These approaches have demonstrated efficacy for improved cognitive and adaptive skills. For older children with more severe symptoms, approaches that use behavioral principles in addition to adjusting the environment may be most effective. Speech and language therapy can help build vocabulary, comprehension, and pragmatic skills. Children with ASD benefit from visual supports for comprehension, understanding expectations, and communicating their needs. Augmentative communication approaches using photographs or picture icons can improve comprehension and ability to communicate. There are a range of options with varying levels of complexity, flexibility, and technology. Using augmentative communication does not inhibit acquisition of verbal language. On the contrary, supporting a child's language development with augmentative supports can facilitate the development of spoken language, even in older children. Additional strategies to build social skills are used for school age children and adolescents and may be administered in the school or community setting by a variety of specialists, including speech therapists, psychologists, and counselors. Social skills programs that include training peer mentors have higher rates of efficacy. Occupational and physical therapy may be indicated for individuals with motor delay and difficulty acquiring adaptive skills such as dressing and toileting. For some high school students with ASD, training in life skills and vocational skills is critical for maximizing independence in adulthood. Training may focus on basic self-care (e.g., dressing, hygiene), functional academics (e.g., money management, banking skills), learning to fill out a job application, and understanding how to behave with strangers and in work settings. Social skills and job coaching may be needed even for adolescents with strong cognitive and academic function, because they may struggle with social perception and may be vulnerable to exploitation by others.

Co-occurring Conditions Additional medical or behavioral health treatment is often required for management of co-occurring conditions in ASD. Seizures occur in up to 35% of children with ASD and should be managed with appropriate antiepileptic therapy (see Chapter 611 ). GI problems (e.g., constipation, esophagitis, GERD) may present with nonspecific irritability, sleep disturbance, self-injury, aggression, and signs of pain or discomfort, such as crying, and can be managed with the same approaches used in typically developing children. Management of co-occurring attention and mood disorders is similar to that for typically developing children. Strategies to increase structure and organization in the environment and use of visual supports (e.g., schedules) can improve attention and reduce anxiety. Some children with ASD benefit from modified cognitive-behavioral therapy to address anxiety and OCD. Strategies to promote sleep hygiene and use of behavioral approaches, such as structured bedtime routines, can address delayed sleep onset. Other medical problems, such as epilepsy or GERD, can also contribute to poor sleep and should be treated directly. In cases refractory to behavioral approaches, medications may be used. (For further discussion of management of sleep problems, see Chapter 31 .) Structured behavioral approaches for delayed toilet training in concert with treatment to prevent constipation are often needed for children with ASD. For children with highly restrictive diets, nutrition counseling and behaviorally based feeding therapy may be needed to address poor caloric intake or lack of nutritional quality. Because of limited diets, children with ASD may be at risk for low levels of calcium, vitamin D, and iron. Children who are overweight may have poor nutrition as a result of restrictive diets. Irritability is a nonspecific symptom and can be a reflection of pain, anxiety, distress, or lack of sleep. Children with ASD are prone to irritability because of their difficulty tolerating change and their limited communication skills. Management of irritability includes evaluating carefully for medical problems that may be causing pain, as well as for any factors in the child's home or school environment that may be causing distress. Possible causes of distress range from common experiences such as changes in the routine to undisclosed abuse or bullying. Treatment should be targeted first at any underlying cause. Medications are often used to treat irritability in ASD but should only be used after appropriate behavioral and communication supports have been implemented.

Pharmacology There are currently no medications that treat the core symptoms of ASD. Medications can be used to target specific co-occurring conditions or symptoms (Table 54.8 ; see also Table 54.5 ). Families should be cautioned, however, that the effect size may be lower and the rate of medication side effects higher in children with ASD. Table 54.8

Common Pharmacologic Treatments in Autism Spectrum Disorder (ASD) TARGET MEDICATION EFFECTS SIDE EFFECTS SYMPTOM CLASS* Hyperactivity Stimulants Decreased Activation, irritability, emotional and/or hyperactivity, lability, lethargy/social Inattention impulsivity, improved withdrawal, stomach ache, attention reduced appetite, insomnia, increased stereotypy α2 -Agonists Decreased Drowsiness, irritability, enuresis, hyperactivity, decreased appetite, dry mouth, impulsivity, improved hypotension attention Selective Decreased Irritability, decreased appetite, norepinephrine hyperactivity, fatigue, stomach ache, nausea, reuptake impulsivity, improved vomiting, racing heart rate inhibitor attention Anxiety Selective Decreased anxiety Activation, hyperactivity, serotonin inattention, sedation, change reuptake in appetite, insomnia, inhibitors stomach ache, diarrhea Citalopram: prolonged QTc interval Irritability Atypical Decreased irritability, Somnolence, weight gain, antipsychotics aggression, selfextrapyramidal movements, (risperidone, injurious behavior, drooling, tremor, dizziness, aripiprazole) repetitive behavior, vomiting, gynecomastia hyperactivity

Insomnia

Melatonin

Shortened sleep onset

Nightmares, enuresis

MONITORING Height, weight, BP, HR

Height, weight, BP, HR

Height, weight, BP, HR

Weight, BP, HR

Weight, BP, HR Monitor CBC, cholesterol, ALT, AST, prolactin, glucose or hemoglobin A1c —

* Specific medications names are provided in parentheses when there is a FDA-approved

indication for the use of the medication to treat the symptom in children with ASD. Further information about these medications is available in Chapter 33 . BP, Blood pressure; HR, heart rate; CBC, complete blood count; ALT, alanine transaminase; AST, aspartate transaminase.

Preliminary data suggest that intranasal therapy with neuropeptide oxytocin may improve social functioning in children with ASD, particularly those with low pretreatment oxytocin levels. There is evidence to support use of stimulant medication, atomoxetine and αagonists for ADHD in ASD. Selective serotonin reuptake inhibitors (SSRI) can be used for anxiety and OCD and in adolescents may also be useful for depression. Benzodiazepines may be useful for situational anxiety, for example, triggered by dental and medical procedures or air travel. Medications used to treat ADHD and anxiety may result in activation or irritability in ASD and require careful monitoring. Melatonin can be used to improve sleep onset but will not address night waking. Clonidine or trazodone may be used for sleep onset and maintenance. No medications are specifically labeled for treatment of insomnia in ASD. The α-adrenergic agonists may be helpful in children who present with significant behavioral dysregulation. There are two atypical antipsychotic medications that have U.S. Food and Drug Administration (FDA) recommendation for irritability and aggression in children with ASD. Both risperidone and aripiprazole have several studies documenting efficacy for reducing irritability, aggression, and self-injury. Secondary improvements in attention and repetitive behavior were also noted. Side effects include weight gain and metabolic syndrome as well as tardive dyskinesia and extrapyramidal movements. Careful laboratory monitoring is recommended. Mood-stabilizing antiepileptic medications have also been used to treat irritability.

Complementary and Alternative Medicine Families of children with ASD often use complementary and alternative medicine (CAM) approaches. These treatments can include supplements, dietary changes, and body or physical treatments. There is a limited evidence to inform families, who often learn about these treatments from friends and family members, alternative medicine providers, or the internet. For most therapies, evidence is insufficient to show benefit. There is strong evidence that secretin and facilitated communication are not effective. Some therapies, such as hyperbaric oxygen, chelation, and high-dose vitamins, are potentially harmful. For children with restrictive diets, taking a daily multivitamin and 400 IU vitamin D may be indicated, although there is no evidence to support megadoses of vitamins. Similarly, for children with evidence of gluten sensitivity, a trial of

gluten-free diet may be indicated. However, current evidence does not support this as a treatment for all children with ASD. When discussing CAM with a family, it is best to use open and collaborative communication, encouraging them to share their current practices and any questions. Specifically ask if they use any herbal treatments, supplements, or other therapies, such as acupuncture, massage, or chiropractic treatment, and what they have observed since trying the treatment. Provide accurate information regarding potential benefit and risk for any treatment. Educate about “red flags” such as treatments that are marketed as a cure for multiple conditions, that report no risk of side effects, or that are marketed by the clinician recommending the treatment. Encourage families to identify a target symptom, “try one thing at a time,” and monitor response carefully.

Transition Navigating a successful transition to adult care is a key role for the pediatric provider. This process should ideally start as early as age 12-13 yr. Parents are faced with a complex and disconnected system of diverse agencies that they need to navigate. Use of structured-visit templates and care coordinators can help ensure that families and their youth with ASD are able to make appropriate decisions about secondary and postsecondary educational programming, vocational training, guardianship, finances, housing, and medical care. High school educational programming should include individualized and meaningful vocational training, as well as instruction regarding sexuality, relationships, safety and abuse prevention, finances, travel training, and general self-advocacy. Individuals with ASD who are higher functioning will need help accessing supports for college or postsecondary skills training and may benefit from referral to their state vocational rehabilitative services as well as personal life coaches or counselors. Families who have adult children with more significant cognitive disability need information about the range of adult disability services, how to apply for supplemental security income (SSI), and the process for considering guardianship or medical and financial conservatorship for their adult child. These decisions are complex and must be individualized for the adult with ASD and the family.

Outcome

Autism spectrum disorder is a lifelong condition. Although a minority of individuals respond so well to therapy that they no longer meet criteria for the diagnosis, most will make progress but continue to have some impairment in social and behavioral function as adults. Adult outcome studies are sobering, indicating that many adults with ASD are socially isolated, lack gainful employment or independent living, and have higher rates of depression and anxiety. It is not clear if these data can be extrapolated to younger children currently receiving intensive educational therapies. There is a growing network of adult self-advocates who promote the unique strengths in individuals with ASD. Outcome as measured by developmental progress and functional independence is better for individuals who have higher cognitive and language skills and lower ASD severity at initial diagnosis.

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PA R T V

Nutrition OUTLINE Chapter 55 Nutritional Requirements Chapter 56 Feeding Healthy Infants, Children, and Adolescents Chapter 57 Nutrition, Food Security, and Health Chapter 58 Refeeding Syndrome Chapter 59 Malnutrition Chapter 60 Overweight and Obesity Chapter 61 Vitamin A Deficiencies and Excess Chapter 62 Vitamin B Complex Deficiencies and Excess Chapter 63 Vitamin C (Ascorbic Acid) Deficiency and Excess Chapter 64 Vitamin D Deficiency (Rickets) and Excess Chapter 65 Vitamin E Deficiency Chapter 66 Vitamin K Deficiency Chapter 67 Micronutrient Mineral Deficiencies

CHAPTER 55

Nutritional Requirements Asim Maqbool, Elizabeth Prout Parks, Ala Shaikhkhalil, Jennifer Panganiban, Jonathan A. Mitchell, Virginia A. Stallings

Nutrition for infants, children, and adolescents should maintain current weight and support normal growth and development. Growth during infancy is rapid, critical for neurocognitive development, and has the highest energy and nutrient requirements relative to body size than any other period of growth. It is followed by growth during childhood, when 60% of total growth occurs, and finally by puberty. Nutrition and growth during the 1st 3 yr of life predict adult stature and some health outcomes. The major risk period for growth stunting (impaired linear growth) is between 4 and 24 mo of age. Therefore, it is critical to identify nutrient deficiencies promptly and to address them aggressively early in life, because missing them can impart lasting adverse effects on later growth and development. Dietary intake should provide energy requirements as well as the essential macronutrient and micronutrient needs for sustaining the function of multiple vital processes. Nutrient deficiencies can limit growth, impair immune function, affect neurodevelopment, and increase morbidity and mortality. Worldwide, malnutrition and undernutrition are the leading causes of acquired immunodeficiency, and a major factor underlying morbidity and mortality in children 97% of the individuals in a population, and it can be used as a guideline for individuals to avoid deficiency. When an EAR cannot be derived, an RDA cannot be calculated; therefore, an adequate intake (AI) is developed as a guideline for individuals based on the best available data and scientific consensus. The UL denotes the highest average daily intake with no associated adverse health effects for almost all individuals in a particular group. Fig. 55.2 shows the relationships among EAR, RDA, and UL.

FIG. 55.1 Dietary reference intakes. Normal requirement distribution of hypothetical nutrient showing percentile rank and placement of the estimated average requirement (EAR) and the recommended dietary allowance (RDA) on the distribution; SD, standard deviation.

FIG. 55.2 Dietary reference intakes: the relationship among the estimated average requirement (EAR), the recommended dietary allowance (RDA), and the tolerable upper limit of intake (UL). This figure shows that the EAR is the intake at which the risk of inadequacy is estimated to be 0.5 (50%). The RDA is the intake at which the risk of inadequacy would be very small, only 0.02-0.03 (2–3%). At intakes between the RDA and the UL, the risk of inadequacy and of excess are estimated to be close to 0.0. At intakes above the UL, the potential risk of adverse effects can increase.

Energy Energy includes both food intake and metabolic expenditure. Deficits and excesses of energy intake yield undesirable health consequences. Inadequate energy intake can lead to growth faltering, catabolism of body tissues, and

inability to provide adequate energy substrate. Excess energy intakes can increase the risk for obesity. Adequacy of energy intake in adults is associated with maintenance of a healthy weight. The three components of energy expenditure in adults are the basal metabolic rate (BMR), thermal effect of food (e.g., energy required for digestion and absorption), and energy for physical activity. In children, additional energy intake is required to support growth and development. Estimated energy requirement (EER) is the average dietary energy intake predicted to maintain energy balance in a healthy individual and takes into account age, gender, weight, stature, and level of physical activity (Table 55.1 ). The 2015–2020 Dietary Guidelines for Americans refer to the 2008 Physical Activity Guidelines for Americans. These guidelines recommend ≥60 min of moderate- or vigorous-intensity aerobic physical daily for children and adolescents. This activity should include vigorous intensity physical activity at least 3 days per week. In addition, as part of their ≥60 min of daily physical activity, children and adolescents are advised to incorporate muscle- and bonestrengthening activity for ≥3 days a week, to maintain a healthy weight and to prevent or delay progression of chronic noncommunicable diseases such as obesity and CV disease. Table 55.1

Equations to Estimate Energy Requirement INFANTS AND YOUNG CHILDREN: EER (kcal/day) = TEE + ED 0-3 mo EER = (89 × weight [kg] − 100) + 175 4-6 mo EER = (89 × weight [kg] − 100) + 56 7-12 mo EER = (89 × weight [kg] − 100) + 22 13-36 mo EER = (89 × weight [kg] − 100) + 20 CHILDREN AND ADOLESCENTS 3-18 yr: EER (kcal/day) = TEE + ED Boys 3-8 yr EER = 88.5 − (61.9 × age [yr] + PA × [(26.7 × weight [kg] + (903 × height [m])] + 20 9-18 yr EER = 88.5 − (61.9 × age [yr] + PA × [(26.7 × weight [kg] + (903 × height [m])] + 25 Girls 3-8 yr EER = 135.3 − (30.8 × age [yr] + PA [(10 × weight [kg] + (934 × height [m])] + 20 9-18 yr EER = 135.3 − (30.8 × age [yr] + PA [(10 × weight [kg] + (934 × height [m])] + 25

EER, Estimated energy requirement; TEE, total energy expenditure; ED, energy deposition (energy required for growth /new tissue accretion). PA indicates the physical activity coefficient: For boys: PA = 1.00 (sedentary, estimated physical activity level 1.0-1.4)

PA = 1.13 (low active, estimated physical activity level 1.4-1.6) PA = 1.26 (active, estimated physical activity level 1.6-1.9) PA = 1.42 (very active, estimated physical activity level 1.9-2.5) For girls: PA = 1.00 (sedentary, estimated physical activity level 1.0-1.4) PA = 1.16 (low active, estimated physical activity level 1.4-1.6) PA = 1.31 (active, estimated physical activity level 1.6-1.9) PA = 1.56 (very active, estimated physical activity level 1.9-2.5) Adapted from Kleinman RE, editor: Pediatric nutrition handbook, ed 7, Elk Grove Village, IL, 2013, American Academy of Pediatrics.

The EER was determined based on empirical research in healthy persons at different levels of physical activity, including levels different from recommended levels. They do not necessarily apply to children with acute or chronic diseases. EER is estimated by equations that account for total energy expenditure (TEE) and energy deposition (ED) for healthy growth. EERs for infants, relative to body weight, are approximately twice those for adults because of the increased metabolic rate and requirements for weight maintenance and tissue accretion (growth). Dietary nutrients that provide energy include fats (approximately 9 kcal/g), carbohydrates (4 kcal/g), and protein (4 kcal/g). These nutrients are called macronutrients . If alcohol is consumed, it also contributes to energy intake (7 kcal/g). The EER does not specify the relative energy contributions of macronutrients. Once the minimal intake of each macronutrient is attained (e.g., sufficient protein intake to meet specific amino acid requirements, sufficient fat intake to meet linoleic acid and α-linolenic acid needs for brain development), the remainder of the intake is used to meet energy requirements, with some degree of freedom and interchangeability among fat, carbohydrate, and protein. This argument forms the basis for the acceptable macronutrient distribution ranges (AMDRs) , expressed as a function of total energy intake (Table 55.2 ). Table 55.2

Acceptable Macronutrient Distribution Ranges AMDA (% OF ENERGY) Macronutrient Fat ω6 PUFAs (linoleic acid)

Age 1-3 yr 30-40 5-10

Age 4-18 yr 25-35 5-10

ω3 PUFAs (α-linolenic acid) Carbohydrate Protein

0.6-1.2 45-65 5-20

0.6-1.2 45-65 10-30

PUFAs, Polyunsaturated fatty acids. Adapted from Otten JJ, Hellwig JP, Meyers LD, editors; Institute of Medicine: Dietary reference intakes: the essential guide to nutrient requirements , Washington, DC, 2006, National Academies Press.

Fat Fat is the most calorically dense macronutrient, providing approximately 9 kcal/g. For infants, human milk and formula are the main dietary sources of fat, whereas older children obtain fat from animal products, vegetable oils, and margarine. The AMDR for fats is 30–40% of total energy intake for children 1-3 yr and 25–35% for children 4-18 yr of age. In addition to being energy dense, fats provide essential fatty acids that have body structural and functional roles (e.g., cholesterol moieties are precursors for cell membranes, hormones, and bile acids). Fat intake facilitates absorption of fat-soluble vitamins (vitamins A, D, E, and K). Both roles are relevant to neurologic and ocular development (Table 55.3 ). Table 55.3

Dietary Reference Intakes: Macronutrients LIFE RDA OR AI* STAGE (g/day) GROUP TOTAL DIGESTIBLE CARBOHYDRATE RDA based on its Infants role as the primary 0-6 mo 60* energy source for 7-12 mo 95* the brain Children AMDR based on >1 yr 130 its role as a source Pregnancy of kcal to maintain ≤18 yr 175 body weight 19-30 yr 175 FUNCTION

SELECTED FOOD SOURCES Major types: starches and sugars, grains, and vegetables (corn, pasta, rice, potatoes, and breads) are sources of starch. Natural sugars are found in fruits and juices. Sources of added sugars: soft drinks, candy, fruit drinks,

ADVERSE EFFECTS OF EXCESSIVE CONSUMPTION No defined intake level for potential adverse effects of total digestible carbohydrate is identified, but the upper end of the AMDR was based on decreasing risk of chronic disease and providing adequate intake of other nutrients. It is suggested that the maximal intake of added sugars be limited to providing no more than 10% of energy.

desserts, syrups, and sweeteners † TOTAL FIBER Improves laxation, reduces risk of coronary artery (heart) disease, assists in maintaining normal blood glucose levels

TOTAL FAT Energy source When found in foods, is a source of ω3 and ω6 PUFAs Facilitates absorption of fatsoluble vitamins

Infants 0-6 mo ND 7-12 mo ND Children 1-3 yr 190* 4-8 yr 25* Males 9-13 yr 31* 14-18 yr 38* 19-21 yr 38* Females 9-13 yr 26* 14-18 yr 26* 19-21 yr 25* Pregnancy ≤18 yr 28* 19-21 yr 28*

Infants 0-6 mo 712 mo 118 yr

31* 30* Insufficient evidence to determine AI or EAR; see AMDR, Table 55.2 .

ω6 POLYUNSATURATED FATTY ACIDS Essential Infants component of 0-6 mo 4.4* structural 7-12 mo 4.6* membrane lipids, Children involved with cell 1-3 yr 7* signaling 4-8 yr 10* Precursor of Males eicosanoids 9-13 yr 12* Required for 14-18 yr 16* normal skin 19-21 yr 17* function

Includes dietary fiber naturally present in grains (e.g., oats, wheat, unmilled rice) and functional fiber synthesized or isolated from plants or animals and shown to be of benefit to health

Dietary fiber can have variable compositions; therefore it is difficult to link a specific source of fiber with a particular adverse effect, especially when phytate is also present in the natural fiber source. As part of an overall healthy diet, a high intake of dietary fiber will not produce deleterious effects in healthy persons. Occasional adverse GI symptoms are observed when consuming some isolated or synthetic fibers, but serious chronic adverse effects have not been observed because of the bulky nature of fibers. Excess consumption is likely to be self-limiting; therefore, UL was not set for individual functional fibers.

Infants: Human milk or infant formula Older children: Butter, margarine, vegetable oils, whole milk, visible fat on meat and poultry products, invisible fat in fish, shellfish, some plant products such as seeds and nuts, bakery products

UL is not set because there is no defined intake of fat at which adverse effects occur. High fat intake will lead to obesity. Upper end of AMDR is also based on reducing risk of chronic disease and providing adequate intake of other nutrients. † Low fat intake (with high carbohydrate) has been shown to increase plasma triacylglycerol concentrations and decrease HDL cholesterol.

Nuts, seeds; vegetable oils such as soybean, safflower, corn oil

There is no defined intake of ω6 level at which adverse effects occur. Upper end of AMDR is based on the lack of evidence that demonstrates long-term safety and human in vitro studies that show increased free radical formation and lipid peroxidation with higher amounts of ω6 fatty acids.

Females 9-13 yr 10* 14-18 yr 11* 19-21 yr 12* Pregnancy ≤18 yr 13* 19-21 yr 13* Lactation ≤18 yr 13* 19-21 yr 13* ω3 POLYUNSATURATED FATTY ACIDS Involved with Infants neurologic 0-6 mo 0.5* development and 7-12 mo 0.5* growth Children Precursor of 1-3 yr 0.7* eicosanoids 4-8 yr 0.9* Males 9-13 yr 1.2* 14-18 yr 1.6* 19-21 yr 1.6* Females 9-13 yr 1.0* 14-18 yr 1.1* 19-21 yr 1.1* Pregnancy ≤18 yr 1.4* 19-21 yr 1.4* Lactation ≤18 yr 1.3* 19-21 yr 1.3*

SATURATED AND TRANS FATTY ACIDS The body can No dietary synthesize its needs for requirement saturated fatty acids from other sources.

CHOLESTEROL

Lipid peroxidation is thought to be a component of atherosclerotic plaques.

Vegetable oils, e.g., soybean, canola, flax seed oil; fish oils, fatty fish, walnuts; † smaller amounts in meats and eggs

Saturated fatty acids are present in animal fats (meat fats and butter fat), and coconut and palm kernel oils. Trans fat: stick margarines, foods containing hydrogenated or partially hydrogenated vegetable shortenings

No defined intake levels for potential adverse effects of ω3 PUFAs are identified. Upper end of AMDR is based on maintaining appropriate balance with ω6 fatty acids and the lack of evidence that demonstrates long-term safety, along with human in vitro studies that show increased free radical formation and lipid peroxidation with higher amounts of PUFAs. Because the longer-chain n -3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are biologically more potent than their precursor, linolenic acid, much of the work on adverse effects of this group of fatty acids has been on DHA and EPA. Lipid peroxidation is thought to be a component in the development of atherosclerotic plaques. There is an incremental increase in plasma total and LDL cholesterol concentrations with increased intake of saturated or trans fatty acids; therefore, saturated fat intake should be limited to 2 yr old and that children 150 mEq/L. Mild hypernatremia is fairly common in children, especially among infants with gastroenteritis. Hypernatremia in hospitalized patients may be iatrogenic—caused by inadequate water administration or, less often, by excessive Na+ administration. Moderate or severe hypernatremia has significant morbidity because of the underlying disease, the effects of hypernatremia on the brain, and the risks of overly rapid correction.

Etiology and Pathophysiology There are 3 basic mechanisms of hypernatremia (Table 68.1 ). Sodium intoxication is frequently iatrogenic in a hospital setting as a result of correction of metabolic acidosis with sodium bicarbonate. Baking soda, a putative home remedy for upset stomach, is another source of sodium bicarbonate; the hypernatremia is accompanied by a profound metabolic alkalosis. In hyperaldosteronism, there is renal retention of sodium and resultant hypertension; hypernatremia may not be present or is usually mild.

Table 68.1

Causes of Hypernatremia Excessive Sodium Improperly mixed formula Excess sodium bicarbonate Ingestion of seawater or sodium chloride Intentional salt poisoning (child abuse or Munchausen syndrome by proxy) Intravenous hypertonic saline Hyperaldosteronism

Water Deficit

Nephrogenic Diabetes Insipidus Acquired X-linked (OMIM 304800) Autosomal recessive (OMIM 222000) Autosomal dominant (OMIM 125800) Central Diabetes Insipidus Acquired Autosomal recessive (OMIM 125700) Autosomal dominant (OMIM 125700) Wolfram syndrome (OMIM 222300/598500) Increased Insensible Losses Premature infants Radiant warmers Phototherapy Inadequate intake: Ineffective breastfeeding Child neglect or abuse Adipsia (lack of thirst)

Water and Sodium Deficits Gastrointestinal Losses Diarrhea Emesis/nasogastric suction Osmotic cathartics (lactulose) Cutaneous Losses Burns Excessive sweating

Renal Losses Osmotic diuretics (mannitol) Diabetes mellitus Chronic kidney disease (dysplasia and obstructive uropathy) Polyuric phase of acute tubular necrosis Postobstructive diuresis OMIM, database number from the Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim ). The classic causes of hypernatremia from a water deficit are nephrogenic and central diabetes insipidus (see Chapters 548 and 574 ). Hypernatremia develops in diabetes insipidus only if the patient does not have access to water or cannot drink adequately because of immaturity, neurologic impairment, emesis, or anorexia. Infants are at high risk because of their inability to control their own water intake. Central diabetes insipidus and the genetic forms of nephrogenic diabetes insipidus typically cause massive urinary water losses and very dilute urine. The water losses are less dramatic, and the urine often has the same osmolality as plasma when nephrogenic diabetes insipidus is secondary to intrinsic renal disease (obstructive uropathy, renal dysplasia, sickle cell disease). The other causes of a water deficit are also secondary to an imbalance between losses and intake. Newborns, especially if premature, have high insensible water losses. Losses are further increased if the infant is placed under a radiant warmer or with the use of phototherapy for hyperbilirubinemia. The renal concentrating mechanisms are not optimal at birth, providing an additional source of water loss. Ineffective breastfeeding, often in a primiparous mother, can cause severe hypernatremic dehydration. Adipsia , the absence of thirst, is usually secondary to damage to the hypothalamus, such as from trauma, tumor, hydrocephalus, or histiocytosis. Primary adipsia is rare. When hypernatremia occurs in conditions with deficits of sodium and water, the water deficit exceeds the sodium deficit. This occurs only if the patient is unable to ingest adequate water. Diarrhea results in depletion of both Na+ and water. Because diarrhea is hypotonic—typical Na+ concentration of 35-65 mEq/L—water losses exceed Na+ losses, potentially leading to hypernatremia. Most children with gastroenteritis do not have hypernatremia because they drink

enough hypotonic fluid to compensate for stool water losses (see Chapter 366 ). Fluids such as water, juice, and formula are more hypotonic than the stool losses, allowing correction of the water deficit and potentially even causing hyponatremia. Hypernatremia is most likely to occur in the child with diarrhea who has inadequate intake because of emesis, lack of access to water, or anorexia. Osmotic agents, including mannitol, and glucose in diabetes mellitus , cause excessive renal losses of water and Na+ . Because the urine is hypotonic (Na+ concentration of approximately 50 mEq/L) during an osmotic diuresis, water loss exceeds Na+ loss, and hypernatremia may occur if water intake is inadequate. Certain chronic kidney diseases, such as renal dysplasia and obstructive uropathy, are associated with tubular dysfunction, leading to excessive losses of water and Na+ . Many children with such diseases have disproportionate water loss and are at risk for hypernatremic dehydration, especially if gastroenteritis supervenes. Similar mechanisms occur during the polyuric phase of acute kidney injury and after relief of urinary obstruction (postobstructive diuresis). Patients with either condition may have an osmotic diuresis from urinary losses of urea and an inability to conserve water because of tubular dysfunction. Essential hypernatremia is rare in children and is thought to occur with injury to the hypothalamic-posterior pituitary axis. It is euvolemic, nonhypertensive, and associated with hypodipsia, possibly related to a reset osmol sensor.

Clinical Manifestations Most children with hypernatremia are dehydrated and show the typical clinical signs and symptoms (see Chapter 70 ). Children with hypernatremic dehydration tend to have better preservation of intravascular volume because of the shift of water from the ICS to the ECS. This shift maintains blood pressure and urine output and allows hypernatremic infants to be less symptomatic initially and potentially to become more dehydrated before medical attention is sought. Breastfed infants with hypernatremia are often profoundly dehydrated, with failure to thrive (malnutrition). Probably because of intracellular water loss, the pinched abdominal skin of a dehydrated, hypernatremic infant has a “doughy” feel. Hypernatremia, even without dehydration, causes central nervous system

(CNS) symptoms that tend to parallel the degree of Na+ elevation and the acuity of the increase. Patients are irritable, restless, weak, and lethargic. Some infants have a high-pitched cry and hyperpnea. Alert patients are very thirsty, even though nausea may be present. Hypernatremia may cause fever, although many patients have an underlying process that contributes to the fever. Hypernatremia is associated with hyperglycemia and mild hypocalcemia; the mechanisms are unknown. Beyond the sequelae of dehydration, there is no clear direct effect of hypernatremia on other organs or tissues, except the brain. Brain hemorrhage is the most devastating consequence of untreated hypernatremia. As the extracellular osmolality increases, water moves out of brain cells, leading to a decrease in brain volume. This decrease can result in tearing of intracerebral veins and bridging blood vessels as the brain moves away from the skull and the meninges. Patients may have subarachnoid, subdural, and parenchymal hemorrhages. Seizures and coma are possible sequelae of the hemorrhage, although seizures are more common during correction of hypernatremia. The cerebrospinal fluid protein is often elevated in infants with significant hypernatremia, probably because of leakage from damaged blood vessels. Neonates, especially if premature, seem especially vulnerable to hypernatremia and excessive sodium intake. There is an association between rapid or hyperosmolar sodium bicarbonate administration and the development of intraventricular hemorrhages in neonates. Even though central pontine myelinolysis is classically associated with overly rapid correction of hyponatremia, both central pontine and extrapontine myelinolysis can occur in children with hypernatremia (see Treatment ). Thrombotic complications occur in severe hypernatremic dehydration, including stroke, dural sinus thrombosis, peripheral thrombosis, and renal vein thrombosis. This is secondary to dehydration and possibly hypercoagulability associated with hypernatremia.

Diagnosis The etiology of hypernatremia is usually apparent from the history. Hypernatremia resulting from water loss occurs only if the patient does not have access to water or is unable to drink. In the absence of dehydration, it is important to ask about sodium intake. Children with excess salt intake do not have signs of dehydration, unless another process is present. Severe Na+ intoxication causes signs of volume overload, such as pulmonary edema and weight gain. Salt poisoning is associated with an elevated fractional excretion of

Na+ , whereas hypernatremic dehydration causes a low fractional excretion of Na+ . Gastric sodium concentrations are often elevated in salt poisoning. In hyperaldosteronism, hypernatremia is usually mild or absent and is associated with edema, hypertension, hypokalemia, and metabolic alkalosis. When there is isolated water loss, the signs of volume depletion are usually less severe initially because much of the loss is from the ICS. When pure water loss causes signs of dehydration, the hypernatremia and water deficit are usually severe. In the child with renal water loss, either central or nephrogenic diabetes insipidus, the urine is inappropriately dilute and urine volume is not low. The urine is maximally concentrated and urine volume is low if the losses are extrarenal or caused by inadequate intake. With extrarenal causes of loss of water, the urine osmolality should be >1,000 mOsm/kg. When diabetes insipidus is suspected, the evaluation may include measurement of ADH and a water deprivation test, including a trial of desmopressin acetate (synthetic ADH analog) to differentiate between nephrogenic diabetes insipidus and central diabetes insipidus (see Chapters 548 and 574 ). A water-deprivation test is unnecessary if the patient has simultaneous documentation of hypernatremia and poorly concentrated urine (osmolality lower than that of plasma). In children with central diabetes insipidus, administration of desmopressin acetate increases the urine osmolality above the plasma osmolality, although maximum osmolality does not occur immediately because of the decreased osmolality of the renal medulla as a result of the chronic lack of ADH. In children with nephrogenic diabetes insipidus, there is no response to desmopressin acetate. Hypercalcemia or hypokalemia may produce a nephrogenic diabetes insipidus–like syndrome. With combined Na+ and water deficits, analysis of the urine differentiates between renal and nonrenal etiologies. When the losses are extrarenal, the kidney responds to volume depletion with low urine volume, concentrated urine, and Na+ retention (urine [Na+ ] 200,000/m3 , can cause a dramatic elevation in the serum [K+ ].

Analysis of a plasma sample usually provides an accurate result. It is important to analyze the sample promptly to avoid K+ release from cells, which occurs if the sample is stored in the cold, or cellular uptake of K+ and spurious hypokalemia, which occurs with storage at high temperatures. Pneumatic tube transport can cause pseudohyperkalemia if cell membranes are fragile (leukemia). Occasionally, heparin causes lysis of leukemic cells and a false elevation of the plasma sample; a blood gas syringe has less heparin and may provide a more accurate reading than a standard tube. There are rare genetic disorders causing in vitro leakage of K+ from red blood cells (RBCs) that may causes familial pseudohyperkalemia. Because of the kidney's ability to excrete K+ , it is unusual for excessive intake, by itself, to cause hyperkalemia. This condition can occur in a patient who is receiving large quantities of IV or oral K+ for excessive losses that are no longer present. Frequent or rapid blood transfusions can acutely increase the [K+ ] because of the K+ content of blood, which is variably elevated. Increased intake may precipitate hyperkalemia if there is an underlying defect in K+ excretion. The ICS has a very high [K+ ], so a shift of K+ from the ICS to the ECS can have a significant effect on the plasma [K+ ]. This shift occurs with metabolic acidosis, but the effect is minimal with an organic acid (lactic acidosis, ketoacidosis). A respiratory acidosis has less impact than a metabolic acidosis. Cell destruction, as seen with rhabdomyolysis, tumor lysis syndrome, tissue necrosis, or hemolysis, releases K+ into the extracellular milieu. The K+ released from RBCs in internal bleeding, such as hematomas, is resorbed and enters the ECS. Normal doses of succinylcholine or β-blockers and fluoride or digitalis intoxication all cause a shift of K+ out of the intracellular compartment. Succinylcholine should not be used during anesthesia in patients at risk for hyperkalemia. β-Blockers prevent the normal cellular uptake of K+ mediated by binding of β-agonists to the β2 -adrenergic receptors. K+ release from muscle cells occurs during exercise, and levels can increase by 1-2 mEq/L with high activity. With an increased plasma osmolality, water moves from the ICS, and K+ follows. This process occurs with hyperglycemia, although in nondiabetic patients the resultant increase in insulin causes K+ to move intracellularly. In diabetic ketoacidosis (DKA) , the absence of insulin causes potassium to leave the ICS, and the problem is compounded by the hyperosmolality. The effect of

hyperosmolality causes a transcellular shift of K+ into the ECS after mannitol or hypertonic saline infusions. Malignant hyperthermia , which is triggered by some inhaled anesthetics, causes muscle release of potassium (see Chapter 629.2 ). Hyperkalemic periodic paralysis is an autosomal dominant disorder caused by a mutated Na+ channel. It results in episodic cellular release of K+ and attacks of paralysis (see Chapter 629.1 ). The kidneys excrete most of the daily K+ intake, so a decrease in kidney function can cause hyperkalemia. Newborn infants in general, and especially premature infants, have decreased kidney function at birth and thus are at increased risk for hyperkalemia despite an absence of intrinsic renal disease. Neonates also have decreased expression of K+ channels, further limiting K+ excretion. A wide range of primary adrenal disorders , both hereditary and acquired, can cause decreased production of aldosterone, with secondary hyperkalemia (see Chapters 593 and 594 ). Patients with these disorders typically have metabolic acidosis and salt wasting with hyponatremia. Children with subtle adrenal insufficiency may have electrolyte problems only during acute illnesses. The most common form of congenital adrenal hyperplasia , 21-hydroxylase deficiency, typically manifests in male infants as hyperkalemia, metabolic acidosis, hyponatremia, and volume depletion. Females with this disorder usually are diagnosed as newborns because of their ambiguous genitalia; treatment prevents the development of electrolyte problems. Renin, via angiotensin II, stimulates aldosterone production. A deficiency in renin, a result of kidney damage, can lead to decreased aldosterone production. Hyporeninemia occurs in many kidney diseases, with some of the more common pediatric causes listed in Table 68.4 . These patients typically have hyperkalemia and a metabolic acidosis, without hyponatremia. Some of these patients have impaired renal function, partially accounting for the hyperkalemia, but the impairment in K+ excretion is more extreme than expected for the degree of renal insufficiency. A variety of renal tubular disorders impair renal excretion of K+ . Children with pseudohypoaldosteronism type 1 have hyperkalemia, metabolic acidosis, and salt wasting (kidney, colon, sweat) leading to hyponatremia and volume depletion; aldosterone values are elevated. In the autosomal recessive variant, there is a defect in the renal Na+ channel that is normally activated by aldosterone. Patients with this variant have severe symptoms (failure to thrive,

diarrhea, recurrent respiratory infections, miliaria-rubra like rash), beginning in infancy. Patients with the autosomal dominant form have a defect in the aldosterone receptor, and the disease is milder, often remitting in adulthood. Pseudohypoaldosteronism type 2 (familial hyperkalemic hypertension), also called Gordon syndrome, is an autosomal dominant disorder characterized by hypertension caused by salt retention and impaired excretion of K+ and acid, leading to hyperkalemia and hyperchloremic metabolic acidosis. Activating mutations in either WNK1 or WNK4 , both serine-threonine kinases located in the distal nephron, cause Gordon syndrome. Patients may respond well to thiazide diuretics. In Bartter syndrome , caused by mutations in the potassium channel ROMK (type 2 Bartter syndrome), there can be transient hyperkalemia in neonates, but hypokalemia subsequently develops (see Chapter 549.1 ). Acquired renal tubular dysfunction, with an impaired ability to excrete K+ , occurs in a number of conditions. These disorders, all characterized by tubulointerstitial disease, are often associated with impaired acid secretion and a secondary metabolic acidosis. In some affected children, the metabolic acidosis is the dominant feature, although a high K+ intake may unmask the defect in K+ handling. The tubular dysfunction can cause renal salt wasting, potentially leading to hyponatremia. Because of the tubulointerstitial damage, these conditions may also cause hyperkalemia as a result of hyporeninemic hypoaldosteronism. The risk of hyperkalemia resulting from medications is greatest in patients with underlying renal insufficiency. The predominant mechanism of medicationinduced hyperkalemia is impaired renal excretion, although ACE inhibitors may worsen hyperkalemia in anuric patients, probably by inhibiting GI potassium loss, which is normally upregulated in renal insufficiency. The hyperkalemia caused by trimethoprim generally occurs only at the very high doses used to treat Pneumocystis jiroveci pneumonia. Potassium-sparing diuretics may easily cause hyperkalemia, especially because they are often used in patients receiving oral K+ supplements. Oral contraceptives containing drospirenone, which blocks the action of aldosterone, may cause hyperkalemia and should not be used in patients with decreased renal function.

Clinical Manifestations The most important effects of hyperkalemia result from the role of K+ in membrane polarization. The cardiac conduction system is usually the dominant

concern. Changes in the electrocardiogram (ECG) begin with peaking of the T waves. This is followed, as K+ level increases, by ST-segment depression, an increased PR interval, flattening of the P wave, and widening of the QRS complex. However, the correlation between K+ level and ECG changes is poor. This process can eventually progress to ventricular fibrillation. Asystole may also occur. Some patients have paresthesias, fasciculations, weakness, and even an ascending paralysis, but cardiac toxicity usually precedes these clinical symptoms, emphasizing the danger of assuming that an absence of symptoms implies an absence of danger. Chronic hyperkalemia is generally better tolerated than acute hyperkalemia.

Diagnosis The etiology of hyperkalemia is often readily apparent. Spurious hyperkalemia is very common in children, so obtaining a 2nd potassium measurement is often appropriate. If there is a significant elevation of WBC or platelet count, the 2nd measurement should be performed on a plasma sample that is evaluated promptly. The history should initially focus on potassium intake, risk factors for transcellular shifts of K+ , medications that cause hyperkalemia, and signs of renal insufficiency, such as oliguria and edema. Initial laboratory evaluation should include creatinine, BUN, and assessment of the acid-base status. Many etiologies of hyperkalemia cause metabolic acidosis , which worsens hyperkalemia through the transcellular shift of K+ out of cells. Renal insufficiency is a common cause of the combination of metabolic acidosis and hyperkalemia, also seen in diseases associated with aldosterone insufficiency or aldosterone resistance. Children with absent or ineffective aldosterone often have hyponatremia and volume depletion because of salt wasting. Genetic diseases, such as congenital adrenal hyperplasia and pseudohypoaldosteronism, usually manifest in infancy and should be strongly considered in the infant with hyperkalemia and metabolic acidosis, especially if hyponatremia is present. It is important to consider the various etiologies of a transcellular K+ shift. In some of these disorders, the K+ level continues to increase, despite the elimination of all K+ intake, especially with concurrent renal insufficiency. This increase is potentially seen in tumor lysis syndrome, hemolysis, rhabdomyolysis, and other causes of cell death. All these entities can cause concomitant hyperphosphatemia and hyperuricemia. Rhabdomyolysis produces an elevated creatinine phosphokinase (CPK) value and hypocalcemia, whereas children with

hemolysis have hemoglobinuria and a decreasing hematocrit. For the child with diabetes, elevated blood glucose suggests a transcellular shift of K+ .

Treatment The plasma K+ level, the ECG, and the risk of the problem worsening determine the aggressiveness of the therapeutic approach. High serum [K+ ] and the presence of ECG changes require vigorous treatment. An additional source of concern is the patient in whom plasma K+ levels are rising despite minimal intake. This situation can happen if there is cellular release of K+ (tumor lysis syndrome), especially in the setting of diminished excretion (renal failure). The first action in a child with a concerning elevation of plasma [K+ ] is to stop all sources of additional K+ (oral, intravenous). Washed RBCs can be used for patients who require blood transfusions. If the [K+ ] is >6.5 mEq/L, an ECG should be obtained to help assess the urgency of the situation. Peak T waves are the first sign of hyperkalemia, followed by a prolonged PR interval, and when most severe, prolonged QRS complex. Life-threatening ventricular arrhythmias may also develop. The treatment of hyperkalemia has 2 basic goals: (1) to stabilize the heart to prevent life-threatening arrhythmias and (2) to remove K+ from the body. The treatments that acutely prevent arrhythmias all have the advantage of working quickly (within minutes) but do not remove K+ from the body. Calcium stabilizes the cell membrane of heart cells, preventing arrhythmias; it is given intravenously over a few minutes, and its action is almost immediate. Calcium should be given over 30 min in a patient receiving digitalis; otherwise the calcium may cause arrhythmias. Bicarbonate causes potassium to move intracellularly, lowering the plasma [K+ ]; it is most efficacious in a patient with a metabolic acidosis. Insulin causes K+ to move intracellularly but must be given with glucose to avoid hypoglycemia. The combination of insulin and glucose works within 30 min. Nebulized albuterol , by stimulation of β1 adrenergic receptors, leads to rapid intracellular movement of K+ . This has the advantage of not requiring an IV route of administration, allowing it to be given concurrently with the other measures. It is critical to begin measures that remove K+ from the body. In patients who are not anuric, a loop diuretic increases renal excretion of K+ . A high dose may be required in a patient with significant renal insufficiency. Sodium polystyrene sulfonate (SPS ; Kayexalate) is an exchange resin that is given either rectally or

orally. Patiromer is an oral exchange resin for treating hyperkalemia. Some patients require dialysis for acute K+ removal. Dialysis is often necessary if the patient has either severe renal failure or an especially high rate of endogenous K+ release, as is sometimes present with tumor lysis syndrome or rhabdomyolysis. Hemodialysis rapidly lowers plasma [K+ ]. Peritoneal dialysis is not nearly as quick or reliable, but it is usually adequate as long as the acute problem can be managed with medications and the endogenous release of K+ is not high. Long-term management of hyperkalemia includes reducing intake through dietary changes and eliminating or reducing medications that cause hyperkalemia (see Chapter 550 ). Some patients require medications to increase potassium excretion, such as SPS, patiromer and loop or thiazide diuretics. Some infants with chronic renal failure may need to start dialysis to allow adequate caloric intake without hyperkalemia. It is unusual for an older child to require dialysis principally to control chronic hyperkalemia. The disorders caused by aldosterone deficiency respond to replacement therapy with fludrocortisone.

Hypokalemia Hypokalemia is common in children, with most cases related to gastroenteritis.

Etiology and Pathophysiology There are 4 basic mechanisms of hypokalemia (Table 68.5 ). Spurious hypokalemia occurs in patients with leukemia and very elevated WBC counts if plasma for analysis is left at room temperature, permitting the WBCs to take up K+ from the plasma. With a transcellular shift, there is no change in total body K+ , although there may be concomitant potassium depletion resulting from other factors. Decreased intake, extrarenal losses, and renal losses are all associated with total body K+ depletion.

Table 68.5

Causes of Hypokalemia Spurious Laboratory Value High white blood cell count

Transcellular Shifts Alkalemia Insulin α-Adrenergic agonists Drugs/toxins (theophylline, barium, toluene, cesium chloride, hydroxychloroquine) Hypokalemic periodic paralysis (OMIM 170400) Thyrotoxic period paralysis Refeeding syndrome

Decreased Intake Anorexia nervosa

Extrarenal Losses Diarrhea Laxative abuse Sweating Sodium polystyrene sulfonate (Kayexalate) or clay ingestion

Renal Losses With Metabolic Acidosis Distal renal tubular acidosis (OMIM 179800/602722/267300) Proximal renal tubular acidosis (OMIM 604278)* Ureterosigmoidostomy Diabetic ketoacidosis Without Specific Acid–Base Disturbance Tubular toxins: amphotericin, cisplatin, aminoglycosides Interstitial nephritis Diuretic phase of acute tubular necrosis

Postobstructive diuresis Hypomagnesemia High urine anions (e.g., penicillin or penicillin derivatives) With Metabolic Alkalosis Low urine chloride Emesis or nasogastric suction Chloride-losing diarrhea (OMIM 214700) Cystic fibrosis (OMIM 219700) Low-chloride formula Posthypercapnia Previous loop or thiazide diuretic use High urine chloride and normal blood pressure Gitelman syndrome (OMIM 263800) Bartter syndrome (OMIM 241200/607364/602522/601678/300971/601198/613090) Autosomal dominant hypoparathyroidism (OMIM 146200) EAST syndrome (OMIM 612780) Loop and thiazide diuretics (current) High urine chloride and high blood pressure Adrenal adenoma or hyperplasia Glucocorticoid-remediable aldosteronism (OMIM 103900) Renovascular disease Renin-secreting tumor 17β-Hydroxylase deficiency (OMIM 202110) 11β-Hydroxylase deficiency (OMIM 202010) Cushing syndrome 11β-Hydroxysteroid dehydrogenase deficiency (OMIM 218030) Licorice ingestion Liddle syndrome (OMIM 177200)

* Most cases of proximal renal tubular acidosis are not caused by this primary

genetic disorder. Proximal renal tubular acidosis is usually part of Fanconi syndrome, which has multiple etiologies.

EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM, database number from the Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim ). Because the intracellular [K+ ] is much higher than the plasma level, a significant amount of K+ can move into cells without greatly changing the intracellular [K+ ]. Alkalemia is one of the more common causes of a transcellular shift. The effect is much greater with a metabolic alkalosis than with a respiratory alkalosis. The impact of exogenous insulin on K+ movement into the cells is substantial in patients with DKA. Endogenous insulin may be the cause when a patient is given a bolus of glucose. Both endogenous (epinephrine in stress) and exogenous (albuterol) β-adrenergic agonists stimulate cellular uptake of K+ . Theophylline overdose, barium intoxication, administration of cesium chloride (a homeopathic cancer remedy), and toluene intoxication from paint or glue sniffing can cause a transcellular shift hypokalemia, often with severe clinical manifestations. Children with hypokalemic periodic paralysis, a rare autosomal dominant disorder, have acute cellular uptake of K+ (see Chapter 629 ). Thyrotoxic periodic paralysis, which is more common in Asians, is an unusual initial manifestation of hyperthyroidism. Affected patients have dramatic hypokalemia as a result of a transcellular shift of potassium. Hypokalemia can occur during refeeding syndrome (see Chapters 58 and 364.8 ). Inadequate K+ intake occurs in anorexia nervosa ; accompanying bulimia and laxative or diuretic abuse exacerbates the K+ deficiency. Sweat losses of K+ can be significant during vigorous exercise in a hot climate. Associated volume depletion and hyperaldosteronism increase renal losses of K+ (discussed later). Diarrheal fluid has a high concentration of K+ , and hypokalemia as a result of diarrhea is usually associated with metabolic acidosis resulting from stool losses of bicarbonate. In contrast, normal acid-base balance or mild metabolic alkalosis is seen with laxative abuse. Intake of SPS or ingestion of clay because of pica increases stool losses of potassium. Urinary potassium wasting may be accompanied by a metabolic acidosis (proximal or distal RTA). In DKA, although it is often associated with normal plasma [K+ ] from transcellular shifts, there is significant total body K+ depletion from urinary losses because of the osmotic diuresis, and the K+ level may decrease dramatically with insulin therapy (see Chapter 607 ). Both the polyuric

phase of acute tubular necrosis and postobstructive diuresis cause transient, highly variable K+ wasting and may be associated with metabolic acidosis. Tubular damage, which occurs either directly from medications or secondary to interstitial nephritis, is often accompanied by other tubular losses, including magnesium, Na+ , and water. Such tubular damage may cause a secondary RTA with metabolic acidosis. Isolated magnesium deficiency causes renal K+ wasting. Penicillin is an anion excreted in the urine, resulting in increased K+ excretion because the penicillin anion must be accompanied by a cation. Hypokalemia from penicillin therapy occurs only with the sodium salt of penicillin, not with the potassium salt. Urinary K+ wasting is often accompanied by a metabolic alkalosis. This condition is usually associated with increased aldosterone, which increases urinary K+ and acid losses, contributing to the hypokalemia and the metabolic alkalosis. Other mechanisms often contribute to both the K+ losses and the metabolic alkalosis. With emesis or nasogastric suction, there is gastric loss of K+ , but this is fairly minimal, given the low K+ content of gastric fluid, approximately 10 mEq/L. More important is the gastric loss of hydrochloric acid (HCl), leading to metabolic alkalosis and a state of volume depletion. The kidney compensates for metabolic alkalosis by excreting bicarbonate in the urine, but there is obligate loss of K+ and Na+ with the bicarbonate. The volume depletion raises aldosterone levels, further increasing urinary K+ losses and preventing correction of metabolic alkalosis and hypokalemia until the volume depletion is corrected. Urinary chloride (Cl− ) is low as a response to the volume depletion. Because the volume depletion is secondary to Cl− loss, this is a state of Cl − deficiency . There were cases of Cl− deficiency resulting from infant formula deficient in Cl, which caused a metabolic alkalosis with hypokalemia and low urine [Cl− ]. Current infant formula is not deficient in Cl− . A similar mechanism occurs in cystic fibrosis because of Cl− loss in sweat. In congenital chloride-losing diarrhea , an autosomal recessive disorder, there is high stool loss of Cl− , leading to metabolic alkalosis, an unusual sequela of diarrhea. Because of stool K+ losses, Cl− deficiency, and metabolic alkalosis, patients with this disorder have hypokalemia. During respiratory acidosis, there is renal compensation, with retention of bicarbonate and excretion of Cl− . After the respiratory acidosis is corrected, the patients have Cl− deficiency and post–hypercapnic alkalosis with

secondary hypokalemia. Patients with Cl− deficiency, metabolic alkalosis, and hypokalemia have a urinary [Cl− ] of 15 mg/dL) causes complete heart block and cardiac arrest. Other manifestations of hypermagnesemia include nausea, vomiting, and hypocalcemia.

Diagnosis Except for the case of the neonate with transplacental exposure, a high index of suspicion and a good history are necessary to make the diagnosis of hypermagnesemia. Prevention is essential; magnesium-containing compounds should be used judiciously in children with renal insufficiency.

Treatment Most patients with normal renal function rapidly clear excess magnesium. Intravenous hydration and loop diuretics can accelerate this process. In severe cases, especially in patients with underlying renal insufficiency, dialysis may be necessary. Hemodialysis works faster than peritoneal dialysis. Exchange transfusion is another option in newborn infants. Supportive care includes monitoring of cardiorespiratory status, provision of fluids, monitoring of electrolyte levels, and the use of pressors for hypotension. In acute emergencies, especially in the context of severe neurologic or cardiac manifestations, 100 mg/kg of IV calcium gluconate is transiently effective.

Bibliography Magnesium Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol . 2015;10:1257–1272. Costello R, Wallace TC, Rosanoff A. Magnesium. Adv Nutr . 2016;7:199–201. Huang JW, Famure O, Li Y, et al. Hypomagnesemia and the risk

of new-onset diabetes mellitus after kidney transplantation. J Am Soc Nephrol . 2016;27:1793–1800. Janett S, Bianchetti MG, Milani GP, et al. Hypomagnesemia following prolonged use of proton-pump inhibitors. J Pediatr Gastroenterol Nutr . 2016;62:e39. Jiang L, Chen C, Yuan T, et al. Clinical severity of Gitelman syndrome determined by serum magnesium. Am J Nephrol . 2014;39:357–366. Konrad M, Schlingmann KP. Inherited disorders of renal hypomagnesaemia. Nephrol Dial Transplant . 2014;29(Suppl 4):iv63–iv71. Tilman M, Wolf F. Inherited and acquired disorders of magnesium homeostasis. Curr Opin Pediatr . 2017;29:187– 198. Van der Made CI, Hoorn EJ, de la Faille R, et al. Hypomagnesemia as first clinical manifestation of ADTKDHNF1B: A case series and literature review. Am J Nephrol . 2015;42:85–90. William JH, Danziger J. Magnesium deficiency and protonpump inhibitor use: a clinical review. J Clin Pharmacol . 2016;56:660–668.

68.6

Phosphorus Larry A. Greenbaum

Keywords hypophosphatemia hyperphosphatemia vitamin D rickets FGF-23 phosphate binders parathyroid hormone PTH refeeding hypophosphatemia hungry bone syndrome hypoparathyroidism hyperparathyroidism osteomalacia chronic kidney disease rhabdomyolysis tumor lysis familial tumoral calcinosis Approximately 65% of plasma phosphorus is in phospholipids, but these compounds are insoluble in acid and are not measured by clinical laboratories. It is the phosphorus content of plasma phosphate that is determined. The result is reported as either phosphate or phosphorus, although even when the term phosphate is used, it is actually the phosphorus concentration that is measured

and reported. The result is that the terms phosphate and phosphorus are often used interchangeably. The term phosphorus is preferred when referring to the plasma concentration. Conversion from the units used in the United States (mg/dL) to mmol/L is straightforward (see Table 68.6 ).

Phosphorus Metabolism Body Content and Physiologic Function Most phosphorus is in bone or is intracellular, with 4,000 mEq of bicarbonate enters Bowman's space each day. This bicarbonate, if not reclaimed along the nephron, would be lost in the urine and would cause a profound metabolic acidosis. The proximal tubule reclaims approximately 85% of the filtered bicarbonate (Fig. 68.6 ). The final 15% is reclaimed beyond the proximal tubule, mostly in the ascending limb of the loop of Henle. Bicarbonate molecules are not transported from the tubular fluid into the cells of the proximal tubule. Rather, hydrogen ions are secreted into the tubular fluid, leading to conversion of filtered bicarbonate into CO2 and water. The secretion of H+ by the cells of the proximal tubule is coupled to generation of intracellular bicarbonate, which is transported across the basolateral membrane of the proximal tubule cell and enters the capillaries. The bicarbonate produced in the cell replaces the bicarbonate filtered at the glomerulus.

FIG. 68.6 Resorption of filtered bicarbonate in the proximal tubule. The Na+ ,K+ -ATPase (1) excretes sodium across the basolateral cell membrane, maintaining a low intracellular sodium concentration. The low intracellular sodium concentration provides the energy for the Na+ ,H+ antiporter (2) , which exchanges sodium from the tubular lumen for intracellular hydrogen ions. The hydrogen ions that are secreted into

the tubular lumen then combine with filtered bicarbonate to generate carbonic acid. CO2 and water are produced from carbonic acid (H2 CO3 ). This reaction is catalyzed by luminal carbonic anhydrase (3) . CO2 diffuses into the cell and combines with OH− ions to generate bicarbonate. This reaction is catalyzed by an intracellular carbonic anhydrase (4) . The dissociation of water generates an OH− ion and an H+ ion. The Na+ ,H+ antiporter (2) secretes the hydrogen ions. Bicarbonate ions cross the basolateral membrane and enter the blood via the 3HCO3 − /1Na+ co-transporter (5) . The energy for the 3HCO3 − /1Na+ co-transporter comes from the negatively charged cell interior, which makes it electrically favorable to transport a net negative charge (i.e., 3 bicarbonates and only 1 sodium) out of the cell.

Increased bicarbonate resorption by the cells of the proximal tubule—the result of increased H+ secretion—occurs in a variety of clinical situations. Volume depletion increases bicarbonate resorption. This is partially mediated by activation of the renin-angiotensin system; angiotensin II increases bicarbonate resorption. Increased bicarbonate resorption in the proximal tubule is one of the mechanisms that accounts for the metabolic alkalosis that may occur in some patients with volume depletion. Other stimuli that increase bicarbonate resorption include hypokalemia and an increased PCO 2 . This partially explains the observations that hypokalemia causes a metabolic alkalosis, and that a respiratory acidosis leads to a compensatory increase in serum [HCO3 − ]. Stimuli that decrease bicarbonate resorption in the proximal tubule may cause a decrease in the serum [HCO3 − ]. A decrease in the PCO 2 (respiratory alkalosis) decreases proximal tubule bicarbonate resorption, partially mediating the decrease in serum [HCO3 − ] that compensates for a respiratory alkalosis. PTH decreases proximal tubule bicarbonate resorption; hyperparathyroidism may cause a mild metabolic acidosis. A variety of medications and diseases cause a metabolic acidosis by impairing bicarbonate resorption in the proximal tubule. Examples are the medication acetazolamide, which directly inhibits carbonic anhydrase, and the many disorders that cause proximal RTA (see Chapter 547.1 ). After reclaiming filtered bicarbonate, the kidneys perform the 2nd step in renal acid-base handling, the excretion of the acid created by endogenous acid production. Excretion of acid occurs mostly in the collecting duct, with a small role for the distal tubule. Along with secretion of H+ by the tubular cells lining the collecting duct, adequate excretion of endogenous acid requires the presence of urinary buffers. The hydrogen pumps in the collecting duct cannot lower the urine pH below 4.5. The [H+ ] at pH 4.5 is 25 L of water with a pH

of 4.5 to excrete 1 mEq H+ . A 10-kg child, with an endogenous acid production of 20 mEq H+ each day, would need to have a daily urinary output of >500 L without the presence of urinary buffers. As in the blood, buffers in the urine attenuate the decrease in pH that occurs with the addition of H+ . The 2 principal urinary buffers are phosphate and ammonia. Urinary phosphate is proportional to dietary intake. Whereas most of the phosphate filtered at the glomerulus is resorbed in the proximal tubule, the urinary phosphate concentration is usually much greater than the serum phosphate concentration. This arrangement allows phosphate to serve as an effective buffer through the following reaction:

The pK a of this reaction is 6.8, making phosphate an effective buffer as the urinary pH decreases from 7.0 to 5.0 within the collecting duct. Although phosphate is an effective buffer, its buffering capacity is limited by its concentration; there is no mechanism for increasing urinary phosphate excretion in response to changes in acid-base status. In contrast, ammonia production can be modified, allowing for regulation of acid excretion. The buffering capacity of ammonia (NH3 ) is based on the reaction of ammonia with hydrogen ions to form ammonium:

The cells of the proximal tubule are the source of the excreted ammonia, mostly through metabolism of glutamine through the following reactions:

The metabolism of glutamine generates 2 ammonium ions. In addition, the

metabolism of α-ketoglutarate generates 2 bicarbonate molecules. The ammonium ions are secreted into the lumen of the proximal tubule, whereas the bicarbonate molecules exit the proximal tubule cells via the basolateral Na+ ,3HCO3 − co-transporter (see Fig. 68.6 ). This arrangement would seem to accomplish the goal of excreting H+ (as NH4 + ) and regenerating bicarbonate molecules. However, the ammonium ions secreted in the proximal tubule do not remain within the tubular lumen. Cells of the TAL of the loop of Henle resorb the ammonium ions. The result is that there is a high medullary interstitial concentration of ammonia, but the tubular fluid entering the collecting duct does not have significant amounts of ammonium ions. Moreover, the hydrogen ions that were secreted with ammonia, as ammonium ions, in the proximal tubule enter the bloodstream, canceling the effect of the bicarbonate generated in the proximal tubule. The excretion of ammonium ions, and thus of hydrogen ions, depends on the cells of the collecting duct. The cells of the collecting duct secrete H+ and regenerate bicarbonate, which is returned to the bloodstream (Fig. 68.7 ). This bicarbonate neutralizes endogenous acid production. Phosphate and ammonia buffer the H+ secreted by the collecting duct. Ammonia is an effective buffer because of the high concentrations in the medullary interstitium and because the cells of the collecting duct are permeable to ammonia but not to ammonium. As ammonia diffuses into the lumen of the collecting duct, the low urine pH causes almost all the ammonia to be converted into ammonium. This process maintains a low luminal ammonia concentration. Because the luminal pH is lower than the pH in the medullary interstitium, there is a higher concentration of ammonia within the medullary interstitium than in the tubular lumen, favoring movement of ammonia into the tubular lumen. Even though the concentration of ammonium in the tubular lumen is higher than in the interstitium, the cells of the collecting duct are impermeable to ammonium, preventing back-diffusion of ammonium out of the tubular lumen and permitting ammonia to be an effective buffer.

FIG. 68.7 Secretion of hydrogen ions in the collecting duct. The dissociation of water generates an OH− ion and an H+ ion. The H+ -ATPase (1) secretes hydrogen ions into the tubular lumen. Bicarbonate is formed when an OH− ion combines with CO2 in a reaction mediated by carbonic anhydrase (2) . Bicarbonate ions cross the basolateral membrane and enter the blood via the HCO3 − /Cl− exchanger (3) . The hydrogen ions in the tubular lumen are buffered by phosphate and ammonia (NH3 ). NH3 can diffuse from the peritubular fluid into the tubular lumen, but ammonium (NH4 + ) cannot pass through the cells of the collecting duct.

The kidneys adjust H+ excretion according to physiologic needs. There is variation in endogenous acid production, largely a result of diet and pathophysiologic stresses, such as diarrheal losses of bicarbonate, which increase the need for acid excretion. H+ excretion is increased by upregulation of H+ secretion in the collecting duct, causing the pH of the urine to decrease. This response is fairly prompt, occurring within hours of an acid load, but it is limited by the buffering capacity of the urine; the hydrogen pumps in the collecting duct cannot lower the pH to 1 primary acid-base disturbance. An infant with bronchopulmonary dysplasia may have a respiratory acidosis from chronic lung disease and a metabolic alkalosis from the furosemide used to treat the chronic lung disease. More dramatically, a child with pneumonia and sepsis may have severe acidemia as a result of a combined metabolic acidosis caused by lactic acid and respiratory acidosis caused by ventilatory failure.

There are formulas for calculating the appropriate metabolic or respiratory compensation for the 6 primary simple acid-base disorders (Table 68.11 ). The appropriate compensation is expected in a simple disorder; it is not optional. If a patient does not have the appropriate compensation, a mixed acid-base disorder is present. A patient has a primary metabolic acidosis with a serum [HCO3 − ] of 10 mEq/L. The expected respiratory compensation is [CO2 ] of 23 mm Hg ± 2 (1.5 × 10 + 8 ± 2 = 23 ± 2; Table 68.11 ). If the patient's [CO2 ] is >25 mm Hg, a concurrent respiratory acidosis is present; [CO2 ] is higher than expected. A patient may have a respiratory acidosis despite a CO2 level below the “normal” value of 35-45 mm Hg. In this example, [CO2 ] 7.4. A mixed disorder is present if the metabolic compensation is inappropriate. A higher-than-expected HCO3 − level occurs in the setting of a concurrent metabolic alkalosis, and a lower-than-expected HCO3 − level occurs in the setting of a concurrent metabolic acidosis. Evaluating whether compensation is appropriate during a respiratory alkalosis requires clinical knowledge of the acuity of the process, because the expected compensation differs according to whether the process is acute or chronic. A low PCO 2 value does not always indicate a respiratory alkalosis. The PCO 2 also decreases as part of the appropriate respiratory compensation for a metabolic acidosis; this is not a respiratory alkalosis. A metabolic acidosis is the dominant acid-base disturbance in a patient with acidemia and a low PCO 2 , even though there could still be a concurrent respiratory alkalosis. In contrast, a respiratory alkalosis is always present in a patient with alkalemia and a low PCO 2 . Even a normal PCO 2 value may be consistent with a respiratory alkalosis in a patient with a metabolic alkalosis, because an elevated PCO 2 is expected as part of appropriate respiratory compensation for the metabolic alkalosis.

Etiology and Pathophysiology A variety of stimuli can increase the ventilatory drive and cause a respiratory alkalosis (Table 68.16 ). Arterial hypoxemia or tissue hypoxia stimulates peripheral chemoreceptors to signal the central respiratory center in the medulla to increase ventilation. The resultant greater respiratory effort increases the oxygen content of the blood (PO 2 ) but depresses the PCO 2 . The effect of hypoxemia on ventilation begins when the arterial oxygen saturation (SaO 2 ) decreases to approximately 90% (PO 2 = 60 mm Hg), and hyperventilation increases as hypoxemia worsens. Acute hypoxia is a more potent stimulus for hyperventilation than chronic hypoxia; thus chronic hypoxia, as occurs in

cyanotic heart disease, causes a much less severe respiratory alkalosis than an equivalent degree of acute hypoxia. The many causes of hypoxemia or tissue hypoxia include primary lung disease, severe anemia, and carbon monoxide (CO) poisoning.

Table 68.16

Causes of Respiratory Alkalosis Hypoxemia or Tissue Hypoxia Pneumonia Pulmonary edema Cyanotic heart disease Congestive heart failure Asthma Severe anemia High altitude Laryngospasm Aspiration Carbon monoxide poisoning Pulmonary embolism Interstitial lung disease Hypotension

Lung Receptor Stimulation Pneumonia Pulmonary edema Asthma Pulmonary embolism Hemothorax Pneumothorax Respiratory distress syndrome (adult or infant)

Central Stimulation

Central nervous system disease Subarachnoid hemorrhage Encephalitis or meningitis Trauma Brain tumor Stroke Fever Pain Anxiety (panic attack) Psychogenic hyperventilation or anxiety Liver failure Sepsis Pregnancy Mechanical ventilation Hyperammonemia Extracorporeal membrane oxygenation or hemodialysis Medications Salicylate intoxication Theophylline Progesterone Exogenous catecholamines Caffeine The lungs contain chemoreceptors and mechanoreceptors that respond to irritants and stretching and send signals to the respiratory center to increase ventilation. Aspiration or pneumonia may stimulate the chemoreceptors, whereas pulmonary edema may stimulate the mechanoreceptors. Most of the diseases that activate these receptors may also cause hypoxemia and can therefore potentially lead to hyperventilation by 2 mechanisms. Patients with primary lung disease may initially have a respiratory alkalosis, but worsening of the disease, combined with respiratory muscle fatigue, often causes respiratory failure and the development of a respiratory acidosis. Hyperventilation in the absence of lung disease occurs with direct stimulation of the central respiratory center. This occurs with CNS diseases such as meningitis, hemorrhage, and trauma. Central hyperventilation caused by lesions, such as infarcts or tumors near the central respiratory center in the midbrain, increases the rate and depth of the respiratory effort. This respiratory

pattern portends a poor prognosis because these midbrain lesions are frequently fatal. Systemic processes may cause centrally mediated hyperventilation. Although the exact mechanisms are not clear, liver disease causes a respiratory alkalosis that is usually proportional to the degree of liver failure. Pregnancy causes a chronic respiratory alkalosis, probably mediated by progesterone acting on the respiratory centers. Salicylates , although often causing a concurrent metabolic acidosis, directly stimulate the respiratory center to produce a respiratory alkalosis. The respiratory alkalosis during sepsis is probably caused by cytokine release. Hyperventilation may be secondary to an underlying disease that causes pain, stress, or anxiety. In psychogenic hyperventilation or in panic attacks , there is no disease process accounting for the hyperventilation. This disorder may occur in a child who has had an emotionally stressful experience. Alternatively, it may be part of a panic disorder, especially if there are repeated episodes of hyperventilation. In such a patient the symptoms of acute alkalemia increase anxiety, potentially perpetuating the hyperventilation. A respiratory alkalosis is quite common in children receiving mechanical ventilation because the respiratory center is not controlling ventilation. In addition, these children may have a decreased metabolic rate and thus less CO2 production because of sedation and paralytic medications. Normally, decreased CO2 production and the resultant hypocapnia decrease ventilation, but this physiologic response cannot occur in a child who cannot reduce ventilatory effort.

Clinical Manifestations The disease process causing the respiratory alkalosis is usually more concerning than the clinical manifestations. Chronic respiratory alkalosis is usually asymptomatic because metabolic compensation decreases the magnitude of the alkalemia. Acute respiratory alkalosis may cause chest tightness, palpitations, lightheadedness, circumoral numbness, and paresthesias of the extremities. Less common manifestations include tetany, seizures, muscle cramps, and syncope. The lightheadedness and syncope probably result from the reduction in cerebral blood flow caused by hypocapnia. The reduction in cerebral blood flow is the rationale for using hyperventilation to treat children with increased intracranial pressure (ICP). The paresthesias, tetany, and seizures may be partially related to

the reduction in ionized calcium that occurs because alkalemia causes more calcium to bind to albumin. A respiratory alkalosis also causes a mild reduction in the serum potassium level. Patients with psychogenic hyperventilation tend to be most symptomatic as a result of the respiratory alkalosis, and these symptoms, along with a sensation of breathlessness, exacerbate the hyperventilation.

Diagnosis In many patients, hyperventilation producing a respiratory alkalosis is not clinically detectable, even with careful observation of the patient's respiratory effort. Metabolic compensation for a respiratory alkalosis causes a low serum [HCO3 − ]. When hyperventilation is not appreciated and only serum electrolytes are evaluated, there is often a presumptive diagnosis of a metabolic acidosis. If a respiratory alkalosis is suspected, only ABG determination can make the diagnosis. Hyperventilation does not always indicate a primary respiratory disorder. In some patients the hyperventilation is appropriate respiratory compensation for a metabolic acidosis. With a primary metabolic acidosis, acidemia is present, and the serum HCO3 − level is usually quite low if there is clinically detectable hyperventilation. In contrast, the serum HCO3 − level never goes below 17 mEq/L as part of the metabolic compensation for acute respiratory alkalosis, and simple acute respiratory alkalosis causes alkalemia. The etiology of a respiratory alkalosis is often apparent from the physical examination or history, and it may consist of lung disease, neurologic disease, or cyanotic heart disease. Hypoxemia is a common cause of hyperventilation, and it is important to diagnose because it suggests a significant underlying disease that requires expeditious treatment. Hypoxemia may be detected on physical examination (cyanosis) or by pulse oximetry. However, normal pulse oximetry values do not eliminate hypoxemia as the etiology of the hyperventilation. There are 2 reasons why pulse oximetry is not adequate for eliminating hypoxemia as a cause of a respiratory alkalosis. First, pulse oximetry is not very sensitive at detecting a mildly low arterial PO 2 (PaO 2 ). Second, the hyperventilation during a respiratory alkalosis causes PaO 2 to increase, possibly to a level that is not identified as abnormal by pulse oximetry. Only ABG measurement can eliminate hypoxia as an explanation for a respiratory alkalosis. Along with hypoxemia, it

is important to consider processes that cause tissue hypoxia without necessarily causing hypoxemia . Examples are CO poisoning, severe anemia, and heart failure. Lung disease without hypoxemia may cause hyperventilation. Although lung disease is often apparent by history or physical examination, a chest radiograph may detect more subtle disease. The patient with a pulmonary embolism may have benign chest radiograph findings, normal PaO 2 , and isolated respiratory alkalosis, although hypoxia may eventually occur. Diagnosis of a pulmonary embolism requires a high index of suspicion and should be considered in children without another explanation for respiratory alkalosis, especially if risk factors are present, such as prolonged bed rest and a hypercoagulable state (e.g., nephrotic syndrome, lupus anticoagulant).

Treatment There is seldom a need for specific treatment of respiratory alkalosis. Rather, treatment focuses on the underlying disease. Mechanical ventilator settings are adjusted to correct iatrogenic respiratory alkalosis, unless the hyperventilation has a therapeutic purpose (e.g., treatment of increased ICP). For the patient with hyperventilation secondary to anxiety, efforts should be undertaken to reassure the child, usually enlisting the parents. Along with reassurance, patients with psychogenic hyperventilation may benefit from benzodiazepines. During an acute episode of psychogenic hyperventilation, rebreathing into a paper bag increases the patient's PCO 2 . Using a paper bag instead of a plastic bag allows adequate oxygenation but permits [CO2 ] in the bag to increase. The resultant increase in the patient's PCO 2 decreases the symptoms of the respiratory alkalosis that tend to perpetuate the hyperventilation. Rebreathing should be performed only when other causes of hyperventilation have been eliminated; pulse oximetry during the rebreathing is prudent.

Bibliography Acid-Base Balance Adrogue HJ, Madias NE. Assessing acid-base status:

physiologic versus physicochemical approach. Am J Kidney Dis . 2016;68:793–802. Faisy C, Meziani F, Planquette B, et al. Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease: a randomized clinical trial. JAMA . 2016;315:480–488. Gomez H, Kellum JA. Understanding acid base disorders. Crit Care Clin . 2015;31:849–860. Hamm LL, Nakhoul N, Hering-Smith KS. Acid-base homeostasis. Clin J Am Soc Nephrol . 2015;10:2232–2242. Kitterer D, Schwab M, Alscher MD, et al. Drug-induced acidbase disorders. Pediatr Nephrol . 2015;30:1407–1423. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med . 2014;371:2309–2319. Protti A, Ronchi D, Bassi G, et al. Changes in whole-body oxygen consumption and skeletal muscle mitochondria during linezolid-induced lactic acidosis. Crit Care Med . 2016;44:e579–e582. Soleimani M, Rastegar A. Pathophysiology of renal tubular acidosis: core curriculum 2016. Am J Kidney Dis . 2016;68:488–498.

CHAPTER 69

Maintenance and Replacement Therapy Larry A. Greenbaum

Maintenance intravenous (IV) fluids are used in a child who cannot be fed enterally. Along with maintenance fluids, children may require concurrent replacement fluids if they have continued excessive losses, as may occur with drainage from a nasogastric (NG) tube or with high urine output because of nephrogenic diabetes insipidus. If dehydration is present, the patient also needs to receive deficit replacement (see Chapter 70 ). A child awaiting surgery may need only maintenance fluids, whereas a child with diarrheal dehydration needs maintenance and deficit therapy and also may require replacement fluids if significant diarrhea continues.

Maintenance Therapy Children normally have large variations in their daily intake of water and electrolytes. The only exceptions are patients who receive fixed dietary regimens orally, via a gastric tube, or as IV total parenteral nutrition (TPN). Healthy children can tolerate significant variations in intake because of the many homeostatic mechanisms that can adjust absorption and excretion of water and electrolytes (see Chapter 68 ). The calculated water and electrolyte needs that form the basis of maintenance therapy are not absolute requirements. Rather, these calculations provide reasonable guidelines for a starting point to estimate IV therapy. Children do not need to be started on IV fluids simply because their intake is being monitored in a hospital and they are not taking “maintenance fluids” orally, unless there is a pathologic process present that necessitates high fluid intake.

Maintenance fluids are most often necessary in preoperative and postoperative surgical patients; many nonsurgical patients also require maintenance fluids. It is important to recognize when it is necessary to begin maintenance fluids. A normal teenager who is given nothing by mouth (NPO) overnight for a morning procedure does not require maintenance fluids because a healthy adolescent can easily tolerate 12 or 18 hr without oral intake. In contrast, a 6 mo old child waiting for surgery should begin receiving IV fluids within 8 hr of the last feeding. Infants become dehydrated more quickly than older patients. A child with obligatory high urine output from nephrogenic diabetes insipidus should begin receiving IV fluids soon after being classified as NPO. Maintenance fluids are composed of a solution of water, glucose, sodium (Na+ ), and potassium (K+ ). This solution has the advantages of simplicity, long shelf life, low cost, and compatibility with peripheral IV administration. Such a solution accomplishes the major objectives of maintenance fluids (Table 69.1 ). Patients lose water, Na+ , and K+ in their urine and stool; water is also lost from the skin and lungs. Maintenance fluids replace these losses, thereby avoiding the development of dehydration and Na+ or K+ deficiency.

Table 69.1

Goals of Maintenance Fluids • Prevent dehydration • Prevent electrolyte disorders • Prevent ketoacidosis • Prevent protein degradation The glucose in maintenance fluids provides approximately 20% of the normal caloric needs of the patient, prevents the development of starvation ketoacidosis, and diminishes the protein degradation that would occur if the patient received no calories. Glucose also provides added osmoles, thus avoiding the administration of hypotonic fluids that may cause hemolysis. Maintenance fluids do not provide adequate calories, protein, fat, minerals, or vitamins. This fact is typically not problematic for a patient receiving IV fluids for a few days. A patient receiving maintenance IV fluids is receiving inadequate calories and will lose 0.5–1% of weight each day. It is imperative that patients not remain on maintenance therapy indefinitely; TPN should be used for

children who cannot be fed enterally for more than a few days, especially patients with underlying malnutrition. Prototypical maintenance fluid therapy does not provide electrolytes such as calcium, phosphorus, magnesium, and bicarbonate. For most patients, this lack is not problematic for a few days, although there are patients who will not tolerate this omission, usually because of excessive losses. A child with proximal renal tubular acidosis wastes bicarbonate in urine. Such a patient will rapidly become acidemic unless bicarbonate (or acetate) is added to the maintenance fluids. It is important to remember the limitations of maintenance fluid therapy.

Maintenance Water Water is a crucial component of maintenance fluid therapy because of the obligatory daily water losses. These losses are both measurable (urine, stool) and not measurable (insensible losses from the skin and lungs). Failure to replace these losses leads to a child who is thirsty, uncomfortable, and ultimately dehydrated. The goal of maintenance water is to provide enough water to replace these losses. Although urinary losses are approximately 60% of the total, the normal kidney can greatly modify water losses, with daily urine volume potentially varying by more than a factor of 20. Maintenance water is designed to provide enough water so that the kidney does not need to significantly dilute or concentrate the urine. It also provides a margin of safety, so that normal homeostatic mechanisms can adjust urinary water losses to prevent overhydration and dehydration. This adaptability obviates the need for absolute precision in determining water requirements. This fact is important, given the absence of absolute accuracy in the formulas for calculation of water needs. Table 69.2 provides a system for calculating maintenance water on the basis of the patient's weight and emphasizes the high water needs of smaller, less mature patients. This approach is reliable, although calculations based on weight do overestimate the water needs of an overweight child, in whom it is better to base the calculations on the lean body weight, which can be estimated by using the 50th percentile of body weight for the child's height. It is also important to remember that there is an upper limit of 2.4 L/24 hr in adult-sized patients. IV fluids are written as an hourly rate. The formulas in Table 69.3 enable rapid calculation of the rate of maintenance fluids.

Table 69.2 Body Weight Method for Calculating Daily Maintenance Fluid Volume BODY WEIGHT 0-10 kg 11-20 kg >20 kg

FLUID PER DAY 100 mL/kg 1,000 mL + 50 mL/kg for each kg >10 kg 1,500 mL + 20 mL/kg for each kg >20 kg*

* The maximum total fluid per day is normally 2,400 mL.

Table 69.3

Hourly Maintenance Water Rate For body weight 0-10 kg: 4 mL/kg/hr For body weight 10-20 kg: 40 mL/hr + 2 mL/kg/hr × (wt – 10 kg) For body weight >20 kg: 60 mL/hr + 1 mL/kg/hr × (wt – 20 kg)*

* The maximum fluid rate is normally 100 mL/hr.

Intravenous Solutions The components of available solutions are shown in Table 69.4 . These solutions are available with 5% dextrose (D5), 10% dextrose (D10), or without dextrose. Except for Ringer lactate (lactated Ringer, LR), they are also available with added potassium (10 or 20 mEq/L). A balanced IV fluid contains a base (lactate or acetate), a more physiologic chloride concentration than NS, and additional physiologic concentrations of electrolytes such as potassium, calcium, and magnesium. Examples include LR and PlasmaLyte, and there is evidence suggesting benefit versus NS in certain clinical situations. A hospital pharmacy can also prepare custom-made solutions with different concentrations of sodium or potassium. In addition, other electrolytes, such as calcium, magnesium, phosphate, acetate, and bicarbonate, can be added to IV solutions. Custom-made solutions take time to prepare and are much more expensive than commercial solutions. The use of custom-made solutions is necessary only for patients who have underlying disorders that cause significant electrolyte imbalances. The use of commercial solutions saves time and expense.

Table 69.4

Composition of Intravenous Solutions* FLUID Normal saline (0.9% NaCl) Half-normal saline (0.45% NaCl) 0.2 normal saline (0.2% NaCl) Ringer lactate

[Na+ ] 154 77 34 130

[Cl− ] 154 77 34 109

[K+ ] — — — 4

[Ca2+ ] — — — 3

[LACTATE− ] — — — 28

* Electrolyte concentrations in mEq/L.

A normal plasma osmolality is 285-295 mOsm/kg. Infusing an IV solution peripherally with a much lower osmolality can cause water to move into red blood cells, leading to hemolysis. Thus, IV fluids are generally designed to have an osmolality that is either close to 285 or greater (fluids with moderately higher osmolality do not cause problems). Thus, 0.2NS (osmolality = 68) should not be administered peripherally, but D5 0.2NS (osmolality = 346) or D5 NS + 20 mEq/L potassium chloride (KCl) with an osmolality of 472 can be administered. Controversy surrounds the appropriate sodium content of maintenance fluids, considering the observation that hypotonic fluids may cause hyponatremia, which may have serious sequelae. Hypotonic fluids seem more physiologic given the low Na+ content of breast milk and formula. However, hospitalized children often have impaired water excretion because of volume depletion or nonosmotic stimuli for antidiuretic hormone (ADH) production, such as respiratory disease, central nervous system (CNS) disease, stress, pain, nausea, and medications (e.g., narcotics). Hypotonic fluids increase the risk of hyponatremia; hence, isotonic fluids with 5% dextrose are recommended as standard maintenance fluid except in neonates .

Glucose Maintenance fluids usually contain D5, which provides 17 calories/100 mL and nearly 20% of the daily caloric needs. This level is enough to prevent ketone production and helps minimize protein degradation, but the child will lose weight on this regimen. The weight loss is the principal reason why a patient needs to be started on TPN after a few days of maintenance fluids if enteral feedings are still not possible. Maintenance fluids are also lacking in such crucial nutrients as protein, fat, vitamins, and minerals.

Selection of Maintenance Fluids An isotonic fluid (NS, LR, PlasmaLyte) with 5% dextrose and KCl (10-20 mEq/L is usually added to NS) is recommended for maintenance IV fluids. Surgical patients typically receive isotonic fluids (NS, LR) during surgery and in the recovery room for 6-8 hr postoperatively; the rate is typically approximately two-thirds the calculated maintenance rate, with dextrose added if clinically indicated. Subsequent maintenance fluids have the addition of 5% dextrose and 10-20 mEq/L KCl based on the serum K+ and the clinical setting. Electrolytes should be measured at least daily in all children receiving >50% of maintenance fluids intravenously unless the child is receiving prolonged IV fluids (TPN). These guidelines assume that no disease process is present that would require an adjustment in either the volume or the electrolyte composition of maintenance fluids. Neonates, and especially premature infants, are outside the scope of these guidelines given their unique physiology. Children with renal insufficiency may be hyperkalemic or unable to excrete K+ and may not tolerate 10 or 20 mEq/L of potassium. Patients with persistent ADH production because of an underlying disease process (syndrome of inappropriate ADH secretion, congestive heart failure, nephrotic syndrome, liver disease) should receive less than maintenance fluids. Children with meningitis are fluid-restricted unless intravascular volume depletion is present (see Chapter 621.1 ). Treatment is individualized, and careful monitoring is critical. In children with complicated pathophysiologic derangements, it may be necessary to adjust empirically the electrolyte composition and rate of maintenance fluids on the basis of electrolyte measurements and assessment of fluid balance. In all children it is critical to monitor weight, urine output, and electrolytes carefully to identify overhydration or underhydration, hyponatremia, and other electrolyte disturbances, and then adjust the rate or composition of the IV solution accordingly.

Variations in Maintenance Water and Electrolytes The calculation of maintenance water is based on standard assumptions regarding water losses. In some patients, however, these assumptions are incorrect. To identify such situations, it is helpful to understand the source and

magnitude of normal water losses. Table 69.5 lists the 3 sources of normal water loss.

Table 69.5

Sources of Water Loss • Urine: 60% • Insensible losses: ≈35% (skin and lungs) • Stool: 5% Urine is the most important contributor to normal water loss. Insensible losses represent approximately one third of total maintenance water (40% in infants; 25% in adolescents and adults). Insensible losses are composed of evaporative losses from the skin and lungs that cannot be quantitated. The evaporative losses from the skin do not include sweat, which would be considered an additional (sensible) source of water loss. Stool normally represents a minor source of water loss. Maintenance water and electrolyte needs may be increased or decreased, depending on the clinical situation. This may be obvious, as in the infant with profuse diarrhea, or subtle, as in the patient who has decreased insensible losses while receiving mechanical ventilation. It is helpful to consider the sources of normal water and electrolyte losses and to determine whether any of these sources is being modified in a specific patient. It is then necessary to adjust maintenance water and electrolyte calculations. Table 69.6 lists a variety of clinical situations that modify normal water and electrolyte losses. The skin can be a source of very significant water loss, particularly in neonates, especially premature infants, who are under radiant warmers or are receiving phototherapy. Very-low-birthweight infants can have insensible losses of 100-200 mL/kg/24 hr. Burns can result in massive losses of water and electrolytes, and there are specific guidelines for fluid management in children with burns (see Chapter 92 ). Sweat losses of water and electrolytes, especially in a warm climate, can also be significant. Children with cystic fibrosis and some children with pseudohypoaldosteronism have increased sodium losses from the skin. Table 69.6

Adjustments in Maintenance Water SOURCE Skin

Lungs Gastrointestinal tract Renal Miscellaneous

CAUSES OF INCREASED WATER NEEDS Radiant warmer Phototherapy Fever Sweat Burns Tachypnea Tracheostomy Diarrhea Emesis Nasogastric suction Polyuria Surgical drain Third spacing

CAUSES OF DECREASED WATER NEEDS Incubator (premature infant)

Humidified ventilator —

Oliguria/anuria

Fever increases evaporative losses from the skin. These losses are somewhat predictable, leading to a 10–15% increase in maintenance water needs for each 1°C (1.8°F) increase in temperature above 38°C (100.4°F). These guidelines are for a patient with a persistent fever; a 1 hr fever spike does not cause an appreciable increase in water needs. Tachypnea or a tracheostomy increases evaporative losses from the lungs. A humidified ventilator causes a decrease in insensible losses from the lungs and can even lead to water absorption via the lungs; a ventilated patient has a decrease in maintenance water requirements. It may be difficult to quantify the changes that take place in the individual patient in these situations.

Replacement Fluids The gastrointestinal (GI) tract is potentially a source of considerable water loss. GI water losses are accompanied by electrolytes and thus may cause disturbances in intravascular volume and electrolyte concentrations. GI losses are often associated with loss of potassium, leading to hypokalemia. Because of the high bicarbonate concentration in stool, children with diarrhea usually have a metabolic acidosis , which may be accentuated if volume depletion causes hypoperfusion and a concurrent lactic acidosis. Emesis or losses from an NG tube can cause a metabolic alkalosis (see Chapter 68 ). In the absence of vomiting, diarrhea, or NG drainage, GI losses of water and electrolytes are usually quite small. All GI losses are considered excessive, and

the increase in the water requirement is equal to the volume of fluid losses. Because GI water and electrolyte losses can be precisely measured, an appropriate replacement solution can be used. It is impossible to predict the losses for the next 24 hr; it is better to replace excessive GI losses as they occur. The child should receive an appropriate maintenance fluid that does not consider the GI losses. The losses should then be replaced after they occur, with use of a solution with a similar electrolyte concentration as the GI fluid. The losses are usually replaced every 1-6 hr, depending on the rate of loss, with very rapid losses being replaced more frequently. Diarrhea is a common cause of fluid loss in children and can result in dehydration and electrolyte disorders. In the unusual patient with significant diarrhea and a limited ability to take oral fluid, it is important to have a plan for replacing excessive stool losses. The volume of stool should be measured, and an equal volume of replacement solution should be given. Data are available on the average electrolyte composition of diarrhea in children (Table 69.4 ). With this information an appropriate replacement solution can be designed. The solution shown in Table 69.7 replaces stool losses of Na+ , K+ , Cl− , and bicarbonate. Each 1 mL of stool should be replaced by 1 mL of this solution. The average electrolyte composition of diarrhea is just an average, and there may be considerable variation. It is therefore advisable to consider measuring the electrolyte composition of a patient's diarrhea if the amount is especially excessive or if the patient's serum electrolyte levels are problematic.

Table 69.7

Replacement Fluid for Diarrhea Average Composition of Diarrhea Sodium: 55 mEq/L Potassium: 25 mEq/L Bicarbonate: 15 mEq/L

Approach to Replacement of Ongoing Losses Solution: D5 NS + 30 mEq/L sodium bicarbonate + 20 mEq/L KCl Replace stool mL/mL every 1-6 hr

D5, 5% dextrose; NS, normal saline. Loss of gastric fluid , through emesis or NG suction, is also likely to cause dehydration, in that most patients with either condition have impaired oral intake of fluids. Electrolyte disturbances, particularly hypokalemia and metabolic alkalosis, are also common. These complications can be avoided by judicious use of a replacement solution. The composition of gastric fluid shown in Table 69.8 is the basis for designing a replacement solution.

Table 69.8

Replacement Fluid for Emesis or Nasogastric Losses Average Composition of Gastric Fluid Sodium: 60 mEq/L Potassium: 10 mEq/L Chloride: 90 mEq/L

Approach to Replacement of Ongoing Losses Solution: normal saline + 10 mEq/L KCl Replace output mL/mL every 1-6 hr Patients with gastric losses frequently have hypokalemia, although the K+ concentration of gastric fluid is relatively low. The associated urinary K+ loss is an important cause of hypokalemia in this situation (see Chapter 68 ). These patients may need additional potassium either in their maintenance fluids or in their replacement fluids to compensate for prior or ongoing urinary losses. Restoration of the patient's intravascular volume, by decreasing aldosterone synthesis, lessens the urinary K+ losses. Urine output is normally the largest cause of water loss. Diseases such as renal failure and syndrome of inappropriate ADH secretion can lead to a decrease in urine volume. The patient with oliguria or anuria has a decreased need for water and electrolytes; continuation of maintenance fluids produces fluid overload. In contrast, postobstructive diuresis, the polyuric phase of acute

tubular necrosis, diabetes mellitus, and diabetes insipidus increase urine production. To prevent dehydration, the patient must receive more than standard maintenance fluids when urine output is excessive. The electrolyte losses in patients with polyuria are variable. In diabetes insipidus the urine electrolyte concentration is usually low, whereas children with diseases such as juvenile nephronophthisis and obstructive uropathy usually have increased losses of both water and sodium. The approach to decreased or increased urine output is similar (Table 69.9 ). The patient receives fluids at a rate to replace insensible losses. This is accomplished by a rate of fluid administration that is 25–40% of the normal maintenance rate, depending on the patient's age. Replacing insensible losses in the anuric child will theoretically maintain an even fluid balance, with the caveat that 25–40% of the normal maintenance rate is only an estimate of insensible losses. In the individual patient, this rate is adjusted on the basis of monitoring of the patient's weight and volume status. Most children with renal insufficiency receive little or no potassium because the kidney is the principal site of K+ excretion.

Table 69.9

Adjusting Fluid Therapy for Altered Renal Output Oliguria/Anuria Replacement of insensible fluid losses (25–40% of maintenance) with D5 NS Replace urine output mL/mL with D5 NS ± KCl

Polyuria Replacement of insensible fluid losses (25–40% of maintenance) with D5 NS ± KCl Measure urine electrolytes Replace urine output mL/mL with solution based on measured urine electrolytes

D5, 5% dextrose; NS, normal saline. For the oliguric child, it is important to add a urine replacement solution to prevent dehydration. This issue is especially important in the patient with acute renal failure, in whom output may increase, potentially leading to volume depletion and worsening of renal failure if the patient remains on only insensible fluids. A replacement solution of D5 NS is usually appropriate initially, although its composition may have to be adjusted if urine output increases significantly. Most children with polyuria (except in diabetes mellitus; see Chapter 607 ) should be started on replacement of insensible fluid plus urine losses. This approach avoids the need to attempt to calculate the volume of urine output that is “normal” so that the patient can be given replacement fluid for the excess. In these patients, urine output is, by definition, excessive, and it is often helpful to measure Na+ and K+ concentrations of the urine to help in formulating the urine replacement solution. Surgical drains and chest tubes can produce measurable fluid output. These fluid losses should be replaced when they are significant. They can be measured and replaced with an appropriate solution. Third space losses , which manifest as edema and ascites, are caused by a shift of fluid from the intravascular space into the interstitial space. Although these losses cannot be quantitated easily, third space losses can be large and may lead to intravascular volume depletion, despite the patient's weight gain. Replacement of third space fluid is empirical but should be anticipated in patients who are at risk, such as children who have burns or abdominal surgery. Third space losses and chest tube output are isotonic, so they usually require replacement with an isotonic fluid, such as NS or LR. Adjustments in the amount of replacement fluid for third space losses are based on continuing assessment of the patient's intravascular volume status. Protein losses from chest tube drainage can be significant, occasionally necessitating that 5% albumin be used as a replacement solution.

Bibliography Foster BA, Tom D, Hill V. Hypotonic versus isotonic fluids in hospitalized children: a systematic review and meta-analysis. J Pediatr . 2014;165:163–169 [e2].

Friedman JN, Beck CE, DeGroot J, et al. Comparison of isotonic and hypotonic intravenous maintenance fluids: a randomized clinical trial. JAMA Pediatr . 2015;169:445–451. Green J, Lillie J. Intravenous fluid therapy in children and young people in hospital N29. Arch Dis Child . 2017;102(6):327–331. McNab S. Isotonic vs hypotonic intravenous fluids for hospitalized children. JAMA . 2015;314:720–721. McNab S, Duke T, South M, et al. 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomized controlled double-blind trial. Lancet . 2015;385:1190–1196. Moritz ML, Ayus JC. Maintenance intravenous fluids in acutely ill patients. N Engl J Med . 2015;373:1350–1360. National Institutes of Health. Intravenous fluid therapy in children and young people in hospital. NICE Guideline . [December] www.nice.org.uk/guidance/ng29 ; 2015. Padua AP, Macaraya JR, Dans LF, et al. Isotonic versus hypotonic saline solution for maintenance intravenous fluid therapy in children: a systematic review. Pediatr Nephrol . 2015;30:1163–1172. Wang J, Xu E, Xiao Y. Isotonic versus hypotonic maintenance IV fluids in hospitalized children: a meta-analysis. Pediatrics . 2014;133:105–113.

CHAPTER 70

Deficit Therapy Larry A. Greenbaum

Dehydration, most often caused by gastroenteritis, is a common problem in children. Most cases can be managed with oral rehydration (see Chapter 366 ). Even children with mild to moderate hyponatremic or hypernatremic dehydration can be managed with oral rehydration.

Clinical Manifestations The 1st step in caring for the child with dehydration is to assess the degree of dehydration (Table 70.1 ), which dictates both the urgency of the situation and the volume of fluid needed for rehydration. The infant with mild dehydration (3– 5% of body weight dehydrated) has few clinical signs or symptoms. The infant may be thirsty; the alert parent may notice a decline in urine output. The history is most helpful. The infant with moderate dehydration has clear physical signs and symptoms. Intravascular space depletion is evident from an increased heart rate and reduced urine output. This patient needs fairly prompt intervention. The infant with severe dehydration is gravely ill. The decrease in blood pressure indicates that vital organs may be receiving inadequate perfusion. Immediate and aggressive intervention is necessary. If possible, the child with severe dehydration should initially receive intravenous (IV) therapy. For older children and adults, mild, moderate, or severe dehydration represents a lower percentage of body weight lost. This difference occurs because water accounts for a higher percentage of body weight in infants (see Chapter 68 ).

Table 70.1

Clinical Evaluation of Dehydration

Mild dehydration (10% in an infant; >6% in an older child or adult): Peripheral pulses either rapid and weak or absent; decreased blood pressure; no urine output; very sunken eyes and fontanel; no tears; parched mucous membranes; delayed elasticity (poor skin turgor); very delayed capillary refill (>3 sec); cold and mottled; limp, depressed consciousness Clinical assessment of dehydration is only an estimate; thus the patient must be continually reevaluated during therapy. The degree of dehydration is underestimated in hypernatremic dehydration because the movement of water from the intracellular space (ICS) to the extracellular space (ECS) helps preserve the intravascular volume. The history usually suggests the etiology of the dehydration and may predict whether the patient will have a normal sodium concentration (isotonic dehydration), hyponatremic dehydration, or hypernatremic dehydration. The neonate with dehydration caused by poor intake of breast milk often has hypernatremic dehydration. Hypernatremic dehydration is likely in any child with losses of hypotonic fluid and poor water intake, as may occur with diarrhea, and poor oral intake because of anorexia or emesis. Hyponatremic dehydration occurs in the child with diarrhea who is taking in large quantities of low-salt fluid, such as water or formula. Some children with dehydration are appropriately thirsty, but in others the lack of intake is part of the pathophysiology of the dehydration. Even though decreased urine output is present in most children with dehydration, good urine output may be deceptively present if a child has an underlying renal defect, such as diabetes insipidus or a salt-wasting nephropathy, or in infants with hypernatremic dehydration. Physical examination findings are usually proportional to the degree of dehydration. Parents may be helpful in assessment of the child for the presence of sunken eyes, because this finding may be subtle. Pinching and gently twisting

the skin of the abdominal or thoracic wall detects tenting of the skin (turgor, elasticity). Tented skin remains in a pinched position rather than springing quickly back to normal. It is difficult to properly assess tenting of the skin in premature infants or severely malnourished children. Activation of the sympathetic nervous system causes tachycardia in children with intravascular volume depletion; diaphoresis may also be present. Postural changes in blood pressure are often helpful for evaluating and assessing the response to therapy in children with dehydration. Tachypnea in children with dehydration may be present secondary to a metabolic acidosis from stool losses of bicarbonate or lactic acidosis from shock (see Chapter 88 ).

Laboratory Findings Several laboratory findings are useful for evaluating the child with dehydration. The serum sodium concentration determines the type of dehydration. Metabolic acidosis may be a result of stool bicarbonate losses in children with diarrhea, secondary renal insufficiency, or lactic acidosis from shock. The anion gap is useful for differentiating among the various causes of a metabolic acidosis (see Chapter 68 ). Emesis or nasogastric losses usually cause a metabolic alkalosis . The serum potassium (K+ ) concentration may be low as a result of diarrheal losses. In children with dehydration as a result of emesis, gastric K+ losses, metabolic alkalosis, and urinary K+ losses all contribute to hypokalemia. Metabolic acidosis, which causes a shift of K+ out of cells, and renal insufficiency may lead to hyperkalemia. A combination of mechanisms may be present; thus, it may be difficult to predict the child's acid-base status or serum K+ level from the history alone. The blood urea nitrogen (BUN) value and serum creatinine concentration are useful in assessing the child with dehydration. Volume depletion without parenchymal renal injury may cause a disproportionate increase in the BUN with little or no change in the creatinine concentration. This condition is secondary to increased passive resorption of urea in the proximal tubule as a result of appropriate renal conservation of sodium and water. The increase in the BUN with moderate or severe dehydration may be absent or blunted in the child with poor protein intake, because urea production depends on protein degradation. The BUN may be disproportionately increased in the child with increased urea production, as occurs with a gastrointestinal bleed or with the use of

glucocorticoids, which increase catabolism. A significant elevation of the creatinine concentration suggests renal insufficiency, although a small, transient increase can occur with dehydration. Acute kidney injury (see Chapter 550.1 ) because of volume depletion is the most common etiology of renal insufficiency in a child with volume depletion, but occasionally the child may have previously undetected chronic renal insufficiency or an alternative explanation for the acute renal failure. Renal vein thrombosis is a well-described sequela of severe dehydration in infants; findings may include thrombocytopenia and hematuria (see Chapter 540.2 ). Hemoconcentration from dehydration causes increases in hematocrit, hemoglobin, and serum proteins. These values normalize with rehydration. A normal hemoglobin concentration during acute dehydration may mask an underlying anemia. A decreased albumin level in a dehydrated patient suggests a chronic disease, such as malnutrition, nephrotic syndrome, or liver disease, or an acute process, such as capillary leak. An acute or chronic protein-losing enteropathy may also cause a low serum albumin concentration.

Calculation of the Fluid Deficit Determining the fluid deficit necessitates clinical determination of the percentage of dehydration and multiplication of this percentage by the patient's weight; a child who weighs 10 kg and is 10% dehydrated has a fluid deficit of 1 L.

Approach to Severe Dehydration The child with dehydration needs acute intervention to ensure that there is adequate tissue perfusion. This resuscitation phase requires rapid restoration of the circulating intravascular volume and treatment of shock with an isotonic solution, such as normal saline (NS), Ringer lactate (lactated Ringer solution, LR), or PlasmaLyte (see Chapter 88 ). The child is given a fluid bolus, usually 20 mL/kg of the isotonic fluid, over approximately 20 min. The child with severe dehydration may require multiple fluid boluses and may need to receive the boluses as fast as possible. In a child with a known or probable metabolic alkalosis (e.g., child with isolated vomiting), LR or PlasmaLyte should not be used because the lactate or acetate would worsen the alkalosis. However, LR or

PlasmaLyte may be preferable to NS in shock since it is a balanced solution (see Chapter 69 ); NS may cause a hyperchloremic metabolic acidosis. Colloids, such as blood, 5% albumin, and plasma, are rarely needed for fluid boluses. A crystalloid solution (NS or LR) is satisfactory, with both lower risk of infection and lower cost. Blood is obviously indicated in the child with significant anemia or acute blood loss. Plasma is useful for children with a coagulopathy. The child with hypoalbuminemia may benefit from 5% albumin, although there is evidence that albumin infusions increase mortality in adults. The volume and the infusion rate for colloids are generally modified compared with crystalloids (see Chapter 500 ). The initial resuscitation and rehydration phase is complete when the child has an adequate intravascular volume. Typically, the child shows clinical improvement, including a lower heart rate, normalization of blood pressure, improved perfusion, better urine output, and a more alert affect. With adequate intravascular volume, it is appropriate to plan the fluid therapy for the next 24 hr. A general approach is outlined in Table 70.2 , with the caveat that there are many different approaches to correcting dehydration. A balanced solution can be substituted for NS. In isonatremic or hyponatremic dehydration, the entire fluid deficit is corrected over 24 hr; a slower approach is used for hypernatremic dehydration (discussed later). The volume of isotonic fluids that the patient has received is subtracted from this total. The remaining fluid volume is then administered over 24 hr. The potassium concentration may need to be decreased or, less frequently, increased, depending on the clinical situation. Potassium is not usually included in the IV fluids until the patient voids and normal renal function is documented by measurement of BUN and creatinine. Children with significant ongoing losses need to receive an appropriate replacement solution (see Chapter 69 ).

Table 70.2

Fluid Management of Dehydration Restore intravascular volume: Isotonic fluid (NS or LR): 20 mL/kg over 20 min Repeat as needed Calculate 24 hr fluid needs: maintenance + deficit volume Subtract isotonic fluid already administered from 24 hr fluid needs Administer remaining volume over 24 hr using 5% dextrose NS + 20

mEq/L KCl Replace ongoing losses as they occur LR, Ringer lactate; NS, normal saline.

Monitoring and Adjusting Therapy The formulation of a plan for correcting a child's dehydration is only the beginning of management. All calculations in fluid therapy are only approximations. This statement is especially true for the assessment of percentage dehydration. It is equally important to monitor the patient during treatment and to modify therapy on the basis of the clinical situation. Table 70.3 lists the cornerstones of patient monitoring. The patient's vital signs are useful indicators of intravascular volume status. The child with decreased blood pressure and an increased heart rate will probably benefit from a fluid bolus.

Table 70.3

Monitoring Therapy Vital signs: Pulse Blood pressure Intake and output: Fluid balance Urine output Physical examination: Weight Clinical signs of depletion or overload Electrolytes The patient's intake and output are critically important in the dehydrated child. The child who, after 8 hr of therapy, has more output than input because of continuing diarrhea needs to be started on a replacement solution. See the guidelines in Chapter 69 for selecting an appropriate replacement solution. Urine output is useful for evaluating the success of therapy. Good urine output indicates that rehydration has been successful.

Signs of dehydration on physical examination suggest the need for continued rehydration. Signs of fluid overload, such as edema and pulmonary congestion, are present in the child who is overhydrated. An accurate daily weight measurement is critical for the management of the dehydrated child. There should be a gain in weight during successful therapy. Measurement of serum electrolyte levels at least daily is appropriate for any child who is receiving IV rehydration. Such a child is at risk for sodium, potassium, and acid-base disorders. It is always important to look at trends. For example, a sodium concentration ([Na+ ]) of 144 mEq/L is normal; but if the [Na+ ] was 136 mEq/L 12 hr earlier, there is a distinct risk that the child will be hypernatremic in 12 or 24 hr. It is advisable to be proactive in adjusting fluid therapy. Both hypokalemia and hyperkalemia are potentially serious (see Chapter 68 ). Because dehydration can be associated with acute renal failure and hyperkalemia, potassium is withheld from IV fluids until the patient has voided. The potassium concentration in the patient's IV fluids is not rigidly prescribed. Rather, the patient's serum K+ level and underlying renal function are used to modify potassium delivery. The patient with an elevated creatinine value and K+ level of 5 mEq/L does not receive any potassium until the serum K+ level decreases. Conversely, the patient with a K+ level of 2.5 mEq/L may require additional potassium. Metabolic acidosis can be quite severe in dehydrated children. Although normal kidneys eventually correct this problem, a child with renal dysfunction may be unable to correct a metabolic acidosis, and a portion of the patient's IV sodium chloride may have to be replaced with sodium bicarbonate or sodium acetate. The serum K+ level is modified by the patient's acid-base status. Acidosis increases serum K+ by causing intracellular K+ to move into the ECS. Thus, as acidosis is corrected, the serum potassium concentration ([K+ ]) decreases. Again, it is best to anticipate this problem and to monitor the serum [K+ ] and adjust potassium administration appropriately.

Hyponatremic Dehydration The pathogenesis of hyponatremic dehydration usually involves a combination of sodium and water loss and water retention to compensate for the volume

depletion. The patient has a pathologic increase in fluid loss, and the lost fluid contains sodium. Most fluid that is lost has a lower sodium concentration, so patients with only fluid loss would have hypernatremia. Diarrhea has, on average, a sodium concentration of 50 mEq/L. Replacing diarrheal fluid with water, which has almost no sodium, causes a reduction in the serum [Na+ ]. The volume depletion stimulates synthesis of antidiuretic hormone (ADH), resulting in reduced renal water excretion. Therefore, the body's usual mechanism for preventing hyponatremia, renal water excretion, is blocked. The risk of hyponatremia is further increased if the volume depletion is a result of loss of fluid with a higher sodium concentration, as may occur with renal salt wasting, third space losses, or diarrhea with high sodium content (cholera). The initial goal in treating hyponatremia is correction of intravascular volume depletion with isotonic fluid. An overly rapid (>12 mEq/L over 1st 24 hr) or overcorrection in the serum [Na+ ] (>135 mEq/L) is associated with an increased risk of central pontine myelinolysis (see Chapter 68 ). Most patients with hyponatremic dehydration do well with the same basic strategy outlined in Table 70.2 . Again, K+ delivery is adjusted according to the initial serum K+ level and the patient's renal function. Potassium is not given until the patient voids. The patient's [Na+ ] is monitored closely to ensure appropriate correction, and the sodium concentration of the fluid is adjusted accordingly. Patients with ongoing losses require an appropriate replacement solution (see Chapter 69 ). Patients with neurologic symptoms (seizures) as a result of hyponatremia need to receive an acute infusion of hypertonic (3%) saline to increase the serum [Na+ ] rapidly (see Chapter 68 ).

Hypernatremic Dehydration Hypernatremic dehydration is the most dangerous form of dehydration because of complications of hypernatremia itself and of its therapy. Hypernatremia can cause serious neurologic damage, including central nervous system hemorrhages and thrombosis. This damage appears to be secondary to the movement of water from the brain cells into the hypertonic extracellular fluid (ECF), causing brain cell shrinkage and tearing blood vessels within the brain (see Chapter 68 ). The movement of water from the ICS to the ECS during hypernatremic dehydration partially protects the intravascular volume. Unfortunately, because the initial manifestations are milder, children with hypernatremic dehydration are

often brought for medical attention with more profound dehydration. Children with hypernatremic dehydration are often lethargic, and they may be irritable when touched. Hypernatremia may cause fever, hypertonicity, and hyperreflexia. More severe neurologic symptoms may develop if cerebral bleeding or thrombosis occurs. Overly rapid treatment of hypernatremic dehydration may cause significant morbidity and mortality. Idiogenic osmoles are generated within the brain during the development of hypernatremia; they increase the osmolality within the cells of the brain, providing protection against brain cell shrinkage caused by movement of water out of the cells and into the hypertonic ECF. Idiogenic osmoles dissipate slowly during the correction of hypernatremia. With overly rapid lowering of the extracellular osmolality during the correction of hypernatremia, an osmotic gradient may be created that causes water movement from the ECS into the cells of the brain, producing cerebral edema. Symptoms of the resultant cerebral edema can range from seizures to brain herniation and death. To minimize the risk of cerebral edema during the correction of hypernatremic dehydration, the serum sodium concentration should not decrease by >10 mEq/L every 24 hr. The deficits in severe hypernatremic dehydration may need to be corrected over 2-4 days (Table 70.4 ).

Table 70.4

Treatment of Hypernatremic Dehydration Restore intravascular volume: Normal saline: 20 mL/kg over 20 min (repeat until intravascular volume restored) Determine time for correction on basis of initial sodium concentration: • [Na] 145-157 mEq/L: 24 hr • [Na] 158-170 mEq/L: 48 hr • [Na] 171-183 mEq/L: 72 hr • [Na] 184-196 mEq/L: 84 hr Administer fluid at constant rate over time for correction: Typical fluid: 5% dextrose + half-normal saline (with 20 mEq/L KCl unless contraindicated) Typical rate: 1.25-1.5 times maintenance

Follow serum sodium concentration Adjust fluid on basis of clinical status and serum sodium concentration: Signs of volume depletion: administer normal saline (20 mL/kg) Sodium decreases too rapidly; either: • Increase sodium concentration of IV fluid • Decrease rate of IV fluid Sodium decreases too slowly; either: • Decrease sodium concentration of IV fluid • Increase rate of IV fluid Replace ongoing losses as they occur The initial resuscitation of hypernatremic dehydration requires restoration of the intravascular volume with NS. LR should not be used because it is more hypotonic than NS and may cause too rapid a decrease in the serum [Na+ ], especially if multiple fluid boluses are necessary. To avoid cerebral edema during correction of hypernatremic dehydration, the fluid deficit is corrected slowly. The rate of correction depends on the initial sodium concentration (Table 70.4 ). There is no general agreement on the choice or the rate of fluid administration for correcting hypernatremic dehydration; these factors are not nearly as important as vigilant monitoring of the serum [Na+ ] and adjustment of the therapy according to the result. The rate of decrease of the serum [Na+ ] is roughly related to the “free water” delivery, although there is considerable variation between patients. Free water is water without sodium. NS contains no free water, half-normal saline ( NS) is 50% free water, and water is 100% free water. Smaller patients, to achieve the same decrease in the sodium concentration, tend to need higher amounts of free water delivery per kilogram because of higher insensible fluid losses . Five percent dextrose (D5) with NS is usually an appropriate starting solution for correction of a patient with hypernatremic dehydration. Some patients, especially infants with ongoing high insensible water losses, may rarely need to receive D5 0.2NS, which should be used with great caution and constant monitoring. Others require D5 NS. A child with dehydration as a result of pure free water loss, as usually occurs with diabetes insipidus, usually needs a more hypotonic fluid than a child with depletion of both sodium and water from diarrhea. Adjustment in the sodium concentration of the IV fluid is the most common approach to modify the rate of decrease in the serum concentration (see Table

70.4 ). For difficult-to-manage patients with severe hypernatremia, having two IV solutions (e.g., D5 NS and D5 NS, both with the same concentration of potassium) at the bedside can facilitate this approach by allowing for rapid adjustments of the rates of the 2 fluids. If the serum [Na+ ] decreases too rapidly, the rate of D5 NS can be increased and the rate of D5 NS can be decreased by the same amount. Adjustment in the total rate of fluid delivery is another approach to modifying free water delivery. For example, if the serum [Na+ ] is decreasing too slowly, the rate of the IV fluid can be increased, thereby increasing the delivery of free water. There is limited flexibility in modifying the rate of the IV fluid because patients generally should receive 1.25-1.5 times the normal maintenance fluid rate. Nevertheless, in some situations, it can be a helpful adjustment. Because increasing the rate of the IV fluid increases the rate of decline of the sodium concentration, signs of volume depletion are treated with additional isotonic fluid boluses. The serum [K+ ] and the level of renal function dictate the potassium concentration of the IV fluid; potassium is withheld until the patient voids. Patients with hypernatremic dehydration need an appropriate replacement solution if they have ongoing, excessive losses (see Chapter 69 ). Seizures and a depressed level of consciousness are the most common manifestations of cerebral edema from an overly rapid decrease of the serum [Na+ ] during correction of hypernatremic dehydration. Signs of increased intracranial pressure or impending herniation may develop quite rapidly (see Chapter 85 ). Acutely, increasing the serum [Na+ ] through an infusion of 3% sodium chloride can reverse the cerebral edema. Each 1 mL/kg of 3% NaCl increases the serum [Na+ ] by approximately 1 mEq/L. An infusion of 4 mL/kg often results in resolution of the symptoms. This strategy is similar to that used for treating symptomatic hyponatremia (see Chapter 68 ). Many patients with mild to moderate hypernatremic dehydration as a result of gastroenteritis can be managed with oral rehydration (see Chapter 366 ). In patients with severe hypernatremia, oral fluids must be used cautiously. Infant formula, because of its low sodium concentration, has a high free water content, and especially if added to IV therapy, it may contribute to a rapid decrease in the serum [Na+ ]. Less hypotonic fluid, such as an oral rehydration solution, may be more appropriate initially. If oral intake is allowed, its contribution to free water delivery must be taken into account, and adjustment in the IV fluid is usually appropriate. Judicious monitoring of the serum [Na+ ] is critical.

Bibliography Ben-Shalom E, Toker O, Schwartz S. Hypernatremic dehydration in young children: is there a solution? Isr Med Assoc J . 2016;18:95–99. Chisti MJ, Ahmed T, Ahmed AM, et al. Hypernatremia in children with diarrhea: presenting features, management, outcome, and risk factors for death. Clin Pediatr (Phila) . 2016;55:654–663. Emrath ET, Fortenberry JD, Travers C, et al. Resuscitation with balanced fluids is associated with improved survival in pediatric severe sepsis. Crit Care Med . 2017;45:1177–1183. Erdemir A, Kahramaner Z, Cosar H, et al. Comparison of oral and intravenous fluid therapy in newborns with hypernatremic dehydration. J Matern Fetal Neonatal Med . 2014;27:491–494. Freedman SB, DeGroot JM, Parkin PC. Successful discharge of children with gastroenteritis requiring intravenous rehydration. J Emerg Med . 2014;46:9–20. Freedman SB, Vandermeer B, Milne A, et al. Diagnosing clinically significant dehydration in children with acute gastroenteritis using noninvasive methods: a meta-analysis. J Pediatr . 2015;166:908–916. Freedman SB, Willan AR, Boutis K, et al. Effect of dilute apple juice and preferred fluids vs electrolyte maintenance solution on treatment failure among children with mild gastroenteritis: a randomized clinical trial. JAMA . 2016;315:1966–1974. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr . 2014;59:132–152.

Janet S, Molina JC, Maranon R, et al. Effects of rapid intravenous rehydration in children with mild-to-moderate dehydration. Pediatr Emerg Care . 2015;31:564–567. Marquard J, Lerch C, Rosen A, et al. Nasogastric vs. intravenous rehydration in children with gastroenteritis and refusal to drink: a randomized controlled trial. Klin Padiatr . 2014;226:19–23. Powers KS. Dehydration: isonatremic, hyponatremic, and hypernatremic recognition and management. Pediatr Rev . 2015;36:274–283 [quiz 84-5]. Sen A, Keener CM, Sileanu FE, et al. Chloride content of fluids used for large-volume resuscitation is associated with reduced survival. Crit Care Med . 2017;45:e146–e153. Shahrin L, Chisti MJ, Huq S, et al. Clinical manifestations of hyponatremia and hypernatremia in under-five diarrheal children in a diarrhea hospital. J Trop Pediatr . 2016;62:206– 212. Toaimah FH, Mohammad HM. Rapid intravenous rehydration therapy in children with acute gastroenteritis: a systematic review. Pediatr Emerg Care . 2016;32:131–135. Weiss SL, Keele L, Balamuth F, et al. Crystalloid fluid choice and clinical outcomes in pediatric sepsis: a matched retrospective cohort study. J Pediatr . 2017;182:304–310.e10.

CHAPTER 71

Fluid and Electrolyte Treatment of Specific Disorders Acute Diarrhea See Chapter 366 .

Pyloric Stenosis See Chapter 355.1 .

Perioperative Fluids See Chapter 74 .

PA R T V I I

Pediatric Drug Therapy OUTLINE Chapter 72 Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics Chapter 73 Principles of Drug Therapy Chapter 74 Anesthesia and Perioperative Care Chapter 75 Procedural Sedation Chapter 76 Pediatric Pain Management Chapter 77 Poisoning Chapter 78 Complementary Therapies and Integrative Medicine

CHAPTER 72

Pediatric Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics Jonathan B. Wagner, Matthew J. McLaughlin, J. Steven Leeder

Interindividual variability in the response to similar doses of a given medication is an inherent characteristic of both adult and pediatric populations. Pharmacogenetics , the role of genetic factors in drug disposition and response, has resulted in many examples of how variations in human genes can lead to interindividual differences in pharmacokinetics and drug response at the level of individual patients. Pharmacogenetic variability contributes to the broad range of drug responses observed in children at any given age or developmental stage. Therefore, it is expected that children will benefit from the promise of personalized medicine —identifying the right drug for the right patient at the right time (Fig. 72.1 ). However, pediatricians are keenly aware that children are not merely small adults. Numerous maturational processes occur from birth through adolescence such that utilization of information resulting from the Human Genome Project and related initiatives must take into account the changing patterns of gene expression that occur over development to improve pharmacotherapeutics in children.

FIG. 72.1 The promise of genomic medicine to human health and disease. The goal of personalized medicine is to identify subgroups of patients who will respond favorably to a given drug with a minimum of side effects, as well as those who will not respond or who will show excessive toxicity with standard doses. A further benefit of pharmacogenomics is the ability to select the most appropriate alternative drug for patients who cannot be treated successfully with conventional drugs and doses. (Adapted from Yaffe SJ, Aranda JV: Neonatal and pediatric pharmacology, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins.)

Definition of Terms The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and precise, consensus definitions are often difficult to determine. Pharmacogenetics classically is defined as the study or clinical

testing of genetic variations that give rise to interindividual response to drugs. Examples of pharmacogenetic traits include specific adverse drug reactions, such as unusually prolonged respiratory muscle paralysis due to succinylcholine, hemolysis associated with antimalarial therapy, and isoniazid-induced neurotoxicity, all of which were found to be a consequence of inherited variations in enzyme activity. The importance of pharmacogenetic differences has become better understood and is exemplified by the half-life of several drugs being more similar in monozygotic twins than in dizygotic twins. However, it is important to note that in addition to pharmacogenetic differences, environmental factors (diet, smoking status, concomitant drug or toxicant exposure), physiologic variables (age, sex, disease, pregnancy), and patient adherence all contribute to variations in drug metabolism and response. Likewise, ethnicity is another potential genetic determinant of drug variability. Chinese patients who are HLA-B*1502 positive have an increased risk of carbamazepine-induced Stevens-Johnson syndrome; white patients who are HLA-B*5701 positive have an increased risk of hypersensitivity to abacavir (Table 72.1 ). Table 72.1

Examples of Effects of Gene Polymorphisms on Drug Response GENE BCHE CYP2C9

ENZYME/TARGET DRUG Butyrylcholinesterase Succinylcholine Cytochrome P450 2C9 Warfarin

CLINICAL RESPONSE Prolonged paralysis Individuals having ≥1 reduced function alleles require lower doses of warfarin for optimal anticoagulation, especially initial anticoagulant control. CYP2C19 Cytochrome P450 Clopidogrel Individuals having ≥1 loss-of-function alleles have 2C19 reduced capacity to form pharmacologically active metabolite of clopidogrel and reduced antiplatelet effect. CYP2D6 Cytochrome P450 2D6 Codeine Poor metabolizers—individuals with 2 loss-offunction alleles—do not metabolize codeine to morphine and thus experience no analgesic effect. Ultrarapid metabolizers—individuals with ≥3 functional alleles—may experience morphine toxicity. G6PD Glucose-6-phosphate Primaquine (others) Hemolysis dehydrogenase HLAHuman leukocyte Carbamazepine Carriers of HLA-A*3101 allele have increased risk of A*3101 antigen A31 SJS and TEN from carbamazepine. HLAHuman leukocyte Allopurinol Han Chinese carriers of HLA-B*1502 allele have B*1502 antigen B15 increased risk of SJS and TEN from carbamazepine. HLAHuman leukocyte Abacavir Carriers of HLA-B*5701 allele have increased risk of hypersensitivity reactions to abacavir- and B*5701 antigen B57 Flucloxacillin

HLAB*5801

Human leukocyte antigen B58

Allopurinol

NAT2

N -Acetyltransferase 2

Isoniazid, hydralazine

SLCO1B1 Organic anion– transporting protein (OATP) 1B1 TPMT Thiopurine S methyltransferase

Simvastatin

flucloxacillin-induced liver injury. Carriers of HLA-B*5801 allele have increased risk of severe cutaneous adverse reactions to allopurinol, including hypersensitivity reactions, SJS, and TEN. Individuals homozygous for “slow acetylation” polymorphisms are more susceptible to isoniazid toxicity, or hydralazine-induced systemic lupus erythematosus. Carriers of the SLCO1B1*5 allele are at increased risk for musculoskeletal side effects from simvastatin.

Azathioprine Individuals homozygous for an inactivating mutation 6have severe toxicity if treated with standard doses of Mercaptopurine azathioprine or 6-mercaptopurine; rapid metabolism causes undertreatment. UGT1A1 Uridine diphosphoIrinotecan UGT1A1*28 allele is associated with decreased glucuronosyltransferase glucuronidation of SN-38, the active metabolite of 1A1 irinotecan, and increased risk of neutropenia. VKORC1 Vitamin K Warfarin Individuals with a haplotype associated with reduced oxidoreductase expression of VKORC1 protein (therapeutic target of complex 1 warfarin) require lower doses of the drug for stable anticoagulation.

SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Pharmacogenomics represents the marriage of pharmacology and genomics and can be defined as the broader application of genome-wide technologies and strategies to identify both disease processes that represent new targets for drug development and factors predictive of efficacy and risk of adverse drug reactions. Pharmacokinetics describes what the body does to a drug. It is often studied in conjunction with pharmacodynamics , which explores what a drug does to the body. The pharmacokinetic properties of a drug are determined by the genes that control the drug's disposition in the body (absorption, distribution, metabolism, excretion). Drug-metabolizing enzymes and drug transporters play a particularly important role in this process (Table 72.2 ), and the functional consequences of genetic variations in many drug-metabolizing enzymes have been described between individuals of both similar and different ethnic groups. The most common clinical manifestation of pharmacogenetic variability in drug biotransformation is an increased risk of concentration-dependent toxicity caused by reduced clearance and consequent drug accumulation. However, an equally important manifestation of this variability is lack of efficacy caused by variations in metabolism of prodrugs that require biotransformation to be converted into a pharmacologically active form of a medication. The pharmacogenetics of drug receptors and other target proteins involved in signal transduction or disease pathogenesis can also be expected to contribute

significantly to interindividual variability in drug disposition and response. Table 72.2

Some Important Relationships Between Drugs and Cytochrome P450 (CYP) Enzymes* and P-Glycoprotein Transporter ENZYME CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP3A4

DRUG SUBSTRATES Caffeine, clomipramine (Anafranil † ), clozapine (Clozaril † ), theophylline

INHIBITORS Cimetidine (Tagamet † ) Fluvoxamine (Luvox † ) Ciprofloxacin (Cipro ) Diclofenac (Voltaren † ), ibuprofen (Motrin † ), Fluconazole piroxicam (Feldene † ), Losartan (Cozaar ), irbesartan (Diflucan ) (Avapro ), celecoxib (Celebrex ), tolbutamide (Orinase † Fluvastatin (Lescol ) Amiodarone ), warfarin (Coumadin † ), phenytoin (Dilantin ) (Cordarone ) Zafirlukast (Accolate ) Omeprazole, lansoprazole (Prevacid ), pantoprazole Cimetidine (Protonix ), (S)-mephenytoin, (S) -citalopram (Lexapro Fluvoxamine ); nelfinavir (Viracept ), diazepam (Valium † ), voriconazole (Vfend ) CNS-active agents: Atomoxetine (Strattera ), Fluoxetine amitriptyline (Elavil † ), desipramine (Norpramin † ), (Prozac † ) imipramine (Tofranil † ), paroxetine (Paxil ), haloperidol Paroxetine (Paxil ) † (Haldol ), risperidone (Risperdal ), thioridazine (Mellaril † ) Antiarrhythmic agents: Mexiletine (Mexitil ), Amiodarone propafenone (Rythmol ) (Cordarone † ) Quinidine (Quinidex † ) † Propranolol ( ), metoprolol Terbinafine β-Blockers: Inderal (Lopressor † ), timolol (Blocadren † ) Narcotics: Codeine, dextromethorphan, hydrocodone (Vicodin † ) Others: Tamoxifen (Nolvadex ) Cimetidine Ritonavir Amiodarone Calcium channel blockers: Diltiazem (Cardizem † ), felodipine (Plendil ), nimodipine (Nimotop ), nifedipine (Adalat † ), nisoldipine (Sular ), nitrendipine, verapamil (Calan † ) Immunosuppressive agents: Cyclosporine A (Sandimmune , Neoral † ), tacrolimus (Prograf )

INDUCERS Omeprazole (Prilosec † ) Tobacco

Rifampin (Rifadin † )

Rifampin

Barbiturates Carbamazepine (Tegretol † ) Phenytoin (Dilantin † ) Efavirenz (Sustiva )

Corticosteroids: Budesonide (Pulmicort ), cortisol, 17β-estradiol, progesterone, testosterone

Macrolide antibiotics: Clarithromycin (Biaxin ), erythromycin (Erythrocin † ), troleandomycin (TAO ) Anticancer agents: Cyclophosphamide (Cytoxan † ), gefitinib (Iressa ), ifosfamide (Ifex ), tamoxifen, vincristine (Oncovin † ), vinblastine (Velban † ), Benzodiazepines: Alprazolam (Xanax † ), midazolam (Versed † ), triazolam (Halcion † ) Opioids: Alfentanil (Alfenta † ), fentanyl (Sublimaze † ), sufentanil (Sufenta † ) HMG-CoA reductase inhibitors: Lovastatin (Mevacor ) † , simvastatin (Zocor ), atorvastatin (Lipitor ) HIV protease inhibitors: Indinavir (Crixivan ), nelfinavir, ritonavir (Norvir ), saquinavir (Invirase, Fortovase ), amprenavir (Agenerase ) Others: Quinidine (Quinidex † ), sildenafil (Viagra ), eletriptan (Relpax ), ziprasidone (Geodon ) PAldosterone, amprenavir, atorvastatin, cyclosporine, glycoprotein dexamethasone (Decadron † ), digoxin (Lanoxin † ), diltiazem, domperidone (Motilium ), doxorubicin (Adriamycin † ), erythromycin, etoposide (VePesid ), fexofenadine (Allegra ), hydrocortisone, indinavir, ivermectin (Stromectol ), lovastatin, loperamide (Imodium † ), nelfinavir, ondansetron (Zofran ), paclitaxel (Taxol ), quinidine, saquinavir, simvastatin, verapamil, vinblastine, vincristine

Fluconazole Nevirapine Ketoconazole (Viramune ) (Nizoral † ) Itraconazole (Sporanox ) Clarithromycin Erythromycin Troleandomycin Imatinib Rifampin Ritonavir ‡ St. John's wort

Ritonavir ‡ Indinavir Grapefruit juice Nefazodone (Serzone ) Amiodarone Carvedilol (Coreg ) Clarithromycin Cyclosporine Erythromycin Itraconazole Ketoconazole Quinidine Ritonavir ‡ Tamoxifen Verapamil

Amprenavir Clotrimazole (Mycelex † ) Phenothiazine Rifampin Ritonavir ‡ St. John's wort

* www.drug-interactions.com . † Also available generically. ‡ Can be both an inhibitor and an inducer.

CNS, Central nervous system. From Med Lett 2003;45:47.

Therapeutic drug monitoring (TDM) programs recognize that all patients are unique and that the serum concentration-time data for an individual patient theoretically can be used to optimize pharmacotherapy. TDM programs have been the earliest application of personalized medicine; however, routine TDM does not necessarily translate to improved patient outcome in all situations.

The concept of personalized medicine is based on the premise that the information explosion accompanying the application of genomic technologies to patient-related problems will allow (1) stratification of patient populations according to their response to a particular medication (e.g., lack of drug efficacy or excessive toxicity) and (2) stratification of diseases into specific subtypes that are categorized according to genomic criteria and by response to particular treatments. Personalized medicine has become supplanted by individualized medicine , which takes into consideration the vast amount of information that can be collected from an individual patient and applied to inform decisions for that patient. Precision medicine is an emerging approach for disease treatment and prevention that considers individual variability in genes, environment, and lifestyle for each person; it reflects the progression in delivery of care for more accurately diagnosing or treating a patient at an individual level. As the amount of data specific to an individual patient increases (e.g., genomic data, electronic health records), precision medicine can be further divided into precision diagnosis and precision therapeutics ; pharmacokinetics, pharmacodynamics, and pharmacogenomics all represent tools that can be applied to implement precision therapeutics for children. Genetic polymorphisms (variations ) result when copies of a specific gene present within a population do not have identical nucleotide sequences. The term allele refers to one of a series of alternative DNA sequences for a particular gene. In humans, there are 2 copies of every gene. An individual's genotype for a given gene is determined by the set of alleles that the individual possesses. The most common form of genetic variation involves a single base change at a given location, referred to as a single nucleotide polymorphism (SNP) (see Chapter 95 ). At the other end of the spectrum are copy number variations (CNVs) , which refer to the deletion or duplication of identical or near-identical DNA sequences that may be thousands to millions of bases in size. CNVs occur less frequently than SNPs, but may constitute 0.5–1% of an individual's genome and thereby contribute significantly to phenotypic variation. Haplotypes are collections of SNPs and other allelic variations that are located close to each other; when inherited together, these create a catalog of haplotypes, or HapMap . When the alleles at a particular gene locus on both chromosomes are identical, a homozygous state exists, whereas the term heterozygous refers to the situation in which different alleles are present at the same gene locus. The term genotype refers to an individual's genetic constitution, whereas the observable characteristics or physical manifestations constitute the phenotype , which is the

net consequence of genetic and environmental effects (see Chapters 94 –101 ). Pharmacogenetics focuses on the phenotypical consequences of allelic variation in single genes. Pharmacogenetic polymorphisms are monogenic traits that are functionally relevant to drug disposition and action and are caused by the presence (within one population) of >1 allele (at the same gene locus) and >1 phenotype with regard to drug interaction with the organism. The key elements of pharmacogenetic polymorphisms are heritability, the involvement of a single gene locus, functional relevance, and the fact that distinct phenotypes are observed within the population only after drug challenge.

Developmental or Pediatric Pharmacogenetics and Pharmacogenomics Our current understanding of pharmacogenetic principles involves enzymes responsible for drug biotransformation . Individuals are classified as being “fast,” “rapid,” or “extensive” metabolizers at one end and “slow” or “poor” metabolizers at the other end of the continuum. This may or may not also include an “intermediate” metabolizer group, depending on the particular enzyme. With regard to biotransformation, children are more complex than adults; fetuses and newborns may be phenotypically “slow” or “poor” metabolizers for certain drug-metabolizing pathways because of their stage of development and may acquire a phenotype consistent with their genotype at some point later in the developmental process as they mature. Examples of drugmetabolizing pathways that are significantly affected by ontogeny include glucuronidation and some of the cytochrome P450 (CYP) activities. It is also apparent that not all infants acquire drug metabolism activity at the same rate, a result of interactions between genetics and environmental factors. Interindividual variability in the trajectory (i.e., rate and extent) of acquired drug biotransformation capacity may be considered a developmental phenotype (Fig. 72.2 ). This helps to explain the considerable variability in some CYP activities observed immediately after birth.

FIG. 72.2 “Developmental” phenotypes. Variability in developmental changes in gene expression and functional enzyme activity are superimposed on pharmacogenetic determinants. Top, Developmental profile of a theoretical drug-metabolizing enzyme over a 25 yr span in 20 individuals. Bottom, At maturity (adults), allelic variation within the coding region of the gene gives rise to 2 distinct phenotypes: high activity in 92% of the population (“extensive metabolizers”; red circles ) and low activity in 8% of the population (“poor metabolizers”; yellow circles ). However, there is also interindividual variability in the rate at which functional activity is acquired after birth. For example, the 2 phenotypes may not be readily distinguishable in newborn infants immediately after birth. Furthermore, there may be discrete periods during childhood in which the genotype-phenotype relationship may differ from that observed in adults (e.g., developmental stages at which enzyme activity appears to be greater in children than in adults). (Adapted from Leeder JS: Translating pharmacogenetics and pharmacogenomics into drug development for clinical pediatric and beyond, Drug Discov Today 9:567–573, 2004.)

In contrast to pharmacogenetic studies that typically target single genes, pharmacogenomic analyses are considerably broader in scope and focus on complex and highly variable drug-related phenotypes with targeting of many genes. Genome-wide genotyping technologies and massively parallel “nextgeneration” sequencing platforms for genomic analyses continue to evolve and allow evaluation of genetic variation at more than 1 million sites throughout an

individual genome for SNP and CNV analyses. Genome-wide association studies (GWAS) have been conducted in several pediatric settings, in part to identify novel genes involved in disease pathogenesis that can lead to new therapeutic targets. GWAS are also being applied to identify genetic associations with response to drugs, such as warfarin and clopidogrel, and risk for drug-induced toxicity, including statin-induced myopathy and flucloxacillin hepatotoxicity. The “Manhattan plot,” a form of data presentation for GWAS, is becoming more common in many medical journals (Fig. 72.3A ). Whole genome and exome sequencing have been applied in a diagnostic setting to identify disease-causing genetic variation, usually in the context of rare, undiagnosed diseases that would otherwise require a “diagnostic odyssey” lasting several years before a definitive diagnosis is made (and thereby delaying therapeutic intervention). Contained within this genome sequence is the pharmacogenome , and an area of intense interest is the development of bioinformatics tools to determine a patient's drug metabolism and response genotype from whole genome sequence data.

FIG. 72.3 Presentations of pharmacogenomic data. A, Manhattan plot from a genomewide association study (GWAS). Derived from its similarity to the Manhattan skyline, the Manhattan plot presents the genome-wide significance of several hundred thousand single nucleotide polymorphisms (SNPs) distributed throughout the genome with the trait or phenotype of interest. In this example, each SNP included on the “chip”

is plotted along the x axis according to its chromosomal coordinate, with each color representing an individual chromosome from chromosome 1 to the X chromosome. The y axis represents the inverse log10 of the p value for the association: the higher the value on the y- axis, the smaller the p value. A value of “15” corresponds to a p value of 10−15 . SNPs exceeding a particular threshold are subject to further verification and validation. B, “Heat map” constructed from gene expression data. In a heat map the level of expression of many genes, as obtained from microarray analysis, is presented as a 2-dimensional matrix of values. Each column represents an individual patient, and each row is an individual RNA transcript designated by the gene name. The level of gene expression is indicated by the color of each rectangle on a continuum from high expression (red) to low expression (green). In this example, acute lymphoblastic leukemia (ALL) patients are clustered by their response to methotrexate (MTX); patients responding to MTX have markedly different patterns of gene expression compared to nonresponders. One of the goals of personalized medicine is to use genomic information (e.g., microarray data) to identify signatures of drug response (or risk of drug toxicity), to select the most appropriate drug among available options for each patient. (A, Reprinted with permission from Search Collaborative Group. SLCO1B1 variants and statin-induced myopathy: a genome-wide study, N Engl J Med 359:789– 799, 2008; B, from Sorich MJ et al. In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile, PLoS Med 5(4):e83, 2008.)

Investigating differential gene expression before and after drug exposure has the potential to correlate gene expression with variable drug responses and uncover the mechanisms of tissue-specific drug toxicities. These types of studies use microarray technology to monitor global changes in expression of thousands of genes (the transcriptome ) simultaneously. Genomic sequencing technologies can also be applied to RNA (RNA-Seq) and result in a more complete and quantitative assessment of the transcriptome. Gene expression profiling data from microarrays or RNA-Seq analyses are used to improve disease classification and risk stratification and are common in oncology. This approach has been widely used to address treatment resistance in acute lymphoblastic leukemia and has provided clinically relevant insights into the mechanistic basis of drug resistance and the genomic basis of interindividual variability in drug response. Subsets of transcripts, or gene expression “signatures,” are being investigated as potential prognostic indicators for identifying patients at risk for treatment failure (Fig. 72.3B ).

Pharmacoproteomic and Metabolomic Tools Proteomic studies use many different techniques to detect, quantify, and identify proteins in a sample (expression proteomics) and to characterize protein function in terms of activity and protein-protein or protein–nucleic acid interactions (functional proteomics ). Mass spectrometry–based analyses are able to provide quantitative data regarding protein abundance, and several studies have been applied to pediatric liver samples, for example, to generate

more accurate developmental trajectories for several drug-metabolizing enzymes and transporters. Metabolomics and metabonomics utilize sophisticated analytical platforms, such as nuclear magnetic resonance (NMR) spectroscopy and liquid or gas chromatography coupled with mass spectral detection, to measure the concentrations of all small molecules present in a sample. Metabolomics refers to the complete set of low-molecular-weight molecules (metabolites) present in a living system (cell, tissue, organ or organism) at a particular developmental or pathologic state. Metabonomics is defined as the study of how the metabolic profile of biologic systems change in response to alterations caused by pathophysiologic stimuli, toxic exposures, or dietary changes. Pharmacometabonomics involves prediction of the outcome, efficacy, or toxicity of a drug or xenobiotic intervention in an individual patient based on a mathematical model of preintervention metabolite signatures.

Drug Biotransformation: Applications to Pediatric Therapy The major consequence of pharmacogenetic polymorphisms in drugmetabolizing enzymes is concentration-dependent toxicity caused by impaired drug clearance. In certain cases, reduced conversion of prodrug to therapeutically active compounds is also of clinical importance (see Table 72.2 ). Chemical modification of drugs by biotransformation reactions generally results in termination of biologic activity through decreased affinity for receptors or other cellular targets as well as more rapid elimination from the body. The process of drug biotransformation can be very complex but is characterized by 3 important features: (1) the concept of broad substrate specificity , in which a single isozyme may metabolize a large variety of chemically diverse compounds; (2) many different enzymes may be involved in the biotransformation of a single drug (enzyme multiplicity ); and (3) a given drug may undergo several different types of reactions. One example of this product multiplicity occurs with racemic warfarin, in which at least 7 different hydroxylated metabolites are produced by different CYP isoforms. Drug biotransformation reactions are conveniently classified into 2 main types, which occur sequentially and serve to terminate biologic activity and enhance elimination (see Chapter 73 ). Phase I reactions introduce or reveal

(through oxidation, reduction, or hydrolysis) a functional group within the substrate drug molecule that serves as a site for a phase II conjugation reaction. Phase II reactions involve conjugation with endogenous substrates, such as acetate, glucuronic acid, glutathione, glycine, and sulfate. These reactions further increase the polarity of an intermediate metabolite, make the compound more water soluble, and thereby enhance its renal excretion. Interindividual variability in drug biotransformation activity (for both phase I and phase II reactions) is a consequence of the complex interplay among genetic (genotype, sex, race or ethnic background) and environmental (diet, disease, concurrent medication, other xenobiotic exposure) factors. The pathway and rate of a given compound's biotransformation are a function of each individual's unique phenotype with respect to the forms and amounts of drug-metabolizing enzymes expressed. The CYP enzymes (CYPs) are quantitatively the most important of the phase I enzymes . These heme-containing proteins catalyze the metabolism of many lipophilic endogenous substances (steroids, fatty acids, fat-soluble vitamins, prostaglandins, leukotrienes, thromboxanes) as well as exogenous compounds, including a multitude of drugs and environment toxins. CYP nomenclature is based on evolutionary considerations and uses the root symbol CYP for cytochrome P450. CYPs that share at least 40% homology are grouped into families denoted by an Arabic number after the CYP root. Subfamilies, designated by a letter, appear to represent clusters of highly related genes. Members of the human CYP2 family, for example, have >67% amino acid sequence homology. Individual P450s in a subfamily are numbered sequentially (e.g., CYP3A4, CYP3A5). CYPs that have been identified as being important in human drug metabolism are predominantly found in the CYP1, CYP2, and CYP3 gene families. Importantly, enzyme activity may be induced or inhibited by various agents (see Table 72.2 ). Phase II enzymes include arylamine N -acetyltransferases (NAT1, NAT2), uridine diphospho-glucuronosyltransferases (UGTs), epoxide hydrolase, glutathione S -transferases (GSTs), sulfotransferases (SULTs), and methyltransferases (catechol O -methyltransferase, thiopurine S methyltransferase, several N -methyltransferases). As with the CYPs, UGTs, SULTs, and GSTs are gene families with multiple individual isoforms, each having its own preferred substrates, mode of regulation, and tissue-specific pattern of expression. For most CYPs, genotype-phenotype relationships are influenced by development in that fetal expression is limited (with the exception of CYP3A7)

and functional activity is acquired postnatally in isoform-specific patterns. Clearance of some compounds appears to be greater in children relative to adults, and the correlation between genotype and phenotype in neonatal life through adolescence may be obscured.

CYP2D6 The CYP2D6 gene locus is highly polymorphic, with >110 allelic variants identified to date (http://www.imm.ki.se/CYPalleles/cyp2d6.htm ; see Table 72.2 ). Individual alleles are designated by the gene name (CYP2D6) followed by an asterisk, and an Arabic number. By convention, CYP2D6*1 designates the fully functional wild-type allele. Allelic variants are the consequence of point mutations, single–base pair deletions or additions, gene rearrangements, or deletion of the entire gene, resulting in a reduction or complete loss of activity. Inheritance of 2 recessive, nonfunctional or “null' alleles results in the poormetabolizer (PM) phenotype , which is found in approximately 5–10% of whites and approximately 1–2% of Asians. In whites the *3, *4, *5, and *6 alleles are the most common loss-of-function alleles and account for approximately 98% of PM phenotypes. In contrast, CYP2D6 activity on a population basis tends to be lower in Asian and African American populations because of a lower frequency of nonfunctional alleles (*3, *4, *5, and *6) and a relatively high frequency of population-selective alleles associated with decreased activity (“reduced function” alleles) relative to the wild-type CYP2D6*1 allele. The CYP2D6*10 allele occurs at a frequency of approximately 50% in Asians, whereas CYP2D6*17 and CYP2D6*29 occur at relatively high frequencies in persons of black African origin. In addition to nonfunctional and partial-function alleles, the presence of gene duplication and multiplication events (≥3 copies of CYP2D6 gene in tandem on a single chromosome) further complicates the prediction of phenotype from genotype information. The concept of “activity score” has been developed to simplify translation of CYP2D6 genotype information into a predicted phenotype of CYP2D6 activity for a particular patient. Fully functional alleles (*1, *2, *35, etc.) are assigned a value of “1”, reduced-function alleles (*9, *10, *17, *29 ) are assigned a value of “0.5”, and nonfunctional alleles (*3-*6, etc.) are assigned a value of “0”; for duplications/multiplication events, the allele score is multiplied by the number of copies detected (*10 × 2 = 0.5 × 2 = “1”). The activity score for an individual is the sum of the scores for each chromosome,

with poor metabolizers (PMs) defined by a score of “0”, whereas a score of “0.5” indicates an intermediate-metabolizer (IM) phenotype , and a score >2 indicating an ultrarapid-metabolizer (UM) phenotype ; scores of 1 to 2 are referred to as extensive metabolizers (EMs) . The activity score classification system has been adopted by the Clinical Pharmacogenetics Implementation Consortium (CPIC; see below). In the past, individuals with an activity score of “1” have been referred to as “IMs,” and any reference to IM status in literature before 2012 likely refers to a genotype with the equivalent of 1 functional allele, in contrast to the current definition (0.5). CYP2D6 is involved in the biotransformation of >40 therapeutic entities, including several β-receptor antagonists, antiarrhythmics, antidepressants, antipsychotics, and morphine derivatives † (see Table 72.2 ). CYP2D6 substrates commonly encountered in pediatrics include selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine), risperidone, atomoxetine, promethazine, tramadol, and codeine. Furthermore, over-the-counter cold remedies (e.g., dextromethorphan, diphenhydramine, chlorpheniramine) are also CYP2D6 substrates. An analysis of CYP2D6 ontogeny in vitro that utilized a relatively large number of samples revealed that CYP2D6 protein and activity remain relatively constant after 1 wk of age up to 18 yr. Similarly, results from an in vivo longitudinal phenotyping study involving >100 infants over the 1st year of life demonstrated considerable interindividual variability in CYP2D6 activity, but no relationship between CYP2D6 activity and postnatal age between 2 wk and 12 mo. Furthermore, a cross-sectional study involving 586 children reported that the distribution of CYP2D6 phenotypes in children was comparable to that observed in adults by at least 10 yr of age. Thus, both available in vitro and in vivo data, although based on phenotype data rather than information on drug clearance from pharmacokinetic studies, imply that genetic variation is more important than developmental factors as a determinant of CYP2D6 variability in children. One consequence of CYP2D6 developmental pharmacogenetics may be the syndrome of irritability, tachypnea, tremors, jitteriness, increased muscle tone, and temperature instability in neonates born to mothers receiving SSRIs during pregnancy. Controversy exists as to whether these symptoms reflect a neonatal withdrawal (hyposerotonergic) state or represent manifestations of serotonin toxicity analogous to the hyperserotonergic state associated with the SSRIinduced serotonin syndrome in adults. Delayed expression of CYP2D6 (and CYP3A4) in the 1st few weeks of life is consistent with a hyperserotonergic state

caused by delayed clearance of paroxetine and fluoxetine (CYP2D6) or sertraline (CYP3A4) in neonates exposed to these compounds during pregnancy. Furthermore, decreases in plasma SSRI concentrations and resolution of symptoms would be expected with increasing postnatal age and maturation of these pathways. Given that treatment of a “withdrawal” reaction may include administration of an SSRI, there is considerable potential for increased toxicity in affected neonates. Resolution of the question whether symptoms are caused by withdrawal vs a hyperserotonergic state is essential for appropriate management of SSRI-induced neonatal adaptation syndromes. Until further data are available, it would be prudent to consider newborns and infants 8 yr of age. Although these results require further replication, the implication is that a better understanding of transporter ontogeny is required to properly design and interpret pharmacogenetic studies of ABCB1 in pediatric populations.

Organic Anion–Transporting Polypeptides Organic anion–transporting polypeptides (OATPs) in the solute carrier organic anion transporter (SLCO) are a family of glycoprotein transporters with 12 transmembrane-spanning domains expressed in various epithelial cells. There are 11 OATPs in humans, some of which are ubiquitously expressed and others whose expression is restricted to specific tissues. Typical substrates include bile

salts, hormones and their conjugates, toxins, and various drugs. The solute carrier, human OATP 1A2 (OATP1A2, OATP-A, OATP1, and OATP) is highly expressed in the intestine, kidney, cholangiocytes, and BBB and may be important in the absorption, distribution, and excretion of a broad array of clinically important drugs. Several nonsynonymous polymorphisms have been identified in the gene encoding OATP1A2, SLCO1A2 (SLC21A3), with some of these variants demonstrating functional changes in the transport of OATP1A2 substrates. OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-specific transporters and promote the cellular uptake of endogenous substrates, such as bilirubin, bile acids, DHEA-sulfate, and leukotriene C4, as well as various drugs, including several statins, methotrexate, and enalapril. Allelic variation in OATP1B1 (specifically the SLCO1B1*5 allele) results in reduced clearance and increased systemic exposure of several statin drugs (atorvastatin, pravastatin, simvastatin) and has been associated with an increased risk of musculoskeletal side effects from simvastatin. The expression of OATP1B1 in human pediatric liver tissue was independent of age in all samples, but age dependency was demonstrated in samples homozygous for the SLCO1B1 reference sequence (i.e., SLCO1B1*1A/*1A genotype). Therefore, not only genotype, but also growth and development, may influence OATP1B1 protein expression in the developing child. To date, only one study has investigated the effect of SLCO1B1 genotype on statin disposition in children, reporting a genotype-phenotype relationship for pravastatin that was discordant with the relationship observed in adults. However, data with simvastatin in dyslipidemic children and adolescents (LDL >130 mg/dL) suggest that the genotype-phenotype relationships observed in adults are also present in this population, but the magnitude of the genetic effect may be greater in pediatric patients. Several studies have confirmed that the 2 SNPs determining the most common SLCO1B1 haplotypes (*1a, *1b, *5, and *15 ), rs4149056 and rs2306283, are associated with decreased clearance of high-dose methotrexate in children with ALL. Genotyping for SLCO1B1 may be helpful in identifying patients at increased risk of toxicity from reduced clearance or increased accumulation of methotrexate. In the pediatric liver proteomic analysis, OATP1B3 expression was age dependent, with a 3-fold difference observed between neonates and adults. Similar to P-gp, expression steadily increased during childhood; however, 50% of adult level expression was much earlier (6 mo) compared with P-gp.

Organic Cation Transporters Organic cation transporters (OCTs) in the SCL22A subfamily are primarily expressed on the basolateral membrane of polarized epithelia and mediate the renal secretion of small organic cations. Originally, OCT1 (also known as SLC22A1) was thought to be primarily expressed in liver, but recent studies have also localized its expression to the apical side of proximal and distal renal tubules. Hepatic OCT1 expression was found to be age dependent with almost a 5-fold difference between neonates and adults. OCT2 (SLC22A2) is predominantly expressed on the basolateral surface of proximal renal tubules. In adults, allelic variation in OCT1 and OCT2 is associated with increased renal clearance of metformin. The role of genetic variation of OCT1 and OCT2 has not been studied in children, but developmental factors appear to be operative. Neonates possess very limited ability to eliminate organic cations, but this function increases rapidly during the 1st few months of life, and when standardized for body weight or surface area, it tends to exceed adult levels during the toddler stage.

Polymorphisms in Drug Receptors Receptors are the targets for drugs and endogenous transmitters because of their inherent molecular recognition sites. Drugs and transmitters bind to the receptor to produce a pharmacologic effect. Variability in the receptor protein or the ion channel may determine the magnitude of the pharmacologic response. Polymorphisms of the β2 -adrenergic receptor gene (ADRB2) are associated with variable responses to bronchodilator drugs. Drug responses are seldom monogenic events because multiple genes are involved in both drug binding to the pharmacologic target and the subsequent downstream signal transduction events that ultimately manifest collectively as a therapeutic effect. Although genotypes at a particular locus may show a statistically significant effect on the outcome of interest, they may account for only a relatively small amount of the overall population variability for that outcome. A particular group of SNPs in the corticotropin-releasing hormone receptor 1 gene (CRHR1) is associated with a statistically significant improvement in forced expiratory volume in 1 second (FEV1 ), but accounts for only 6% of the overall variability in response to inhaled corticosteroids. A series of subsequent studies has determined that allelic variation in several genes in the

steroid pathway contributes to overall response to this form of therapy. The listing and classification of receptors is a major initiative of the International Union of Pharmacology (IUPHAR). The list of receptors and voltage-gated ion channels is available on the IUPHAR website (http://www.iuphar-db.org ). The effect of growth and development on the activities and binding affinities of these receptors, effectors, and ion channels has been studied in animals to some extent but remains to be elucidated in humans.

Current and Future Applications in Pediatrics Progress in the treatment of acute lymphoblastic leukemia shows how the application of pharmacogenomic principles can improve pediatric drug therapy (see Chapter 522.1 ). Despite improved understanding of the genetic determinants of drug response, however, many complexities remain to be resolved. Patients with ALL who have 1 wild-type allele and intermediate TPMT activity tend to have a better response to 6MP therapy than patients with 2 wildtype alleles and full activity. Reduced TPMT activity also places patients at risk for irradiation-induced secondary brain tumors and etoposide-induced acute myeloid leukemia. Pharmacogenetic polymorphisms of several additional genes, such as NUDT15, also have the potential to influence successful treatment of ALL. Multiple genetic and treatment-related factors interact to create patient subgroups with varying degrees of risk. These represent an opportunity for pharmacogenomic approaches to identify subgroups of patients who will benefit from specific treatment regimens and those who will be at risk for short-term and long-term toxicities (Fig. 72.6 ).

FIG. 72.6 Polygenic determinants of drug response. The potential effects of 2 genetic polymorphisms are illustrated. In each panel, there is a profile for individuals who have 2 wild-type alleles (WT/WT), those who are heterozygous for 1 wild-type and 1 variant (V) allele (WT/V), and those who have 2 variant alleles (V/V) for the depicted gene. The top panels illustrate a potential polymorphism involving a drug-metabolizing enzyme where variant alleles result in decreased drug metabolism and greater exposure (as shown by the increasing area under the concentration-time curve [AUC]). The middle panels illustrate a potential polymorphism involving a drug receptor and depicts variant alleles which result in decreased receptor sensitivity. Note that for each receptor type, there are 3 possibilities for drug exposure. The bottom table shows the 9 resulting combinations of drug-metabolism and drug-receptor genotypes and the

corresponding drug-response phenotypes calculated from data shown in the middle panels. These phenotypes allow for calculation of a therapeutic index (i.e., efficacy:toxicity; here this ranges from 13 [65%:5%] to 0.1 [10%:80%]), which results in the ability to perform an individualized risk/benefit assessment. (Adapted from Evans WE, McLeod HL: Pharmacogenomics—drug disposition, drug targets, and side effects, N Engl J Med 348:538–549, 2003.)

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CHAPTER 73

Principles of Drug Therapy Tracy L. Sandritter, Bridgette L. Jones, Gregory L. Kearns, Jennifer A. Lowry

The clinical pharmacology of a given drug reflects a multifaceted set of properties that pertain to not only the disposition and action of drugs, but also the response (e.g., adverse effects, therapeutic effects, therapeutic outcomes) to their administration or use. The 3 most important facets of clinical pharmacology are pharmacokinetics, pharmacodynamics, and pharmacogenomics. Pharmacokinetics describes the movement of a drug throughout the body and the concentrations (or amounts) of a drug that reach a given body space or tissue and its residence time there. Pharmacokinetics of a drug are conceptualized by considering the characteristics that collectively are the determinants of the doseconcentration-effect relationship: absorption, distribution, metabolism, and excretion. Pharmacodynamics describes the relationship between drug dose or drug concentration and response. The response may be desirable (effectiveness) or untoward (toxicity). Although in clinical practice the response to drugs in different patient populations is often described by a standard dosing or concentration range, response is best conceptualized along a continuum where the relationship between dose and response(s) is not linear. Pharmacogenomics is the study of how variant forms of human genes contribute to interindividual variability in drug response. The finding that drug responses can be influenced by the patient's genetic profile has offered great hope for realizing individualized pharmacotherapy, in which the relationship between genotype and phenotype (either disease and/or drug response) is predictive of drug response (see Chapter 72 ). In the developing child, ontogeny has the potential to modulate drug response through altering both pharmacokinetics and pharmacodynamics.

General Pharmacokinetic and

Pharmacodynamic Principles A drug effect is produced only when an exposure (both amount and duration) occurs that is sufficient to produce a drug-receptor interaction capable of modulating the cellular milieu and inducing a physiologic response. Thus, exposure-response relationships for a given drug represent an interface between pharmacokinetics and pharmacodynamics, which can be simply conceptualized by consideration of 2 profiles: plasma concentration vs effect (Fig. 73.1 ) and plasma concentration vs time (Fig. 73.2 ).

FIG. 73.1 Plasma concentration vs effect curve. The percent effect is measured as a function of increasing drug concentration in the plasma. E0 , Dose at which no effect is seen in the population; EC50 , dose of a drug required to produce a specified effect in 50% of the population; Emax , concentration associated with the maximal effect that can be produced by a drug. (From Abdel-Rahman SM, Kearns GL: The pharmacokineticpharmacodynamic interface: determinants of anti-infective drug action and efficacy in pediatrics. In Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, editors: Textbook of pediatric infectious disease, ed 6, Philadelphia, 2009, Saunders-Elsevier, pp 3156– 3178; reproduced with permission.)

FIG. 73.2 Semilogarithmic plot of the plasma concentration vs time curve for a hypothetical drug following extravascular administration. The area under the plasma level-time curve (AUC) is a concentration- and time-dependent measure of systemic drug exposure. After administration, the drug is absorbed and reaches the maximal concentration (Cmax ) at its peak time (Tmax ). Following completion of drug absorption and distribution, plasma drug concentrations decline in an apparent monoexponential manner in which the slope of the apparent elimination phase represents the apparent elimination rate constant (ke). (From Abdel-Rahman SM, Kearns GL: The pharmacokinetic-pharmacodynamic interface: determinants of anti-infective drug action and efficacy in pediatrics. In Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, editors: Textbook of pediatric infectious disease, ed 6, Philadelphia, 2009, Saunders-Elsevier, pp 3156–3178; reproduced with permission.)

The relationship between drug concentration and effect for most drugs is not linear (Fig. 73.1 ). At a drug concentration of zero, the effect from the drug is generally zero or not perceptible (E0 ). After drug administration and with dose escalation, the concentration increases, as does the effect, first in an apparent linear fashion (at low drug concentrations), followed by a nonlinear increase in effect to an asymptotic point in the relationship where a maximal effect (Emax ) is attained that does not perceptibly change with further increases in drug concentration. The point in the concentration-effect relationship where the observed effect represents 50% of the Emax is defined as EC50 , a common pharmacodynamic term used to compare concentration-effect relationships between patients (or research participants) and between drugs that may be in a given drug class. Because it is rarely possible to measure drug concentrations at or near the receptor, it is necessary to utilize a surrogate measurement to assess exposureresponse relationships . In most cases this surrogate is represented by the plasma drug concentration vs time curve. For drugs whose pharmacokinetic properties are best described by first-order (vs zero- or mixed-order) processes, a semilogarithmic plot of plasma drug concentration vs time data for an agent

given by an extravascular route of administration (e.g., intramuscular, subcutaneous, intracisternal, peroral, transmucosal, transdermal, rectal) produces a pattern depicted by Fig. 73.2 . The ascending portion of this curve represents a time during which the liberation of a drug from its formulation, dissolution of the drug in a biologic fluid (e.g., gastric or intestinal fluid, interstitial fluid; a prerequisite for absorption), and absorption of the drug are rate limiting relative to its elimination. After the time (Tmax ) where maximal plasma concentrations (Cmax ) are observed, the plasma concentration decreases as metabolism and elimination become rate limiting; the terminal portion of this segment of the plasma concentration vs time curve is representative of drug elimination from the body. Finally, the area under the plasma concentration vs time curve (AUC ), a concentration- and time dependent parameter reflective of the degree of systemic exposure from a given drug dose, can be determined by integrating the plasma concentration data over time. Being able to characterize the pharmacokinetics of a specific drug allows the clinician to use the data to adjust “normal” dosing regimens and individualize them to produce the degree of systemic exposure associated with desired pharmacologic effects. For drugs where a therapeutic plasma concentration range or “target” systemic exposure (i.e., AUC) is known, a priori knowledge of pharmacokinetic parameters for a given population or patient within a population can facilitate the selection of a drug dosing regimen. Along with information on the pharmacodynamic behavior of a drug and the status of the patient (e.g., age, organ function, disease state, concomitant medications), the application of pharmacokinetics allows the practitioner to exercise a real degree of adaptive control over therapeutic decision-making through the selection of a drug and dosing regimen with the greatest likelihood of producing both efficacy and safety.

Impact of Ontogeny on Drug Disposition Development represents a continuum of biologic events that enable adaptation, somatic growth, neurobehavioral maturation, and eventually reproduction. The impact of development on the pharmacokinetics of a given drug is determined to a great degree by age-related changes in body composition and the acquisition of function in organs and organ systems important in determining drug metabolism and excretion. Although it is often convenient to classify pediatric patients on

the basis of postnatal age in providing drug therapy, with neonates ≤1 mo of age, infants 1-24 mo, children 2-12 yr, and adolescents 12-18 yr, it is important to recognize that the changes in physiology are not linearly related to age and may not correspond to these age-defined breakpoints. In fact, the most dramatic changes in drug disposition occur during the 1st 18 mo of life, when the acquisition of organ function is most dynamic. It is important to note that the pharmacokinetics of a given drug may be altered in pediatric patients because of intrinsic (e.g., gender, genotype, ethnicity, inherited diseases) or extrinsic (e.g., acquired diseases, xenobiotic exposure, diet) factors that may occur during the 1st 2 decades of life. Selection of an appropriate drug dose for a neonate, infant, child, or adolescent requires an understanding of the basic pharmacokinetic properties of a given compound and how the process of development impacts each facet of drug disposition. Accordingly, it is most useful to conceptualize pediatric pharmacokinetics by examining the impact of development on the physiologic variables that govern drug absorption, distribution, metabolism, and elimination (ADME) . Pediatrics encompasses a broad range of ages at which certain stages of life profoundly influence drug response and disposition. Dramatic pharmacokinetic, pharmacodynamic, and psychosocial changes occur as preterm infants mature toward term, as infants mature through the 1st few years of life, and as children reach puberty and adolescence (Fig. 73.3 ). To meet the needs of these different pediatric groups, different formulations are needed for drug delivery that can influence drug absorption and disposition, and different psychosocial issues influence compliance, timing of drug administration, and reactions to drug use. These additional factors must be considered in conjunction with known pharmacokinetic and pharmacodynamic influences of age when developing an optimal, patient-specific drug therapy strategy.

FIG. 73.3 Developmental changes in physiologic factors that influence drug disposition in infants, children, and adolescents. Physiologic changes in multiple organ systems during development are responsible for age-related differences in drug disposition. As reflected by panel A, the activity of many cytochrome P450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the 1st 2 mo of life. In addition, the acquisition of adult activity over time is enzyme and isoform specific. Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution of drugs. Infants in the 1st 6 mo of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, compared with older infants and adults. Panel C summarizes the age-dependent changes in both structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (A ), the activity of CYP1A1 in the intestine is low during early life. Panel D shows the effect of postnatal development on the processes of active tubular secretion, represented by the clearance of paraaminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6-12 mo of age. Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood. (From Kearns GL et al: Developmental pharmacology—drug disposition, action, therapy in infants and children, N Engl J Med 349:1160–1167, 2003. Copyright © 2003, reproduced with permission.)

Drug Absorption Drug absorption mainly occurs through passive diffusion, but active transport or facilitated diffusion may also be necessary for drug entry into cells. Several physiologic factors affect this process, one or more of which may be altered in certain disease states (e.g., inflammatory bowel disease, diarrhea), and thus produce changes in drug bioavailability. The rate and extent of absorption can be significantly affected by a child's normal growth and development.

Peroral Absorption The most important factors that influence drug absorption from the gastrointestinal (GI) tract are related to the physiology of the stomach, intestine, and biliary tract (Fig. 73.3C and Table 73.1 ). The rate and extent of peroral absorption of drugs depend primarily on the pH-dependent passive diffusion and motility of the stomach and intestinal tract, because both these factors will influence transit time of the drug. Gastric pH changes significantly throughout development, with the highest (alkaline) values occurring during the neonatal period. In the fully mature neonate the gastric pH ranges from 6-8 at birth and drops to 2-3 within a few hours of birth. However, after the 1st 24 hr of life, the gastric pH increases because of the immaturity of the parietal cells. As the parietal cells mature, the gastric acid secretory capacity increases (pH decreases) over the 1st few months of life, reaching adult levels by age 3-7 yr. As a result, the peroral bioavailability of acid-labile drugs (e.g., penicillin, ampicillin) is increased. In contrast, the absorption of weak organic acids (e.g., phenobarbital, phenytoin) is relatively decreased, a condition that may necessitate administration of larger doses in very young patients to achieve therapeutic plasma levels. Table 73.1

Developmental Alterations in Intestinal Drug Absorption PHYSIOLOGIC ALTERATION Gastric pH Gastric emptying time Intestinal motility Intestinal surface area Microbial colonization Biliary function

NEONATES >5 Irregular Reduced Reduced Reduced Immature

INFANTS 4 to 2 Increased Increased Near adult Near adult Near adult

CHILDREN Normal (2-3) Slightly increased Slightly increased Adult pattern Adult pattern Adult pattern

Direction of alteration given relative to expected normal adult pattern. Data from Morselli PL: Development of physiological variables important for drug kinetics. In Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York, 1983, Raven Press.

Gastric emptying time is prolonged throughout infancy and childhood as a result of reduced motility, which may impair drug passage into the intestine, where most absorption takes place. Gastric emptying rates reach or exceed adult values by 6-8 mo of life. As such, intestinal motility is important for the rate of drug absorption and, as with other factors, is dependent on the age of the child. Consequently, the rate of absorption of drugs with limited water solubility (e.g., phenytoin, carbamazepine) can be dramatically altered consequent to changes in GI motility. In older infants and young children, more rapid rates of intestinal drug transit can reduce the bioavailability for some drugs (e.g., phenytoin) and drug formulations (e.g., sustained-release) by reducing their residency time at the absorption surfaces in the small intestine. Neonates, particularly premature neonates, have a reduced bile acid pool and biliary function, resulting in a decreased ability to solubilize and absorb lipophilic drugs. Biliary function develops in the 1st few months of life, but it may be difficult for the neonate and young infant to absorb fat-soluble vitamins because low concentrations of bile acids are necessary for their absorption.

Extravascular Drug Absorption Intravenous (IV) drug administration is assumed to be the most dependable and accurate route for drug delivery, with a bioavailability of 100%. Absorption of drugs from tissues and organs (e.g., intramuscular, transdermal, rectal) can also be affected by development (Table 73.2 ). Intramuscular (IM) blood flow changes with age, which can result in variable and unpredictable absorption. Reduced muscular blood flow in the 1st few days of life, the relative inefficiency of muscular contractions (useful in dispersing an IM drug dose), and an increased percentage of water per unit of muscle mass may delay the rate and extent of drugs given intramuscularly to the neonate. Muscular blood flow increases into infancy, and thus the bioavailability of drugs given by the IM route is comparable to that seen in children and adolescents. Table 73.2

Influence of Ontogeny on Drug Absorption

PHYSIOLOGIC ALTERATION Oral absorption Intramuscular absorption Percutaneous absorption Rectal absorption

NEONATES Erratic Variable Increased Very efficient

INFANTS Increased Increased Increased Efficient

CHILDREN Near adult Near adult Near adult Near adult

Direction of alteration given relative to expected normal adult pattern. Data from Morselli PL: Development of physiological variables important for drug kinetics. In Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York, 1983, Raven Press.

In contrast, mucosal permeability (rectal and buccal) in the neonate is increased and thus may result in enhanced absorption by this route. Transdermal drug absorption in the neonate and very young infant is increased because of the thinner and more hydrated stratum corneum (Fig. 73.3E ). In addition, the ratio of body surface area to body weight is greater in infants and children than in adults. Collectively, these developmental differences may predispose the child to increased exposure and risk for toxicity for drugs or chemicals placed on the skin (e.g., silver sulfadiazine, topical corticosteroids, benzocaine, diphenhydramine), with higher likelihood of occurrence during the 1st 8-12 mo of life. Normal developmental differences in drug absorption from most all extravascular routes of administration can influence the dose–plasma concentration relationship in a manner sufficient to alter pharmacodynamics. The presence of disease states that influence a physiologic barrier for drug absorption or the time that a drug spends at a given site of absorption can further influence drug bioavailability and effect.

Drug Distribution Drug distribution is influenced by a variety of drug-specific physiochemical factors, including the role of drug transporters, blood-tissue protein binding, blood-tissue pH, and perfusion. However, age-related changes in drug distribution are primarily related to developmental changes in body composition and the quantity of plasma proteins capable of drug binding. Age-dependent changes in the relative sizes of body water —total body water (TBW) and extracellular water (ECW)—and fat compartments may alter the apparent volume of distribution (VD) for a given drug. The absolute amounts and distribution of body water and fat depend on a child's age and nutritional status. Also, certain disease states (e.g., ascites, dehydration, burn injuries, skin

disruption involving large surface area) can influence body water compartment sizes and thereby, further impact the VD for certain drugs. Newborns have a much higher proportion of body mass in the form of water (approximately 75% TBW) than older infants and children (Fig. 73.3B ). In addition, the percentage of ECW changes (decreases) from the newborn stage (approximately 45%) into adulthood (20–30%). In fact, the increase of TBW in the neonate is attributable to ECW. The reduction in TBW is rapid in the 1st year of life, with adult values (approximately 55%) achieved by approximately 12 yr of age. In contrast, the percentage of intracellular water (ICW) as a function of body mass remains stable from the 1st months of life through adulthood. The impact of developmental changes in body water spaces are exemplified by drugs such as the aminoglycoside antibiotics; compounds that distribute predominantly throughout the extracellular fluid space and have a higher VD (0.4-0.7 L/kg) in neonates and infants than in adults (0.2-0.3 L/kg). Body fat percentage and composition increase during normal development. The body fat percentage in a neonate is approximately 16% (60% water and 35% lipid). Despite the relatively low body fat content in the neonate, it is important to note that the lipid content in the developing central nervous system (CNS) is high, which has implications for the distribution of lipophilic drugs (e.g., propranolol) and their CNS effects during this period. The body fat percentage tends to increase up to about age 10 yr, then changes composition with respect to puberty and sex to approach adult body fat composition (26% water and 71% lipid). In addition, a sex difference exists as the child transitions into adolescence. Whereas the total body fat in males is reduced to 50% between 10 and 20 yr of life, the reduction in females is not as dramatic and decreases 28– 25% during this same developmental stage. Albumin, total proteins, and total globulins (e.g., α1 -acid glycoprotein) are the most important circulating proteins responsible for drug binding in plasma. The absolute concentration of these proteins is influenced by age, nutrition, and disease (Table 73.3 ). The concentrations of almost all circulating plasma proteins are reduced in the neonate and young infant (approximately 80% of adult) and reach adult values by 1 yr of age. A similar pattern of maturation is observed with α1 -acid glycoprotein (an acute-phase reactant capable of binding basic drugs), for which neonatal plasma concentrations are approximately 3 times lower than in maternal plasma and attain adult values by approximately 1 yr of age.

Table 73.3

Factors Influencing Drug Binding in Pediatric Patients PHYSIOLOGIC ALTERATION Plasma albumin Fetal albumin Total proteins Total globulins Serum bilirubin Serum free fatty acids

NEONATES Reduced Present Reduced Reduced Increased Increased

INFANTS Near adult Absent Decreased Decreased Normal Normal

CHILDREN Near adult Absent Near adult Near adult Adult pattern Adult pattern

Direction of alteration given relative to expected normal adult pattern. Data from Morselli PL: Development of physiological variables important for drug kinetics. In Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York, 1983, Raven Press.

The extent of drug binding to proteins in the plasma may influence distribution characteristics. Only free, unbound drug can be distributed from the vascular space into other body fluids and, ultimately, to tissues where drugreceptor interaction occurs. Drug protein binding depends on a number of agerelated variables, including the absolute amount of proteins and their available binding sites, the conformational structure of the binding protein (e.g., reduced binding of acidic drugs to glycated albumin in patients with poorly controlled diabetes mellitus), the affinity constant of the drug for the protein, the influence of pathophysiologic conditions that either reduce circulating protein concentrations (e.g., ascites, major burn injury, chronic malnutrition, hepatic failure) or alter their structure (e.g., diabetes, uremia), and the presence of endogenous or exogenous substances that may compete for protein binding (i.e., protein displacement interactions). Developmentally associated changes in drug binding can occur because of altered protein concentrations and binding affinity. Circulating fetal albumin in the neonate has significantly reduced binding affinity for acid drugs such as phenytoin, which is extensively (94–98%) bound to albumin in adults, compared to 80–85% in the neonate. The resultant 6-8-fold difference in the free fraction can result in CNS adverse effects in the neonate when total plasma phenytoin concentrations are within the generally accepted “therapeutic range” (10-20 mg/L). The importance of reduced drug-binding capacity of albumin in the neonate is exemplified by interactions between endogenous ligands (e.g., bilirubin, free fatty acids) and drugs with greater binding affinity (e.g., ability of sulfonamides to produce kernicterus).

Drug transporters such as P-glycoprotein and multidrug-resistant proteins 1 and 2 can influence drug distribution. These drug transporters can greatly influence the extent that drugs cross membranes in the body and whether drugs can penetrate or are secreted from the target sites (inside cancer cells or microorganisms or crossing the blood-brain barrier). Thus, drug resistance to cancer chemotherapy, antibiotics, or epilepsy may be conferred by these drug transport proteins and their effect on drug distribution. Growing evidence on the ontogeny of drug transport proteins demonstrates their presence as early as 12 wk gestation and low levels in the neonatal period, which rapidly increase to adult values by 1 to 2 yr of age, depending on the transporter. In addition, genetic variation can affect drug transporter expression and function but may not be readily apparent until adult levels are obtained (see Chapter 72 ).

Drug Metabolism Metabolism reflects the biotransformation of an endogenous or exogenous molecule by one or more enzymes to moieties that are more hydrophilic and thus can be more easily eliminated by excretion, secretion, or exhalation. Although metabolism of a drug generally reduces its ability to produce a pharmacologic action, metabolism also can result in metabolites that have significant potency and thereby contribute to the drug's overall pharmacodynamic profile (e.g., biotransformation of the tricyclic antidepressant amitriptyline to nortriptyline; codeine to morphine; cefotaxime to desacetyl cefotaxime; theophylline to caffeine). In the case of prodrugs (e.g., zidovudine, enalapril, fosphenytoin) or some drug salts or esters (e.g., cefuroxime axetil, clindamycin phosphate), biotransformation is required to produce a pharmacologically active moiety. Finally, for some drugs, cellular injury and associated adverse reactions are the result of drug metabolism (e.g., acetaminophen hepatotoxicity, Stevens-Johnson syndrome associated with sulfamethoxazole). The primary organ responsible for drug metabolism is the liver, although the kidney, intestine, lung, adrenals, blood (phosphatases, esterases), and skin can also biotransform certain compounds. Drug metabolism occurs primarily in the endoplasmic reticula of cells through 2 general classes of enzymatic processes: phase I (nonsynthetic) and phase II (synthetic) reactions. Phase I reactions include oxidation, reduction, hydrolysis, and hydroxylation reactions. Phase II reactions primarily involve conjugation with an endogenous ligand (e.g., glycine, glucuronide, glutathione or sulfate). Many drug-metabolizing enzymes

demonstrate an ontogenic profile with generally low activity at birth and maturation over months to years (Table 73.4 and Fig. 73.3A ). Table 73.4

Impact of Development on Drug Metabolism PHYSIOLOGIC ALTERATION Cytochrome P450 activity Phase II enzyme activity Blood esterase activity Presystemic enzyme activity

NEONATE Reduced Reduced Reduced Reduced

INFANTS Increased Increased Normal (by 1 yr) Increased

CHILDREN Slightly increased Near adult Adult pattern Near adult

Direction of alteration given relative to expected normal adult pattern. Data from Morselli PL: Development of physiological variables important for drug kinetics. In Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York, 1983, Raven Press.

Many enzymes are capable of catalyzing the biotransformation of drugs and xenobiotics, but quantitatively the most important are represented by cytochrome P450 (CYP ), a supergene family with at least 16 primary enzymes. The specific CYP isoforms responsible for the majority of human drug metabolism are represented by CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. These enzymes represent the products of genes that in some cases are polymorphically expressed, with allelic variants producing enzymes generally resulting in either no or reduced catalytic activity (a notable exception being the *17 allele of CYP2C19, which may have increased activity) (see Chapter 72 ). At birth the concentration of drug-oxidizing enzymes in fetal liver (corrected for liver weight) appears similar to that in adult liver. However, the activity of these oxidizing enzyme systems is reduced, which results in slow clearance (and prolonged elimination) of many drugs that are substrates for them (e.g., phenytoin, caffeine, diazepam). Postnatally, the hepatic CYPs appear to mature at different rates. Within hours after birth, CYP2E1 activity increases rapidly, with CYP2D6 being detectable soon thereafter. CYP2C (CYP2C9 and CYP2C19) and CYP3A4 are present within the 1st mo of life, a few months before CYP1A2. CYP3A4 activity in young infants may exceed that observed in adults, as reflected by the clearance of drugs that are substrates for this enzyme (e.g., cyclosporine, tacrolimus). Compared to phase I drug-metabolizing enzymes, the impact of development on the activity of phase II enzymes (acetylation, glucuronidation, sulfation) is not characterized as well. Phase II enzyme activity is decreased in the newborn

and increases into childhood. Conjugation of compounds metabolized by isoforms of glucuronosyltransferase (UGT ) (e.g., morphine, bilirubin, chloramphenicol) is reduced at birth but can exceed adult values by 3-4 yr of age. Also, the ontogeny of UGT expression is isoform specific. Newborns and infants primarily metabolize the common analgesic acetaminophen by sulfate conjugation, since the UGT isoforms responsible for its glucuronidation (UGT1A1 and UGT1A9) have greatly reduced activity. As children age, the glucuronide conjugate becomes predominant in the metabolism of therapeutic doses of acetaminophen. In contrast, the glucuronidation of morphine (a UGT2B7 substrate) can be detected as early as 24 wk gestation. The activity of certain hydrolytic enzymes, including blood esterases, is also reduced during the neonatal period. Blood esterases are important for the metabolic clearance of cocaine, and the reduced activity of these plasma esterases in the newborn may account for the delayed metabolism (prolonged effect) of local anesthetics in the neonate. In addition, this may account for the prolonged effect that cocaine has on the fetus with prenatal exposures. Adult esterase activity is achieved by 10-12 mo of age. The development of presystemic clearance or “first-pass” metabolism is unclear given the involvement of multiple enzymes and transporters in the small intestine, many of which have patterns of developmental expression that may be more or less concordant. However, given that the activity of almost all drugmetabolizing enzymes is markedly reduced in the neonate, the extent of bioavailability of drugs given by the peroral route that may be subjected to significant presystemic clearance in older children and adults would appear to be greatly increased during the 1st days to weeks of life. It is important for the clinician to recognize that estimates of bioavailability for a host of drugs available in reference texts and therapeutic compendia are most often derived from studies conducted in young adults. Thus, estimates of the rate and extent of absorption (including a propensity to be affected by presystemic clearance) from adults cannot be accurately used to extrapolate how a peroral drug dose may need to be age-adjusted for a neonate or infant. With regard to the impact of development on drug metabolism, it must be recognized that most therapeutic drugs are polyfunctional substrates for a host of enzymes and transporters. It is the isoform-specific ontogenic profile (Fig. 73.3 ) that must be considered in the context of deducing how development can affect the metabolic portion of drug clearance. True developmental dependence of drug clearance must also consider the role of pharmacogenetic constitution on the

activity of enzymes and transporters (see Chapter 72 ) and the impact of ontogeny on the nonmetabolic routes (e.g., renal drug excretion, salivary/biliary drug excretion, pulmonary drug excretion), which contribute to the overall drug clearance (Total CL = CLhepatic + CLrenal + CLnonrenal ).

Renal Drug Elimination The kidney is the primary organ responsible for the elimination of drugs and their metabolites. The development of renal function begins during early fetal development and is complete by early childhood (Fig. 73.3D and Table 73.5 ). Total renal drug clearance (CLrenal ) can be conceptualized by considering the following equation: Table 73.5

Impact of Development on Renal Drug Elimination PHYSIOLOGIC ALTERATION Glomerular filtration Active tubular secretion Active tubular reabsorption Active drug excretion Passive drug excretion Excretion of basic drugs

NEONATE Reduced Reduced Reduced Reduced Reduced Increased

INFANTS Normal (by 1 yr) Near normal Near normal Near normal Increased Increased

CHILDREN Adult pattern Adult pattern Adult pattern Adult pattern Adult pattern Near normal

Direction of alteration given relative to expected normal adult pattern. Data from Morselli PL: Development of physiological variables important for drug kinetics. In Morselli PL, Pippenger CE, Penry JK, editors: Antiepileptic drug therapy in pediatrics, New York, 1983, Raven Press.

where glomerular filtration rate (GFR), active tubular secretion (ATS), and active tubular reabsorption (ATR) of drugs can contribute to overall clearance. As for hepatic drug metabolism, only free (unbound) drug and metabolite can be filtered by a normal glomerulus and secreted or reabsorbed by a renal tubular transport protein. Renal clearance is limited in the newborn because of anatomic and functional immaturity of the nephron unit. In both the term and the preterm neonate, GFR

averages 2-4 mL/min/1.73 m2 at birth. During the 1st few days of life, a decrease in renal vascular resistance results in a net increase in renal blood flow and a redistribution of intrarenal blood flow from a predominantly medullary to a cortical distribution. All these changes are associated with a commensurate increase in GFR. In term neonates, GFR increases rapidly over the 1st few months of life and approaches adult values by 10-12 mo (Fig. 73.3D ). The rate of GFR acquisition is blunted in preterm neonates because of continued nephrogenesis in the early postnatal period. In young children 2-5 yr of age, GFR may exceed adult values, especially during periods of increased metabolic demand (e.g., fever). In addition, a relative glomerular/tubular imbalance results from a more advanced maturation of glomerular function. Such an imbalance may persist up to 6 mo of age and may account for the observed decrease in the ATS of drugs commonly used in neonates and young infants (e.g., β-lactam antibiotics). Finally, some evidence suggests that ATR is reduced in neonates and that it appears to mature at a slower rate than the GFR. Altered renal drug clearance in the newborn and infants result in the different dosing recommendations seen in pediatrics. The aminoglycoside antibiotic gentamicin provides an illustrative example. In adolescents and young adults with normal values for GFR (85-130 mL/min/1.73 m2 ), the recommended dosing interval for gentamicin is 8 hours. In young children who may have a GFR >130 mL/min/1.73 m2 , a gentamicin dosing interval of every 6 hr may be necessary in selected patients who have serious infections that require maintaining steady-state peak and trough plasma concentrations near the upper boundary of the recommended therapeutic range. In contrast, to maintain “therapeutic” gentamicin plasma concentrations in neonates during the 1st few weeks of life, a dosing interval of 18-24 hr is required. The impact of developmental differences in GFR on the elimination characteristics of a given drug can be assessed by estimating the apparent elimination rate constant (Kel) for a drug by using the following equation:

where the Fel represents the fraction of the drug excreted unchanged in an

adult with normal renal function; GFRobserved is the value calculated (from creatinine clearance or age-appropriate estimation equation) for the patient (in mL/min/1.73 m2 ); and GFRnormal is the average value considered for a healthy adult (120 mL/min/1.73 m2 ). Kelnormal is estimated from the average elimination T1/2 for a drug taken from the medical literature using the following equation:

Likewise, the elimination half-life (T1/2 ) for a drug in patients with reduced renal function can be estimated as follows:

An estimate of the drug elimination T1/2 in patients with reduced renal function with knowledge of the desired interdose excursion in steady-state plasma concentrations can allow determination of the desired drug dosing interval.

Impact of Ontogeny on Pharmacodynamics Although it is generally accepted that developmental differences exist in drug action, there is little evidence of true age related pharmacodynamic variation among children of differing age-groups and adults. Drug action is typically mediated by interaction of a small molecule with 1 or more receptors that may be located either on or in a cell. Drug effect is mediated at the receptor by 4 main biochemical mechanisms involved in cell signaling. Binding of the receptors on the cell surface or within the cell activates downstream pathways that mediate a specific cellular action. Some receptors act as enzymes, whereby on ligand binding the enzyme phosphorylates downstream effector proteins, thereby activating or inhibiting a cellular signal (e.g., guanosine triphosphate– binding regulatory protein, also known as G-protein–coupled receptors). Other receptors mediate their actions through ion channels, whereby on ligand binding

the cell's membrane potential or ionic composition is altered, allowing cellular activation or inhibition. Lastly, some receptors act as transcription factors, which when bound by a ligand activate transcription of specific genes within the cell. Drug action is concentration dependent, with onset and offset generally associated with appearance and disappearance, respectively, of the drug at the receptor(s) in an amount that is sufficient to initiate the cascade of biologic effects that terminate in drug action (see Fig. 73.1 ). The minimum effective concentration of a drug is that observed with the immediate onset of effect, whereas the duration of action is predicated on the maintenance of drug concentrations at the receptor within a range associated with the desirable pharmacologic action(s). Receptor binding by a drug may have varying consequences. Drugs that are agonists bind to and activate the receptor, directly or indirectly achieving the desired effect. An agonist binding to a receptor results in the same biologic effect as binding of the endogenous ligand. Partial agonist binding results in activation of the receptor, but maximal effect is not achieved, even in the presence of receptor saturation. Antagonists bind to a receptor, preventing binding of other molecules, thereby preventing activation of the receptor. Evidence supports developmental differences in receptor number, density, distribution, function, and ligand affinity for some drugs. Human data are limited, so much of what is known has been derived from animal studies. In the CNS, unique developmental aspects of drug-receptor interaction affect therapeutic efficacy of both analgesics and sedatives in neonates. The number of γ-aminobutyric acid (GABA) receptors, which mediate inhibitory signal transduction in the CNS, is reduced in newborns compared to adults. Functional differences have also been observed between neonatal and adult brain on GABA receptor activation. These changes may explain observed differences in dosing of drugs such as midazolam in infants and in part may explain seizures experienced by infants on benzodiazepine exposure. Another CNS example is the µ-opioid receptor, whereby receptor number is reduced in newborns and receptor distribution also differs between newborns and adults. For the clinician, consideration of age-dependent differences in pharmacodynamics is particularly relevant when associated with adverse drug reactions (e.g., higher incidence of valproic acid-associated hepatotoxicity in young infants; greater frequency of paradoxical CNS reactions to diphenhydramine in infants; weight gain associated with atypical antipsychotic

drugs in adolescents) or when drugs have a narrow therapeutic index (Fig. 73.4 ). The age-associated pharmacodynamics of warfarin observed in children with congenital heart disease is related to developmental differences in serum concentrations of vitamin K–dependent coagulation factors (II, VII, IX, X) between children and adults. Developmental differences in drug action have been observed between prepubertal children and adults in regard to warfarin action. Prepubertal children exhibit a more profound response, demonstrated by lower protein C concentration, prothrombin fragments 1 and 2, and greater rise in INR, to comparable doses of warfarin. Thus, when age-dependent pharmacodynamics of a given drug is evident, the use of simple allometric approaches for “scaling” the pediatric dose from the usual adult dose may not produce the desired pharmacologic effects. Pharmacokinetic and pharmacodynamic (PK/PD) modeling techniques that use known developmental changes in body composition, enzyme function, renal function, effector proteins, and receptors are being used to predict optimal dosing in children. However, data regarding differences in pharmacodynamic response across the age continuum remain lacking and limit the application of these techniques to accurately predict dose-response relationships in the pediatric population.

FIG. 73.4 Quantal dose–effect curve. Age-related pharmacokinetic variation may result in alterations in drug concentration at the receptor resulting in ineffective, therapeutic or toxic results. LD50, Dose at which 50% of the population is lethal. The ratio of the LD50 to the ED50 is an indication of the therapeutic index, which is a reflection of drug potency relative to its concentration.

Surrogate Endpoints

Biomarkers and surrogate endpoints (markers) are ideally simple, reliable, inexpensive, and easily obtainable measures of a biologic response or disease phenotype that can be used to facilitate either clinical research or patient care. Biomarkers have been defined by the U.S. National Institutes of Health as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” A surrogate endpoint is defined “as a biomarker that is intended to substitute for a specific clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.” Reliable surrogate endpoints predict a specific physiologic event (e.g., intraesophageal pH to assess gastroesophageal reflux) that may be used diagnostically, prognostically, or in predicting a specific drug response (therapeutic, subtherapeutic, or adverse) or potentially the impact of ontogeny on pharmacodynamics. Specific examples of surrogate endpoints used in pediatric pharmacology include measurement of esophageal pH to assess the action of prokinetic or acid-modifying drugs and pulmonary function tests (e.g., FEV1 ) to evaluate the effect of drugs on pulmonary function in patients with conditions such as asthma and cystic fibrosis. Biomarkers used in pediatric studies to assess drug disposition or effect include hemoglobin A1c plasma concentration (to assess efficacy of peroral hypoglycemic agents), urinary leukotriene concentrations (to assess effects of nonsteroidal antiinflammatory drugs), and minimal inhibitory concentration (MIC) and minimal bacteriocidal concentration (MBC) of drugs to select antiinfective agents.

Additional Considerations in Pediatric Therapeutics Pediatric Dose and Regimen Selection Incomplete developmental profiles for hepatic and extrahepatic drugmetabolizing enzymes and drug transporters that may influence drug clearance and bioavailability prevent the use of simple formulas or allometric scaling for effective pediatric dose prediction. Although these approaches may have some clinical utility in older children (>8 yr) and adolescents whose organ function and body composition approximate that of young adults, their utility is severely

limited in neonates, infants, and young children, in whom ontogeny produces dramatic differences in drug disposition. This is especially problematic for therapeutic drugs whose doses cannot be easily individualized using patientspecific pharmacokinetic data obtained from therapeutic drug monitoring. In the absence of such pharmacokinetic data or established pediatric dosing guidelines, alternate methods must often be employed. To date, >20 different approaches for initial selection of a drug dose for pediatric patients have been described. The majority use either total body weight (BW) or body surface area (BSA) as surrogates that reflect the developmental changes of body composition or organ function, which collectively are the major determinants of drug disposition. Selection based on BW or BSA will generally produce similar relationships between drug dose and resultant plasma concentration, except for those drugs whose apparent volume of distribution (VD) corresponds to the extracellular fluid pool (i.e., VD 0.3 L/kg), a BW-based approach for dose selection is preferable, which is the most frequently used method in pediatrics. When the pediatric dose for a given drug is not known, these principles can be used to best approximate a proper dose for the initiation of treatment, as illustrated by the following equations:

It should be noted that this approach assumes that the child's weight, height, and body composition are age appropriate and normal, and that the “reference” normal adult has a BW and BSA of 70 kg and 1.73 m2 , respectively. It is useful only for selection of dose size and does not offer information regarding dosing interval, because the equations contain no specific variable that describes potential age-associated differences in drug clearance. Similar to obese adults, obesity in children would be expected to result in to alterations in drug pharmacokinetics. Unfortunately, few data exist on drug

dosing in obese pediatric patients. Alterations in VD, which is important for loading-dose calculations, is related to the lipophilicity or water solubility of the medication to be administered. Some limited data are available on the impact of obesity on VD in children with the antibiotics cefazolin and tobramycin. The impact of obesity in pediatric patients on absorption and drug metabolism (phase I and II pathways) is not known. No validated estimate of GFR in obese children exists, but current information suggests that serum creatinine concentration may be higher or no different in obese children than in those of normal weight. Drug dosing in normal-weight children typically uses age-based dosing, allometric scaling, BSA, or BW. These same estimates can be used in obese children, although use of an adjusted BW should be considered. Variations on weight used in adults include ideal body weight (IBW), lean body weight, adjusted body weight, and total body weight. However, in children, standards for calculating adjusted weights may not be standardized (e.g., IBW). When dosing medications in obese children, it is important to consider information regarding drug dosing in obese adults, recommended adult maximum doses, and the physiochemical properties of the drug to be given. In neonates and young infants with developmental immaturity in GFR or ATS, it is often necessary to adjust the “normal” dosing interval (i.e., that used for older infants and children who have attained developmental competence of renal function) for drugs with significant (>50%) renal elimination, to prevent excessive drug accumulation (and possible associated toxicity) with administration of multiple doses. To accomplish this therapeutic goal, it is necessary to estimate the apparent elimination half-life (T1/2 ) of the drug (see equations earlier).

Therapeutic Drug Monitoring Clinically, systemic drug exposure is usually evaluated through assessing the plasma drug concentration, a surrogate measurement for a drug reaching its pharmacologic receptor(s). In the patient, drug level monitoring can be used to facilitate 2 approaches for evaluating the dose-concentration-effect relationship: single-concentration (e.g., trough or random level) therapeutic drug monitoring (TDM) and multilevel pharmacokinetic-based TDM. Both lead to dose individualization for a given patient. Drug-level monitoring largely entails measurement of drug concentrations in plasma (primarily) or other biologic fluids at some point during a drug's dosing

interval. These levels are then compared with those that are “desired” for a given drug based on published information and used to adjust the dose/dosing regimen. For single trough-level measurement (at the end of a dosing interval) or randomlevel measurement (nonspecific time point during a dosing interval), adjustment of the medications dose is done empirically without pharmacokinetic parameters. In using a TDM approach, it should be recognized that for many drugs which are therapeutically monitored in the clinical setting (e.g., aminoglycoside antibiotics, vancomycin, phenytoin, phenobarbital, cyclosporine, tacrolimus, mycophenolate mofetil, selected antiretroviral drugs, acyclovir), “desired” plasma concentrations are generally determined from studies in adult patients where drug disposition and disease states may be quite different from those in infants and children. Clinical pharmacokinetics represents a proactive approach where multiple plasma drug concentrations are used to estimate pharmacokinetic parameters for a specific patient to a specific drug at that point in time (e.g., apparent elimination rate constant, elimination T1/2 , apparent VD, total plasma clearance, AUC), which are then used to calculate a dosing regimen required to attain a desired level of systemic exposure (e.g., AUC, steady-state peak/trough plasma drug concentrations) that would portend a desired pharmacologic response. Of these 2 approaches, the use of drug-level data for performing clinical pharmacokinetics provides the better approach for individualizing dose/dosing regimen and maintaining some adaptive control over the dose-concentrationeffect relationship. This approach is particularly useful for patients who may have “abnormal” pharmacokinetics because of their age and/or disease states. Approaches used to enable the performance of clinical pharmacokinetics include the manual use of established formulas for calculating pharmacokinetic parameters (generally using a simple 1-compartment open model consequent to the few plasma drug-level observations obtained in clinical patient care) or computer-based algorithms (e.g., bayesian estimation, population-based pharmacokinetic approaches). Common to both of the aforementioned approaches is the need to accurately assess plasma drug concentrations in a given patient. Fig. 73.5 represents a hypothetical general steady-state plasma concentration vs time profile for a drug given by an extravascular route, illustrating the following general principles to recognize and follow when plasma drug-level monitoring is used in patients as a “tool” to individualize drug treatment:

FIG. 73.5 Plasma concentration vs time profile for a hypothetical drug at steady state. When dose size, route of administration, time of administration, and dosing interval remain constant, the resultant true peak (Cmax ) and trough (Cmin ) plasma concentrations and AUC from dose to dose are identical. Apparent values for Cmax and Cmin are denoted to illustrate the potential difference from true values that can result when the actual times for obtaining samples for either therapeutic drug monitoring or clinical pharmacokinetic applications are not realized.

◆ When a drug reaches a pharmacokinetic steady state (a period corresponding to 5 times the apparent elimination T1/2 for a given drug), both the excursion between the peak (Cmax ) and trough (Cmin ) plasma concentration and the AUC are identical between dose intervals provided that (1) the dose is not changed; (2) an exact dose-to-dose interval is maintained for drug administration; and (3) the route or rate of drug administration between dosing intervals has not changed. ◆ Steady-state plasma drug concentrations provide the best surrogate for assessing exposure-response relationships for a given drug. These drug concentrations provide the most accurate estimation

of patient-specific pharmacokinetic parameters. Plasma concentrations assessed before the attainment of steady state can be useful for evaluating exaggerated drug response or predicting eventual steady-state drug levels and exposure. ◆ To reliably interpret any drug plasma concentration, it is imperative that the clinician know and consider the following: 1. The expected pharmacokinetic profile for a given drug (e.g., time after dosing required for completion of drug absorption [for extravascularly administered drugs] and distribution) 2. The exact time that the drug was administered 3. For drugs given by IV infusion, the total duration of infusion (including time required to flush the dose from the IV tubing) 4. Pertinent limitations of the analytic method used to measure the plasma drug level (e.g., range of linearity, potential for analytic interference from concomitant drugs) 5. The method used to obtain the blood specimen(s) used for plasma level determination (e.g., venous puncture vs cutaneous puncture; use of vascular

catheter different from one used for drug administration) 6. Whether the blood specimen was adequate for accurate drug-level measurement (e.g., sufficient volume, presence or absence of hemolysis or lipemia) 7. The exact time that the blood specimens were obtained in relationship to the time of drug administration and the drug dosing interval This last point is illustrated by Fig. 73.5 , which denotes the “true” peak (Cmax ) and trough (Cmin ) plasma concentrations in relationship to apparent values. This situation frequently occurs when “peak” and “trough” blood levels are ordered, and nursing/phlebotomy procedures allow some period of leeway as to when they can be obtained. When such a discrepancy is realized, and the exact timing of the samples relative to dose administration is known, corrections can be made to insure pharmacokinetic parameters estimated from the data are accurate. If such a discrepancy is not realized, errant parameter estimation and dose regimen calculation/determination may result, thereby compromising safety or efficacy of drug treatment.

Drug Formulation and Administration One of the more unique challenges in pediatric therapeutics is the drug formulation itself. Despite the increasing sensitivity for the need to study pediatric drugs before their use in children and to have available “pediatricfriendly” formulations, many drug products formulated only for adult use are routinely given to pediatric patients. Their use can result in inaccurate dosing (e.g., administration of a fixed dose to children with widely varying body weights), loss of desired performance characteristics of the formulation (e.g., crushing sustained-release tablet, cutting transdermal patch), and exposure of

infants and children to excipients (e.g., binding agents, preservatives) in amounts capable of producing adverse effects.

Peroral Drug Administration One of the principal determinants of peroral drug administration in children is the ability to get the drug into the body. Peroral formulations are often expelled by children because of poor taste and texture. This is a significant issue, especially when considering that taste sensation differs because of development and on an interindividual basis. Solid peroral formulations such as tablets and capsules are not easily administered to the majority of infants and children because of their inability to swallow them easily and safely. Incomplete development of swallowing coordination may result in choking or aspiration when solid peroral formulations are given to infants and small children. Further, solid peroral formulations limit the ability for dose titration and dosing flexibility. Drug developers are working to address this limitation with new techniques suitable for both oral and peroral drug administration that encompass both products (e.g., dispersible peroral tablets, oral films, titratable granules, oral melts) and drug administration devices (e.g., dosing straws, graduated cylinders for peroral granules). With regard to dosing accuracy with peroral formulations, liquids (e.g., drops, solutions, syrups, suspensions, elixirs) are preferred for infants and young children. The utility of these formulations is often limited by palatability when taste-masking of the active ingredient(s) cannot be effectively achieved. In the case of suspension formulations, improper reconstitution and/or resuspension before dose administration can introduce problems related to accuracy of dosing. Other potential limitations of peroral liquid formulations (e.g., those that may be extemporaneously compounded by the pharmacist from drug powder or from solid peroral dosage forms of a given drug) include potential problems related to drug stability, contamination (chemical or bacterial), portability, and for some products the need for refrigeration. Administration of liquid medications can be associated with risk if the device for administering the medication is not appropriate (e.g., use of a kitchen teaspoon vs 5.0 mL dosing spoon) or is used improperly to insure the drug dose is measured appropriately for the patient's age or weight. The low cost and convenience of hypodermic syringes has prompted many physicians and pharmacists to dispense them with liquid medications in order to improve

accuracy. While this approach would seemingly be associated with greater accuracy in dosing, parents/caregivers can have difficulty in reading the graduations on a syringe, and the plastic caps on the plungers of syringes can produce a choking hazard for infants and young children. These problems can be obviated by education of parents/caregivers on how to reliably use peroral dosing syringes, which pharmacists should dispense with every liquid drug formulation.

Parenteral Drug Administration In contrast to adults, in whom vascular access is relatively easy to obtain, difficulties are often present in the infant and young child, resulting from the smaller diameter of peripheral vessels (relative to size of IV cannula), developmentally associated differences in body composition (e.g., body fat distribution), and use of topical anesthetic agents, which can produce venous constriction. The small peripheral blood vessels in infants and young children can also limit the volume and rate of parenteral drug administration due to issues of capacity and with drugs capable of producing venous irritation, which induces infusion-related pain. An underappreciated complicating issue for parenteral drug administration to infants is the relative lack of formulations in concentrations suitable for IV administration. Errors consequent to improper dilution of adult formulations necessary to ensure appropriate osmolarity and volume for IV administration (the most common resulting in a 10-fold overdose) are not uncommon. Morphine, a drug commonly used in neonates, infants, and children, is commonly available in an 8 mg/mL concentration. A usual 0.1 mg/kg morphine dose for a 1 kg infant using this formulation would require a nurse or pharmacist to accurately withdraw 0.013 mL and administer it into a length of IV tubing with a dead space volume that may exceed that of the dose by 100-fold. In this situation, accuracy of dose and infusion time can be significantly compromised. Although underdosing is often a serious problem when attempting to administer very small volumes, overdoses also occur from inaccurate extemporaneous dilutions. Moreover, attempts to compensate for the volumes present within the IV tubing further predispose the patient to receive an incorrect, possibly unsafe, dose. Whenever such concentrated drug formulations are the only source for use, appropriate alteration of the stock parenteral solution should be performed and manufactured by the pharmacy department. Also, many errors can be avoided by

the use of standard dilutions that all practitioners are aware of and using standardized approaches for IV drug administration that minimize complications associated with unrealized drug dilution and errant infusion times (e.g., pediatric syringe pumps attached to low-volume tubing). Although used rather infrequently, intramuscular (IM) drug administration offers a route of administration for many drugs when venous access is not immediately available or when a therapeutic drug regimen involves use of a single or limited number of doses. While appealing with respect to immediacy, this route of administration can be associated with problems (e.g., muscle/nerve damage, sterile abscess formation, variable rate of drug absorption because of developmental differences in vascular perfusion of muscle beds), especially in the neonate and small infant. Lastly, the decision to use the IM route must take into consideration the physicochemical properties (e.g., pH, osmolarity, solubility) of the drug formulation and any diluent used to prepare it.

Other Routes for Drug Administration Neonates, infants, children, and adolescents with certain pulmonary conditions (e.g., reactive airway disease, viral-induced bronchiolitis, asthma, cystic fibrosis) frequently receive drugs (e.g., corticosteroids, β-adrenergic agonists, antimicrobial agents, mucolytic drugs) by inhalation . The pulmonary surface area in pediatric patients of all ages is a very effective, easily traversable barrier for drug absorption. Rate-limiting factors for pulmonary drug absorption include physicochemical factors associated with the drug and delivery system (e.g., particle size, diffusion coefficient, chemical stability of drug molecule in the lung) and physical factors that influence intrapulmonary drug disposition (e.g., active vs passive drug delivery to tracheobronchial tree, respiratory minute volume, internal airway diameter), many of which are developmentally determined. For drugs formulated for delivery using a metered-dose inhaler (either drug powder or suspended particles using a carrier gas), developmental factors (e.g., incoordination of device actuation with inhalation, inability to follow instructions for clearing of airway, passive inhalation with actuation of delivery device) either prevent their use (as in infants and small children) or limit the bioavailability of the drug to be administered. In these instances, specific devices (e.g., masks, spacer chambers) and methods of delivery (e.g., continuous aerosolization by mask) can be used to improve the efficiency of drug delivery and thus drug efficacy.

In pediatric patients, percutaneous drug administration is generally reserved for agents intended to produce a local effect within the dermis. Development has an impact on the barrier of the skin that, if not recognized and controlled for with proper drug administration techniques, can produce situations in which systemic toxicity can result. Similar therapeutic challenges occur when transmucosal routes (e.g., buccal, sublingual, rectal) are used for drug administration. Specifically, unpredictable systemic bioavailability may complicate treatment consequent to variability in the rate and/or extent of drug absorption. As a consequence, transmucosal drug administration to pediatric patients is no longer widely used as a matter of convenience but, rather, when the condition of the patient does not enable drug administration by the peroral or the parenteral routes. Direct intraosseous drug administration through puncture of the tibia is occasionally used in infants and small children for administration of drugs and crystalloid fluids given acutely during resuscitation efforts. It is particularly useful when vascular access sufficient for drug administration cannot be immediately accomplished, since the onset of action by the intraosseous route is comparable to that after IV administration.

Adherence and Compliance The success of drug treatment in a pediatric patient depends on the successful administration of the drug. Physical and cognitive immaturity makes the infant and the child a dependent creature in almost all respects, including those related to therapeutic drug administration. Until a child reaches an age at which the child can physically self-administer a drug in an accurate, proficient manner and can mentally assume this responsibility (generally 7-14 yr of age, depending on the individual child), compliance with a drug regimen becomes the responsibility of an adult. In a hospital environment, compliance is ensured through the actions of physicians, nurses, and pharmacists who, collectively through an integrated system of medical care, assume this responsibility. On discharge, the responsibility is transferred to parents/guardians or other adult caregivers in an environment that is generally nonmedical. At this juncture, therapeutic compliance morphs into adherence , as defined by the potential for conflicting demands, such as multiple adult caregivers, different external environments (e.g., home, daycare, school), and parents tending to the needs of multiple children, to introduce variability (anticipated and unpredictable) in drug administration. Whether treatment is for a self-limiting (e.g., antibiotic

administration) or chronic (e.g., asthma, diabetes) condition, challenges to therapeutic adherence can serve as rate-limiting events in the determination of drug safety and efficacy in infants and young children. In contrast to the period encompassing infancy and childhood, adolescence poses its own unique challenges to therapeutic adherence. During this period, psychosocial maturation almost always lags behind physical maturation. Development of cognitive and physical skills in most adolescents enables them to self-administer a prescribed medication in a proper manner with little to no supervision. However, psychodynamic issues experienced by a substantial number of adolescents (e.g., complete understanding of the ramifications of undertreatment, disease progression, and roles of disease prevention and health maintenance; perceptions of immortality and associated lack of need for treatment; disorganized patterns of thinking capable of confounding treatment schedules; defiant/oppositional behavior toward authority figures) can often precipitate therapeutic failure, through either undertreatment or overtreatment, the latter occasionally leading to drug toxicity. Unfortunately, the only approach that can be used to facilitate therapeutic compliance and adherence in the pediatric patient is the combination of vigilance (on behalf of all caregivers) and repetitive education coupled with positive reinforcement. When children reach the age of assent (generally by 7 yr in children who have normal neurobehavioral development), they have the beginning level of cognitive ability sufficient to engender understanding about their medical condition(s) and how effective treatment can be used to improve their life. Through diligent patient education and reeducation, older children and adolescents can assume a level of responsibility for active partnership in their overall medical management, one that will mature as educational efforts, driven by a shared desire for an optimal outcome, are regularly made.

Drug-Drug Interactions Pharmacokinetic and pharmacodynamic properties of drugs may be altered when ≥2 drugs are administered to a patient (Table 73.6 ). Interactions largely occur at the level of drug metabolism but may occur at the level of drug absorption (e.g., inhibition of intestinal CYP3A4 activity by grapefruit juice or St. John's wort and consequent reduction in presystemic clearance of CYP3A4 substrates), distribution (e.g., displacement of warfarin plasma protein binding by ibuprofen with consequent increased hemorrhagic risk), or elimination (e.g., inhibition of

ATS of β-lactam antibiotics by probenecid). Also, drug-drug interactions may occur at the level of the receptor (through competitive antagonism); many of which are intentional and produce therapeutic benefit in pediatric patients (e.g., antihistamine reversal of histamine effects, naloxone reversal of opiate adverse effects). Table 73.6

Mechanism of Drug Interactions 1 EXAMPLE DRUG COMBINATION PHARMACODYNAMIC Additive

Synergy

Fentanyl + midazolam Class 1A antiarrhythmic 2 + erythromycin 3 Vancomycin + an aminoglycoside 4 Penicillin + an aminoglycoside 4

Antagonism Opioid + naloxone Donepezil + an anticholinergic

PHARMACOKINETIC Absorption Inhibition of P-gp 5 : Amiodarone + digoxin

Complex formation: Oral quinolone and tetracycline antibiotics + divalent/trivalent cations (eg, Ca2+ , Mg2+ , Fe3+ , Al3+ ) Distribution Ceftriaxone + endogenous bilirubin Metabolism Induction of CYP isozymes 5 , 6 : Rifampin + protease inhibitors 7

Inhibition of CYP isozymes 5 ,

RESULT Use of multiple drugs with similar adverse effect profiles can lead to additive effects: Increased sedation Increased QT prolongation Increased potential for nephrotoxicity

Improved bactericidal efficacy against some gram-positive organisms; penicillin inhibits bacterial cell wall synthesis, which for some gram-positive organisms can improve the intracellular penetration of the aminoglycoside Competitive receptor antagonism; decreased efficacy of the opioid, reversal of sedation, respiratory depression, and hypotension Oppositional effects; acetylcholinesterase inhibitors such as donepezil increase acetylcholine concentrations by slowing the degradation of acetylcholine, and anticholinergic drugs antagonize the effect of acetylcholine

Increased digoxin concentration; gut P-gp is an efflux transporter that takes drugs from cell cytoplasm and transports them back into the intestinal lumen for excretion, limiting bioavailability Decreased antibiotic concentrations due to binding in the gut

Displacement of bilirubin from albumin binding site, increased risk of kernicterus in neonates

Decreased serum concentrations of protease inhibitors metabolized by CYP3A4 due to induction of CYP3A4-mediated metabolism; may result in subtherapeutic levels and resistance

6 :

Azole antifungals 8 + CYP3A4 substrates Elimination Penicillin + probenecid Methotrexate + aspirin

Increased serum concentrations of CYP3A4 substrates due to inhibition of CYP3A4-mediated metabolism; may result in drug toxicity Decreased tubular secretion of penicillin resulting in increased serum concentrations Inhibition of tubular secretion of methotrexate resulting in increased methotrexate concentrations

1 Drug interactions from The Medical Letter. Available at: www.medicalletter.org/subDIO . 2 Disopyramide, procainamide, quinidine 3

Woosley RL, Romero KA: QT drugs list. Available at: www.crediblemeds.org

4 Gentamicin, tobramycin, amikacin, streptomycin, neomycin 5

Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2017; September 18 (epub). Available at: www.medicalletter.org/downloads/CYP_PGP_Tables.pdf 6 Cytochrome P450 (CYP) isozymes that can affect drug metabolism include CYP1A2, 2C8, 2C9,

2C19, 2D6, and 3A4. 7 Some protease inhibitors metabolized by CYP3A4 include atazanavir, darunavir, fosamprenavir,

indinavir, lopinavir/ritonavir, nelfinavir, and saquinavir. 8

Itraconazole, ketoconazole, posaconazole, and voriconazole are strong inhibitors of CYP3A4. Fluconazole is a moderate CYP3A4 inhibitor. This table is not an all-inclusive list of drug interactions. The prescriber is encouraged to assess the possibility of drug interactions when prescribing medications. This table does not address the chemical compatibility of drugs (eg, IV-line compatibility). CYP = cytochrome P-450; P-gp = P-glycoprotein. Modified from Rizack M, Hillman C: The Medical Letter Handbook of Adverse Drug Interactions. New Rochelle, NY, The Medical Letter, 1989. IBM Micromedex DRUGDEX, Copyright IBM Corporation 2018; Med Lett Drugs Ther 2018;60:e160.

Drug interactions may also occur at a pharmaceutical level as a result of a physicochemical incompatibility of 2 medications when combined. Such interactions generally alter the chemical structure of one or both constituents and thereby renders them inactive and potentially dangerous (e.g., IV infusion of crystalline precipitate or unstable suspension). Ceftriaxone should be avoided in infants nurses > pharmacists), parents/caregivers, and patients (who may not recognize signs/symptoms and/or may be unable to report them) and in many countries (including the United States) the lack of a standardized surveillance and real-time reporting system. Despite the limitations associated with determining the incidence of ADRs in children, it is estimated that their occurrence in patients 0-4 yr of age (3.8%) is more than double that seen at any other time during childhood or adolescence. In the outpatient setting, children age 0-4 yr accounted for 43% of clinic and emergency department visits for ADRs. One study reported that 60% of the ADRs occurred in those 2 MAC hr.

Isoflurane Isoflurane is a pungent volatile anesthetic and airway irritant, not suitable for induction because of the high incidence of complications, such as laryngospasm. However, maintenance of anesthesia with isoflurane is common after induction with sevoflurane or an intravenous (IV) hypnotic. Emergence from anesthesia with isoflurane is slower than for sevoflurane. Isoflurane administration in the setting of desiccated CO2 absorbents may yield the production of carbon monoxide.

Desflurane Desflurane is a potent airway irritant associated with coughing, breath holding, and laryngospasm and is not useful for induction. Desflurane has the lowest solubility and potency of all commonly used volatile agents. It is frequently administered for maintenance of anesthesia. Emergence from desflurane anesthesia is rapid due to its low tissue solubility.

Nitrous Oxide Nitrous oxide (N2 O) is a tasteless, colorless, odorless gas with potent analgesic properties. It produces a state of euphoria (thus its nickname, “laughing gas”). The MAC of N2 O is >100; consequently, it may not be used as a sole agent to maintain anesthesia. N2 O produces little hemodynamic or respiratory depression. N2 O is typically used in combination with volatile and IV anesthetic agents during maintenance of general anesthesia. The deleterious effects of N2 O include postoperative nausea and vomiting and, with long-term use (i.e., days), bone marrow suppression. N2 O diffuses out of blood rapidly and is contraindicated in patients with closed gas-filled body cavities (pneumothorax, lung cysts, bowel injury).

Intravenous Anesthetic Agents Intravenous anesthetics may be administered for induction and maintenance of anesthesia in bolus form or as continuous infusions. Common IV agents include propofol, opioids, benzodiazepines, ketamine, dexmedetomidine, and barbiturates. For children with vascular access, IV induction should be routine. All IV agents affect cardiorespiratory function.

Propofol Propofol is the most commonly administered IV induction agent. Administered in doses of 2-5 mg/kg, propofol rapidly produces unconsciousness. Propofol may burn and itch on injection. After induction of anesthesia, propofol is a useful agent for maintaining hypnosis and amnesia and may be used as a sole anesthetic agent for nonpainful procedures (e.g., radiation therapy) and imaging studies. When combined with opioids, propofol provides excellent anesthesia for brief painful procedures, such as lumbar puncture and bone marrow aspiration.

Although hemodynamic stability, and even spontaneous respirations, may be maintained during propofol administration, it remains a potent anesthetic that obtunds airway reflexes, respiration, and hemodynamic function, and should not be considered a “sedation agent.” Propofol frequently induces both respiratory depression and hypotension. Extrapyramidal symptoms are a rarer complication. Prolonged use may cause hemodynamic collapse, bradycardia, metabolic acidosis, cardiac failure, rhabdomyolysis, hyperlipidemia, profound shock, and death (propofol infusion syndrome) . Prolonged propofol administration (>2448 hr) in the ICU in children is not recommended. Propofol is formulated in 10% soy emulsion with egg emulsifiers and was once thought to be contraindicated in patients with soy or egg allergy. According to the American Academy of Allergy, Asthma, and Immunology, however, patients with soy and egg allergies may safely receive propofol for anesthesia.

Etomidate Etomidate is an imidazole derivative used for the induction of anesthesia, frequently in emergent situations. Its onset of action is slower than propofol. Etomidate lacks significant cardiovascular depressant effects, making it a popular induction agent in patients with hemodynamic compromise, cardiac disease, and septic shock. However, etomidate inhibits 11β-hydroxylase, thereby suppressing mineralocorticoid and glucocorticoid synthesis for up to 72 hr after a single induction dose. Etomidate is associated with increased mortality when used as a sedative in the ICU (for which it is now contraindicated), even with a single induction dose. Any decision to use etomidate must weigh the short-term benefits of hemodynamic stability with the serious risks of adrenal suppression.

Ketamine Ketamine (1-3 mg/kg IV) produces rapid induction of general anesthesia that lasts for 15-30 min. Ketamine is effective when given intramuscularly, subcutaneously, nasally, or orally. However, the dose must be increased for alternative routes. Ketamine dissociates connections between the cerebral cortex and limbic system (dissociative anesthesia) through inhibition of N -methyl-D aspartate receptors. Ketamine is also an analgesic and may be used as a sole IV agent to provide general anesthesia. It has few side effects and generally preserves blood pressure and cardiac output. However, ketamine increases myocardial oxygen demand and should be used cautiously in patients with

impaired myocardial oxygen delivery or ventricular outflow tract obstruction. With low-dose (1-2 mg/kg) ketamine, airway reflexes and spontaneous ventilation may be maintained; at higher doses (3-5 mg/kg), loss of airway reflexes, apnea, and respiratory depression occur. Aspiration of gastric contents remains a risk during deep sedation with ketamine. IV ketamine is a useful general anesthetic agent for short procedures. Ketamine has been linked to disturbing postanesthetic dreams and hallucinations following emergence from anesthesia. In adults the incidence of this effect is 30–50%; in prepubertal children it may be 5–10%. Benzodiazepines (e.g., midazolam) reduce these sequelae and should be routinely given to children receiving ketamine. Ketamine is also a potent secretagogue, enhancing oral and bronchial secretions. An antisialogue, such as atropine or glycopyrrolate, should also be considered before the administration of ketamine. Ketamine is a bronchodilator and is a useful agent for sedating asthmatic patients in the ICU. Ketamine has been reported to increase ICP and therefore is contraindicated in patients with elevated ICP.

Opioids Opioids are superb analgesics for painful procedures and postprocedural pain (see Chapter 75 ). Opioids are respiratory depressants that suppress CO2 responsiveness and can produce apnea. Importantly, in equianalgesic doses, all opioids are equally potent respiratory depressants. Other inhalational or IV anesthetics generally potentiate opioid-induced respiratory depression. Morphine is a long-acting opioid analgesic with important age-dependent pharmacokinetics. Large doses of morphine (0.5-2 mg/kg), combined with N2 O provide adequate analgesia for painful procedures. Equivalent doses of morphine per kilogram are associated with higher blood levels in neonates than in older children, with plasma concentrations approximating 3 times those of adults. Morphine exhibits a longer elimination half-life (14 hr) in young children than in adults (2 hr). The immature blood-brain barrier of neonates is more permeable to morphine. Morphine is often associated with hypotension and bronchospasm from histamine release and should be used with caution in children with asthma. Morphine has renally excreted active metabolites and is relatively contraindicated in renal failure. Because of morphine's prolonged duration of action and cardiorespiratory side effects, the fentanyl class of synthetic opioids has increased in popularity for perioperative analgesia.

Fentanyl is a potent synthetic opioid with a shorter duration of action and a more stable hemodynamic profile than morphine. Fentanyl attenuates the hemodynamic response to surgery and provides stable operating conditions. Effective analgesia and anesthesia may be provided with IV fentanyl administered as a 2-3 µg/kg bolus followed by a 1-3 µg/kg/hr continuous infusion. Nitrous-narcotic anesthetic techniques that incorporate fentanyl are effective for maintenance of stable hemodynamics while still providing adequate hypnosis and analgesia. Fentanyl is the most commonly used synthetic opioid, but other formulations of varying potency are available (alfentanil < fentanyl < sufentanil). Sufentanil is 10 times more potent than fentanyl and is frequently used during pediatric cardiac anesthesia. Alfentanil is approximately as potent as fentanyl. Remifentanil has very rapid onset and offset of action. In doses of 0.25 µg/kg/min, surgical anesthesia can be maintained with this agent. Remifentanil is metabolized through nonspecific ester hydrolysis and has a short elimination half-life (9 REQUIRED FOR DISCHARGE 2 1 0 2 1 0 2 1

>50% outside preanesthetic value COLOR Pink Pale, blotchy, dusky Cyanotic CONSCIOUSNESS Fully aware, responds Arouses to stimulus Unresponsive STEWARD RECOVERY SCORE ACTIVITY Moves limbs purposefully Nonpurposeful movement Still CONSCIOUSNESS Awake Responsive Unresponsive AIRWAY Coughing on command or crying Maintaining patent airway Requires airway maintenance

0 2 1 0 2 1 0 6 REQUIRED FOR DISCHARGE 2 1 0 2 1 0 2 1 0

Postanesthetic Complications Respiratory insufficiency following general anesthesia is common. Prolonged emergence from anesthesia and respiratory depression may be caused by the residual effects of opioids, hypnotic agents, or NMBAs. Pain may also cause significant hypoventilation, especially after thoracic or abdominal surgery. Delayed emergence from anesthesia may result from retention of inhaled anesthetics worsened by hypoventilation. Hypothermia, especially in neonates, delays metabolism and excretion of anesthetics and prolongs NMB. Hypoventilation after surgery is associated with the development of atelectasis . Microatelectasis may lead to postoperative infections. When airway obstruction is present, maintenance of airway patency may necessitate oropharyngeal or nasopharyngeal airway placement. In the setting of profound respiratory depression, endotracheal intubation and mechanical ventilation may be indicated. Opioid reversal with naloxone may be indicated in rare instances when excessive opioid effect is suspected. However, naloxone reverses both the respiratory depressant and the analgesic effects of opioids. Following naloxone reversal, a somnolent child with respiratory depression may experience increased pain. Opioid reversal requires bedside attention by the physician to monitor the

child's behavioral, hemodynamic, and respiratory status. Importantly, naloxone is shorter-acting than most opioid analgesics, which may result in re-narcotization. Postoperative stridor occurs in up to 2% of all pediatric patients. The use of appropriately sized ETTs and assurance of an air leak 30 mL/kg) in the postoperative period may be an indication of evolving shock physiology, and sources of hypovolemia (e.g., occult bleeding) or myocardial dysfunction (e.g., tamponade, pneumothorax) should be considered. Emergence delirium immediately after anesthesia is noted in 5–10% of children and is more common in those 3-9 yr old. Manifestations include restlessness, combativeness, disorientation, and inconsolability. Almost all anesthetic agents have been linked to the development of delirium, especially newer volatile anesthetic agents (e.g., sevoflurane, desflurane). Potential postoperative complications, such as hypoglycemia and hypoxemia, should also be ruled out. Occasionally, it is necessary to provide additional sedation (e.g., propofol, dexmedetomidine, benzodiazepines) although these agents prolong postanesthesia recovery time and may not effectively reduce delirium.

Awareness During Anesthesia A fundamental aim of anesthesia is to prevent recall by inducing hypnosis and amnesia. In adults, certain anesthetic techniques and surgical procedures have been associated with recall during anesthesia. The long-term sequelae of recall in children are unknown. Continuous cerebral bispectral index (BIS) electroencephalographic monitoring has been used to assess intraoperative awareness. Unfortunately, pediatric studies have not confirmed the usefulness of BIS monitoring as a means of determining anesthetic depth. Existing data do not support the routine use of BIS monitoring during pediatric anesthesia. Volatile anesthetic agents reliably produce dose-dependent hypnotic and amnestic effects and remain a mainstay of general anesthesia.

Postoperative Nausea and Vomiting Following general anesthesia, 40–50% of children may experience postoperative nausea and vomiting (PONV) that generally lasts for several hours. This complication prolongs recovery room times and requires significant nursing attention. The etiology is not completely understood but is likely multifactorial related to the emetic effects of anesthetics, pain, and surgical stress. Opioid analgesics may provoke nausea and vomiting. Importantly, preoperative fasting does not decrease the incidence of PONV. Indeed, hydration and glucose supplementation appear to be important factors in decreasing PONV. Multimodal analgesia with nonopioid agents (e.g., acetaminophen, ibuprofen, ketorolac) and regional or local anesthesia may decrease PONV. The serotonin antagonist ondansetron is an effective treatment of PONV. Ondansetron prophylaxis is also recommended for patients at increased risk of PONV, such as after eye and otolaryngology surgery. Serotonin antagonists are contraindicated in children taking serotonin reuptake inhibitors for migraine headaches. Dexamethasone may also be used for the treatment of PONV.

Thermoregulation and Malignant Hyperthermia Following anesthesia, thermoregulation remains abnormal for several hours. Hypothermia , especially in neonates, may to cardiorespiratory depression and prolongation of the effect of opioids and NMBAs. Although hypothermia has deleterious effects, active rewarming should be performed cautiously to avoid hyperthermia and cutaneous burns. Postoperative shivering is common and may occur in the absence of hypothermia. Hyperthermia , with temperatures in excess of 39°C (102.2°F), is of concern in the postoperative period. When high fevers occur within hours of the use of an inhalational anesthetic, especially if succinylcholine was used, malignant hyperthermia must be ruled out. Malignant hyperthermia (MH) is a hypermetabolic syndrome triggered by volatile anesthetic agents and succinylcholine. The onset of MH may be acute, fulminant, and lethal without appropriate interventions. The disease is genetically heterogeneous, with >10 genes contributing to susceptibility, but typically displays an autosomal dominant inheritance pattern. A family history of death or febrile reactions during anesthesia should alert the anesthesiologist to its potential. Mutations within the gene encoding for the ryanodine receptor (the calcium channel of the sarcoplasmic reticulum) predispose to MH susceptibility and have been identified in 20–40% of humans with MH. Certain myopathies

are associated with the risk of MH, including Duchenne muscular dystrophy, central core disease, and King Denborough syndrome. The pathophysiology of MH involves uncontrolled intracellular calcium release from skeletal muscle sarcolemma, resulting in prolonged muscle contraction, adenosine triphosphate (ATP) depletion, and muscle cell death. Myolysis results in the release of myoglobin, creatine phosphokinase (CPK), and potassium into the blood. The clinical course of MH is characterized by rapid onset of high fever (>38.5°C), muscle rigidity, acidosis (metabolic and respiratory), high end-tidal CO2 , and multiorgan dysfunction. Death may ensue secondary to hemodynamic collapse from shock and cardiac dysrhythmias. Signs of MH generally occur within the 1st 2 hr of anesthesia, but (rarely) can occur up to 24 hr later. Aggressive therapy involves discontinuation of all inhalational anesthetics, correction of the metabolic acidosis, and treatment with the muscle relaxant dantrolene. IV dantrolene (2.5 mg/kg as initial dose) should be initiated when MH is suspected. The need for repeat doses, up to a maximum of 10 mg/kg, is indicated for persistent fever, muscle rigidity, acidosis, and tachycardia. Once symptoms are controlled, the patient should be observed for at least 24 hr, because recrudescence may occur. The MH mortality rate was once >70% and is now 5-7 days. • Addiction, a psychiatric pathology, refers to psychological craving, compulsive drug-seeking behavior, and drug use despite medical harm. Addiction has strong genetic and environmental determinants. Opioid therapy will not lead to addiction in nonsusceptible individuals, and opioid underdosing does not prevent addiction; it may in fact increase drugseeking behavior for relief of pain (e.g., watching the clock), referred to as “pseudoaddiction.” Table 76.6

Pediatric Dosage Guidelines for Opioid Analgesics DRUG Fentanyl

EQUIANALGESIC PARENTERAL DOSING DOSES IV Oral 50 kg 10 µg 100 0.5-1 0.5-1 µg µg/kg µg/kg q1-2h q1-2h 0.5-1.5 0.5-1.5 µg/kg/hr µg/kg/hr

IV:PO DOSE RATIO Oral transmucosal: 1 : 10 Transdermal: 1 : 1

ORAL DOSING 50 kg Transdermal patches available; patch reaches steady state at 24 hr and should be changed q72h

Hydrocodone

N/A

Hydromorphone 0.2 mg

1.5 mg N/A

0.6 mg

0.01 mg q2-4h 0.002 mg/kg/hr

N/A

N/A

0.01 mg 1 : 3 q2-4h 0.002 mg/kg/hr

0.15 mg/kg

10 mg

0.04-0.08 mg/kg q3-4h

2-4 mg q3-4h

100-150 mg q3-4h

Meperidine

10 mg 30 mg 0.5 mg/kg q2-4h

0.5 mg/kg q2-4h

1 : 4

2-3 mg/kg q3-4h

Methadone

1 mg

0.1 mg/kg q8-24h

1 : 2

0.2 mg/kg q8-12h 2.5 mg TID PO; available as liquid or tablet

2 mg

0.1 mg/kg q8-24h

Morphine

1 mg

3 mg

Oxycodone

N/A

3 mg

0.05 Bolus: 5-8 mg/kg mg q2-4h q2-4h 0.010.03 mg/kg/hr

N/A

N/A

1 : 3

Immediate release: 0.3 mg/kg q3-4h Sustained release: 20-35 kg: 1015 mg q8-12h 35-50 kg: 1530 mg q8-12h

Immediate release: 15-20 mg q3-4h Sustained release: 30-90 mg q8-12h

N/A

0.1-0.2 mg q3-4h; available in liquid (1 mg/mL)

Immediate release: 510 mg q4h Sustained release: 10-120 mg q812h

N/A, not available.

Table 76.7

Management of Opioid-Induced Adverse Effects Respiratory

Naloxone: 0.01-0.02 mg/kg up to a full reversal dose of 0.1 mg/kg. May be given IV, IM,

depression

SC, or via ET. The full reversal dose should initially be used for apnea in opioid-naive patients. In opioidtolerant patients, a reduced dose should be given and titrated up slowly to treat symptoms but prevent acute withdrawal. Ventilation may need to be supported during this process. Dose may be repeated every 2 min to a total of 10 mg. Adult maximum dose is 2 mg/dose. Give with caution to patients who are receiving longterm opioid therapy, as it may precipitate acute withdrawal. Duration of effect is 1-4 hr; therefore close observation for re-narcotization is essential to prevent re-narcotization. Excessive sedation Methylphenidate * : 0.3 mg/kg per dose PO (typically 10-20 mg/dose to a teenager) before without evidence of breakfast and lunch. Do not administer to patients receiving clonidine, because respiratory dysrhythmias may develop. depression Dextroamphetamine : 2.5-10 mg on awakening and at noon. Not for use in young children or in patients with cardiovascular disease or hypertension. Modafinil: Pediatric dose not established. May be useful in selected patients. Typical adult dose: 50-200 mg/day. Change opioid or decrease the dose. Nausea and Metoclopramide † : 0.15 mg/kg IV up to 10 mg/dose q6-12h for 24 hr. vomiting Trimethobenzamide: PO or PR if weight 15 kg, 200 mg q6h. (Note: Suppository contains benzocaine 2%.) Not for use in newborn infants or premature infants. 5-HT3 receptor blockers: Ondansetron: 0.15 mg/kg up to 8 mg IV q6-8h not to exceed 32 mg/day (also available as a sublingual tablet). Granisetron: 10 to 20 µg/kg IV q12-24h. Prochlorperazine * (Compazine): >2 yr or >20 kg, 0.1 mg/kg per dose q8h IM or PO up to 10 mg/dose. Change opioid. Pruritus Hydroxyzine : 0.5 mg/kg PO q6h. Nalbuphine: 0.1 mg/kg IV q6h for pruritus caused by intraaxial opioids, especially fentanyl. Administer slowly over 15-20 min. May cause acute reversal of systemic µ-receptor effects and leave κ-agonism intact. Naloxone: 0.003 to 0.1 mg/kg/hr IV infusion (titrate up to decrease pruritus and reduce infusion if pain increases). Ondansetron: 0.05 to 0.1 mg/kg IV or PO q8h. Cyproheptadine † : 0.1-0.2 mg/kg PO q8-12h. Maximum dose 12 mg. Change opioid. Constipation

Encourage water consumption, high-fiber diet, and vegetable fiber. Bulk laxatives: Metamucil, Maltsupex. Lubricants: Mineral oil 15-30 mL PO qd as needed (not for use in infants because of aspiration risk). Surfactants: Sodium docusate (Colace): 12 yr: 100 mg PO q8h Stimulants: Bisacodyl suppository (Dulcolax): 2 yr: 10 mg PR qhs Senna syrup (218 mg/5 mL): >3 yr: 5 mL qhs. Enema: Fleet hypertonic phosphate enema (older children; risk of hyperphosphatemia). Electrolytic/osmotic: Milk of magnesia; for severe impaction: polyethylene glycol

Urinary retention

(GoLYTELY, MiraLax). Methylnaltrexone is an opioid antagonist that works in the colon and does not cross the blood-brain barrier to reverse analgesia; given as subcutaneous injection every day or every other day (0.15 mg/kg) and is effective in producing stool in 30-60 min in most patients. Straight catheterization, indwelling catheter.

*

Avoid in patients taking monoamine oxidase inhibitors.

† May be associated with extrapyramidal side effects, which may be more often seen in children

than in adults. ET, Endotracheal tube; IV, intravenously; IM, intramuscularly; PO, orally; PR, rectally; SC, subcutaneously. Modified from Burg FD, Ingelfinger JR, Polin RA, et al, editors: Current pediatric therapy, ed 18, Philadelphia, 2006, Saunders/Elsevier, p 16.

Table 76.8

Equianalgesic Doses and Half-Life (T1/2β ) of Some Commonly Used Opioids OPIOID Morphine Meperidine Oxycodone Fentanyl Alfentanil Sufentanil Diamorphine Methadone

IM/IV DOSE (mg) 10 100 15 0.15-0.2 0.75-1.5 0.02 5 10

ORAL DOSE (mg) 30 400 20-30 — — — 60 10-15

T1/2β (hr) 2-3 3-4 2-3 3-5 1-2 2-3 0.5* 15-40

Hydromorphone Tramadol † Buprenorphine Pentazocine Nalbuphine Butorphanol

1.5 100 0.4 60 10-20 2

7.5 100 0.8 (sublingual) 150 — —

3-4 5-7 3-5 3-5 2-4 2-3

* Rapidly hydrolyzed to morphine. † Only part of its analgesic action results from action on µ-opioid receptors.

NOTES:

• Published reports vary in the suggested doses considered to be equianalgesic to morphine. Therefore, titration to clinical response in each patient is necessary. • Suggested doses are the results of single-dose studies

only. Therefore, use of the data to calculate total daily dose requirements and repeated or continuous doses may not be appropriate. • There may be incomplete cross-tolerance between these drugs. In patients who have been receiving one opioid for a prolonged period, it is usually necessary to use a dose lower than the expected equianalgesic dose when changing to another opioid, and to titrate to effect. Modified from Macintyre PE, Ready LB: Acute pain management: a practical guide, ed 2, Philadelphia, 2001, Saunders, p 19.

Opioids act by mimicking the actions of endogenous opioid peptides, binding to receptors in the brain, brainstem, spinal cord, and to a lesser extent in the peripheral nervous system, and thus leading to inhibition of nociception. Opioids also bind to µ receptors in the pleasure centers of the midbrain, particularly in genetically susceptible individuals, a factor responsible for the euphoric effect in some individuals as well as the predilection to psychological dependence and addictive behavior. Opioids also have dose-dependent respiratory depressant effects when interacting with the µ-opioid receptors in the respiratory centers of the brainstem, depressing ventilator drive and blunting ventilatory responses to both hypoxia and hypercarbia. These respiratory depressant effects are increased with co-administration of other sedating drugs, particularly benzodiazepines or barbiturates. Optimal use of opioids requires proactive and anticipatory management of side effects (see Table 76.7 ). Common side effects include sedation, constipation, nausea, vomiting, urinary retention, and pruritus. Tolerance usually develops to the side effect of nausea , which typically subsides with long-term dosing, but nausea may require treatment with antiemetics, such as a phenothiazine, butyrophenones, antihistamines, or a serotonin receptor antagonist such as ondansetron or granisetron. Pruritus and other complications during patient-controlled analgesia with opioids may be effectively managed by low-dose IV naloxone. The most common, troubling, but treatable side effect is constipation . Patients who take opioids for chronic pain for long periods predictably develop tolerance to the sedative and analgesic effects of opioids over time, but tolerance

to constipation does not occur, and constipation remains a troublesome and distressing problem in almost all patients with long-term opioid administration. Stool softeners and stimulant laxatives should be administered to most patients receiving opioids for more than a few days. Osmotic and bulk laxatives are less effective, usually producing more distention and discomfort. A peripherally acting opiate µ-receptor antagonist, methylnaltrexone, promptly and effectively reverses opioid-induced constipation in patients with chronic pain who are receiving opioids daily. Methylnaltrexone is approved for use as either an injectable or oral formulation, but only the SC injection is commercially available, which most children will object to receiving. Naldemedine and naloxegol are other agents with actions similar to methylnaltrexone. A novel laxative, lubiprostone , is a colonic chloride channel inhibitor that impairs water reabsorption in the colon and is very effective for opioid-induced constipation. Media and government attention the “opioid epidemic” has reasonably led to scrutiny of the prescription of opioids to children, and recent FDA approval of opioid formulations for children has raised alarm and criticism by some vocal critics of the use of opioids for medical purposes. Thus, one of the potent barriers to effective management of pain with opioids is the fear of addiction held by many prescribing pediatricians and parents alike. Pediatricians should understand the phenomena of tolerance, dependence, withdrawal, and addiction (see Table 76.5 ). Opioid addiction is the result of the complex interplay of genetic predisposition, psychiatric pathology, and social forces, including poverty, joblessness, hopelessness, and despair. The dramatic increase in the amount of opioid abuse and overdoses and opioid-related deaths since 2001 has been largely restricted to the adult white population age 30-55 yr, not in children or adolescents. A longitudinal study of children and adolescents treated for medical reasons with opioids found that there was no increased risk of the development of substance abuse, at least until their mid-20s. Other epidemiologic studies have shown a negligible increase in opioid overdoses and deaths in the black and Latino populations, but rather a relationship to the unemployment rate. Thus the rational short- or even long-term use of opioids in children does not lead to a predilection for or risk of addiction in a child not otherwise at risk because of genetic background, race, or social milieu. It is equally important for pediatricians to realize that even patients with recognized substance abuse diagnoses are entitled to effective analgesic management, which often includes the use of opioids. If legitimate concerns exist about addiction in a patient, safe effective opioid pain management is often

best managed by specialists in pain management and addiction medicine. Table 76.9 outlines the U.S. Centers for Disease Control and Prevention (CDC) opioid recommendations for chronic pain (primarily in adults).

Table 76.9

CDC Recommendations for Prescribing Opioids for Chronic Pain Outside of Active Cancer, Palliative, and End-of-Life Care Determining When to Initiate or Continue Opioids for Chronic Pain 1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. 2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. 3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation 4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids. 5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or

carefully justify a decision to titrate dosage to ≥90 MME/day. 6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed. 7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids. Assessing Risk and Addressing Harms of Opioid Use 8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present. 9. Clinicians should review the patient's history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months. 10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs. 11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.

12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder. All recommendations are category A (apply to all patients outside of active cancer treatment, palliative care, and end-of-life care) except recommendation 10 (designated category B, with individual decision making required); see full guideline for evidence ratings. From Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain—United States, 2016, MMWR 65(1):1–49, 2016. There is no longer a reason to administer opioids by IM injection. Continuous IV infusion of opioids is an effective option that permits more constant plasma concentrations and clinical effects than intermittent IV bolus dosing, without the pain associated with IM injection. The most common approach in pediatric centers is to administer a low-dose basal opioid infusion, while permitting patients to use a patient-controlled analgesia (PCA) device to titrate the dosage above the infusion (Fig. 76.3 ) (see Chapter 74 ). Compared with children given intermittent IM morphine, children using PCA reported better pain scores. PCA has several other advantages: (1) dosing can be adjusted to account for individual pharmacokinetic and pharmacodynamic variation and for changing pain intensity during the day; (2) psychologically the patient is more in control, actively coping with the pain; (3) overall opioid consumption tends to be lower; (4) therefore fewer side effects occur; and (5) patient satisfaction is generally much higher. Children as young as 5-6 yr can effectively use PCA. The device can also be activated by parents or nurses, known as PCA-by-proxy (PCA-P), which produces analgesia in a safe, effective manner for children who cannot activate the PCA demand button themselves because they are too young or intellectually or physically impaired. PCA overdoses have occurred when wellmeaning, inadequately instructed parents pushed the PCA button in medically complicated situations, with or without the use of PCA-P, highlighting the need for patient and family education, use of protocols, and adequate nursing supervision.

FIG. 76.3 Patient-controlled analgesia is more likely to keep blood concentrations of opioid within the “analgesic corridor” and allows rapid titration if there is an increase in pain stimulus requiring higher blood levels of opioid to maintain the analgesia. (From Burg FD, Ingelfinger JR, Polin RA, et al, editors: Current pediatric therapy, ed 18. Philadelphia, 2006, Saunders/Elsevier, p 16.)

Because of the high risk of adverse side effects (respiratory depression), the FDA has issued contraindications for the pediatric use of codeine and tramadol (Table 76.10 ).

Table 76.10

Summary of FDA Recommendations • Use of codeine to treat pain or cough in children 6 mg may cause side effects similar to those of typical antipsychotics. Clozapine (Clozaril), which causes increased incidence of lifethreatening agranulocytosis, should generally be avoided as a treatment for children and adolescents with chronic pain. Aripiprazole (Abilify) has been used for severe anxiety and/or for treatment-resistant depression. All antipsychotics are associated with the rare, but potentially lethal neuroleptic malignant syndrome , which includes severe autonomic instability, muscular rigidity, hyperthermia, catatonia, and altered mental status.

Other Pain Control Medications

Alpha-adrenergic receptor agonists such as clonidine are typically used as antihypertensive agents. However, they are often helpful as both anxiolytics and sleep-onset agents in the anxious hospitalized child. The α-agonists also have central effects on pain reduction. Clonidine can be given orally or transdermally, if the child's blood pressure permits. In the ICU, IV dexmedetomidine , an αagonist sedating agent, can be used for the anxious, medically unstable child. Weaning off the dexmedetomidine can often be accomplished with a transition to clonidine. Propranolol is a β-blocking agent typically used for the child with autonomic instability and for thalamic storm. There are reports that a β-blocker can enhance depression in a child who already has a major depressive disorder, and discussion with a child psychiatrist can be helpful in decisions about using propranolol if needed. Both clonidine and propranolol have been found useful for the agitated child with ASD. Another α-agonist, guanfacine , is more likely to be used during the day for the child with ASD because it is less sedating than clonidine. Despite research on the impact of clonidine on chronic pain, no data are available to determine if guanfacine is as effective in reducing pain. Lastly, ketamine , a blocker of N -methyl-D -aspartate (NMDA) receptors, has been used for intractable pain in hospitalized children and in outpatients with severe sickle cell disease–related chronic pain, as well as others in palliative care for whom opioids are not sufficient to reduce pain. Since ketamine can have central hallucinatory effects, such children should be monitored closely.

Nonpharmacologic Treatment of Pain Numerous psychological and physical treatments for relieving pain, fear, and anxiety as well as enhancing functioning have excellent safety profiles and proven effectiveness and should always be considered for incorporation into pediatric pain treatment (Fig. 76.5 ). In acute and procedural pain, nonpharmacologic strategies have long been used to help reduce distress in children undergoing medical procedures and surgery. Many of these methods aim to help children shift attention from pain and alter pain perception (e.g., distraction, hypnosis, imagery). Similarly, in the treatment of chronic pain, several strategies, often falling under the umbrella category of cognitivebehavioral therapies (CBTs) , have been shown to reduce pain and improve functioning and quality of life. CBT was developed with the goal of modifying social/environmental and behavioral factors that may exacerbate the child's experience of pain and pain-related disability. Several decades of research is

available on CBTs for pediatric chronic pain. Meta-analyses of randomized controlled trials (RCTs) of CBT interventions have found large positive effects of psychological intervention on reductions in pain and/or its deleterious effects in children with headache, abdominal pain, and fibromyalgia, with relative or comparative effectiveness of different interventions examined in areas such as headache and abdominal pain in children. Biofeedback and relaxation therapies have been found to have superior effects to pharmacologic treatments in reducing headache pain in children and adolescents. Similarly, for recurrent abdominal pain, positive effects for CBT were found relative to attention-control conditions and pharmaceutical, botanical, and dietary interventions (which had very weak evidence). Positive results have even resulted from very brief (3 sessions) and remotely delivered (telephone or internet) therapies, with outcomes lasting as long as 12 mo after intervention.

FIG. 76.5 Nonpharmacologic interventions for pediatric pain. (From Krauss BS, Calligaris L, Green SM, Barbi E: Current concepts in management of pain in children in the emergency department, Lancet 387:83–92, 2016).

When deciding how to incorporate nonpharmacologic techniques to treat pain, the practitioner should (1) conduct a thorough assessment of individual, social, and environmental factors that may be contributing to the patient's pain and functioning limitations; (2) based on this assessment, decide whether nonpharmacologic techniques alone may be sufficient as a beginning to treatment, or if these treatments should be integrated with appropriate analgesics; (3) give children (and family members) developmentally and situationally appropriate information as to the rationale for treatment selection, and what to expect, given the child's medical condition, procedures, and treatments; (4) include patients and their families in decision making to ensure an appropriate treatment choice and to optimize adherence to treatment

protocols; and (5) above all, develop a communication plan among the different care providers , typically with the pediatrician as the case manager, so that the messages to the child and parent are consistent and the modes of therapy are organized into an integrative team approach. Finally, it is important to recognize that in addition to pain, other psychological disorders (e.g., anxiety disorders, major depression) may impact the presenting pain complaint and may need to be identified and addressed as part of, or separate from, the pain management plan. Individual psychotherapy or psychiatric intervention may be warranted to adequately treat a comorbid disorder. CBT strategies refer to a range of techniques that teach children (and their caregivers) how to manage pain by learning new ways to think about the pain and how to change behaviors associated with the pain. Strategies focusing on cognitions are typically aimed at enhancing parents' and children's confidence and self-efficacy to handle pain and decrease fear of pain. In addition, pain coping skills may shift the child's attentional focus away from pain and painful stimuli. The goals of those strategies focusing on behavior change are to modify (1) contingencies in the child's environment, such as teaching parents how to respond to pain behaviors in ways that encourage wellness, rather than illness behaviors; (2) the ways parents model reactions to pain or discomfort; (3) child and parent coping techniques when psychosocial distress or problems in social relations exist; and (4) the child's behavioral reactions to situations, such as relaxation and exposure to previously avoided activities. Common examples of these strategies are discussed next. Whereas comprehensive CBTs are typically conducted by trained mental health specialists over several sessions, some basic CBT strategies can be briefly and easily introduced by practitioners into most medical settings. If more in-depth CBT treatment is needed, a referral to a qualified mental health specialist with CBT skills would be warranted. Parent and family education and/or psychotherapy , particularly within cognitive-behavioral family approaches, is one treatment modality through which these goals are accomplished, and thus has been shown to be effective for treating chronic pain. Parents can learn to cope with their own distress and to understand pain mechanisms and appropriate treatment of pain. Key components include teaching parents to alter family patterns that may inadvertently exacerbate pain through developing behavior plans. Parents are taught to create plans for the child to manage the child's own symptoms and increase independent functioning. Often, adult caregivers (e.g., parents, teachers) need

only guidance on developing a behavioral incentive plan to help the child return to school, gradually increase attendance, and receive tutoring, after a prolonged, pain-related absence. Suggested sample brief strategy: Ask caregivers how they react to the child's pain complaints; assess whether they encourage wellness activities or give attention and “rewards” primarily when the child says he or she does not feel well; and suggest that caregivers respond to the child in ways that encourage wellness both when complaining and not complaining. Relaxation training is often employed to promote muscle relaxation and reduction of anxiety, which often accompanies and increases pain. Relaxation training, along with distraction and biofeedback, are treatments often included in CBT, but also are discussed in the literature without mention of CBT. Controlled breathing and progressive muscle relaxation are commonly used relaxation techniques taught to preschool-age and older children. Suggested sample brief strategy: Ask the child (or instruct the caregiver to do so) to practice the following and use if pain is coming on: focus on the breath, and pretend to be blowing up a big balloon, while pursing the lips and exhaling slowly. This is one way to help induce controlled breathing. Distraction can be used to help a child of any age shift attention away from pain and onto other activities. Common attention sustainers in the environment include bubbles, music, video games, television, the telephone, conversation, school, and play. Asking children to tell stories, asking parents to read to the child, and even mutual storytelling can be helpful distracters. Being involved with social, school, physical, or other activities helps the child in chronic pain to regain function. Suggested sample brief strategy: Encourage the child (or instruct the caregiver to do so) to shift attention away from the pain by continuing to engage in other activities and/or think of something else. Biofeedback involves controlled breathing, relaxation, or hypnotic techniques with a mechanical device that provides visual or auditory feedback to the child when the desired action is approximated. Common targets of actions include muscle tension, peripheral skin temperature through peripheral vasodilation, and anal control through rectal muscle contraction and relaxation. Biofeedback also enhances the child's sense of mastery and control, especially for the child who needs more “proof” of change than that generated through hypnotherapy alone. Hypnotherapy has also been used in the treatment of chronic pain in children, although the evidence for its effectiveness has not been as extensively studied as CBT. Hypnotherapy helps a child focus on an imaginative experience that is comforting, safe, fun, or intriguing. Hypnotherapy captures the child's

attention, alters his or her sensory experiences, reduces distress, reframes pain experiences, creates time distortions, helps the child dissociate from the pain, and enhances feelings of mastery and self-control. Children with chronic pain can use metaphor, for example, imagining they have overcome something feared because of pain in real life. As the child increases mastery of imagined experiences, the enhanced sense of control can be used during actual pain rehabilitation. Hypnotherapy is best for children of school age or older. Nonpharmacologic treatments of pain may also be applied to other treatment needs. A child who learns relaxation to reduce distress from lumbar punctures in cancer treatment may also apply this skill to other stressful medical and nonmedical situations, such as stressors caused by school. Yoga is intended to achieve balance in mind, body, and spirit. Therapeutic yoga can be helpful in treating chronic pain; improving mood, energy, and sleep; and reducing anxiety. Yoga involves a series of asanas (body poses) oriented to the specific medical condition or symptoms. Some forms of yoga use poses within a movement flow and format. Iyengar yoga is unique in its use of props, such as blankets, bolsters, blocks, and belts, to support the body while the child assumes more healing poses. Yoga promotes a sense of energy, relaxation, strength, balance, and flexibility and, over time, enhances a sense of mastery and control. Within a yoga practice, the child may learn certain types of breathing (pranayama) for added benefit. With a focus on body postures or in types of flow yoga, the child learns mindfulness or being present and in the moment. By focusing on body and breath, the child can develop strategies to avoid ruminating about the past or worrying about the future. Mindfulness meditation involves a focus on the present, “in-the-moment” experience using a variety of strategies. Many studies in adults report the value of meditation for chronic pain states as well as for anxiety and depression. These strategies help children learn how to be mindful and in the present, with enhanced parasympathetic control. Many mindfulness smartphone applications are geared to children of different ages, as well as books for parents on how to help their children achieve a mindful state to enhance relaxation (see Susan Kaiser-Greenland's book). Although there are different schools of mindfulness, such as Vipassana (insight-oriented meditation often using a focus on the breath) and transcendental meditation (in which the child learns the use of a silent mantra to facilitate acquiring a deeper inner calmness), the goal is to help the child learn strategies that enhance self-competence in reducing stress and enhancing a state of well-being.

Massage therapy involves the therapist's touching and applying varied degrees of pressure on the child's muscles. Massage is very useful for children with chronic pain and especially helpful for those with myofascial pain. There are several types of massage, including craniosacral therapy. For young children, it can be helpful to have parents learn and perform brief massage on their children before bedtime. Massage therapy likely will not be helpful to or tolerated by the child with sensory sensitivity and sensory aversion. Physical therapy can be especially useful for children with chronic, musculoskeletal pain and for those deconditioned from inactivity. Exercise appears specifically to benefit muscle functioning, circulation, and posture, also improving body image, body mechanics, sleep, and mood. The physical therapist and the child can develop a graded exercise plan for enhancing the child's overall function and for the child to continue at home. Recent research indicates that physical therapy affects central neurobiologic mechanisms that enhance “topdown” pain control. Acupuncture involves the placement of needles at specific acupuncture points along a meridian , or energy field, after the acupuncturist has made a diagnosis of excess or deficiency energy in that meridian as the primary cause of the pain. Acupuncture is a feasible, popular part of a pain management plan for children with chronic pain. Acupuncture alleviates chronic nausea, fatigue, and several chronic pain states, including migraine and chronic daily headaches, abdominal pain, and myofascial pain. Acupuncture also has efficacy in adults with myofascial pain, primary dysmenorrhea, sickle cell crisis pain, and sore throat pain. The acupuncturist must relate well to children so that the experience is not traumatic, because added stress would undo the benefits gained. Transcutaneous electrical nerve stimulation (TENS) is the use of a batteryoperated tool worn on the body to send electrical impulses into the body at certain frequencies set by the machine. TENS is believed to be safe and can be tried for many forms of localized pain. Children often find TENS helpful and effective. Music therapy and art therapy can be especially helpful for young and nonverbal children who would otherwise have trouble with traditional talk psychotherapies. Also, many creative children can more easily express fears and negative emotions through creative expression and, with the therapist's help, learn about themselves in the process. There is also increasing research on the impact of art and music therapy on altering central neural circuits that maintain and enhance pain.

Dance, movement, and pet therapies , and aromatherapy have also been used and may be helpful, but these have not been as well studied in children for pain control as have other complementary therapies. Often, clinical experience helps guide the pediatrician in the benefits of these therapies with individual patients. For example, pet therapy is gaining favor in hospitals and in stress reduction for sick children. Pets often can become self-regulators for the child with ASD, although the neurobiologic mechanisms are not yet understood.

Invasive Interventions for Treating Pain Interventional neuraxial and peripheral nerve blocks provide intraoperative anesthesia, postoperative analgesia (see Chapter 74 ), and treatment of acute pain (e.g., long-bone fracture, acute pancreatitis) and contribute to the management of chronic pain such as headache, abdominal pain, complex regional pain syndrome (CRPS), and cancer pain. Interventional procedures are often used in the treatment of nonmalignant chronic pain in children in some centers and are described here so that the pediatrician will understand the different types of procedures available to children but rarely described in pediatric texts. Interventional procedures may be useful in some children who have specific types of chronic pain, but their use in children (as widely practiced in adult pain clinics) generally is not recommended because the pediatric research is insufficient. Therefore the data are largely extrapolated from the adult population. In children with CRPS receiving multiple focal blocks at an adult pain center, the first block may work “wonders,” but the pain-free intervals between blocks may become shorter, until the blocks are no longer effective, and the CRPS pain spreads, including to the sites of the blocks. This does not mean that no block should be recommend in children, but that blocks should be used judiciously and in conjunction with other biopsychosocial treatments. Regional anesthesia provides several benefits. As an alternative to or in augmentation of opioid-based pain control, regional anesthesia minimizes opioid requirements and therefore opioid side effects, such as nausea, vomiting, somnolence, respiratory depression, pruritus, constipation, and physical dependence. It generally provides better-quality pain relief than systemic medication because it interrupts nociceptive pathways and more profoundly inhibits endocrine stress responses. Regional anesthesia also results in earlier ambulation in recovering surgical patients, helps prevent atelectasis in the patient with chest pain, and usually results in earlier discharge from the hospital.

Theoretically, the interruption of nociceptive pathways in the periphery by regional anesthetics will prevent, or reverse, the process of amplification of pain signals induced by nociception (e.g., CNS wind-up, glial cell activation). For postoperative pain, effective regional anesthesia reduces the risks of acute pain evolving to chronic pain. Regional anesthesia is considered safe and effective if performed by trained staff with the proper instruments and equipment. Most frequently, nerve blocks are performed by an anesthesiologist or pain management physician; a few are easily performed by a nonanesthesiologist with appropriate training.

Head and Neck Blocks Primary pain syndromes of the head, such as trigeminal neuralgia, are distinctly unusual in the pediatric population, and few surgical procedures in the head and neck are amenable to regional anesthesia. Pain following tonsillectomies is not amenable to nerve blockade, and neurosurgical incisional pain is usually mitigated by local infiltration of local anesthetic into the wound margins by the surgeon. Headache disorders, very common in the pediatric age-group, often respond well to regional anesthesia of the greater occipital nerve (2nd cervical, C2), which provides sensation to much of the cranial structures, from the upper cervical region, the occiput to the apex of the head, or even to the hairline. The greater occipital nerve can be blocked medial to the occipital artery, which can usually be identified at the occipital ridge midway between the occipital prominence and the mastoid process by palpation, Doppler sound amplification, or visually by high-frequency ultrasound. The short-term and especially longlasting effects of nerve blocks for chronic headaches in children have not been documented by research. Studies are needed to determine which children with which types of headaches will benefit most from occipital nerve blocks.

Upper-Extremity Blocks The brachial plexus block controls pain of the upper extremity. This block also protects the extremity from movement, reduces arterial spasm, and blocks sympathetic tone of the upper extremity. The brachial plexus, responsible for cutaneous and motor innervation of the upper extremity, is an arrangement of nerve fibers originating from spinal nerves C5 through 1st thoracic (T1), extending from the neck into the axilla, arm, and hand. The brachial plexus

innervates the entire upper limb, except for the trapezius muscle and an area of skin near the axilla. If pain is located proximal to the elbow, the brachial plexus may be blocked above the clavicle (roots and trunks); if the pain is located distal to the elbow, the brachial plexus may be blocked at the axilla (cords and nerves). The block may be given as a single injection with a long-acting anesthetic (bupivacaine or ropivacaine, sometimes augmented with clonidine or dexamethasone to prolong block duration and intensity) to provide up to 12 hr of analgesia, or by a percutaneous catheter attached to a pump that can provide continuous analgesia over days or even weeks.

Trunk and Abdominal Visceral Blocks Trunk blocks provide somatic and visceral analgesia and anesthesia for pain or surgery of the thorax and abdominal area. Sympathetic, motor, and sensory blockade may be obtained. These blocks are often used in combination to provide optimal relief. Intercostal and paravertebral blocks may be beneficial in patients for whom a thoracic epidural injection or catheter is contraindicated (e.g., patient with coagulopathy). Respiratory function is maintained, and the side effects of opioid therapy are eliminated. The intercostal, paravertebral, rectus sheath, and transverse abdominal plane blocks are most useful for pediatric chest and somatic abdominal pain. The celiac plexus and splanchnic nerve block is most useful for abdominal visceral pain, such as caused by malignancy or pancreatitis. These blocks are best performed by an experienced anesthesiologist, pain physician, or interventional radiologist using ultrasound or CT imaging guidance. The intercostal block is used to block the intercostal nerves, the anterior rami of the thoracic nerves from T1 to T11. These nerves lie inferior to each rib, between the inner and innermost intercostal muscles with their corresponding vein and artery, where they can be blocked, generally posterior to the posterior axillary line. Ultrasound imaging of the intercostal nerves helps avoid injury to intercostal vessels or insertion of the needle through the pleura, which may result in pneumothorax. The paravertebral block , an alternative to intercostal nerve block or epidural analgesia, is useful for pain associated with thoracotomy or with unilateral abdominal surgery, such as nephrectomy or splenectomy. Essentially this block results in multiple intercostal blocks with a single injection. The thoracic paravertebral space, lateral to the vertebral column, contains the sympathetic

chain, rami communicantes, dorsal and ventral roots of the spinal nerves, and dorsal root ganglion. Because it is a continuous space, local anesthetic injection will provide sensory, motor, and sympathetic blockade to several dermatomes. The paravertebral block may be performed as a single injection or, for a very prolonged effect, as a continuous infusion over several days or weeks via a catheter. This block is best performed by an anesthesiologist or interventional pain physician under ultrasound guidance. Ilioinguinal and iliohypogastric nerve blocks are indicated with surgery for inguinal hernia repair, hydrocele, or orchiopexy repair, as well as for chronic pain subsequent to these procedures. The 1st lumbar (L1) nerve divides into the iliohypogastric and ilioinguinal nerves, which emerge from the lateral border of the psoas major muscle. The iliohypogastric nerve supplies the suprapubic area as it pierces the transversus abdominis muscle and runs deep to the internal oblique muscle. The ilioinguinal nerve supplies the upper medial thigh and superior inguinal region as it also pierces the transversus abdominis muscle and runs across the inguinal canal. Ultrasound guidance has made this nerve block almost always successful. The celiac plexus block is indicated for surgery or pain of the pancreas and upper abdominal viscera. The celiac plexus, located on each side of the L1 vertebral body, contains 1-5 ganglia. The aorta lies posterior, the pancreas anterior, and the inferior vena cava lateral to these nerves. The celiac plexus receives sympathetic fibers from the greater, lesser, and least splanchnic nerves, as well as from parasympathetic fibers from the vagus nerve. Autonomic fibers from the liver, gallbladder, pancreas, stomach, spleen, kidneys, intestines, and adrenal glands originate from the celiac plexus. This block is best performed with CT guidance to provide direct visualization of the appropriate landmarks, avoid vascular and visceral structures, and confirm correct needle placement. The close proximity of structures such as the aorta and vena cava make this a technical procedure best performed by an anesthesiologist, interventional pain physician, or interventional radiologist.

Lower-Extremity Blocks Lumbar plexus and sciatic nerve blocks provide pain control for painful conditions or surgical procedures of the lower extremities, with the benefit of providing analgesia to only one extremity while preserving motor and sensory function of the other. The lumbosacral plexus is an arrangement of nerve fibers originating from spinal nerves L2-L4 and S1-S3. The lumbar plexus arises from

L2-L4 and forms the lateral femoral cutaneous, femoral, and obturator nerves. These nerves supply the muscles and sensation of the upper leg, with a sensory branch of the femoral nerve (saphenous nerve) extending below the knee to innervate the medial aspect of the foreleg, ankle, and foot. The sacral plexus arises from L4-S3 and divides into the major branches of the sciatic, tibial, and common peroneal nerves. These nerves in turn supply the posterior thigh, lower leg, and foot. Unlike the brachial plexus block, blockade of the entire lower extremity requires >1 injection because the lumbosacral sheath is not accessible. Separate injections are necessary for the posterior (sciatic) and anterior (lumbar plexus) branches, and the injections can be performed at any of several levels during the course of the nerve, as is clinically expedient. The lumbar plexus can be blocked in the back, resulting in analgesia of the femoral, lateral femoral cutaneous, and obturator nerves. Alternatively, any of these 3 nerves can be individually anesthetized, depending on the location of the pain. Similarly, the sciatic nerve can be anesthetized proximally as it emerges from the pelvis or more distally in the posterior thigh, or its major branches (tibial and peroneal nerves) can be individually anesthetized. These nerve blocks are generally best performed by an anesthesiologist, pain physician, or radiologist.

Sympathetic Blocks Sympathetic blocks were once thought to be useful in the diagnosis and treatment of sympathetically mediated pain, CRPS, and other neuropathic pain conditions, but more recently, large meta-analyses have shown their utility to be minimal. The peripheral sympathetic trunk is formed by the branches of the thoracic and lumbar spinal segments, and it extends from the base of the skull to the coccyx. The sympathetic chain, which consists of separate ganglia containing nerves and autonomic fibers with separate plexuses, can be differentially blocked. These separate plexuses include the stellate ganglion in the lower neck and upper thorax, the celiac plexus in the abdomen, the 2nd lumbar plexus for the lower extremities, and the ganglion impar for the pelvis. When blocks of these plexuses are performed, sympathectomy is obtained without attendant motor or sensory anesthesia. The stellate ganglion block is indicated for pain in the face or upper extremity as well as for CRPS, phantom limb pain, amputation stump pain, or circulatory insufficiency of the upper extremities. The stellate ganglion arises from spinal nerves C7-T1 and lies anterior to the 1st rib. It contains ganglionic

fibers to the head and upper extremities. Structures in close proximity include the subclavian and vertebral arteries anteriorly, the recurrent laryngeal nerve, and the phrenic nerve. Chassaignac tubercle, the transverse process of the C6 vertebral body superior to the stellate ganglion, is a useful and easily palpable landmark for the block, but radiographic or ultrasound imaging is used more often than surface anatomy and palpation. The lumbar sympathetic block addresses pain in the lower extremity, CRPS, phantom limb pain, amputation stump pain, and pain from circulatory insufficiency. The lumbar sympathetic chain contains ganglionic fibers to the pelvis and lower extremities. It lies along the anterolateral surface of the lumbar vertebral bodies and is most often injected between the L2 and L4 vertebral bodies. The analgesia produced by peripheral sympathetic blocks usually outlives the duration of the local anesthetic, often persisting for weeks or indefinitely. If analgesia is transient, the blocks may be performed with catheter insertion for continuous local anesthesia of the sympathetic chain over days or weeks. Because precise, radiographically guided placement of the needle and/or catheter is required for safety and success, sympathetic blocks are generally best performed by an anesthesiologist, interventional pain physician, or interventional radiologist.

Epidural Anesthesia (Thoracic, Lumbar, and Caudal) Epidural anesthesia and analgesia are indicated for pain below the clavicles, management of regional pain syndromes, cancer pain unresponsive to systemic opioids, and pain limited by opioid side effects. The 3 layers of the spinal meninges—dura mater (outer), arachnoid mater (middle), and pia mater (inner)—envelop the spinal neural tissue. The subarachnoid space contains cerebrospinal fluid between the arachnoid mater and pia mater. The epidural space extends from the foramen magnum to the sacral hiatus and contains fat, lymphatics, blood vessels, and the spinal nerves as they leave the spinal cord. The epidural space separates the dura mater from the periosteum of the surrounding vertebral bodies. In children the fat in the epidural space is not as dense as in adults, predisposing to greater spread of the local anesthetic from the site of injection. Epidural local anesthetics block both sensory and sympathetic fibers, and if

the local anesthetic is of sufficient concentration, they also block motor fibers. Mild hypotension may occur, although it is unusual in children 90% of children and adolescents with cancer can be made comfortable by standard escalation of opioids according to the WHO protocol. A small subgroup (5%) has enormous opioid dose escalation to >100 times the standard morphine or other opiate infusion rate. Most of these patients have spread of solid tumors to the spinal cord, roots, or plexus, and signs of neuropathic pain are evident. Methadone given orally is often used in palliative care, not only end-of-life care, because of its long half-life and its targets at both opioid and NMDA receptors. The type of pain experienced by the patient (neuropathic, myofascial) should determine the need for adjunctive agents. Complementary measures, such as massage, hypnotherapy, and spiritual care, must also be offered in palliative care. Although the oral route of opioid administration should be encouraged, especially to facilitate care at home if possible, some children are unable to take oral opioids. Transdermal and sublingual routes, as well as IV infusion with PCA, are likely next choices. Small, portable infusion pumps are convenient for home use. If venous access is limited, a useful alternative is to administer opioids (especially morphine or hydromorphone, but not methadone or

meperidine) through continuous SC infusion, with or without a bolus option. A small (e.g., 22-gauge) cannula is placed under the skin and secured on the thorax, abdomen, or thigh. Sites may be changed every 3-7 days, as needed. As noted, alternative routes for opioids include the transdermal and oral transmucosal routes. These latter routes are preferred over IV and SC drug delivery when the patient is being treated at home.

Chronic and Recurrent Pain Syndromes Chronic pain is defined as recurrent or persistent pain lasting longer than the normal tissue healing time, 3-6 mo. Children may experience pain related to injury (e.g., burns) or to a chronic or underlying disease process (e.g., cancer, arthritis), or pain can also be the chronic condition itself (e.g., CRPS, fibromyalgia, functional abdominal pain) (see Chapter 147 ). During childhood, abdominal, musculoskeletal, and headache pain are the most frequently occurring conditions. However, definitions of chronic pain do not take into account standard criteria for assessing particular pain symptoms or for evaluating the intensity or impact of pain, and therefore includes individuals with varying symptoms and experiences. Consequently, in epidemiologic surveys, prevalence estimates vary widely. Overall prevalence rates for different childhood pains range from 4–88%. For example, an average of 13.5–31.8% of adolescents in a community sample reported having weekly abdominal, headache, or musculoskeletal pains. Most epidemiologic studies report prevalence and do not report the severity or impact of the pain. Research indicates that only a subset of children and adolescents with chronic pain (approximately 5%) experience moderate to severe disability, and this likely better represents the estimated population for whom help is needed to treat pain and associated problems.

Neuropathic Pain Syndromes Neuropathic pain is caused by abnormal excitability in the peripheral or central nervous system that may persist after an injury heals or inflammation subsides. The pain, which can be acute or chronic, is typically described as burning or stabbing and may be associated with cutaneous hypersensitivity (allodynia), distortion of sensation (dysesthesia), and amplification of noxious sensations (hyperalgesia and hyperpathia). Neuropathic pain conditions may be responsible

for >35% of referrals to chronic pain clinics, conditions that typically include posttraumatic and postsurgical peripheral nerve injuries, phantom pain after amputation, pain after spinal cord injury, and pain caused by metabolic neuropathies. Patients with neuropathic pain typically respond poorly to opioids. Evidence supports the efficacy of antidepressants (nortriptyline, amitriptyline, venlafaxine, duloxetine) and anticonvulsants (gabapentin, pregabalin, oxcarbazepine) for treatment of neuropathic pain (see Tables 76.12 and 76.13 ). Complex regional pain syndrome , formerly known as “reflex sympathetic dystrophy” (RSD), is well described in the pediatric population. CRPS type 1 is a syndrome of neuropathic pain that typically follows an antecedent and usually minor injury or surgery to an extremity without identifiable nerve injury. It is often seen in oncology patients as a complication of their malignancy, IV infiltrations in the periphery, or surgery. The syndrome of CRPS type 1 includes severe spontaneous neuropathic pain, hyperpathia, hyperalgesia, severe cutaneous allodynia to touch and cold, changes in blood flow (typically extremity cyanosis), and increased sweating. In more advanced cases, symptoms include dystrophic changes of the hair, nails, and skin, immobility of the extremity (dystonia), and muscle atrophy. In the most advanced cases, symptoms include ankylosis of the joints of the extremity. Specific causal factors in CRPS type 1 in both children and adults remain elusive, although coincidental events may be noted. CRPS type 2 , formerly referred to as “causalgia,” is less common and describes a very similar constellation of symptoms but is associated with a known nerve injury. CRPS type 2 pain may be restricted to the distribution of the injured nerve or too much of the involved limb in a stockingglove distribution, whereas CRPS type 1 is generally seen in a stocking-glove distribution and by definition is not limited to a peripheral nerve or dermatomal distribution of signs and symptoms. Treatment of CRPS in children has been extrapolated from that in adults, with some evidence for efficacy of physical therapy, CBT, nerve blocks, antidepressants, AEDs, and other related drugs. All experts in pediatric pain management agree on the value of aggressive physical therapy. Some centers provide aggressive therapy without the use of pharmacologic agents or interventional nerve blocks. Unfortunately, recurrent episodes of CRPS may be seen in up to 50% of patients, particularly adolescent females. Physical therapy can be extraordinarily painful for children to endure; it is tolerated only by the most stoic and motivated patients. If children have difficulty enduring the pain, there is a well-established role for pharmacologic agents with or without

peripheral or central neuraxial nerve blocks to render the affected limb sufficiently analgesic so that physical therapy can be tolerated. Pharmacologic interventions include the use of AEDs such as gabapentin and/or TCAs such as amitriptyline (see Fig. 76.4 ). Although there is clear evidence of a peripheral inflammatory component of CRPS, with release of cytokines and other inflammatory mediators from the peripheral nervous system in the affected limb, the use of antiinflammatory agents has been disappointing. Common nerve block techniques include IV regional anesthetics, epidural analgesia, and peripheral nerve blocks. In extreme and refractory cases, more invasive strategies have been reported, including surgical sympathectomy and spinal cord stimulation. Although an array of treatments has some benefit, the mainstay of treatment remains physical therapy emphasizing desensitization, strengthening, and functional improvement. Additionally, pharmacologic agents and psychological and complementary therapies are important components of a treatment plan. Invasive techniques, although not curative, can be helpful if they permit the performance of frequent and aggressive physical therapy that cannot be carried out otherwise. A good biopsychosocial evaluation will help determine the orientation of the treatment components. There are insufficient data to indicate the superior value of interventional blocks, such as epidural anesthesia, in children with CRPS over physical and psychological interventions, with or without pharmacologic support.

Myofascial Pain Disorders and Fibromyalgia Myofascial pain disorders are associated with tender points in the affected muscles as well as with muscle spasms (tight muscles). Treatment is targeted at relaxing the affected muscles through physical therapy, Iyengar yoga, massage, and acupuncture. Rarely are pharmacologic muscle relaxants helpful other than for creating tiredness at night for sleep. Dry needling or injections of local anesthetic into the tender points has been advocated, but the data do not support this as a standard treatment. Similarly, although botulinum toxin injections may be used, no data support this practice in children. Often, poor body postures, repetitive use of a body part not accustomed to that movement, or carrying heavy backpacks initiates pain. When it becomes widespread with multiple tender points, the diagnosis may be made of juvenile fibromyalgia, which may or may not continue to subsequently become adult fibromyalgia. Likely there are different subtypes of widespread pain syndromes, and physical therapy is a key

component of treatment. Psychological interventions may play an important role to assist the child in resuming normal activities and to manage any psychological comorbidities. Any pain rehabilitation plan should enhance return to full function. Because there is a high incidence of chronic pain in parents of children presenting with a chronic pain condition, especially fibromyalgia, attention to parent and family factors is important. Parent training may entail teaching the parent to model more appropriate pain coping behaviors and to recognize the child's independent attempts to manage pain and function adaptively. Parents may also need referrals to obtain appropriate pain management for their own pain condition. Pregabalin and duloxetine are FDA approved for management of fibromyalgia in adults, but no clinical studies have confirmed their effectiveness in children and adolescents. One recent large study in adolescents with fibromyalgia found that CBT and physical therapy were superior to typical pharmacologic agents used in adults.

Erythromelalgia Erythromelalgia in children is generally primary, whereas in adults it may be either primary or secondary to malignancy or other hematologic disorders, such as polycythemia vera. Patients with erythromelalgia exhibit red, warm, hyperperfused distal limbs. The disorder is usually bilateral and may involve either or both the hands and feet. Patients perceive burning pain and typically seek relief by immersing the affected extremities in ice water, sometimes so often and for so long so that skin pathology results. Primary erythromelalgia is caused by a genetic mutation (autosomal dominant) in the gene for the NaV1.7 neuronal sodium channel on peripheral C nociceptive fibers, resulting in their spontaneous depolarization, and thus continuous burning pain. The most common mutation identified is in the SCN9A gene, although there are several mutations that affect the NaV1.7 channel. Interestingly, another mutation in the NaV1.7 channel results in a rare but devastating genetic condition, the congenital indifference to pain. It is easy to distinguish erythromelalgia (or related syndromes) from CRPS. The limb afflicted with CRPS is typically cold and cyanotic, the disease is typically unilateral, and children with CRPS have cold allodynia, making immersion in cold water exquisitely painful. In erythromelalgia, ice water immersion is analgesic, the condition is bilateral and symmetric, and it is

associated with hyperperfusion of the distal extremity. The evaluation of hyperperfused limbs with burning pain should include genetic testing for Fabry disease and screening for hematologic malignancies, with diagnosis of primary erythromelalgia being one of exclusion. At present, few clinical laboratories are Clinical Laboratory Improvement Amendments (CLIA) certified to perform the DNA analysis required to identify the common NaV1.7 mutations. The definitive treatment of Fabry disease includes enzyme replacement as disease-modifying treatment and administration of neuropathic pain medications such as gabapentin, although the success of antineuropathic pain drugs in smallfiber neuropathies has not been impressive. The treatment of erythromelalgia is much more problematic. Antineuropathic pain medications (AEDs, TCAs) are typically prescribed but rarely helpful (see Fig. 76.4 ). Although one might predict that sodium channel–blocking AEDs might be effective in this sodium channelopathy, oxcarbazepine has not proved to be a particularly effective modality. The pain responds well to regional anesthetic nerve blocks, but it returns immediately when the effects of the nerve block resolve. In contrast, in other neuropathic syndromes, the analgesia usually (and inexplicably) persists well after the resolution of the pharmacologic nerve block. Aspirin and even nitroprusside infusions have been anecdotally reported to be of benefit with secondary erythromelalgia, but have not been reported to be helpful in children with primary erythromelalgia. Case reports in adults and clinical experience in children suggest that periodic treatment with high-dose capsaicin cream is effective in alleviating the burning pain and disability of erythromelalgia. Capsaicin (essence of chili pepper) cream is a vanilloid receptor (TRPV1) agonist that depletes small-fiber peripheral nerve endings of the neurotransmitter substance P, an important neurotransmitter in the generation and transmission of nociceptive impulses. Once depleted, these nerve endings are no longer capable of generating spontaneous pain until the receptors regenerate, a process that takes many months.

Other Chronic Pain Conditions in Children A variety of genetic and other medical/surgical conditions are often associated with chronic pain. Examples include Fabry disease, Chiari/syringomyelia, epidermolysis bullosa, juvenile idiopathic arthritis, porphyria, mitochondrial disorders, degenerative neurologic diseases, cerebral palsy, ASD, intestinal pseudoobstruction, inflammatory bowel disease, chronic migraine/daily

headaches, and irritable bowel disease. In many cases, treating the underlying disease, such as enzyme replacement in Fabry disease and in other lysosomal disorders, will reduce what otherwise might be progression of symptoms, but may not totally reduce pain and suffering, and other modalities will be needed. Finally, pain that persists and is not well treated can lead to central sensitization and widespread pain, such as seen in children with one pain source who develop fibromyalgia.

Managing Complex Chronic Pain Problems Some patients with chronic pain have a prolonged course of evaluation in attempts to find what is expected as the singular “cause” of the pain and thus also undergo many failed treatments (see Chapter 147 ). Parents worry that the doctors have not yet discovered the cause that may be serious and life threatening, and children often feel not believed, that they are faking their pain, or are “crazy.” There may be no identifiable or diagnosable condition, and families may seek opinions from multiple treatment facilities in an attempt to find help for their suffering child. For some children, what may have begun as an acute injury or infectious event may result in a chronic pain syndrome, with changes in the neurobiology of the pain-signaling system. In the context of disabling chronic pain, it is very important for the pediatrician to avoid overmedication because this can exacerbate associated disability, maintain an open mind and reassess the diagnosis if the clinical presentation changes, and understand and communicate to the family that pain has a biologic basis (likely related to neural signaling and neurotransmitter dysregulation), and that the pain is naturally distressing to the child and family. All patients and families should receive a simple explanation of pain physiology that helps them understand the importance of (1) functional rehabilitation to normalize pain signaling, (2) the low risk of causing further injury with systematic increases in normal functioning, and (3) the likely failure of treatment if pain is managed as if it were acute. Because it is counterintuitive for most people to move a part of the body that hurts, many patients with chronic pain have atrophy or contractures of a painful extremity from disuse. Associated increases in worry and anxiety may exacerbate pain and leave the body even more vulnerable to further illness, injury, and disability. Pain can have a

significant impact on many areas of normal functioning and routines for children, and school absenteeism and related consequences of missed schooling are often significant problems. Appropriate assessment and evaluation of the child with chronic pain and the family is the critical 1st step necessary in developing a treatment plan. For example, a high–academically functioning child might have an acute injury that leads to chronic pain and significant school absenteeism. While many downstream contributors to pain and disability maintenance can accumulate the more school that is missed, often previously unrecognized focal learning disabilities may become the increasing trigger for a downhill cascade of pain, disability, and school absenteeism. Even for the child with outstanding grades, it may be helpful to learn about the amount of time spent on each subject. As certain subjects become more complicated, such as math, the child with a previously unrecognized math learning disability may be spending hours on math homework each night, even with good grades in math. In this case the acute illness or injury becomes the “final straw” that breaks down the child's coping and turns the acute pain into a chronic problem. Interdisciplinary pediatric pain programs have become the standard of care for treating complex chronic pain problems in youth. Although available in many parts of the United States, Canada, Europe, Australia, and New Zealand, the overall number of programs is still small. Therefore, many children and adolescents with chronic pain will be unable to receive specialized pain treatment in their local communities. In recognition of the severity and complexity of pain and disability for some children, different settings and treatment delivery models for providing pain care have been explored. One option is inpatient and day hospital treatment programs, which often address barriers to access to outpatient treatment and coordination of care. In addition, these programs provide an intensive treatment option for children who do not make adequate progress in outpatient treatment or who are severely disabled by pain. Early programs developed in the 1990s focused on CRPS treatment through intensive inpatient rehabilitation and exercise-based programs. Later programs expanded to other clinical populations and broadened the treatment focus to incorporate a range of rehabilitation and psychological therapies delivered both individually and in groups. The typical length of inpatient admissions for children with chronic pain in such programs is 3-4 wk, and emerging evidence suggests benefit from these programs. A major problem that limits such care for children with complex chronic disabling pain is the long waiting list for entry into these still relatively few programs, as well as obtaining

insurance approval. Additional more widespread models of care are needed. Another intervention delivery option is remote management, referring to pain interventions utilized outside the clinic/hospital setting to reach children in their homes or communities. Interventions are typically delivered using some form of technology, such as the internet, or may rely on other media, such as telephone counseling or written self-help materials. Typically, remote management of pain includes monitoring, counseling, and delivery of behavioral and CBT interventions. Internet interventions have received the most research attention to date, with published examples of several different pediatric chronic pain conditions with promising findings for pain reduction. Telemedicine, while in widespread use clinically for many pediatric health conditions, has not yet been formally evaluated in pediatric pain. Within any community, the pediatrician will need to locate appropriate referral sources for patients with complex chronic pain. However, while psychological interventions can be delivered through these telemedicine strategies, the pediatrician is still relied on to obtain the needed biopsychosocial history, complete a thorough physical examination, and provide the pharmacologic management as needed. The pediatrician also communicates with the family to help the child and family understand the pain and how the different pharmacologic and nonpharmacologic treatments will enhance function and alter the long-term neural processes underlying pain.

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CHAPTER 77

Poisoning Jillian L. Theobald, Mark A. Kostic

Poisoning is the leading cause of injury-related death in the United States, surpassing that from motor vehicle crashes. Most these deaths are unintentional (i.e., not suicide). In adolescents, poisoning is the 3rd leading cause of injuryrelated death. Of the >2 million human poisoning exposures reported annually to the National Poison Data Systems (NPDS) of the American Association of Poison Control Centers (AAPCC), approximately 50% occur in children 40 mg/kg of elemental iron should be referred to medical care for evaluation, although moderate to severe toxicity is typically seen with ingestions >60 mg/kg. Clinical and Laboratory Manifestations. Iron toxicity is described in 5 often-overlapping stages. The 1st stage , 30 min to 6 hr after ingestion, consists of profuse vomiting and diarrhea (often bloody), abdominal pain, and significant volume losses leading to potential hypovolemic shock. Patients who do not develop GI symptoms within 6 hr of ingestion are unlikely to develop serious toxicity. The 2nd stage , 6-24 hr after ingestion, is often referred to as the “quiescent phase” since the GI symptoms typically have resolved. However, careful clinical examination can reveal subtle signs of hypoperfusion, including tachycardia, pallor, and fatigue. During the 3rd stage , 12-36 hr after ingestion, patients develop multisystem organ failure, shock, hepatic and cardiac dysfunction, acute lung injury, and profound metabolic acidosis. Death usually occurs during the 3rd stage. The 4th stage (hepatic) results in fulminant liver failure and coagulopathy about 2-5 days after ingestion. The 5th stage , 4-6 wk after ingestion, is marked by formation of strictures and signs of GI obstruction. Symptomatic patients and patients with a large exposure by history should have serum iron levels drawn 4-6 hr after ingestion. Serum iron concentrations of 500 µg/dL indicate that significant toxicity is likely. Additional laboratory evaluation in the ill patient should include arterial or venous blood gas, CBC, serum glucose level, liver transaminases, and coagulation parameters. Careful attention should be paid to the patient's hemodynamic status. An abdominal radiograph might reveal the presence of iron tablets, although not all formulations of iron are radiopaque. Treatment.

Close clinical monitoring, combined with aggressive supportive and symptomatic care, is essential to the management of iron poisoning. Activated charcoal does not adsorb iron, and WBI remains the decontamination strategy of choice. Deferoxamine , a specific chelator of iron, is the antidote for moderate to severe iron intoxication (see Table 77.7 ). Indications for deferoxamine treatment include a serum iron concentration >500 µg/dL or moderate to severe symptoms of toxicity (e.g., acidosis), regardless of serum iron concentration. Deferoxamine is preferably given by continuous IV infusion at 15 mg/kg/hr. Hypotension is a common side effect of deferoxamine infusion and is managed by slowing the rate of the infusion and administering fluids and vasopressors as needed. Prolonged deferoxamine infusion (>24 hr) has been associated with pulmonary toxicity (acute respiratory distress syndrome, ARDS) and Yersinia sepsis. The deferoxamine-iron complex can color the urine reddish (“vin rosé”), although the degree of this coloration should not guide therapy. Deferoxamine is typically continued until clinical symptoms and acidosis resolve. Consultation with a PCC or medical toxicologist can yield guidelines for discontinuing deferoxamine.

Oral Hypoglycemics Oral medications used in the management of type 2 diabetes include sulfonylureas, biguanides (e.g., metformin), thiazolidinediones, and meglitinides. Of these, only the sulfonylureas and meglitinides have the potential to cause profound hypoglycemia in both diabetic and nondiabetic patients. These classes of medications are widely prescribed and thus readily available for both unintentional and intentional exposures. In toddlers, ingestion of a single sulfonylurea tablet can lead to significant toxicity. Pathophysiology. Sulfonylureas work primarily by enhancing endogenous insulin secretion. In binding to the sulfonylurea receptor, these drugs induce closure of K+ channels, leading to membrane depolarization, opening of Ca2+ channels, and stimulation of Ca2+ -mediated insulin release. Even in therapeutic use, the duration of hypoglycemic action can last up to 24 hr. Clinical and Laboratory Manifestations. Hypoglycemia and symptoms associated with hypoglycemia are the primary

clinical manifestations of sulfonylurea toxicity. These signs and symptoms can include diaphoresis, tachycardia, lethargy, irritability, coma, seizures, and even focal neurologic findings. As with other hyperinsulinemic states, sulfonylurea overdoses are associated with a nonketotic hypoglycemia. In the majority of patients, hypoglycemia develops within 6 hr of ingestion but can be delayed up to 16-18 hr after ingestion. Toddlers are particularly susceptible to hypoglycemia during an overnight fast. Treatment. Patients with symptomatic hypoglycemia should be promptly treated with dextrose. In patients with mild symptoms, oral dextrose may be sufficient. However, patients with severe symptoms or profound hypoglycemia should be treated with a bolus of IV dextrose. Continuous dextrose infusions and repeated IV dextrose boluses should be avoided if possible, because this can stimulate further insulin release and lead to recurrent and prolonged hypoglycemia. Instead, the preferred antidote for persistent (i.e., requiring ≥2 doses of IV dextrose) sulfonylurea toxicity is octreotide (see Table 77.7 ). Octreotide is a somatostatin analog that inhibits insulin release. Octreotide is given intravenously (IV) or subcutaneously (SC), typically in doses of 1-2 µg/kg (50100 µg in teens or adults) every 6-8 hr. Given the potential for significant hypoglycemia, toddlers with witnessed or suspected sulfonylurea ingestions should be admitted to the hospital for serial glucose measurements for at least 12 hr, including an overnight fast. Patients of any age who develop hypoglycemia are also candidates for admission given the prolonged duration of hypoglycemic activity. Prophylactic IV dextrose infusions are not recommended because they can mask the symptoms of toxicity and stimulate further insulin secretion. Patients who require IV dextrose and/or octreotide should be monitored until they can demonstrate euglycemia for at least 8 hr off all therapy. With the increasing numbers of adolescents with type 2 diabetes, pediatricians should be familiar with the toxic effects of metformin as well. Although metformin does not cause hypoglycemia, its association with lactic acidosis is well documented (metformin-associated lactic acidosis, MALA). This state typically arises after a large overdose in which the agent interferes with the liver's ability to clear lactic acid. Dangerously high serum lactate levels can result, leading to hemodynamic instability. Hemodialysis is usually the best option for patients with severe MALA.

Psychiatric Medications: Antidepressants Selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline, paroxetine, citalopram) are the most commonly prescribed class of antidepressants. This trend largely results from their wide therapeutic index and more favorable side effect profile compared with older agents such as tricyclic antidepressants (TCAs; amitriptyline, clomipramine, desipramine, doxepin, nortriptyline, imipramine) and monoamine oxidase inhibitors (MAOIs). Other agents include the serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine) and atypical antidepressants (e.g., bupropion).

Tricyclic Antidepressants. Although now prescribed less often for depression, TCAs remain in use for a variety of other conditions, including chronic pain syndromes, enuresis, ADHD, and obsessive-compulsive disorder. TCAs can cause significant toxicity in children, even with ingestion of 1 or 2 pills (10-20 mg/kg). Pathophysiology. TCAs achieve their desired antidepressant effects primarily through blockade of norepinephrine and serotonin reuptake. TCAs have complex interactions with other receptor types. Antagonism at muscarinic acetylcholine receptors leads to clinical features of the anticholinergic toxidrome. Antagonism at peripheral αreceptors leads to hypotension and syncope. Key to the toxicity of TCAs is their ability to block fast sodium channels, leading to impaired cardiac conduction and arrhythmias. Clinical and Laboratory Manifestations. Cardiovascular and CNS symptoms dominate the clinical presentation of TCA toxicity. Symptoms typically develop within 1-2 hr of ingestion, and serious toxicity usually manifests within 6 hr of ingestion. Patients can have an extremely rapid progression from mild symptoms to life-threatening dysrhythmias. Patients often develop features of the anticholinergic toxidrome , including delirium, mydriasis, dry mucous membranes, tachycardia, hyperthermia, urinary retention, and slow GI motility. CNS toxicity can include lethargy, coma, myoclonic jerks, and seizures. Sinus tachycardia is the most common cardiovascular manifestation of toxicity; however, patients can also develop widening of the QRS complex, premature ventricular contractions, and

ventricular dysrhythmias. Refractory hypotension is a poor prognostic indicator and is the most common cause of death in TCA overdose. An ECG is a readily available bedside test that can help determine the diagnosis and prognosis of the TCA-poisoned patient (Fig. 77.2 ; see Table 77.6 ). A QRS duration >100 msec identifies patients who are at risk for seizures and cardiac arrhythmias. An R wave in lead aVR of ≥3 mm is also an independent predictor of toxicity. Both ECG parameters are superior to measured serum TCA concentrations for identifying patients at risk for serious toxicity, and obtaining levels is rarely helpful in management of the acutely ill patient.

FIG. 77.2 Electrocardiographic findings in tricyclic antidepressant toxicity. Note the tachycardia, widened QRS interval (144 msec), and prominent R wave in lead aVR. These findings are consistent with blockade of fast sodium channels.

Treatment. Initial attention should be directed to supporting vital functions, including airway and ventilation as needed. Gastric decontamination can be accomplished with activated charcoal in appropriate patients. Treating clinicians should obtain an ECG as soon as possible and follow serial ECGs to monitor for progression of toxicity. The 4 primary effects described next are seen at the bedside. 1 Altered Mental State. TCA-poisoned patients can become deeply comatose relatively quickly, so careful and prompt attention to the airway and placement of an endotracheal tube is of paramount importance. The airway should be secured before any GI decontamination efforts.

2 Widened QRS on ECG. TCAs, as well as with other agents (e.g., diphenhydramine, cocaine), will block the fast Na+ channels on the myocardial cells, slowing the upstroke of the QRS complex. Because the effect on Na+ channels is greatest within the 1st 6 hr, frequent ECGs (i.e., every 20-30 min) during this period are important. As the QRS approaches 160 msec, the risk of the patient developing monomorphic ventricular tachycardia rises to 30%. Sodium, usually in the form of sodium bicarbonate, is the antidote of choice. Indications for sodium bicarbonate include a QRS duration ≥110 msec, ventricular dysrhythmias, and hypotension . Multiple bolus doses of sodium bicarbonate, 1-2 mEq/kg each, may be needed to narrow the QRS to upper extremities). One or all of these signs may be present to varying degrees. Table 77.11 Drugs Associated With the Serotonin Syndrome DRUG TYPE Selective serotonin reuptake inhibitors Antidepressant drugs Monoamine oxidase inhibitors Anticonvulsants Analgesics Antiemetic agents Antimigraine drugs Bariatric medications Antibiotics

DRUGS Sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram

Trazodone, nefazodone, buspirone, clomipramine, venlafaxine Phenelzine, moclobemide, clorgyline, isocarboxazid

Valproate Meperidine, fentanyl, tramadol, pentazocine Ondansetron, granisetron, metoclopramide Sumatriptan Sibutramine

Linezolid (a monoamine oxidase inhibitor), ritonavir (through inhibition of cytochrome P450 enzyme isoform 3A4) Nonprescription Dextromethorphan

cough and cold remedies Drugs of abuse

Methylenedioxymethamphetamine (MDMA, “Ecstasy”), lysergic acid diethylamide (LSD), 5methoxydiisopropyltryptamine (“foxy methoxy”), Syrian rue (contains harmine and harmaline, both monoamine oxidase inhibitors) Tryptophan, Hypericum perforatum (St. John's wort), Panax ginseng (ginseng)

Dietary supplements and herbal products Other Lithium

From Boyer EW, Shannon M: The serotonin syndrome, N Engl J Med 352:1112–1120, 2005.

Treatment. Initial management includes a careful assessment for signs and symptoms of serotonin syndrome and an ECG. Most patients simply require supportive care and observation until their mental status improves and tachycardia, if present, resolves. Management of serotonin syndrome is directed by the severity of symptoms; possible therapeutic interventions include benzodiazepines in mild cases and intubation, sedation, and paralysis in patients with severe manifestations (e.g., significant hyperthermia). Because agonism at the 5-HT2A serotonin receptor is thought to be primarily responsible for the development of serotonin syndrome, use of the 5-HT2A receptor antagonist cyproheptadine may also be helpful. Cyproheptadine is only available in an oral form.

Atypical Antidepressants. The atypical antidepressant class includes agents such as venlafaxine and duloxetine (SNRIs), bupropion (dopamine, norepinephrine, and some serotonin reuptake blockade), and trazodone (serotonin reuptake blockade and peripheral α-receptor antagonism). The variable receptor affinities of these agents lead to some distinctions in their clinical manifestations and management. Clinical and Laboratory Manifestations. In overdose, venlafaxine and other SNRIs have been associated with cardiac conduction defects, including QRS and QTc prolongation, and seizures. Bupropion warrants special consideration because it is one of the most common etiologies of toxicant-induced seizures in the United States. After ingestion of SR or extended-release (ER) preparations, seizures can occur as late as 18-20 hr after ingestion. In addition, bupropion can cause tachycardia, agitation, and QRS and QTc prolongation. These cardiac effects are thought to result from a reduction in cardiac intracellular coupling caused by inhibition at gap junctions

in the heart. Mortality results from not only status epilepticus but also the cardiac conduction disturbances causing ventricular tachycardia. Bupropion is of growing concern with the rising popularity of the drug, especially in the ER formulation. In addition to sedation and signs of serotonin excess, trazodone overdose may be associated with hypotension from blockade of peripheral αreceptors. Treatment. Management is directed to clinical signs and symptoms. QRS and QTc interval prolongation after bupropion poisoning is typically resistant to the standard treatments of sodium bicarbonate and magnesium. Seizures are often brief and self-limited but can be treated with benzodiazepines if necessary. A patient poisoned with bupropion who shows unstable hemodynamics with prolonged ECG intervals or persistent seizure activity should receive Intralipid emulsion therapy. Because of the potential for delayed seizures, asymptomatic patients who have ingested an SR preparation of bupropion should be admitted to a monitored setting for at least 20-24 hr. Trazodone-associated hypotension typically responds to fluids, though it can require vasopressors in extreme cases.

Monoamine Oxidase Inhibitors. Although now rarely used therapeutically, MAOIs remain important agents given their potential for serious and delayed toxicity. Ingestions of only 1 or 2 pills (6 mg/kg) are associated with toxicity in children. Clinical manifestations initially include hypertension, hyperthermia, tachycardia, muscle rigidity, and seizures, followed up to 24 hr later by hemodynamic instability and CV collapse. Any child who ingests a MAOI should be admitted to a monitored setting for at least 24 hr, regardless of symptoms. Management includes blood pressure control, cooling and benzodiazepines for hyperthermia, serial monitoring of CK and renal function, and fluid and vasopressor therapy for hemodynamic instability.

Psychiatric Medications: Antipsychotics Clinicians are increasingly prescribing antipsychotic medications in the pediatric population. Antipsychotics are usually classified as either typical or atypical. In general, typical agents are associated with more side effects and toxicity than the atypical agents.

Pathophysiology. Typical or “traditional” antipsychotics (haloperidol, droperidol, thioridazine, chlorpromazine, fluphenazine) are characterized by their antagonism at D2 dopamine receptors. In therapeutic use, these agents are associated with extrapyramidal symptoms, tardive dyskinesia, and development of the neuroleptic malignant syndrome (NMS) . The atypical agents (aripiprazole, clozapine, quetiapine, risperidone, ziprasidone) were developed with relatively less dopamine (D2 -receptor) antagonism in the nigrostriatum in an effort to avoid these side effects and improve their efficacy in managing the “negative” symptoms of schizophrenia. Instead, these agents have complex and varied interactions with multiple receptor types, including α-receptors, serotonin receptors, muscarinic acetylcholine receptors, and histamine receptors. Clinical and Laboratory Manifestations. Typical antipsychotic toxicity usually includes sedation, tachycardia, and QTc prolongation. Patients can present with acute dystonia, akathisia, and NMS, although these are seen less frequently in acute overdoses than in therapeutic use. The phenothiazines (e.g., thioridazine) can cause widening of the QRS interval from blockade of fast sodium channels. Clinically, NMS can be difficult to distinguish from serotonin syndrome. Although the presentation of atypical antipsychotic toxicity can vary based on the receptor affinities of the specific agent, sedation, tachycardia, and QTc prolongation are common. Peripheral α-receptor blockade (e.g., with quetiapine) is associated with hypotension. In therapeutic use, clozapine is associated with agranulocytosis. Diagnostic testing should include an ECG. Patients with hyperthermia or muscle rigidity should have a serum CK level sent to monitor for possible rhabdomyolysis. Antipsychotic levels are not readily available and are not helpful in managing acute poisoning.

Management. Initial management involves assessing and supporting vital functions. In some patients, CNS depression may be so profound as to require intubation for airway control. Acute dystonia is treated with diphenhydramine and benztropine. Management of NMS includes conscientious supportive care, IV fluids, cooling, benzodiazepines, and bromocriptine or dantrolene in severe cases. QTc

prolongation is managed with repletion of electrolytes (especially calcium, magnesium, and potassium), continuous cardiac monitoring, prevention of bradycardia (overdrive pacing, isoproterenol, atropine), and defibrillation if the patient develops torsades de pointes. Seizures typically are well controlled with benzodiazepines. Hypotension usually responds to boluses of IV fluids, although vasopressor therapy is necessary in some patients.

Household Products Caustics Caustics include acids and alkalis as well as a few common oxidizing agents (see Chapter 353 ). Strong acids and alkalis can produce severe injury even in smallvolume ingestions. Pathophysiology. Alkalis produce a liquefaction necrosis, allowing further tissue penetration of the toxin and setting the stage for possible perforation. Acids produce a coagulative necrosis, which limits further tissue penetration, although perforation can still occur. The severity of the corrosive injury depends on the pH and concentration of the product as well as the length of contact time with the product. Agents with a pH of 12 are most likely to produce significant injury. Clinical Manifestations. Ingestion of caustic materials can produce injury to the oral mucosa, posterior pharynx, vocal cords, esophagus, and stomach. Patients can have significant esophageal injury even in the absence of visible oral burns. Symptoms include pain, drooling, vomiting, abdominal pain, and difficulty swallowing or refusal to swallow. Laryngeal injury can manifest as stridor and respiratory distress, necessitating intubation. In the most severe cases, patients can present in shock after perforation of a hollow viscus. Circumferential burns of the esophagus are likely to cause strictures when they heal, which can require repeated dilation or surgical correction and long-term follow-up for neoplastic changes in adulthood. Caustics on the skin or in the eye can cause significant tissue damage.

Treatment.

Initial treatment of caustic exposures includes thorough removal of the product from the skin or eye by flushing with water. Emesis and lavage are contraindicated . Activated charcoal should not be used because it does not bind these agents and can predispose the patient to vomiting and subsequent aspiration. Stridor or other signs of respiratory distress should alert the provider to the need for a thorough evaluation of the airway for potential intubation or surgical airway management. Endoscopy can be performed within 12-24 hr of ingestion for prognostic and diagnostic purposes in symptomatic patients or those with suspected injury on the basis of history and known characteristics of the ingested product. Endoscopy's role is purely diagnostic. Whether the risks of the procedure are justified is debatable. Expectant management with a period of nothing by mouth (NPO) and proton pump inhibitor therapy is likely appropriate for the majority of patients without airway burns or signs of mediastinitis or peritonitis. Endoscopy is contraindicated in such patients, who instead require immediate surgical consultation. Corticosteroids or prophylactic antibiotics are not beneficial.

Pesticides Cholinesterase-Inhibiting Insecticides. The most commonly used insecticides in agriculture are organophosphates and carbamates ; both are inhibitors of cholinesterase enzymes: acetylcholinesterase (AChE), pseudocholinesterase, and erythrocyte AChE. Most pediatric poisonings occur as the result of unintentional exposure to insecticides in and around the home or farm. The chemical warfare weapons known as “nerve agents” are also organophosphate compounds with a similar mechanism of action but much greater potency. Pathophysiology. Organophosphates and carbamates produce toxicity by binding to and inhibiting AChE, preventing the degradation of acetylcholine (ACh) and resulting in its accumulation at nerve synapses. If left untreated, organophosphates form an irreversible bond to AChE, permanently inactivating the enzyme. This process, called aging , occurs over a variable time period depending on the characteristics of the specific organophosphate. A period of weeks to months is required to regenerate inactivated enzymes. In contrast, carbamates form a temporary bond to the enzymes, typically allowing reactivation of AChE within 24 hr.

Clinical and Laboratory Manifestations. Clinical manifestations of organophosphate and carbamate toxicity relate to ACh accumulation at peripheral nicotinic and muscarinic synapses and in the CNS. Symptoms of carbamate toxicity are usually less severe than those seen with organophosphates. A commonly used mnemonic for the symptoms of cholinergic excess at muscarinic receptors is DUMBBELS : diarrhea/defecation, urination, miosis, bronchorrhea/bronchospasm, bradycardia, emesis, lacrimation, and salivation. Nicotinic signs and symptoms include muscle weakness, fasciculation, tremors, hypoventilation (diaphragm weakness), hypertension, tachycardia, and dysrhythmias. Severe manifestations include coma, seizures, shock, arrhythmias, and respiratory failure. Diagnosis of poisoning is based primarily on history and physical exam findings. Red blood cell cholinesterase and pseudocholinesterase activity levels can be measured in the laboratory. These are only helpful when compared to the patient's known baseline. As such, these assessments are typically limited to farmworkers undergoing ongoing occupational surveillance. Treatment. Basic decontamination should be performed, including washing all exposed skin with soap and water and immediately removing all exposed clothing. Activated charcoal is unlikely to be of benefit because these are liquids that are rapidly absorbed. Basic supportive care should be provided, including fluid and electrolyte replacement, intubation, and ventilation if necessary. The use of succinylcholine for rapid sequence intubation should be avoided because the same cholinesterase enzymes that are poisoned metabolize this neuromuscular blocking agent, leading to prolonged paralysis. Two antidotes are useful in treating cholinesterase inhibitor poisoning: atropine and pralidoxime (see Table 77.7 ). Atropine , which antagonizes the muscarinic ACh receptor, is useful for both organophosphate and carbamate intoxication. Often, large doses of atropine must be administered by intermittent bolus or continuous infusion to control symptoms. Atropine dosing is primarily targeted to drying the respiratory secretions. Pralidoxime breaks the bond between the organophosphate and the enzyme, reactivating AChE. Pralidoxime is only effective if it is used before the bond ages and becomes permanent. Pralidoxime is not necessary for carbamate poisonings because the bond between the insecticide and the enzyme degrades spontaneously. Without treatment, symptoms of organophosphate poisoning can persist for

weeks, requiring continuous supportive care. Even with treatment, some patients develop a delayed polyneuropathy and a range of chronic neuropsychiatric symptoms.

Pyrethrins and Pyrethroids. Pyrethrins are derived from the chrysanthemum flower and along with pyrethroids, synthetic derivatives, are the most commonly used pesticides in the home. Although >1,000 pyrethrins and pyrethroids exist, 50 mg/dL, acidosis, severe electrolyte disturbances, and renal failure. However, in the absence of acidosis and kidney failure, even massive ethylene glycol ingestions have been managed without dialysis. Methanol, however, because its elimination in the setting of alcohol dehydrogenase inhibition is prolonged, often warrants dialysis to remove the parent compound. Therapy (fomepizole and/or dialysis) should be continued until ethylene glycol and methanol levels are 200 times that of oxygen, forming carboxyhemoglobin (HbCO). In doing so, CO displaces oxygen and creates a conformational change in hemoglobin that impairs the delivery of oxygen to the tissues, leading to tissue hypoxia. HbCO levels are not well correlated with clinical signs of toxicity, likely because CO interacts with multiple proteins in addition to hemoglobin. CO binds to cytochrome oxidase, disrupting cellular respiration. CO displaces nitric oxide (NO) from proteins, allowing NO to bind with free radicals to form the toxic metabolite peroxynitrite, leading to lipid peroxidation and cellular damage. NO is also a potent vasodilator, in part responsible for clinical symptoms such as headache, syncope, and hypotension.

Clinical and Laboratory Manifestations. Early symptoms are nonspecific and include headache, malaise, nausea, and vomiting. These symptoms are often misdiagnosed as indicating flu or food poisoning. At higher exposure levels, patients can develop mental status changes, confusion, ataxia, syncope, tachycardia, and tachypnea. Severe poisoning is manifested by coma, seizures, myocardial ischemia, acidosis, cardiovascular collapse, and potentially death. Physical examination should focus on the cardiovascular and neurologic systems because these are the most detrimentally effected by CO. Emergency department evaluation should include arterial or venous blood gas analysis with HbCO determined by CO-oximetry, CK level in severely poisoned patients, pregnancy test, and ECG in any patient with cardiac symptoms.

Treatment. Prevention of CO poisoning is paramount and should involve educational initiatives and the use of home CO detectors. Treatment of CO poisoning focuses on the administration of 100% oxygen to enhance elimination of CO. In ambient air the average half-life of HbCO is 4-6 hr. This is dramatically reduced to 60-90 min by providing 100% oxygen at normal atmospheric pressures by nonrebreather face mask. Severely poisoned patients might benefit from hyperbaric oxygen (HBO) , which decreases the half-life of HbCO to 20-30 min and is thought also to decrease the risk of delayed neurologic sequelae. Although the clinical benefits and referral guidelines for HBO therapy remain controversial, frequently cited indications include syncope, coma, seizure, altered mental status, acute coronary syndrome, HbCO level >25%, abnormal cerebellar examination, and pregnancy. Consultation with a PCC, medical toxicologist, or HBO facility can assist clinicians in determining which patients could benefit from HBO therapy. Sequelae of CO poisoning include persistent and delayed cognitive and cerebellar effects. HBO advocates believe that the risk of such sequelae is minimized through the delivery of 100% oxygen at 3 atm of pressure. Patients typically receive oxygen, by non-rebreather mask or hyperbaric chamber, for 6-24 hr.

Hydrogen Cyanide Pathophysiology. Cyanide inhibits cytochrome-c oxidase, part of the electron transport chain, interrupting cellular respiration and leading to profound tissue hypoxia. Patients may be exposed to hydrogen cyanide (HCN) gas in the workplace (manufacturing of synthetic fibers, nitriles, and plastics) or by smoke inhalation in a closed-space fire. Clinical and Laboratory Manifestations. Onset of symptoms is rapid after a significant exposure. Clinical manifestations of toxicity include headache, agitation/confusion, sudden loss of consciousness, tachycardia, cardiac dysrhythmias, and metabolic acidosis. Cyanide levels can be measured in whole blood but are not readily available at most institutions. A severe lactic acidosis (lactate >10 mmol/L) in fire victims suggests cyanide toxicity. Impaired oxygen extraction by tissues is implied by elevated mixed-

venous oxyhemoglobin saturation, another laboratory finding suggesting cyanide toxicity. Treatment. Treatment includes removal from the source of exposure, rapid administration of high concentrations of oxygen, and antidotal therapy. The cyanide antidote kit (no longer manufactured) includes nitrites (amyl nitrite and sodium nitrite) used to produce methemoglobin, which then reacts with cyanide to form cyanomethemoglobin. The 3rd part of the kit is sodium thiosulfate, given to hasten the metabolism of cyanomethemoglobin to hemoglobin and the less toxic thiocyanate. In patients for whom induction of methemoglobinemia could produce more risk than benefit, the sodium thiosulfate component of the kit may be given alone. The U.S. Food and Drug Administration (FDA) has approved hydroxocobalamin for use in known or suspected cyanide poisoning (see Table 77.7 ). This antidote reacts with cyanide to form the nontoxic cyanocobalamin (vitamin B12 ), which is then excreted in urine. Side effects of hydroxocobalamin include red discoloration of the skin and urine, transient hypertension, and interference with colorimetric lab assays. Hydroxocobalamin has an overall safety profile that appears superior to that of the cyanide antidote kit and thus is the preferred antidote for cyanide poisoning.

Miscellaneous Toxic Agents Found in the Home Nicotine-Containing Products Nicotine poisoning has become increasingly common with the recent advent of vaporizer (“vaping”) and e-cigarette devices. Although there are many nicotinecontaining products (patches, gums, snuff, chewing tobacco, sprays, lozenges), tobacco cigarettes remain the main source of exposure. Prescription medications (varenicline and cytisine) are available that are partial nicotine receptor agonists. For children, some of the most concerning exposures are from the bottles of liquid nicotine used to refill vaping and e-cigarette devices. These bottles typically do not have childproof caps and contain a large amount of concentrated nicotine. Pathophysiology. Nicotine acts on nicotinic ACh receptors in the nervous system, neuromuscular

junctions, and adrenal medulla, stimulating neurotransmitter release. Nicotine's effects on the dopaminergic reward pathway play a significant role in its addictive properties. The effects of nicotine are dose dependent; at lower doses it primarily acts on the brain, causing stimulation. At higher doses, nicotine overstimulates receptors, leading to inhibition and resulting in neuromuscular and nervous system blockade. Clinical and Laboratory Manifestations. Clinical effects of nicotine also depend on the dose. At low doses typically achieved through smoking, nicotine results in cognitive and mood enhancement, increased energy, and appetite suppression. At higher doses, significant toxicity follows a biphasic pattern, where cholinergic stimulation symptoms predominate and are later followed by inhibition. The first signs of nicotine poisoning are nausea, vomiting, diarrhea, and often muscle fasciculations. Tachycardia and hypertension occur initially, although in severe poisoning these progress to bradycardia, hypotension, coma, and respiratory muscle failure, which typically leads to death if not treated. Serum and urinary levels of nicotine and its metabolite cotinine can be obtained, but these rarely are available in real time and therefore have little effect on diagnosis and management. Treatment. Treatment of nicotine poisoning focuses on maximizing symptomatic and supportive care. Aggressive airway management should be the priority, especially in severe poisonings, because death usually occurs from respiratory muscle paralysis. IV fluids with escalation to vasopressors should be used for hypotension. Seizures should be managed with benzodiazepines, barbiturates, or propofol.

Single-Use Detergent Sacs Commonly known as laundry “pods” for clothing, these products resemble candy to many children. When bitten into, a relatively large dose of concentrated detergent is expelled under pressure onto the posterior pharynx and vocal cords. This can lead to stridor and other signs of respiratory distress. Occasionally, and for unknown reasons, these children may also develop altered mental status. Supportive care with attention to any airway and breathing issues is warranted. Admission to the hospital is often indicated. Importantly, these are not considered caustic ingestions; the pH of these products is in the neutral zone. As

such, upper GI endoscopy is rarely indicated. Curiously, laundry detergent drank from a bottle is rarely of significant concern.

Electric Dishwasher Detergent Especially when in the form of crystals, these products are highly alkaline (pH >13), and exposure by ingestion can cause significant burns to the vocal cords and GI tract. Admission for expectant management or upper GI endoscopy is usually indicated.

Magnets Most foreign body ingestions pass through the GI tract once known to have passed into the stomach. However, ingestion of ≥2 magnets (unless very weak refrigerator-style magnets) cause concern for bowel obstruction and perforation. Admission for attempted retrieval by endoscopy or clearance by WBI should be considered.

Batteries Any disk or button-style battery lodged in the esophagus or airway should be considered a true emergency warranting immediate referral to an endoscopist for removal. These batteries can cause necrosis of the tissues in which they are lodged by continued electrical discharge and leaking of their contents (the former is likely the primary method of injury). Mucosal contact for even 2 hr might induce necrosis. Once past the lower esophageal sphincter, button or even larger batteries (e.g., AA, AAA) can usually be allowed to pass through the GI tract with close follow-up.

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CHAPTER 78

Complementary Therapies and Integrative Medicine Paula M. Gardiner, Caitlin M. Neri

Integrative medicine focuses on promoting physical, mental, emotional, spiritual, social, and educational well-being in the context of a medical home in a healthy family and community. The foundations of integrative medicine are health-promoting practices such as optimal nutrition and dietary supplements to prevent deficiencies, avoidance of addictive substances (e.g., nicotine, illicit drugs), physical activity, adequate sleep, a healthy environment, and supportive social relationships. Evidence-based complementary therapies such as dietary supplements, massage, chiropractic, other forms of bodywork, yoga, meditation practices, hypnosis, guided imagery, biofeedback, and acupuncture may also be used. Although prayer and healing rituals are sometimes included under the rubric of complementary and integrative therapies, they are not covered in this chapter. Not including multivitamins and mineral supplements such as iron and calcium, an estimated 10–40% of healthy children and >50% of children with chronic conditions use integrative medicine in the United States. The prevalence could be even higher because these treatments usually occur without disclosure to the children's primary care physician. Common therapies include dietary supplements, deep breathing, guided imagery, mediation, biofeedback, hypnosis, yoga, acupuncture, massage, and aromatherapy. Use of complementary therapies is most common among youth with chronic, incurable, or recurrent conditions such as cancer, depression and other mental health conditions, asthma, autism, headaches, abdominal pain, and other chronic painful conditions. Children's hospitals and pediatric subspecialty programs are increasingly offering integrative medicine strategies alongside traditional medicine, as part of the care of children in both inpatient and outpatient settings.

In a 2014 survey the American Pain Society identified 48 pediatric chronic pain clinics, with most offering some type of integrative medicine or behavioral health strategies with conventional medicine. For example, integrative therapies are increasingly being used in pediatric chronic pain clinics to treat functional bowel disorders. Recent reviews include supplements (e.g., ginger, peppermint oil) and mind-body techniques (e.g., hypnotherapy, biofeedback, acupuncture/acupressure) with traditional medical management for these common pediatric conditions.

Dietary Supplements Under the 1994 U.S. Dietary Supplement Health and Education Act, a dietary supplement is a product taken by mouth that contains a dietary ingredient intended to supplement the diet. These may include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glands, and metabolites. Dietary supplements are the most frequently used complementary therapies for children and adolescents (Table 78.1 ). Some uses are common and recommended, such as vitamin D supplements for breastfed infants and probiotics to prevent antibiotic-associated diarrhea, whereas other uses are more controversial, such as using herbal products to treat otitis media. Table 78.1

Commonly Used Dietary Supplements in Pediatrics PRODUCT VITAMINS B2 (riboflavin) B6 (pyridoxine) B9 (folate) D Multivitamins MINERALS Iodine (salt) Iron Magnesium Zinc HERBS Aloe vera Chamomile Echinacea

USES Migraine headache prophylaxis Pyridoxine-dependent epilepsy; neuropathy; nausea associated with pregnancy Prevention of neural tube defects Prevention of rickets; treatment of vitamin D deficiencies General health promotion Prevent goiter and mental retardation Prevent and treat iron-deficiency anemia Constipation, asthma, migraine prevention Diarrhea in nutrient-poor populations Mild burns Mild sedative, dyspepsia Prevention of upper respiratory infections

Ginger Lavender (aromatherapy) Peppermint Tea tree oil OTHER Melatonin Omega-3 fatty acids Probiotics

Nausea Mild sedative Irritable bowel syndrome Antibacterial (acne remedies), pediculicide (lice) Insomnia ADHD, allergies, inflammation, anxiety and mood disorders Antibiotic-associated diarrhea; Clostridium difficile –associated diarrhea; constipation; irritable bowel syndrome; pouchitis; inflammatory bowel disorders

ADHD, Attention-deficit/hyperactivity disorder.

In the United States, dietary supplements do not undergo the same stringent evaluation and postmarketing surveillance as prescription medications. Although they may not claim to prevent or treat specific medical conditions, product labels may make structure-function claims. For example, a label may claim that a product “promotes a healthy immune system,” but it may not claim to cure the common cold. According to the 2012 National Health Interview Survey, 5% of U.S. children used non-vitamin/mineral dietary supplements. (e.g., fish oil, melatonin, prebiotics, probiotics) Use of dietary supplements is most common among children whose families have higher income and education and whose parents use supplements, among older children, and among those with chronic conditions. Despite this widespread use, many patients and their parents who use dietary supplements do not talk with their physician about their use. Several guidelines have called for more complete dietary supplement history taking by healthcare professionals. The Joint Commission recommends that clinicians routinely ask patients about their use of dietary supplements and include this information as part of the medication reconciliation process.

Dietary Supplement Safety Dietary supplements may have safety issues in children, but toxicity is much less common with nonprescription dietary supplements than with prescription medications (Table 78.2 ). Toxicity depends on dose, use of other therapies, and the child's underlying medical condition. Current use of a dietary supplement (e.g., ephedra for weight loss) may not reflect its traditional use (e.g., ephedra as a component of a traditional Chinese medicine tea in small doses to improve allergic or respiratory symptoms). Moreover, herbs that are apparently safe for

most adults may be more hazardous in specific conditions (e.g., newborns, patients with impaired renal or hepatic function), under special circumstances (e.g., after organ transplantation or other surgery), or when combined with prescription medications. Some natural products are toxic in and of themselves. Even when a product is safe when used correctly, it can cause mild or severe toxicity when used incorrectly. For example, although peppermint is a commonly used and usually benign gastrointestinal spasmolytic included in after-dinner mints, it can exacerbate gastroesophageal reflux. Table 78.2

Clinical Toxicity of Selected Herbs COMMON NAME Aconite (monkshood, wolfsbane) Aloe Betel nut Bloodroot Chaparral (greasewood) Compound Q Dandelion Figwort (xuan shen) Ginseng Goldenseal Hellebore Hyssop Juniper Kava kava

BOTANICAL THERAPEUTIC USES NAME Aconitum spp. Sedative, analgesic, antihypertensive

Aloe spp. Areca catechu Sanguinaria canadensis Larrea tridentata Trichosanthes kirilowii Taraxacum officinale Scrophularia spp. Panax quinquefolium Hydrastis canadensis Veratrum spp. Hyssopus officinalis Juniperus communis Piper methysticum

Kombucha Licorice Lily of the valley Linn (willow)

Burns, skin diseases Mood elevation Emetic, cathartic, eczema Aging, free radical scavenging Anthelmintic, cathartic

Cardiac arrhythmias

Nephritis, GI upset Bronchoconstriction, oral cancers GI upset, vertigo, visual disturbances Hepatitis

Diuretic, heartburn remedy

Diarrhea, hypoglycemia, CNS toxicity Anaphylaxis

Antiinflammatory, antibacterial

Cardiac stimulation

Antihypertensive, aphrodisiac, Ginseng abuse syndrome stimulant, mood elevation, digestive aid Digestive aid, mucolytic, anti-infective Uterine, cardiac stimulation; GI upset, leukopenia Antihypertensive Vomiting, bradycardia, hypotension Asthma, mucolytic Seizures Hallucinogen Sedative Stimulant

Glycyrrhiza spp. Convallaria spp. Salix caprea

POTENTIAL TOXICITY

Indigestion Cardiotonic Purgative

GI upset, seizures, renal injury, hypotension, bradycardia Inebriation Metabolic acidosis, hepatotoxicity, death Mineralocorticoid effects GI (nausea, vomiting), cardiac arrhythmias Hemolysis with glucose-6phosphate dehydrogenase

Lobelia (Indian tobacco) Ma Huang Mandrake Mormon tea Nutmeg Oleander Passionflower Periwinkle Pokeweed Sabah Sage Snakeroot Squill Thorn apple (jimsonweed) Tonka bean Valerian root Wild (squirting) cucumber Wormwood (mugwort) Yohimbine

Lobelia spp.

Stimulant

Ephedra sinica Mandragora officinarum Ephedra nevadensis Myristica fragrans Nerium oleander Passiflora caeruliea Vinca spp. Phytolacca spp. Sauropus androgynus Salvia spp. Rauwolfia serpentina Urginea maritima Datura stramonium Dipteryx odorata Valeriana spp. Ecballium elaterium Artemisia spp.

Stimulant

Corynanthe yohimbe

Aphrodisiac, stimulant

deficiency Nicotine intoxication

Hallucinogen

Sympathetic crisis, especially with monamine oxidase inhibitors Anticholinergic syndrome

Stimulant, asthma, antipyretic

Hypertension, sympathomimetic

Hallucinogen, abortifacient

Hallucinations, GI upset

Cardiac stimulant

Cardiac arrhythmias

Hallucinogen Antiinflammatory, diabetes Arthritis, chronic pain

Hallucinations, seizures, hypotension Alopecia, seizures, hepatotoxicity GI upset, seizures, death

Weight loss, vision

Pulmonary injury

CNS stimulant Sedative, antihypertensive

Seizures Bradycardia, coma

Arthritis, cardiac stimulant

Seizures, arrhythmias, death

Hallucinations

Anticholinergic

Anticoagulant

Bleeding diathesis

Sedative Constipation, antiinflammatory, rheumatic disease Stimulant, hallucinogen

Sedation, obtundation Airway obstruction Hallucinations, seizures, uterine stimulation Hypertension, sympathetic crisis

CNS, Central nervous system; GI, gastrointestinal. From Kingston RL, Foley C: Herbal, traditional, and alternative medicines. In Haddad and Winchester's clinical management of poisoning and drug overdose, ed 4, Philadelphia, 2007, Saunders/Elsevier, p 1081.

Although there are good manufacturing practices for dietary supplements in the United States, dietary supplement labels might not accurately reflect the contents or concentrations of ingredients. Because of natural variability, variations of 10-1,000–fold have been reported for several popular herbs, even across lots produced by the same manufacturer. Herbal products may be contaminated with pesticides, microbial agents or products, or the wrong herb misidentified during harvesting. Products from developing countries (e.g., Ayurvedic products from South Asia) might contain toxic levels of mercury,

cadmium, arsenic, or lead, either from unintentional contamination during manufacturing or from intentional additions by producers who believe that these metals have therapeutic value. Approximately 30–40% of Asian patent medicines include potent pharmaceuticals, such as analgesics, antibiotics, hypoglycemic agents, or corticosteroids; typically the labels for these products are not written in English and do not note the inclusion of pharmaceutical agents. Even conventional mineral supplements, such as calcium, have been contaminated with lead or had significant problems with product variability. Many families use supplements concurrently with medications, posing hazards of interactions (Table 78.3 ). Using the same principles of drug-drug interactions can help determine if a supplement-drug interaction is a concern. For example, St. John's wort induces CYP3A4 activity of the cytochrome P450 enzyme system and thus can enhance elimination of most drugs that use this pathway, including digoxin, cyclosporine, protease inhibitors, oral contraceptives, and numerous antibiotics, leading to subtherapeutic serum levels. Table 78.3

Common Herbal Dietary Supplement (HDS)–Drug Interactions HDS Aloe vera

DRUGS Glibenclamide (glyburide)

Bitter orange Garlic

Phenelzine

Ritonavir Saquinavir Licorice Warfarin Grapefruit Calcium channel blockers

Melatonin Zolpidem Valerian Alprazolam, phenobarbital Goldenseal Inhibition of CYP2D6 and CYP3A4 St. John's wort

Cyclosporine, tacrolimus, warfarin, protease inhibitors, digoxin, theophylline, venlafaxine, oral contraceptives

↓, Decreasing; ↑, increasing.

POTENTIAL CONSEQUENCES/REACTIONS ↑ Oral aloe vera gel can cause additive glycemic-lowering effects when taken concurrently with a hypoglycemic agent. ↑ Risk of hypertensive crisis ↓ Effect of ritonavir ↓ Effect of saquinavir ↑ Risk of bleeding Grapefruit juice has been found to increase bioavailability of certain drugs by inhibition of cytochrome P450 (CYP) 3A4 isozyme in liver and gut wall. ↑ Sedative effects ↑ Central nervous system depression May affect approximately 50% of common pharmaceutical agents May decrease drug effectiveness

Dietary Supplement Efficacy Evidence about the effectiveness of dietary supplements to prevent or treat pediatric problems is mixed, depending on the product used and condition treated. Some herbal products may be helpful adjunctive treatments for common childhood problems; some herbs have proved helpful for colic (fennel and the combination of chamomile, fennel, vervain, licorice, and balm mint), nausea (ginger), irritable bowel syndrome (peppermint), and diarrhea (probiotics).

Massage and Chiropractic Massage is usually provided at home by parents and in clinical settings by professional massage therapists, physical therapists, and nurses. Infant massage is routinely provided in many neonatal intensive care units to promote growth and development in preterm infants. Massage also has been demonstrated to be beneficial for pediatric patients with asthma, insomnia, colic, cystic fibrosis, or juvenile arthritis and patients undergoing cancer therapy. Massage therapy is generally safe. Professional massage practice is regulated by state government and may be in the form of a license, registration, or certification. More than 40 states license massage therapists, with licensure being the strictest form of regulation, making it illegal for any nonlicensed professional to practice massage therapy. Chiropractic healthcare deals with the diagnosis, treatment, and prevention of disorders of the neuromusculoskeletal system and their effects on general health. Currently, >60,000 chiropractors have licensure in the United States, with licensure in all 50 states. Most medical insurance companies cover chiropractic funding. Children and families seek chiropractic care for common childhood conditions such as asthma, infantile colic, nocturnal enuresis, constipation, and headache. A recent consensus update on chiropractic care in children overall found limited support in a small number of high-quality studies for effectiveness of chiropractic care for such common childhood conditions. With respect to safety, the evidence is also limited; however, published cases of serious adverse events in infants and children receiving chiropractic care are rare. If children and families are seeking chiropractic care, it is appropriately done in collaboration with the child's pediatric primary care provider to ensure patient safety.

Mind-Body Therapies Mind-body therapies such as slow, deep breathing, meditation, guided imagery, biofeedback, hypnosis, tai chi, and yoga are also frequently used complementary therapies in pediatrics. These practices can be learned informally through books, YouTube videos, compact discs, digital video discs, smartphone apps, or classes, as well as in therapeutic sessions with health professionals, such as psychologists and social workers (Table 78.4 ). Substantial research suggests that such practices can aid in reducing anxiety, insomnia, and stress-related conditions, including migraine headaches and functional abdominal pain. These therapies can also help patients struggling with chronic pain. Table 78.4 Commonly Used Mind-Body Practices in Pediatrics PRACTICE USES Biofeedback Preventing migraine headaches; reducing stress and anxiety; encopresis/constipation treatment; treatment of stress incontinence; neurofeedback is experimental for ADHD. Deep Relaxation; stress management breathing Guided Stress management; anxiety reduction; pain relief imagery Hypnosis Correcting habit disorders; preventing headaches; managing pain Meditation Stress management; improving concentration Tai chi Improving balance, coordination, concentration, and discipline Yoga Improving balance, coordination, and concentration

ADHD, Attention-deficit/hyperactivity disorder.

Acupuncture Modern acupuncture incorporates treatment traditions from China, Japan, Korea, France, and other countries. In the United States, acupuncturists are licensed to practice in 45 states. Acupuncture can be delivered to pediatric patients in hospital and clinic settings to treat a variety of ailments. Acupuncture is particularly useful for children experiencing pain, and acupuncture services are offered alongside conventional medicine and psychology by >50% of North American academic pediatric chronic pain programs. The technique that has undergone most scientific study involves penetrating the skin with thin, solid, metallic needles manipulated by hand or by electrical stimulation. Variants

include rubbing (shiatsu ), heat (moxibustion ), lasers, magnets, pressure (acupressure ), or electrical currents. Although pediatric patients may be averse to needles, when approached in a developmentally appropriate way by an acupuncturist trained in pediatrics, children are often amenable to acupuncture and report that it is helpful. Acupuncture can offer significant benefits in the treatment of recurrent headache, anxiety, back and other types of pain, depression, abdominal pain, and nausea. As with any needle therapy, infections and bleeding are rare but can occur, and more serious complications, such as pneumothorax, occur in 95% of all injury deaths occur. For each of these deaths, many more children are permanently disabled, and an even larger number are treated and released without permanent sequelae. The World Health Organization (WHO) and United Nations Children's Fund (UNICEF) have outlined several proven injury prevention strategies, of which child health practitioners in the global community must be aware. The top 3 causes of injury mortality are traffic-related injuries, burns, and drowning. There are 7 specific effective strategies for reducing traffic-related injuries : a minimum drinking age, appropriate child restraints and seatbelts, helmets for motorcycle and bicycle riders, reduced vehicle speeds around schools and

residential areas, running lights on motorcycles, graduated licensing for drivers, and separation of different types of road users. There is insufficient evidence to demonstrate that school-based programs on drunk driving, increased pedestrian visibility, or designated driver programs are effective. Although these strategies have proved effective, the data are based on U.S. research and may not be generalizable to other countries. It may be difficult to reduce vehicle speeds around schools when there is insufficient infrastructure for street signs. Alternatively, lack of separation of car and bus traffic from bicyclists and pedestrians contributes to unsafe and dangerous road conditions. This is more of a problem in lower- and middle-income countries, where bicycles and motorized 2-wheel vehicles are used to carry children as well as goods, while the drivers negotiate among rapidly moving vehicles. With rising income, these countries have seen increases in both the number of cars and the number of 2-wheeled vehicles, with a corresponding increase in the number of related injuries. For reducing drowning deaths , strategies that have proven effective focus on creating barriers between children and water hazards, such as covering wells, buckets, and other standing sources of water, and placing high fences around pools (see Chapter 91 ). Burns have been addressed by advocating for installation of smoke detectors and lowering the temperature of water from water heaters (see Chapter 92 ).

Out-of-Hospital Care Out-of-hospital care comprises access to emergency services, prehospital care, and interfacility transport of patients. Morbidity and mortality arise from delayed or limited access to emergency care, lack of prehospital care, transport without proper monitoring or trained personnel, or delayed transport to a higher level of care. Safe transport of seriously ill children is a neglected global health issue. An emergency response system must address the following links in the patient's care: a communication system with prompt activation of EMS, the correct assessment and initial treatment of the patient, and the rapid transport to definitive care.

Access to Care When a child is injured or ill, a parent or caretaker must be able to access help and activate EMS. Many countries worldwide have dedicated emergency numbers to rapidly dispatch medical, police, or fire services. The simple 112

emergency number has been adopted and is being phased in throughout the European Union (EU) member states, to access medical, fire, and police services, in addition to secondary regional emergency access numbers. The universal U.S. emergency number system 911 today covers the large majority of the country (98%) and has enhanced features of automatically linking the phone number to an address. However, there remain limitations to universal access resulting from absence of phones in some households, unclear addresses in rural areas, and insufficient reach of the emergency system. In the majority of low- and middle-income countries, no such universal emergency numbers have been established, requiring access by direct dialing to an ambulance, if such private services exist. In most low- and middle-income countries, the family must bring the ill or injured child to the health facility for stabilization and treatment. For this to occur, families must overcome financial and geographic barriers, which can result in delayed presentation for care. This delay predictably increases the acuity of the illness or injury and associated complications and decreases the likelihood of full recovery and survival.

Prehospital Care In regions with maturing EMS systems, there must be adequately trained personnel to stabilize and transport the child to a medical facility. The quality and level of training of such prehospital personnel vary tremendously among countries and within regions of the same country. In urban areas, there is a greater concentration of medical care and therefore a greater opportunity to have strong prehospital training. In most of Asia and sub-Saharan Africa, trained personnel are used primarily to transfer patients between health facilities, not from the initial site of illness or injury. In most high-income countries, medical services are dispatched to the patient. In the French model, Service d'Aide Médicale Urgente (SAMU), a physician, often an emergency medicine specialist, will review calls for acuity and can dispatch a physician-led team by ambulance to go to the patient's home to assess, stabilize, and initiate treatment. This Franco-German system is used in other countries, including many in Latin America and Europe. There are no clear data on the cost-effectiveness and patient outcomes associated with delivery of patients to the nearest facility vs bringing hospital resources to the patient. Around the world, the effort to establish standardized approaches to prehospital care exists primarily in the form of courses to educate EMS and hospital personnel in the emergency management of patients. For trauma care,

the WHO manuals Prehospital Trauma Care Systems and Guidelines for Essential Trauma Care both focus on guidelines for prehospital and trauma care systems that are affordable and sustainable. The AAP course Pediatric Education for Prehospital Professionals is a dynamic, modularized teaching tool designed to provide specific pediatric prehospital education that can be adapted to any EMS system. Table 79.6 describes additional prehospital resources.

Table 79.6

Pediatric Emergency Care Resources Prehospital Advanced Medical Life Support (AMLS) Newest course developed by the National Association of Emergency Medical Technicians (NAEMT) to provide more clinical teaching and reasoning around emergent medical problems. Course is open to physicians, nurses EMTs and paramedics. www.naemt.org/education/amls/amls.aspx Prehospital Trauma Life Support Available in 33 countries, PHTLS is the leading continuing education program for prehospital emergency trauma care. www.phtls.org International Trauma Life Support Training course for prehospital trauma care. www.itrauma.org Pediatric Education for Prehospital Professionals (PEPP) Curriculum designed specifically to teach prehospital professionals how to assess and manage ill or injured children. www.peppsite.org

Hospital Care Pocket Book of Hospital Care for Children WHO publication providing guidelines for the management of common illnesses with limited resources; incorporates both the Emergency Triage Assessment and Treatment (ETAT) and Integrated Management of Childhood Illness (IMCI) guidelines.

www.who.int/maternal_child_adolescent/documents/9241546700/en/index.html AFEM Handbook of Acute and Emergency Care Management strategies based on available resources. It leads providers through a rapid, systematic, and integrated approach to stabilization and resuscitation of patients stratified to 3 resource levels: where there are no available resources, where there are minimal resources, and where there are full resources. Available for purchase online. Where There Is No Doctor: A Village Health Handbook Healthcare manual for health workers, clinicians, and others involved in primary healthcare delivery and health promotion programs around the world. Available for purchase or as a free download. www.hesperian.org International Federation for Emergency Medicine 2012 International Standards of Care for Children in Emergency Departments. https://www.ifem.cc/wp-content/uploads/2016/07/International-Standardsfor-Children-in-Emergency-Departments-V2.0-June-2014-1.pdf

Humanitarian Emergencies CHILDisaster Network Registry for those with education and experience in humanitarian emergencies to volunteer their time when needed in a disaster. www.aap.org/disaster The Sphere Project Downloadable modules on disaster preparedness. www.sphereproject.org Management of Complex Humanitarian Emergencies: Focus on Children and Families Training course offered by the Children in Disasters Project, sponsored by the Rainbow Center for Global Child Health (RCGCH) in Cleveland, OH. Held in early June annually. Manual for the Health Care of Children in Humanitarian Emergencies WHO publication that provides comprehensive guidance on childcare in emergencies; includes information on care of traumatic injuries and mental health emergencies.

www.who.int/child_adolescent_health/documents/9789241596879/en/index.html

Access to Academic Publications Relevant to PEM PEMdatabase.org A website devoted to pediatric emergency medicine (PEM). Contains links to conferences, evidence-based medicine reviews, research networks, and professional organizations. www.pemdatabase.org HINARI Access to Research Initiative Program established by WHO and others to enable developing countries to gain access to one of the world's largest collections of biomedical and health literature. www.who.int/hinari/en

Involvement ACEP Ambassador Program Provides the names of U.S.-boarded emergency medicine physicians who can provide advice and information on issues pertaining to the progress and status of emergency medicine in their assigned countries. www.acep.org/content.aspx?id=25138 Section on International Emergency Medicine, American College of Emergency Physicians This group maintains a list of international organizations and clinical opportunities, many of which involve emergency care of children. http://www.acep.org/_InternationalSection/International-EmergencyMedicine-Related-Resources/ Section of International Child Health, American Academy of Pediatrics Lists non-U.S. clinical opportunities, many of which involve emergency care. http://www2.aap.org/sections/ich/working_overseas.htm

Organizations Involved in International PEM Activities

U.S. Agency for International Development (USAID) Government agency providing U.S. economic and humanitarian assistance worldwide. www.usaid.gov World Health Organization (WHO) Publication catalog, media resources, health articles, and current health news. www.who.int/topics/child_health/en United Nations Children's Fund (UNICEF) Organization dedicated to providing lifesaving assistance to children affected by disasters and to protecting their rights in any circumstances; formerly United Nations International Children's Emergency Fund. www.unicef.org Safe Kids Worldwide The first and only international nonprofit organization dedicated solely to preventing unintentional childhood injury. www.safekids.org Although most middle- and high-income countries have a system of trained EMS workers, low-income countries lack this advanced tier of emergency care. In these countries, commercial drivers, volunteers, and willing bystanders provide the first line of care. Training a cadre of first responders can rely on existing networks of aid or can be drawn from specific populations, such as students, soldiers, or public servants. Training needs to emphasize basic lifesaving and limb-saving interventions, including how to stop bleeding and support breathing, access advanced care, and splint broken limbs. In Ghana, for example, taxi drivers participated in a first-aid course that relied heavily on demonstration and practice rather than knowledge transfer through didactic sessions. Taxi drivers were selected because they already provided much of the transport for injured patients, either voluntarily or for pay by the family. Two years after the course, external evaluators favorably rated the quality of their care compared with untrained drivers. In rural areas, such first responders become vital in providing emergency interventions when more definitive care is distant. Thus a system of trained first responders forms the foundation of an effective prehospital system.

Methods of Transport

In many low-income countries, there is no means of transport other than the family's motorized or other type of transport. Health centers may only have 1 vehicle for transport to a higher-level facility. This vehicle may also be used for outreach primary care services, such as offering immunizations and collecting drugs and equipment from a central supply location, and sometimes, improperly for personal reasons by local officials or politicians. In large cities, taxis and auto rickshaws are frequently used because they are rapidly available, well disseminated, and able to pass around traffic jams. Where organized prehospital systems exist, different types of vehicles are adapted for emergency transportation, from fully equipped ambulances to basic transport with trained personnel. The WHO recommends identifying transport vehicles in advance, choosing vehicles that can be repaired and maintained locally, and equipping the vehicles according to recognized standards. Therefore the provision of available and appropriately staffed and equipped transport vehicles is crucial to the realization of recommended emergency care plans.

Hospital-Based Care Once a child has reached a medical facility for the care of an injury or illness, adequate emergency services must be available. In many countries the ED serves only as a triage area where patients are distinguished by their likely disease process and directed for admission to the corresponding unit within the hospital. Strengthening emergency services includes seeing the ED as a unit where definitive treatment can be provided to the ill and injured child. Critically ill children must receive not only prompt care but also correct care. Such expedience and accuracy are ensured by implementation of an effective triage system, moving the sickest patients to immediate care and standardizing the initial care of emergency conditions.

Triage Children requiring emergency care frequently are not promptly recognized. Too often, children presenting to EDs are treated on a first-come first-served basis, in an approach that creates long waiting times for critically ill children, a contributor to unnecessary mortality. Medical facilities need to adopt an efficient and effective triage system to respond rapidly to the needs of patients and to assign the appropriate amount of resources. To this end, WHO has developed a course entitled Emergency Triage Assessment and Treatment (ETAT) . This

course teaches to triage patients on arrival as having emergency, priority, or nonurgent signs and to provide emergency treatment for life-threatening conditions. ETAT emphasizes the evaluation of a patient's ABCD status to identify emergency situations—the patency of the airway (A), the quality of breathing (B), the quality of circulation and presence of coma or convulsions (C), and the presence of severe dehydration (D). One of the benefits of the ETAT guidelines is that they can be adapted to centers with limited resources and are applicable to areas with high morbidity and mortality from meningitis, dehydration, malaria, respiratory illness, and malnutrition. Another benefit is that the care algorithms are based on limited diagnostic studies, that is, hemoglobin measurement, blood smear for malaria, and bedside blood glucose testing. Widely accepted triage assessment guidelines are teachable to emergency care staff, and their adoption can provide better organization within a healthcare center. At the Queen Elizabeth Central Hospital in Blantyre, Malawi, for example, the institution of triage and rapid treatment in its emergency care center led to a 50% decrease in the mortality of children within 24 hr of presentation to the hospital, with a further 50% decrease as implementation and practice of triaging patients have continued. Beyond triage, education on overall emergency center organization is a lowresource intervention that can obviate some of the obstacles to quality care delivery. Additionally, the arrangement of short-stay areas (hydration and infusion rooms) can lessen the burden on inpatient units.

Pediatric-Specific Emergency Centers Anecdotally, most countries have developed at least 1 pediatric-capable center, usually as part of an academic medical center. The emergency services in these centers are variable, but certainly can be a starting point from which to build overall improvement in pediatric emergency care.

Practitioners Throughout the world, nurses, paramedics, and nonspecialist physicians provide most of the care to acutely ill or injured children. The majority of sick children attend local clinics or district or central hospitals, where financial and human resources are not always matched to the potential acuity of presenting patient complaints. Nominal supervision is provided to staff attending these patients. Pediatric EDs located in tertiary hospitals are often staffed by training physicians

with little or no supervision from faculty, who themselves may have limited exposure to or training in PEM. General hospitals lack dedicated pediatric staff; guidelines as to which patients should be moved to a higher level of care are often not standardized and depend on local influences and/or cultural beliefs about health and illness.

Clinical Guidelines The Integrated Management of Childhood Illnesses (IMCI) guidelines were developed by the WHO and UNICEF to provide assistance in the initial triage and management of the presenting signs and symptoms of the major killers of children 40% of blood volume cause severe hypotension that, if prolonged, may become irreversible. Direct pressure should be applied to control external hemorrhage. When direct pressure does not control hemorrhage, a tourniquet should be applied to a proximal pressure point. Blind clamping of bleeding vessels, which risks damaging adjacent structures, is not advisable. Table 82.4

Systemic Responses to Blood Loss in Pediatric Patients MILD BLOOD LOSS (45%) (30–45%) Markedly increased heart rate; Tachycardia followed by bradycardia; weak, thready central pulses; central pulses very weak or absent;

Central nervous Skin

Urine output

peripheral pulses; normal systolic blood pressure; normal pulse pressure Anxiety; irritability; confusion Cool, mottled; capillary refill prolonged Low to very low

peripheral pulses absent; low peripheral pulses absent; hypotension; normal systolic blood pressure; narrowed pulse pressure (or narrowed pulse pressure undetectable diastolic blood pressure). Lethargy; dulled response to pain Cyanotic; capillary refill markedly prolonged

Coma

Minimal

None

Pale and cold

Adapted from American College of Surgeons Committee on Trauma: Advanced trauma life support for doctors: student course manual, ed 9, Chicago, 2012, American College of Surgeons.

Cannulating a larger vein, such as an antecubital vein, is usually the quickest way to achieve intravenous (IV) access. A short, large-bore catheter offers less resistance to flow, allowing for more rapid fluid administration. Ideally, a 2nd catheter should be placed within the first few minutes of resuscitation in a severely injured child. If IV access is not rapidly obtainable, an intraosseous (IO) needle should be inserted; all medications and fluids can be administered intraosseously. Other alternatives are central venous access using the Seldinger technique (e.g., in the femoral vein) and, rarely, surgical cutdown (e.g., in saphenous vein). Ultrasonography should be used to facilitate central venous catheter placement, if possible. Traditionally, fluids are administered aggressively early in hemorrhagic shock to reverse and prevent further clinical deterioration. Isotonic crystalloid solution, such as lactated Ringer injection or normal saline (20 mL/kg), should be infused rapidly. When necessary, repeated crystalloid boluses may be given. Most children are stabilized with administration of crystalloid solution alone. However, if the patient remains in shock after boluses totaling 40-60 mL/kg of crystalloid, packed red blood cells should be transfused. Massive transfusion protocols (including fresh-frozen plasma) should be initiated early to prevent coagulopathy. When shock persists despite these measures, surgery to stop internal hemorrhage is usually indicated. Although literature is emerging regarding the benefits of permissive hypotension, hemostatic resuscitation, and damage control surgery for adult trauma patients, currently there are no pediatric data.

Neurologic Deficit Neurologic status is briefly assessed by determining the level of consciousness and evaluating pupil size and reactivity. The level of consciousness can be

classified using the mnemonic AVPU : Alert, responsive to Verbal commands, responsive to Painful stimuli, or Unresponsive. At least 75% of pediatric blunt trauma deaths are accounted for by head injuries. Primary direct cerebral injury occurs within seconds of the event and is irreversible. Secondary injury is caused by subsequent anoxia or ischemia. The goal is to minimize secondary injury by ensuring adequate oxygenation, ventilation, and perfusion, and maintaining normal cerebral perfusion pressure. A child with severe neurologic impairment—i.e., with a Glasgow Coma Scale (GCS; see Chapter 85 ) score of ≤8—should undergo endotracheal intubation and supportive mechanical ventilation. Signs of increased intracranial pressure (ICP), including progressive neurologic deterioration and evidence of transtentorial herniation, must be treated immediately (see Chapter 85 ). Hyperventilation lowers the arterial partial pressure of carbon dioxide (PaCO 2 ), resulting in cerebral vasoconstriction, reduced cerebral blood flow, and decreased ICP. Brief hyperventilation remains an immediate option for patients with acute increases in ICP. Prophylactic hyperventilation, or vigorous or prolonged hyperventilation, is not recommended, because the consequent vasoconstriction may excessively decrease cerebral perfusion and oxygenation. Mannitol lowers ICP and may improve survival. Because mannitol induces an osmotic diuresis, it can exacerbate hypovolemia and must be used cautiously. Hypertonic saline may be a more useful agent for control of increased ICP in patients with severe head injury. Neurosurgical consultation is mandatory. If signs of increased ICP persist, the neurosurgeon must decide whether to operate emergently.

Exposure and Environmental Control All clothing should be cut away to reveal any injuries. Cutting is quickest and minimizes unnecessary patient movement. Children often arrive in the ED mildly hypothermic because of their higher body surface area-to-mass ratios. They can be warmed with use of radiant heat as well as heated blankets and IV fluids.

Secondary Survey During the secondary survey, the physician completes a detailed, head-to-toe physical examination.

Head Trauma A GCS or Pediatric GCS score (see Chapter 85 ) should be assigned to every child with significant head trauma. This scale assesses eye opening and motor and verbal responses. In the Pediatric GCS, the verbal score is modified for age. The GCS helps categorize neurologic disability, and serial measurements identify improvement or deterioration over time. Patients with low scores 6-24 hr after injuries have poorer prognosis. In the ED, cranial CT scanning of the head without a contrast agent has become standard to determine the type of injury in patients with concerning findings. Diffuse cerebral injury with edema is a common and serious finding on CT scan in severely brain-injured children. Focal hemorrhagic lesions (e.g., epidural hematoma) that can be evacuated occur less often but may require immediate neurosurgical intervention (Fig. 82.3 ).

FIG. 82.3 Epidural hematoma. CT head scan from 7 mo old girl who, according to the history provided, did not wake up for her nightly feeding and began vomiting in the morning. The mother's boyfriend reported that the infant had fallen from a chair the previous day. The CT scan shows a large epidural hematoma on the right and marked shift of the midline from right to left. The right lateral ventricle is compressed as a result of the mass effect, and the left lateral ventricle is slightly prominent. The infant underwent emergency surgical evacuation of the epidural hematoma and recovered uneventfully. (From O'Neill JA Jr: Principles of pediatric surgery, ed 2, St Louis, 2003, Mosby, p 191.)

Monitoring of ICP should be strongly considered for children with severe brain injury, particularly for those with a GCS score of ≤8 and abnormal head CT findings (see Chapter 85 ). One advantage of an intraventricular catheter over an intraparenchymal device is that cerebrospinal fluid can be drained to treat acute increases in ICP. Hypoxia, hypercarbia, hypotension, and hyperthermia must be aggressively managed to prevent secondary brain injury. Cerebral perfusion pressure (i.e., the difference between mean arterial blood pressure and mean ICP) should be maintained >40 mm Hg, at least (and an even higher minimum, >50 mm Hg, especially for older children). A child with a severe brain injury must be treated aggressively in the ED because it is difficult to predict the long-term neurologic outcome.

Cervical Spine Trauma Cervical spine injuries occur in 20 mm Hg. Other first-tier therapies include the osmolar agents hypertonic saline (often given as a continuous infusion of 3% saline at 0.1-1.0 mL/kg/hr) and mannitol (0.25-1.0 g/kg IV over 20 min), given in response to ICP spikes >20 mm Hg or with a fixed (every 4-6 hr) dosing interval. Use of hypertonic saline is more common and has stronger literature support than mannitol, although both are used; these 2 agents can be used concurrently. It is recommended to avoid serum osmolality >320 mOsm/L. A Foley urinary catheter should be placed to monitor urine output. If increased ICP remains refractory to treatment, careful reassessment of the patient is needed to rule out unrecognized hypercarbia, hypoxemia, fever, hypotension, hypoglycemia, pain, and seizures. Repeat imaging should be considered to rule out a surgical lesion. Guidelines-based second-tier therapies for refractory raised ICP are available, but evidence favoring a given second-tier therapy is limited. In some centers, surgical decompressive craniectomy is used for refractory traumatic intracranial hypertension. Others use a pentobarbital infusion , with a loading dose of 5-10 mg/kg over 30 min followed by 5 mg/kg every hour for 3 doses and then maintenance with an infusion of 1 mg/kg/hr. Careful blood pressure monitoring is required because of the possibility of druginduced hypotension and the frequent need for support with fluids and pressors.

Mild hypothermia (32-34°C [89.6-93.2°F]) in an attempt to control refractory ICP may be induced and maintained by means of surface cooling. Hypothermia for increased ICP after traumatic brain injury remains controversial for pediatric and adult patients. Hyperthermia must be avoided and if present should be treated aggressively. Sedation and neuromuscular blockade are used to prevent shivering, and rewarming should be slow, no faster than 1°C (1.8°F) every 4-6 hr. Hypotension should be prevented during rewarming. Refractory raised ICP can also be treated with hyperventilation (PaCO 2 25-30 mm Hg). Combinations of these second-tier therapies are often required.

Supportive Care Euvolemia should be maintained, and isotonic fluids are recommended throughout the ICU stay. SIADH and CSW can develop and are important to differentiate, because management of SIADH is fluid restriction and that of CSW is sodium replacement. Severe hyperglycemia (blood glucose level >200 mg/dL) should be avoided and treated. The blood glucose level should be monitored frequently. Early nutrition with enteral feedings is advocated. Corticosteroids should generally not be used unless adrenal insufficiency is documented. Tracheal suctioning can exacerbate raised ICP. Timing of the use of analgesics or sedatives around suctioning events and use of tracheal or IV lidocaine can be helpful. Seizures are common after severe acute TBI. Early posttraumatic seizures (within 1 wk) will complicate management of TBI and are often difficult to treat. Anticonvulsant prophylaxis with fosphenytoin, carbamazepine, or levetiracetam is a common treatment option. Late posttraumatic seizures (≥7 days after TBI) and, if recurrent, late posttraumatic epilepsy are not prevented by prophylactic anticonvulsants, whereas early posttraumatic seizures are prevented by initiating anticonvulsants soon after TBI. Antifibrinolytic agents (tranexamic acid) reduce hemorrhage size, as well as the development of new focal ischemic cerebral lesions, and improve survival in adults with severe TBI.

Prognosis Mortality rates for children with severe TBI who reach the pediatric ICU range between 10% and 30%. Ability to control ICP is related to patient survival, and the extent of cranial and systemic injuries correlates with quality of life. Motor

and cognitive sequelae resulting from severe TBI generally benefit from rehabilitation to minimize long-term disabilities. Recovery from TBI may take months to achieve. Physical therapy, and in some centers methylphenidate or amantadine, helps with motor and behavioral recovery. Pituitary insufficiency may be an uncommon but significant complication of severe TBI.

Bibliography Adelson PD, Wisniewski SR, Beca J, et al. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (cool kids): a phase 3, randomized controlled trial. Lancet Neurol . 2013;12:546–553. Andrews PJD, Sinclair L, Rodriguez A, et al. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med . 2015;373(25):2403–2412. Babl FE, Borland ML, Phillips N, et al. Accuracy of PECARN, CATCH, and CHALICE head injury decision rules in children: prospective cohort study. Lancet . 2017;389:2393– 2402. Bell MJ, Adelson PD, Hutchison JS, et al. Differences in medical therapy goals for children with severe traumatic brain injury—an international study. Pediatr Crit Care Med . 2013;14:811–818. Chesnut RM, Temkin N, Carney N, et al. A trial of intracranialpressure monitoring in traumatic brain injury. N Engl J Med . 2012;367:2471–2481. Chin KH, Bell MJ, Wisniewski SR, et al. Effect of administration of neuromuscular blocking agents in children with severe traumatic brain injury (TBI) on acute complication rates and outcomes: a secondary analysis from a randomized, controlled trial of therapeutic hypothermia. Pediatr Crit Care Med . 2015;16:352–358. Crompton EM, Lubomiriva I, Cotlarcius I, et al. Meta-analysis

of therapeutic hypothermia for traumatic brain injury in adult and pediatric patients. Crit Care Med . 2017;45(4):575–583. Edlow JA, Rabinstein A, Traub SJ, et al. Diagnosis of reversible causes of coma. Lancet . 2014;384:2064–2076. Heather N, Cutfield W. Traumatic brain injury: is the pituitary out of harm's way? J Pediatr . 2011;159:686–690. Hutchinson PJ, Kolias AG, Czosnyka M, et al. Intracranial pressure monitoring in severe traumatic brain injury. BMJ . 2013;346:f1000. Hutchinson PJ, Kolias AG, Timofeev EA, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med . 2016;375(12):1119–1130. Jamal A, Sankhyan N, Jayashree M, et al. Full outline of unresponsiveness score and the Glasgow coma scale in prediction of pediatric coma. World J Emerg Med . 2017;8:55–60. Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents—second edition. Pediatr Crit Care Med . 2012;13(Suppl 1):S1–S82. Meinert E, Bell MJ, Buttram S, et al. Initiating nutritional support before 72 hours is associated with favorable outcome after severe traumatic brain injury in children: a secondary analysis of a randomized, controlled trial of therapeutic hypothermia. Pediatr Crit Care Med . 2018;19:345–352. Mellion SA, Bennett KS, Ellsworth GL, et al. High-dose barbiturates for refractory intracranial hypertension in children with severe traumatic brain injury. Pediatr Crit Care Med . 2013;14:239–247. Miller Ferguson N, Shein SL, Kochanek PM, et al. Intracranial hypertension and cerebral hypoperfusion in children with severe traumatic brain injury: thresholds and burden in accidental and abusive insults. Pediatr Crit Care Med .

2016;17:444–450. Mtaweh H, Smith R, Kochanek PM, et al. Energy expenditure in children after severe traumatic brain injury. Pediatr Crit Care Med . 2014;15:242–249. National Center for Health Statistics. Percentage of traumatic brain injury (TBI)–related deaths by underlying cause and age group—United States. MMWR Morb Mortal Wkly Rep . 2013;64(19):539–2015. Rhee CJ, Kobler KK, Brady KM, et al. Detection of neurologic injury using vascular reactivity monitoring and glial fibrillary acidic protein. Pediatrics . 2013;131:e950–e954. Shein SL, Ferguson NM, Kochanek PM, et al. Effectiveness of pharmacological therapies for intracranial hypertension in children with severe traumatic brain injury—results from an automated data collection system time-synched to drug administration. Pediatr Crit Care Med . 2016;17:236–245. Smith RL, Lin JC, Adelson PD, et al. Relationship between hyperglycemia and outcome in children with severe traumatic brain injury. Pediatr Crit Care Med . 2012;13:85–91. Tasker RC, Vonberg FW, Ulano ED, Akhondi-Asl A. Updating evidence for using hypothermia in pediatric severe traumatic brain injury: conventional and bayesian meta-analytic perspectives. Pediatr Crit Care Med . 2017;18(4):355–362. The Lancet. The burden of traumatic brain injury in children. Lancet . 2018;391:813. Vavilala M, Lee LA, Lam AM. The lower limit of cerebral autoregulation in children during sevoflurane anesthesia. J Neurosurg Anesthesiol . 2003;15:307–312. Watson HI, Shepherd AA, Rhodes JKJ, Andrews PJD. Revisited: a systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Crit Care Med . 2018;46(6):972–979. Welch TP, Wallendorf MJ, Kharasch ED, et al. Fentanyl and

midazolam are ineffective in reducing episodic intracranial hypertension in severe pediatric traumatic brain injury. Crit Care Med . 2016;44:809–818.

CHAPTER 86

Brain Death K. Jane Lee, Binod Balakrishnan

Brain death is the irreversible cessation of all functions of the entire brain, including the brainstem. It is also known as death by neurologic criteria and is legally accepted as death in the United States.

Epidemiology In children, brain death usually develops after traumatic brain injury (TBI, including brain injury from nonaccidental trauma) or asphyxial injury. Pathogenesis is multifactorial, with the end result being irreversible loss of brain and brainstem function.

Clinical Manifestations and Diagnosis Current guidelines do not apply to preterm infants 20 mm Hg above baseline is a sufficient stimulus. Apnea is clinically confirmed through the apnea test. Because the apnea test has the potential to destabilize the patient, it is performed only if the 1st 2 criteria for brain death (irreversible coma and absence of brainstem reflexes) are already confirmed. The apnea test assesses the function of the medulla in driving ventilation. It is performed by first ensuring appropriate hemodynamics and temperature (>35°C) and the absence of apnea-producing drug effects or significant metabolic derangements. The patient is then preoxygenated with 100% oxygen for approximately 10 min, and ventilation is adjusted to achieve a PaCO 2 of approximately 40 mm Hg. A baseline arterial blood gas (ABG) result documents

the starting values. During the test, oxygenation can be maintained with 100% oxygen via a T -piece attached to the endotracheal tube or via a resuscitation bag such as a Mapleson device. Throughout the test, the child's hemodynamics and pulse oximetry oxygen-hemoglobin saturation (SpO 2 ) are monitored while the physician observes for respiratory efforts. An ABG sample is obtained approximately 10 min into the test and every 5 min thereafter until the target PaCO 2 is surpassed; ventilatory support is resumed at that time. If at any point during the test the patient becomes hypoxic (SpO 2 20 mm Hg above baseline is consistent with brain death.

Observation Periods To determine brain death in the United States, the findings must remain consistent for 2 examinations performed by different attending physicians (apnea testing may be performed by the same physician) separated by an observation period. The 1st exam determines that the child has met the criteria for brain death, whereas the 2nd exam confirms brain death based on an unchanged and irreversible condition. Recommended observation periods are 24 hr for neonates from 37 wk gestation to term infants 30 days old, and 12 hr for infants and children >30 days old. An observation period of 24-48 hr before initiation of brain death assessment is recommended after CPR or severe acute brain injury.

Ancillary Studies Ancillary studies are not required for the diagnosis of brain death unless the clinical examination including the apnea test cannot be safely or reliably completed. Examples include cervical spinal cord injury, presence of high therapeutic or supratherapeutic levels of sedative medications, or hemodynamic instability or SpO 2 desaturation during an apnea test. Ancillary studies may also be used to shorten the recommended observation period. In this case, 2 complete clinical examinations, including apnea test, should be carried out and documented along with the ancillary study. Ancillary studies are no substitute for the neurologic examination.

The 2 most widely used ancillary tests are EEG and radionuclide CBF studies. A valid electroencephalogram to support suspected brain death must be performed according to the American EEG Society standards and technical requirements, under conditions of normothermia and appropriate hemodynamics, and in the absence of drug levels sufficient to suppress the EEG response. An EEG that demonstrates electrocerebral silence over a 30 min recording time under these conditions supports the diagnosis of brain death. Advantages of this study are its wide availability and low risk. Disadvantages include potential confounders, such as artifact in the tracing and the presence of suppressing levels of drugs such as barbiturates. A radionuclide cerebral blood flow study consists of intravenous (IV) injection of a radiopharmaceutical agent followed by imaging of the brain to look for cerebral uptake. As with EEG, nuclear medicine scans are widely available and low risk. Unlike EEG, radionuclide CBF studies are not affected by drug levels. A study that shows absence of uptake in the brain demonstrates absence of CBF and is supportive of brain death. Four-vessel intracranial contrast angiography was previously used as the definitive ancillary test, but practical technical difficulties and risks have led to the use of nuclear medicine scans instead. Interpretation of both EEG and radionuclide CBF studies should be done by appropriately trained and qualified individuals. If the studies show electrical activity or presence of CBF, brain death cannot be declared. A 24 hr waiting period is recommended before repeating the clinical examination or ancillary study.

Documentation Documentation is an important aspect of diagnosing brain death. Complete documentation should include statements of the following: 1. Etiology and irreversibility of the coma. 2. Absence of confounding factors: hypothermia, hypotension, hypoxia, significant metabolic derangement, and significant drug levels. 3. Absence of motor response to noxious stimulation. 4. Absence of brainstem reflexes: pupillary light reflex, oculocephalic/oculovestibular reflex, corneal reflex, cough reflex, and

gag reflex. 5. Absence of respiratory effort in response to an adequate stimulus; ABG values should be documented at the start and end of the apnea test.

Supportive Care Following a diagnosis of brain death, supportive care may continue for hours to days as the family makes decisions about potential organ donation and comes to terms with the diagnosis. A diagnosis of brain death may not be accepted by the family for personal, religious, or cultural reasons. It is important for care providers to be patient and supportive of the family dealing with this difficult situation.

Objections to the Idea of Brain Death Although the concept of brain death is widely accepted and very useful in facilitating organ transplantation, it is not accepted by all. Several countries do not recognize brain death, and some individuals, both medical personnel and laypeople, object to the idea of brain death. It has been pointed out that some patients who meet brain death criteria continue to show evidence of integrative functioning, such as control over freewater homeostasis (absence of diabetes insipidus), control of temperature regulation, capacity for growth and wound healing, and variability of heart rate and blood pressure in response to stimulus. Along with scientific arguments, there are also philosophical arguments about what constitutes death and whether a person who lacks function of the brain, but not of the body, is truly dead.

Bibliography American Academy of Pediatrics Task Force on Brain Death in Children. Guidelines for the determination of brain death in children. Pediatrics . 1987;80:298–300. Nakagawa TA, Ashwal S, Mathur M, et al. Guidelines for the determination of brain death in infants and children: an update of the 1987 task force recommendations. Pediatrics .

2011;128:e720–e740.

CHAPTER 87

Syncope Aarti S. Dalal, George F. Van Hare

Syncope is defined as a sudden transient loss of consciousness with inability to maintain postural tone. The most common cause of syncope in the normal pediatric population is neurocardiogenic syncope (vasovagal syncope, fainting). Vasovagal syncope is classically associated with a prodrome that includes diaphoresis, warmth, pallor, or feeling lightheaded and is often triggered by a specific event or situation such as pain, medical procedures, or emotional distress (Table 87.1 ). This type of syncope is characterized by hypotension and bradycardia. Approximately 30–50% of children will have had a fainting episode before 18 yr of age.

Table 87.1

Noncardiac Causes of Syncope Reflex vasodepressor syncope Neurocardiogenic (vasovagal) Emotion (seeing blood) Pain (needle phobia) Miscellaneous situational reflex Tussive Sneeze Exercise, after exercise Swallowing Stretching Defecation Micturition Hair grooming

Valsalva (increased intrathoracic pressure) Trumpet playing Weightlifting Breath-holding spells Systemic illness Hypoglycemia Anemia Infection Hypovolemia, dehydration Adrenal insufficiency Narcolepsy, cataplexy Pulmonary embolism Pheochromocytoma Mastocytosis Ruptured ectopic pregnancy Central nervous system Seizure (atonic, absence, myoclonic-astatic) Stroke, transient ischemic attack Subarachnoid hemorrhage Dysautonomia Myotonic dystrophy Kearns-Sayre syndrome Friedreich ataxia Basilar artery migraine Drug effects β-Blocking agents Vasodilating agents Opiates Sedatives Drugs prolonging QT interval Diuretics Anticonvulsant agents Antihistamines Antidepressant agents Anxiolytic agents Drugs of abuse Insulin, oral hypoglycemic agents

Carbon monoxide Other etiologies Carotid sinus sensitivity Subclavian steal Panic attack, anxiety Conversion disorder Most patients with a vasovagal syncope episode will have prodromal features followed by loss of motor tone. Once in a horizontal position, consciousness returns rapidly, in 1-2 min; some patients may have 30 sec of tonic-clonic motor activities, which should not be confused with a seizure (Table 87.2 ). Syncope must also be distinguished from vertigo and ataxia (Table 87.3 ). Table 87.2 Comparison of Clinical Features of Syncope and Seizures FEATURES Relation to posture Time of day Precipitating factors Skin color Diaphoresis Aura or premonitory symptoms Convulsion Other abnormal movements Injury

SYNCOPE Common Diurnal Emotion, injury, pain, crowds, heat, exercise, fear, dehydration, coughing, micturition Pallor Common Long

SEIZURES No Diurnal or nocturnal Sleep loss, drug/alcohol withdrawal Cyanosis or normal Rare Brief

Rare, brief Minor twitching

Common Rhythmic jerks

Rare

Common (with convulsive seizures) Common Can occur with convulsive seizures Common Common Occasional No Common

Urinary incontinence Tongue biting

Rare No

Postictal confusion Postictal headache Focal neurologic signs Cardiovascular signs Abnormal findings on EEG

Rare No No Common (cardiac syncope) Rare (generalized slowing may occur during the event)

From Bruni J: Episodic impairment of consciousness. In Daroff RB, Jankovic JM, Mazziotta JC, Pomeroy SL, editors: Bradley's neurology in clinical practice, ed 7, Philadelphia, 2016, Elsevier.

Table 87.3

Syncope and Dizziness Patient complaint

VERTIGO “My head is spinning.” “The room is whirling.”

Associated Motion, swaying, features spinning, nystagmus

Usual cause

Vestibular disorders

PRESYNCOPE “I feel I might pass out.” “I feel faint.” “I feel like blacking out.” Syncope: loss of postural tone, brief loss of consciousness Situational Impaired cerebral perfusion

Key Peripheral Neurocardiogenic (vagal) differential (labyrinthine-cochlear) vs cardiac syncope vs diagnoses vs central neurologic neuropsychiatric syncope disorder

DISEQUILIBRIUM LIGHTHEADEDNESS “I feel unsteady.” “I feel dizzy.” “My balance is “I feel disconnected, off.” drugged.”

Poor balance No vertigo or ataxia Sensory and/or central neurologic dysfunction Sensory deficit vs central neurologic disease

Anxiety, hyperventilation, paresthesias, respiratory alkalosis, panic attacks Anxiety and/or depressive disorders Anxiety/depression vs hyperventilation vs medication effects

From Cohen G: Syncope and dizziness. In Nelson pediatric symptom-based diagnosis, Philadelphia, 2018, Elsevier (Table 6.1, p 84).

Although this type of syncope is very common in adolescence and has an excellent prognosis, other causes for loss of consciousness are more dangerous; thus syncope may be the first sign of more serious conditions (Table 87.4 ). Indeed, the occurrence of syncope may well be the pediatrician's best opportunity to diagnose a life-threatening condition before the patient subsequently succumbs. The task of the clinician, therefore, is not only to counsel the family and the patient concerning the common form, but also to rule out a number of important life-threatening cardiac problems.

Table 87.4

Life-Threatening Cardiac Causes as Risk With Syncope Long QT syndromes (congenital and drug induced) Short QT syndromes Cardiomyopathies Hypertrophic cardiomyopathy Dilated cardiomyopathy Arrhythmogenic right ventricular dysplasia Brugada syndrome

Catecholaminergic polymorphic ventricular tachycardia Myocarditis Lyme myocarditis Chagas disease Wolff-Parkinson-White syndrome Coronary artery anomalies Late postoperative arrhythmias Adult congenital heart patients Congenital or acquired complete atrioventricular block Aortic, mitral, or pulmonic valve stenosis Primary pulmonary hypertension Eisenmenger syndrome Dissecting aortic aneurysm (Marfan syndrome) Cardiac tumor Pacemaker malfunction Takotsubo cardiomyopathy

Mechanisms Syncope by whatever mechanism is caused by a lack of adequate cerebral blood flow with loss of consciousness and inability to remain upright. Primary cardiac causes of syncope (Table 87.4 ) include arrhythmias such as long QT syndrome (LQTS), Wolff-Parkinson-White syndrome (particularly with atrial fibrillation), ventricular tachycardia (VT), and occasionally supraventricular tachycardia (see Chapter 462 ). VT may be associated with hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy, repaired congenital heart disease, or a genetic cause such as catecholaminergic polymorphous ventricular tachycardia (CPVT). Other arrhythmias that may lead to syncope are bradyarrhythmias such as sinus node dysfunction and high-grade second- or third-degree atrioventricular (AV) block. Patients with congenital complete AV block may present with syncope. Syncope may also be caused by cardiac obstructive lesions, such as critical aortic stenosis, or coronary artery anomalies, such as an aberrant left coronary artery arising from the right sinus of Valsalva. Patients with primary pulmonary hypertension or Eisenmenger syndrome may experience syncope. In all the obstructive forms of syncope, exercise increases the likelihood of an episode because the obstruction interferes with the ability of the heart to increased cardiac output in response to exercise.

Noncardiac causes of loss of consciousness include epilepsy, as well as basilar artery migraine, hysterical syncope, and pseudoseizures (see Table 87.1 ). Occasionally, patients with narcolepsy may present with syncope. Hypoglycemia and hyperventilation may also present as syncope.

Evaluation The most important goal in the evaluation of the new patient with syncope is to diagnose life-threatening causes of syncope so that these causes can be managed. Many patients presenting with sudden cardiac arrest caused by conditions such as LQTS will have previously experienced an episode of syncope, so the presentation with syncope is an opportunity to prevent sudden death. The most important tool in evaluation is a careful history . The characteristics of cardiac syncope differ significantly from the prodrome seen in neurocardiogenic syncope (Table 87.5 ). Several red flags can be identified that should lead the clinician to suspect that the mechanism is a life-threatening cardiac cause rather than simple fainting (Table 87.6 ). The occurrence during exercise suggests an arrhythmia or coronary obstruction. Injury because of an episode of syncope indicates sudden occurrence with a lack of adequate prodromal symptoms and suggests an arrhythmia. The occurrence of syncope while recumbent would be quite unusual in a patient with neurocardiogenic syncope and therefore suggests a cardiac or neurologic cause. Occasionally, a patient with syncope caused by a tachyarrhythmia will report the sensation of a racing heart before the event, but this is unusual. Table 87.5

Differentiating Features for Causes of Syncope NEUROCARDIOGENIC Symptoms after prolonged motionless standing, sudden unexpected pain, fear, or unpleasant sight, sound, or smell; pallor Syncope in a well-trained athlete after exertion (without heart disease) Situational syncope during or immediately after micturition, cough, swallowing, or defecation Syncope with throat or facial pain (glossopharyngeal or trigeminal neuralgia) ORGANIC HEART DISEASE (PRIMARY ARRHYTHMIA, OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY, PULMONARY HYPERTENSION) Brief sudden loss of consciousness, no prodrome, history of heart disease Syncope while sitting or supine Syncope with exertion History of palpitations

Family history of sudden death NEUROLOGIC Seizures: preceding aura, post event symptoms lasting > 5 min (includes postictal state of decreased level of consciousness, confusion, headache or paralysis) Migraine: syncope associated with antecedent headaches with or without aura OTHER VASCULAR Carotid sinus: syncope with head rotation or pressure on the carotid sinus (as in tumors, shaving, tight collars) Orthostatic hypotension: syncope immediately on standing especially after prolonged bed rest DRUG INDUCED Patient is taking a medication that may lead to long QT syndrome, orthostasis, or bradycardia PSYCHIATRIC ILLNESS Frequent syncope, somatic complaints, no heart disease

From Cohen G: Syncope and dizziness. In Kliegman RM, Lye PS, Bordini BJ, et al, editors: Nelson pediatric symptom-based diagnosis. Philadelphia, 2018, Elsevier, Table 6.4.

Table 87.6

Red Flags in Evaluation of Patients With Syncope Syncope with activity or exercise or supine Syncope not associated with prolonged standing Syncope precipitated by loud noise or extreme emotion Absence of presyncope or lightheadedness Family history of syncope, drowning, sudden death, familial ventricular arrhythmia syndromes,* cardiomyopathy Syncope requiring CPR Injury with syncope Anemia Other cardiac symptoms Chest pain Dyspnea Palpitations History of cardiac surgery History of Kawasaki disease Implanted pacemaker Abnormal physical examination Murmur Gallop rhythm Loud and single second heart sound Systolic click

Increased apical impulse (tachycardia) Irregular rhythm Hypo- or hypertension Clubbing Cyanosis

* Long QT syndrome, Brugada syndrome, catecholamine polymorphic

ventricular tachycardia, arrhythmogenic right ventricular dysplasia. A careful family history is essential in evaluation of syncope. Specifically, if there are first-degree relatives with inherited syndromes, such as a LQTS or HCM, this should lead to more specific evaluation of the patient. Also, if relatives died suddenly at a young age without a clear and convincing cause, inherited cardiac arrhythmias or cardiomyopathies should also be suspected. Patients with a history of heart disease, especially cardiac repair, may have causes that are specific to their repair. Sinus node dysfunction is common after the Senning or Mustard procedure for transposition of the great vessels. VT may be seen after repair of tetralogy of Fallot. A patient with a history of septal defect repair should be evaluated for the late occurrence of AV block, and patients with an implanted pacemaker should be evaluated for pacemaker lead failure. The physical examination may also offer clues (Table 87.6 ). Patients with HCM may have a prominent cardiac impulse and/or an ejection murmur, as will patients with aortic stenosis. The patient with primary pulmonary hypertension will have a loud and single second heart sound and may also have an ejection click and the murmur of pulmonary insufficiency. Scars from prior cardiac surgery and pacemaker implantation would be evident. All patients presenting with a first episode of syncope must have an electrocardiogram obtained, looking primarily for QT interval prolongation, preexcitation, ventricular hypertrophy, T-wave abnormalities, and conduction abnormalities. Other tests that may be needed depending on the results of the initial evaluation may include echocardiography, exercise testing, cardiac MRI, or 24 hr Holter monitoring. In patients for whom there is a strong suspicion of a paroxysmal arrhythmia, an implantable loop recorder may be the most effective means of diagnosis. Additional tests to look for anemia, hypoglycemia, drugs of abuse, and other etiologies noted in Table 87.1 will be determined by the history

and physical examination.

Treatment Therapy for vasovagal syncope includes avoiding triggering events (if possible), fluid and salt supplementation, and if needed, midodrine (see Chapter 87.1 , Table 87.7 ). Immediately after the event, the patient should remain supine until symptoms abate to avoid recurrence. Table 87.7

First-Line Medications in Treatment of Postural Tachycardia Syndrome (POTS) DRUG Fludrocortisone

Midodrine

MECHANISM OF ACTION Low dose: sensitizes α receptors Higher doses: mineralocorticoid effect α1 -Agonist; produces vasoconstriction

Metoprolol β-Blocker succinate/tartrate

Propranolol

Nonselective β-blocker

Pyridostigmine

Peripheral acetylcholinesterase inhibitor that increases synaptic acetylcholine in autonomic ganglia and at peripheral muscarinic receptors

TREATMENT GUIDELINES Peripheral edema, headache, Monitor basic irritability, hypokalemia, metabolic panel and hypomagnesemia, acne magnesium. Scalp tingling, urinary Monitor supine retention, goose bumps, blood pressure 30headache, supine 60 min after dose. hypertension Worsening of asthma, Use with dizziness, fatigue caution in asthma. If fatigue is severe, use at bedtime. Bradycardia, gastrointestinal Use with caution in symptoms, lightheadedness, diabetes and sleepiness, hypotension, asthma. syncope Symptoms of excessive Very useful if cholinergic activity patient has (diarrhea, urinary POTS and incontinence, salivation) constipation. Use with caution in asthma. Contraindicated in urinary or bowel obstruction.

SIDE EFFECTS

Treatment for cardiac causes of syncope will be determined by the diagnosis. If a reentrant tachycardia (AVNRT, AVRT) is found, then a catheter ablation is

indicated. If bradycardia from AV block was the cause of the syncope, a pacemaker may be warranted. Patients with syncope from medically refractory malignant arrhythmias, as may be seen in HCM, LQTS, arrhythmogenic cardiomyopathy, or CPVT, require an implantable cardioverter-defibrillator. Patients with structural heart disease (valvular disease or coronary artery anomalies) should be referred for surgery.

87.1

Postural Tachycardia Syndrome Gisela G. Chelimsky, Thomas C. Chelimsky

Keywords orthostatic hypotension POTS reflex syncope Several complex and interrelated mechanisms allow humans to stand despite the pull of gravity on the cerebral circulation. In the supine posture, most blood sits in the thoracic cavity, with 25–30% of total volume in the splanchnic vasculature. When an adult stands up, about 500 mL of blood shifts to the lower extremities and to the splanchnic vasculature. The decrease in hydrostatic pressure in the carotid sinuses produces vasoconstriction in the peripheral vessels mediated by sympathetic outflow, as well as in the splanchnic vasculature. This action is mediated by norepinephrine, adenosine triphosphate (ATP), and neuropeptide Y. The muscles in the legs and gluteal area work as a pump when the individual is upright and during exercise, to help return the blood to the heart. Understanding postural tachycardia syndrome (POTS ), or postural orthostatic tachycardia syndrome, requires an understanding of other orthostatic conditions.

Many adolescents have lightheadedness or tunnel vision in the first few seconds of assuming the upright posture. This phenomenon, termed initial orthostatic hypotension (IOH) , can lead to syncope , but usually is very short, perhaps 3060 sec, and occurs primarily with active standing, not passive upright tilt. Blood pressure (BP) may drop 30% of baseline at 10-20 sec of standing and may be associated with tachycardia. BP returns to baseline in 30-60 sec, whereas heart rate (HR) typically returns to a new, higher value above the baseline when supine. Because of its transient rapidity, IOH escapes detection with standard BP machines and requires beat-to-beat monitoring of BP and HR. The clinical diagnosis requires a careful history. The symptoms usually happen after prolonged recumbence and when the individual stands. The person complains of lightheadedness and “blacking out” or tunnel vision 5-10 sec after standing. In contrast to IOH, orthostatic hypotension (OH) is defined as a sustained decrease in the systolic BP of >20 mm Hg or diastolic BP >10 mm Hg in the 1st 3 min of upright tilt. This 2nd type of orthostatic disorder rarely occurs in children. The patient frequently has no orthostatic symptoms while upright despite very low pressures (Fig. 87.1 ). This distinguishes OH from POTS, which requires symptoms while upright. A 3rd orthostatic disorder, reflex syncope (i.e., vasovagal or neurally mediated), is defined as relatively sudden change in autonomic nervous system activity that leads to a sudden decrease in BP, HR, and cerebral perfusion (Fig. 87.2 ).

FIG. 87.1 Example of orthostatic hypotension.

FIG. 87.2 Example of neurally mediated syncope.

In children, POTS is defined as a syndrome characterized by HR increase of >40 beats/min during the 1st 10 min of upright tilt test without associated hypotension, (>30 beats/min if >19 yr old) while replicating orthostatic symptoms that occur when upright (Fig. 87.3 ). Improvement of symptoms in the supine position is expected. The diagnosis of POTS also requires daily orthostatic symptoms. In patients with POTS, the larger decline in cardiac stroke volume appears to be the primary trigger for the tachycardia, which may result from various pathophysiologic mechanisms, such as the following:

FIG. 87.3 Example of postural tachycardia syndrome.

◆ Neuropathic POTS, an autonomic neuropathy impairing sympathetic venoconstriction in the lower extremities or splanchnic circulation, decreasing stroke volume, and consequently resulting in a tachycardia ◆ Hypovolemic POTS, a common contributor, often related to decreased aldosterone with reduced renin activity, resulting in a tachycardia caused by decrease blood volume ◆ Hyperadrenergic POTS, with norepinephrine levels rising 3-4–fold in the standing position (norepinephrine normally doubles on standing), which

may occur in norepinephrine transporter deficiency or strong stimulation of central baroreflex responses ◆ Autoimmune POTS, typically assumed based on a postviral chronology, but seldom proven; such a form may or may not exist. The antiganglionic antibody is almost never elevated in these patients. Nonetheless, a group of patients report that intravenous immune globulin (IVIG) is helpful to them. Whether they benefit from the increase in intravascular volume or an actual immune effect is unknown. Some patients have orthostatic symptoms while upright but do not meet criteria for syncope, OH, or POTS. This group has orthostatic intolerance otherwise not specified (OI-NOS) .

Clinical Presentation The symptoms that intrinsically relate to POTS are those that are replicated during upright tilt testing or standing. Many other symptoms also occur in patients with POTS, fitting the description of comorbid conditions, but not reproduced while upright. A patient may have nausea while upright associated with lightheadedness and has a diagnosis of POTS. Another patient may complain of nausea on awakening and have POTS, but has no nausea while upright. In the former patient the nausea is a symptom of POTS itself, whereas in the latter nausea is an associated condition. The symptoms that often directly relate to POTS include lightheadedness, orthostatic nausea, sometimes orthostatic headaches, fatigue, tunnel vision, and brain fog. About 20–30% of pediatric patients with POTS will also have syncope (Fig. 87.4 ). Other comorbid conditions frequently occur in these patients but are not caused by POTS (i.e., not an orthostatic phenomenon). These comorbidities include (1) sleep issues, usually delayed onset of sleep, frequent awakening, and not feeling refreshed in the morning; (2) aches in different parts of the body; (3) abdominal pain; (4) headaches and migraines; (5) nausea and vomiting; and (6) Raynaud

like symptoms and other, less frequent problems (e.g., urinary symptoms).

FIG. 87.4 Example of postural tachycardia syndrome (POTS) followed by a neurally mediated syncope.

The association of upper gastrointestinal (GI) symptoms and POTS are well described. Nausea, early satiety, and bloating are described in association with POTS. Such GI symptoms relate mechanistically to POTS only when they occur in the upright position. Many patients with POTS have comorbid GI symptom that are not a consequence of the orthostatic challenge. Therefore, only the GI symptoms replicated during tilt testing will improve with treatment aimed at orthostasis. Patients with POTS have changes in the electrical activity of the stomach while upright, which may explain the upright GI symptoms; they usually do not have delayed gastric emptying. The emptying is either normal or accelerated, implying that the cause of nausea is not gastroparesis. Patients with hypermobility Ehlers-Danlos syndrome (h-EDS) may have POTS. Typically, such individuals have more migraine and syncope. Joint hypermobility itself in adults is associated with more autonomic complaints such as syncope, presyncope, palpitations, chest discomfort, fatigue, and heat

intolerance. Those with hypermobility have more frequent positive tilt tests than healthy controls. Interestingly, in children, joint hypermobility does not influence the number of comorbidities or autonomic disorders. Similarly, those with pediatric chronic overlapping pain conditions with or without POTS have the same comorbidities, suggesting that neither POTS nor hypermobility are drivers of the comorbidities or the chronic overlapping pain condition, but rather another associated disorder (Chapter 147 ).

Diagnosis Orthostatic intolerance is clinically diagnosed by detailed history attending specifically to symptoms as they relate to body position. Dizziness that begins in the supine position cannot be a manifestation of orthostatic intolerance. Furthermore, those symptoms that do develop while upright should improve or resolve when supine. Importantly, the history should include a detailed description of current physical exercise habits, with frequency, type, and endurance. One should also assess sleep, diet (mainly evaluating intake of salt), fluid intake, and other comorbidities. The physical examination is also important and should include a cardiac and neurologic evaluation with supine and standing BP and HR. Examination of the extremities may provide information about venous pooling, such as mild edema or reddish purple discoloration when sitting or standing. Cold, clammy hands can signify excess sympathetic activity. To diagnose POTS the patient needs to undergo a head-up tilt test for at least 10 min . It is important to have the patient supine for at least 20 min before the tilt test. POTS can also be assessed by a standing test, measuring BP and HR at 1, 3, 5, and 10 min standing, but to have a reliable test similar to the tilt test, the patient needs to be supine for 1 hr before standing. The HR increase with active standing is typically less than with tilt, because the lower-extremity muscle pump is less active in tilt. The diagnosis of POTS requires replication of the dayto-day symptoms while upright, not just the increased HR while upright. A small but significant proportion of healthy teenagers in school will have an increased HR that may be diagnosed as POTS but will not have associated symptoms. Other tests may include electrocardiogram, echocardiogram, and Holter monitor when there is concern of a primary cardiac cause of tachycardia, or if there is a need to determine if symptoms correlate with tachycardia (see Chapter 87). Supine and standing plasma catecholamines help confirm the diagnosis of POTS, as one expects to see either the normal doubling of norepinephrine levels

from supine to standing, or a tripling with hyperadrenergic POTS. Beyond tilt table testing, autonomic testing will also include cardiac response to deep breathing (checking cardiac parasympathetic function), Valsalva maneuver (checking cardiac sympathetic and parasympathetic functions and vasomotor sympathetic function), and quantitative axon reflex sudomotor test (to assess for an autonomic neuropathy and vasomotor sympathetic dysfunction). Additional studies depend on the clinical symptoms and include morning cortisol (to rule out Addison disease) and hypo- or hyperthyroid studies if the patient has unusually severe fatigue or is not responsive to usual treatment. Serum tryptase and urine methylhistamine are tested if mast cell activation disorder is suspected, based on a history of flushing during the spells. If an autoimmune cause for the POTS is a concern, antibodies such as voltage-gated potassium channel and acetylcholine receptor antibodies could be checked, but this etiology for POTS is being questioned. Patients rarely (80 oz of fluids daily and to add 2 g of salt to usual diet in both the morning and the early afternoon. Salt supplementation increases plasma and blood volume, improves orthostatic tolerance, and decreases baroreflex sensitivity. Salt also reduces nitric oxide production, resulting in less vasodilation. Trial and error of different salt formulation can help to identify the best method for each individual patient. Salt tablets are simple and inexpensive but may make some people nauseous. An alternative is simply to obtain empty capsules on the internet and fill them with table salt. A “0” size capsule contains about 400 mg of salt. The content of sodium in the body determines the extracellular fluid volume that in turn dictates orthostatic tolerance. Patients with POTS who have lower urinary sodium excretion have more symptoms than those with higher urinary sodium (> 123 mmol/24 hr), and they often respond less well to salt supplementation. Those with severe orthostatic symptoms either in the morning or before sports should drink 16 oz of plain water, which is known to increase sympathetic response mainly in individuals with baroreflex dysregulation. The effect starts soon after drinking the water and lasts for about 1 hr. Compression garments may also be useful. These can be thigh or waist high; the waist-high compression garments may not be tolerated. Medications can be added when the nonpharmacologic interventions are not insufficient (). Different centers use different strategies, and there is no single correct evidence-based approach. Table 87.3 addresses first-line medications that primary care physicians could use; only the most common side effects are included.

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Bibliography Al Dhahri KN, Potts JE, Chiu CC, et al. Are implantable loop recorders useful in detecting arrhythmias in children with unexplained syncope? Pacing Clin Electrophysiol . 2009;32:1422–1427. Anderson JB, Czosek RJ, Cnota J, et al. Pediatric syncope: national hospital ambulatory medical care survey results. J Emerg Med . 2012;43:575–583. Dovgalyuk J, Holstege C, Mattu A, et al. The electrocardiogram in the patient with syncope. Am J Emerg Med . 2007;25:688– 701. Evans WN, Acherman R, Kip K, et al. Hair-grooming syncope in children. Clin Pediatr (Phila) . 2009;48:834–836. Frangini PA, Cecchin F, Jordao L, et al. How revealing are insertable loop recorders in pediatrics? Pacing Clin Electrophysiol . 2008;31:338–343. Friedman KG, Alexander ME. Chest pain and syncope in children: a practical approach to the diagnosis of cardiac disease. J Pediatr . 2013;163:896–901. MacCormick JM, Crawford JR, Chung SK, et al. Symptoms and signs associated with syncope in young people with primary cardiac arrhythmias. Heart Lung Circ . 2011;20:593–598. Moodley M. Clinical approach to syncope in children. Semin Pediatr Neurol . 2013;20:12–17. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope. J Am Coll Cardiol . 2017;14(8):e155–e217. Singer W, Sletten DM, Opfer-Gehrking TL, et al. Postural tachycardia in children and adolescents: what is abnormal? J

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CHAPTER 88

Shock David A. Turner, Ira M. Cheifetz

Shock is an acute process characterized by the body's inability to deliver adequate oxygen to meet the metabolic demands of vital organs and tissues. Insufficient oxygen at the tissue level is unable to support normal aerobic cellular metabolism, resulting in a shift to less efficient anaerobic metabolism. As shock progresses, increases in tissue oxygen extraction are unable to compensate for this deficiency in oxygen delivery, leading to progressive clinical deterioration and lactic acidosis. If inadequate tissue perfusion persists, adverse vascular, inflammatory, metabolic, cellular, endocrine, and systemic responses worsen physiologic instability. Compensation for inadequate oxygen delivery involves a complex set of responses that attempt to preserve oxygenation of the vital organs (i.e., brain, heart, kidneys, liver) at the expense of other organs (i.e., skin, gastrointestinal tract, muscles). Of importance, the brain is especially sensitive to periods of poor oxygen supply given its lack of capacity for anaerobic metabolism. Initially, shock is often well compensated, but it may rapidly progress to an uncompensated state requiring more aggressive therapies to achieve clinical recovery. The combination of a continued presence of an inciting trigger and the body's exaggerated and potentially harmful neurohumoral, inflammatory, and cellular responses lead to the progression of shock. Irrespective of the underlying cause of shock, the specific pattern of response, pathophysiology, clinical manifestations, and treatment may vary significantly depending on the specific etiology (which may be unknown), the clinical circumstances, and an individual patient's biologic response to the shock state. Untreated shock causes irreversible tissue and organ injury (i.e., irreversible shock ) and, ultimately, death.

Epidemiology Shock occurs in approximately 2% of all hospitalized infants, children, and adults in developed countries, and the mortality rate varies substantially depending on the etiology and clinical circumstances. Of patients who do not survive, most do not die in the acute hypotensive phase of shock, but rather as a result of associated complications and multiple-organ dysfunction syndrome (MODS). MODS is defined as any alteration of organ function that requires medical support for maintenance, and the presence of MODS in patients with shock substantially increases the probability of death. In pediatrics, educational efforts and the utilization of standardized management guidelines that emphasize early recognition and intervention along with the rapid transfer of critically ill patients to a pediatric intensive care unit (PICU) have led to decreases in the mortality rate for shock (Figs. 88.1 and 88.2 ).

FIG. 88.1 American College of Critical Care Medicine algorithm for time-sensitive, goal-directed stepwise management of hemodynamic support in newborns . Proceed to next step if shock persists. (1) First-hour goals—restore and maintain heart rate thresholds, capillary refill ≤ 2 sec, and normal blood pressure in the 1st hr. (2) Subsequent ICU goals—restore normal perfusion pressure (mean arterial pressure – central venous pressure), preductal and postductal oxygen saturation difference < 5%, and either ScvO 2 > 70% (*except congenital heart patients with mixing lesions), superior vena cava flow > 40 mL/kg/min, or cardiac index > 3.3 L/min/m2 in NICU. (From Davis AL, Carcillo JA, Aneja RK, et al: American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock, Crit Care Med 45:1061–1093, 2017, Fig 4.)

FIG. 88.2 American College of Critical Care Medicine algorithm for time-sensitive, goal-directed stepwise management of hemodynamic support in infants and children . Proceed to next step if shock persists. (1) First-hour goals—restore and maintain heart rate thresholds, capillary refill ≤ 2 sec, and normal blood pressure in the 1st hr/emergency department. (2) Subsequent ICU goals—if shock not reversed, proceed to restore and maintain normal perfusion pressure (MAP – CVP) for age, ScvO 2 > 70% (*except congenital heart patients with mixing lesions), and cardiac index > 3.3 and < 6.0 L/min/m2 in PICU. (From Davis AL, Carcillo JA, Aneja RK, et al: American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock, Crit Care Med 45:1061–1093, 2017, Fig 2.)

Types of Shock Shock classification systems generally define 5 major types of shock:

hypovolemic, cardiogenic, distributive, obstructive, and septic (Table 88.1 ). Hypovolemic shock , the most common cause of shock in children worldwide, is most frequently caused by diarrhea, vomiting, or hemorrhage. Cardiogenic shock is seen in patients with congenital heart disease (before or after surgery, including heart transplantation) or those with congenital or acquired cardiomyopathies, including acute myocarditis. Obstructive shock stems from any lesion that creates a mechanical barrier that impedes adequate cardiac output, which includes pericardial tamponade, tension pneumothorax, pulmonary embolism, and ductus-dependent congenital heart lesions. Distributive shock is caused by inadequate vasomotor tone, which leads to capillary leak and maldistribution of fluid into the interstitium. Septic shock is often discussed synonymously with distributive shock, but the septic process usually involves a more complex interaction of distributive, hypovolemic, and cardiogenic shock. Table 88.1

Types of Shock HYPOVOLEMIC Decreased preload secondary to internal or external losses

CARDIOGENIC Cardiac pump failure secondary to poor myocardial function

POTENTIAL ETIOLOGIES Blood loss: Congenital heart hemorrhage disease Plasma loss: burns, Cardiomyopathies: nephrotic infectious or syndrome acquired, dilated Water/electrolyte or restrictive loss: vomiting, Ischemia diarrhea Arrhythmias

DISTRIBUTIVE SEPTIC Abnormalities of Encompasses multiple vasomotor tone forms of shock from loss of venous Hypovolemic: third and arterial spacing of fluids into capacitance the extracellular, interstitial space Distributive: early shock with decreased afterload Cardiogenic: depression of myocardial function by endotoxins Anaphylaxis Neurologic: loss of sympathetic vascular tone secondary to spinal cord or brainstem injury Drugs

Pathophysiology

OBSTRUCTIVE Decreased cardiac output secondary to direct impediment to right- or left-sided heart outflow or restriction of all cardiac chambers

Bacterial Tension Viral pneumothorax Fungal Pericardial tamponade (immunocompromised Pulmonary embolism patients are at Anterior mediastinal increased risk) masses Critical coarctation of aorta

An initial insult triggers shock, leading to inadequate oxygen delivery to organs and tissues. Compensatory mechanisms attempt to maintain blood pressure (BP) by increasing cardiac output and systemic vascular resistance (SVR). The body also attempts to optimize oxygen delivery to the tissues by increasing oxygen extraction and redistributing blood flow to the brain, heart, and kidneys at the expense of the skin and gastrointestinal (GI) tract. These responses lead to an initial state of compensated shock in which BP is maintained. If treatment is not initiated or is inadequate during this period, decompensated shock develops, with hypotension and tissue damage that may lead to multisystem organ dysfunction and, ultimately, death (Tables 88.2 and 88.3 ). Table 88.2

Criteria for Organ Dysfunction ORGAN CRITERIA FOR DYSFUNCTION SYSTEM Cardiovascular Despite administration of isotonic intravenous fluid bolus ≥60 mL/kg in 1 hr: decrease in BP (hypotension) systolic BP 2× upper limit of normal Oliguria: urine output 5 sec Core-to-peripheral temperature gap: >3°C (5.4°F) Respiratory PaO 2 /FIO 2 ratio 65 torr or 20 mm Hg over baseline PaCO 2 or Need for >50% FIO 2 to maintain saturation ≥92% or Need for nonelective invasive or noninvasive mechanical ventilation Neurologic GCS score ≤11 or Acute change in mental status with decrease in GCS score ≥3 points from abnormal baseline Hematologic Platelet count 1.5 or Activated prothrombin time >60 sec Renal Serum creatinine >0.5 mg/dL, ≥2× upper limit of normal for age, or 2-fold increase in baseline creatinine value

Hepatic

Total bilirubin ≥4 mg/dL (not applicable for newborn) Alanine transaminase level 2× upper limit of normal for age

BP, Blood pressure; FIO 2 , fraction of inspired oxygen; GCS, Glasgow Coma Scale; INR, international normalized ratio; PaCO 2 , arterial partial pressure of carbon dioxide; PaO 2 , partial pressure arterial oxygen; SD, standard deviations.

Table 88.3

Signs of Decreased Perfusion ORGAN SYSTEM ↓ PERFUSION Central nervous — system Respiration — Metabolism — Gut Kidney

Skin Cardiovascular system

↓↓ PERFUSION Restless, apathetic, anxious ↑ Ventilation Compensated metabolic acidemia ↓ Motility Oliguria (96 hr) Rapid effect Risk of increased intracranial pressure Can lead to hypotension Risk of apnea

Load 50 Phosphodiesterase inhibitor—slows µg/kg cyclic adenosine monophosphate over 15 breakdown min 0.5-1.0 µg/kg/min

For patients with obstructive shock , fluid resuscitation may be briefly temporizing in maintaining cardiac output, but the primary insult must be

immediately addressed. Examples of lifesaving therapeutic interventions for such patients are pericardiocentesis for pericardial effusion, pleurocentesis or chest tube placement for pneumothorax, thrombectomy/thrombolysis for pulmonary embolism, and the initiation of a prostaglandin infusion for ductusdependent cardiac lesions. There is often a last-drop phenomenon associated with some obstructive lesions, in that small additional amounts of intravascular volume depletion may lead to a rapid deterioration, including cardiac arrest, if the obstructive lesion is not corrected. Regardless of the etiology of shock, metabolic status should be meticulously maintained (see Table 88.8 ). Electrolyte levels should be monitored closely and corrected as needed. Hypoglycemia is common and should be promptly treated. Neonates and infants in particular may have profound glucose dysregulation in association with shock. Glucose levels should be checked routinely and treated appropriately, especially early in the course of illness. Hypocalcemia, which may contribute to myocardial dysfunction, should be treated with a goal of normalizing the ionized calcium concentration. There is no evidence that supranormal calcium levels benefit the myocardium, and hypercalcemia may be associated with increased myocardial toxicity. Adrenal function is another important consideration in shock, and hydrocortisone replacement may be beneficial. Up to 50% of critically ill patients may have absolute or relative adrenal insufficiency. Patients at risk for adrenal insufficiency include those with congenial adrenal hypoplasia, abnormalities of the hypothalamic-pituitary axis, and recent therapy with corticosteroids (including those with asthma, rheumatic diseases, malignancies, and inflammatory bowel disease). These patients are at high risk for adrenal dysfunction and should receive stress doses of hydrocortisone. Corticosteroids may also be considered in patients with shock that is unresponsive to fluid resuscitation and catecholamines. Although a subset of pediatric septic shock patients may benefit from treatment with hydrocortisone, currently available pediatric data do not demonstrate an overall survival benefit in patients with shock treated with hydrocortisone. Determination of baseline cortisol levels before corticosteroid administration may be beneficial in guiding therapy, although this approach remains controversial.

Considerations for Continued Therapy After the 1st hr of therapy and attempts at early reversal of shock, focus on goal-

directed end-points should continue in an intensive care setting (see Figs. 88.1 and 88.2 and Table 88.8 ). Clinical end-points serve as global markers for organ perfusion and oxygenation. Laboratory parameters such as SvO 2 (or ScvO2 ), serum lactate concentration, cardiac index, and hemoglobin serve as adjunctive measures of tissue oxygen delivery. Hemoglobin should be generally maintained at 10 g/dL, SvO 2 (or ScvO2 ) >70%, and cardiac index at 3.3-6.0 L/min/m2 to optimize oxygen delivery in the acute phase of shock. It is important to note that cardiac index is rarely monitored in the clinical setting because of the limited use of pulmonary artery catheters and lack of accurate noninvasive cardiac output monitors for infants and children. Blood lactate levels and calculation of base deficit from arterial blood gas values are very useful markers for the adequacy of oxygen delivery. These traditional markers are indicators of global oxygen utilization and delivery. There is increasing use of measures of local tissue oxygenation, including near-infrared spectroscopy of the cerebrum, flank, or abdomen. Respiratory support should be used as clinically appropriate. When shock leads to ARDS requiring mechanical ventilation, lung-protective strategies to keep plateau pressure 94%. Although no studies have formally assessed its use in pediatric patients, anecdotal reports have demonstrated efficacy of acetazolamide in treating mild AMS in this population. AMS that becomes worse or does not respond to maintenance of altitude, rest, and pharmacologic intervention after 48 hr mandates descent. Descent (500-1,000 m, ~1,600-3,300 ft) is effective treatment for all forms of altitude illness and should be tailored to the individual response. The presence of neurologic abnormalities (ataxia or altered mentation) or evidence of pulmonary edema (dyspnea at rest) mandates descent because these signs indicate a progression of AMS to severe altitude illness.

High-Altitude Cerebral Edema The incidence of HACE is very low and practically unheard of below 4,000 m (~13,100 ft), but it is rapidly fatal if unrecognized. Generally seen in adults with prolonged stays above 4,000 m, HACE is usually associated with concurrent AMS or HAPE but can occur on its own. HACE is regarded as the extreme expression of the same pathophysiology underlying AMS. The etiology is believed to be secondary to increased cerebral blood flow leading to increased intracranial pressure (ICP). Cerebral venous congestion caused by compression and/or elevated central venous pressure may be an underappreciated mechanism of the increased ICP. In patients with HACE, MRI reveals white matter changes consistent with vasogenic edema that correlate with symptoms; evidence of cytotoxic edema has also been described. HACE is frequently preceded by AMS, but it is differentiated from severe AMS by the presence of neurologic signs , most often ataxia and altered mental status, including confusion, progressive decrease in responsiveness, and eventually coma. Less common signs are focal cranial nerve palsies, motor and

sensory deficits, and seizures. The CT scan is consistent with edema and increased ICP. MRI shows a high T2 signal in the white matter, specifically in the splenium of the corpus callosum, with diffusion-weighted technique. Descent remains the most effective treatment for HACE. If available, supplemental oxygen is useful, especially when descent is not possible or delayed. Portable hyperbaric treatment is beneficial, but its use should not delay descent. Dexamethasone should be administered at a dose of 0.15 mg/kg orally every 6 hr. The few children reported with mild cases of HACE have recovered with dexamethasone and descent.

High-Altitude Pulmonary Edema Epidemiology and Risk Factors HAPE is a noncardiogenic pulmonary edema caused by intense pulmonary vasoconstriction and subsequent high capillary pressure, secondary to hypoxia, resulting in altered permeability of the alveolocapillary membrane and the extravasation of intravascular fluid into the extravascular space of the lung. HAPE is the deadliest of the high-altitude illnesses ; its reported incidence is 0.5%, without an underlying predisposition, and typically requires recent ascent above 3,000 m. The development of HAPE depends on genetic factors typically affecting pulmonary vasoreactivity, rate of ascent, altitude achieved, and time spent at that altitude. Among children, HAPE occurs in 2 distinct settings. Type I HAPE (or simply HAPE) occurs in a child who resides at low altitude who travels to high altitude. Type II HAPE (also termed reentry or reascent HAPE) affects children who reside at high altitude but become ill on their return home after descent to lower altitudes. HAPE may also occur in children who develop acute respiratory illnesses that exacerbate hypoxia at high altitude. Fatal outcomes of HAPE in children have been reported. Most mild and moderate cases resolve without difficulty; however, if unrecognized and untreated, rapid progression to death can occur, especially when infection or cardiac conditions complicate the illness. HAPE affects male and female children more equally than adults, among whom the observed male predominance appears to result from strenuous sport activities and military assignments. The occurrence and even the pathophysiology of HAPE may vary by population and genetic background. Individuals of Tibetan ancestry, resident on the Himalayan plateau and having

minimal admixture with other populations, represent the extreme of adaptation to high altitude and rarely experience HAPE. Other native populations residing at high altitude, such as Andeans, do not appear to be protected from HAPE, and certain populations may have genetic polymorphisms associated with pulmonary edema. A number of conditions may predispose a child to HAPE (Table 90.2 ). Preexisting viral respiratory infections have been linked to HAPE, especially in children. Cardiorespiratory conditions associated with pulmonary hypertension, such as atrial and ventricular septal defects, pulmonary vein stenosis, congenital absence of a pulmonary artery, and OSA, also predispose to HAPE. Down syndrome is a risk factor for HAPE development, as are previously repaired congenital heart defects and the presence of hypoplastic lungs. Undiagnosed structural cardiopulmonary abnormalities may result in severe hypoxia and/or altitude illness once ascent occurs.

Table 90.2

Conditions Associated With Increased Risk of High-Altitude Pulmonary Edema (HAPE) Environmental Ascent above 2,500 m (~8,200 ft) Rapid rate of ascent (generally >1,000 m [~3,300 ft] per day) Cold exposure

Cardiac Anomalies causing increased pulmonary blood flow or increased pulmonary artery pressure Ventricular septal defect, atrial septal defect, patent foramen ovale, patent ductus arteriosus Anomalous pulmonary venous return or pulmonary vein stenosis Unilateral absent pulmonary artery or isolated pulmonary artery of ductal origin Coarctation of the aorta Congestive heart failure

Pulmonary Chronic lung disease Bronchopulmonary dysplasia Pulmonary hypoplasia Supplemental oxygen requirement at sea level Pulmonary hypertension Perinatal respiratory distress Persistent pulmonary hypertension of the newborn Perinatal asphyxia or depression Sleep apnea

Infectious Upper respiratory tract infection Bronchitis/bronchiolitis Pneumonitis Otitis media

Pharmacologic Any medication causing central nervous system and respiratory depression Alcohol Sympathomimetics

Systemic Down syndrome (trisomy 21) History of premature birth or low birthweight

Pathophysiology Alveolar hypoxia results in vasoconstriction of pulmonary arterioles just proximal to the alveolar capillary bed. Hypoxic pulmonary vasoconstriction is a normal physiologic response to optimize ventilation/perfusion (V̇/Q̇) matching

by redistributing regional pulmonary blood flow to areas of highest ventilation, thereby optimizing arterial oxygenation. Under conditions that result in widespread alveolar hypoxia, extensive pulmonary vasoconstriction will lead to significant elevations in pulmonary arterial pressure; uneven pulmonary vasoconstriction can result in localized overperfusion, increased capillary pressures, distention, and leakage in the remaining vessels. This explains the patchy and heterogeneous edema that is classically observed in HAPE. The combination of pulmonary hypertension and uneven pulmonary vasoconstriction appears to be necessary in the pathogenesis of HAPE. Children and adolescents acutely exposed to high-altitude hypoxia demonstrated pulmonary hypertension, with increases in pulmonary artery pressure inversely related to age. Once the vascular leak occurs and alveolar fluid accumulates, a defect in transepithelial sodium transport impairs the clearance of alveolar fluid and contributes to HAPE.

Diagnosis The diagnosis of HAPE is based on clinical findings and their evolution in the context of recent ascent from lower elevation. There is no single diagnostic test or constellation of laboratory findings. Symptoms usually develop within 24-96 hr, with onset of symptoms the 1st or 2nd night at altitude, when hypoxia may be exacerbated during sleep. HAPE generally is not observed beyond 5 days after ascent to altitude (unless additional ascent occurs) because pulmonary vascular remodeling and acclimatization have taken place. The minimum criteria to diagnose HAPE include recent exposure to altitude, dyspnea at rest, radiographic evidence of alveolar infiltrates, and near-complete resolution of both clinical and radiographic signs within 48 hr after descent or institution of oxygen therapy. Portable ultrasound is useful to diagnose HAPE through the finding of comet tails , artifacts created by microreflections of the ultrasound beam within interlobular septa thickened by interstitial and alveolar edema. Frequently, patients first exhibit general malaise that may progress to more specific signs of dyspnea at rest, then cardiopulmonary distress. In preverbal toddlers and infants, HAPE may manifest as worsening respiratory distress over 1-2 days, pallor, depressed consciousness, increased fussiness, decreased playfulness, crying, decreased appetite, poor sleep, and sometimes vomiting. Young children may show agitation and general debility. Older children and adolescents may complain of headache and orthopnea and present with cough,

dyspnea not relieved by rest or out of proportion to effort, and production of frothy, rust-colored sputum. Physical exam findings include tachypnea, cyanosis, elevated jugular venous pressure, and diffuse crackles on lung auscultation. Dyspnea at rest, orthopnea, cyanosis, tachycardia, and chest pain herald worsening compromise, which may advance within hours to production of pinktinged sputum. Findings on physical examination frequently are less severe than the patient's chest radiograph and hypoxemia on pulse oximetry would predict. Children often appear pale, with or without visible cyanosis. Low-grade fever (6 yr old because of the ultrarapid metabolizers of codeine into morphine. For anxiety,

lorazepam is given on a consistent schedule, 0.05-0.1 mg/kg/dose every 6-8 hr. To control pain during a procedure (dressing change or debridement), oral morphine, (0.3-0.6 mg/kg) is given 1-2 hr before the procedure, supplemented by a morphine IV bolus (0.05-0.1 mg/kg) given immediately before the procedure. Lorazepam, 0.04 mg/kg, is given orally or intravenously, if necessary, for anxiety before the procedure. Midazolam is also very useful for conscious sedation at a dose of 0.01-0.02 mg/kg for nonintubated patients and 0.05-0.1 mg/kg for intubated patients, as an IV infusion or bolus, and may be repeated in 10 min. During the process of weaning from analgesics, the dose of oral opiates is reduced by 25% over 1-3 days, sometimes with the addition of acetaminophen as opiates are tapered. When weaning off antianxiety medications, the approach involves reducing the dose of benzodiazepines, at 25–50% per dose, daily over 1-3 days. Risperidone, up to 2.5 mg/day, is being used in children with severe burns. For ventilated patients, pain control is accomplished by using morphine sulfate intermittently as an IV bolus at 0.05-0.1 mg/kg every 2 hr. Doses may need to be increased gradually, and some children may need continuous infusion; a starting dose of 0.05 mg/kg/hr as an infusion is increased gradually as the need of the child changes. Naloxone is rarely needed but should be immediately available to reverse the effect of morphine, if necessary; if needed for an airway crisis, it should be given in a dose of 0.1 mg/kg up to a total of 2 mg, either intramuscularly or intravenously. For patients undergoing assisted respiration who require treatment of anxiety, midazolam is used as an intermittent IV bolus (0.04 mg/kg by slow push every 4-6 hr) or as a continuous infusion. For intubated patients, opiates do not need to be discontinued during the process of weaning from the ventilator. Benzodiazepine should be reduced to approximately half the dose over 24-72 hr before extubation; too-rapid weaning from a benzodiazepine can lead to seizures. There is a growing use of psychotropic medication in the care of children with burns, including prescription of selective serotonin reuptake inhibitors as antidepressants, the use of haloperidol as a neuroleptic in the critical care setting, and the treatment of PTSD with benzodiazepines. Conscious sedation using ketamine or propofol may be used for major dressing changes.

Reconstruction and Rehabilitation To ensure maximum cosmetic and functional outcome, occupational and

physical therapy must begin on the day of admission, continue throughout hospitalization, and for some patients, continue after discharge. Physical rehabilitation involves body and limb positioning, splinting, exercises (active and passive movement), assistance with activities of daily living, and gradual ambulation. These measures maintain adequate joint and muscle activity with as normal a range of movement as possible after healing or reconstruction. Pressure therapy is necessary to reduce hypertrophic scar formation; a variety of prefabricated and custom-made garments are available for use in different body areas. These custom-made garments deliver consistent pressure on scarred areas, shorten the time of scar maturation, and decrease scar thickness, redness, and associated itching. Continued adjustments to scarred areas (scar release, grafting, rearrangement) and multiple minor cosmetic surgical procedures are necessary to optimize long-term function and improve appearance. Replacement of areas of alopecia and scarring has been achieved with the use of tissueexpander techniques. The use of ultrapulse laser for reduction of scarring is an adjunct in scar management.

School Reentry and Long-Term Outcome It is best for the child to return to school immediately after discharge. Occasionally, a child may need to attend a few half-days (because of rehabilitation needs). It is important for the child to return to the normal routine of attending school and being with peers. Planning for a return to home and school often requires a school reentry program that is individualized to each child's needs. For a school-age child, planning for the return to school occurs simultaneously with planning for discharge. The hospital schoolteacher contacts the local school and plans the program with the school faculty, nurses, social workers, recreational/child-life therapists, and rehabilitation therapists. This team should work with students and staff to ease anxiety, answer questions, and provide information. Burns and scars evoke fears in those who are not familiar with this type of injury and can result in a tendency to withdraw from or reject the burned child. A school reentry program should be appropriate to a child's development and changing educational needs. Major advances have made it possible to save the lives of children with massive burns. Although some children have had lingering physical difficulties, most have a satisfactory quality of life. The comprehensive burn care that includes experienced multidisciplinary aftercare plays an important role in

recovery. Table 92.8 lists the long-term disabilities and complications of burns.

Table 92.8

Common Long-Term Complications and Disabilities in Patients With Burn Injuries Complications Affecting the Skin and Soft Tissue Hypertrophic scars Susceptibility to minor trauma Dry skin Contractures Itching and neuropathic pain Alopecia Chronic open wounds Skin cancers

Orthopedic Disabilities Amputations Contractures Heterotopic ossification Temporary reduction in bone density

Metabolic Disabilities Heat sensitivity Obesity

Psychiatric and Neurologic Disabilities Sleep disorders Adjustment disorders Posttraumatic stress disorder Depression

Body image issues Neuropathy and neuropathic pain Long-term neurologic effects of carbon monoxide poisoning Anoxic brain injury

Long-Term Complications of Critical Care Deep vein thrombosis, venous insufficiency, or varicose veins Tracheal stenosis, vocal cord disorders, or swallowing disorders Renal or adrenal dysfunction Hepatobiliary or pancreatic disease Cardiovascular disease Reactive airway disease or bronchial polyposis

Preexisting Disabilities That Contributed to the Injuries Risk-taking behavior Untreated or poorly treated psychiatric disorder Modified from Sheridan RL, Schultz JT, Ryan CM, et al: Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 62004: a 35-year-old woman with extensive, deep burns from a nightclub fire, N Engl J Med 350:810–821, 2004.

Electrical Burns There are 3 types of electrical burns: extension cord (minor), high-tension wire, and lightning. Minor electrical burns usually occur as a result of biting on an extension cord. These injuries produce localized burns to the mouth, which usually involve the portions of the upper and lower lips that come in contact with the extension cord. The injury may involve or spare the corners of the mouth. Because these are nonconductive injuries (do not extend beyond the site of injury), hospital admission is not necessary, and care is focused on the area of the injury visible in the mouth, ensuring it is low voltage and does not cause entry or exit wounds or cardiac issues. Treatment with topical antibiotic creams

is sufficient until the patient is seen in a burn unit outpatient department or by a plastic surgeon. A more serious category of electrical burn is the high-tension electrical wire burn , for which children must be admitted for observation, regardless of the extent of the surface area burn. Deep muscle injury is typical and cannot be readily assessed initially. These injuries result from high voltage (>1,000 V) and occur particularly at high-voltage installations, such as electric power stations or railroads; children climb an electric pole and touch an electric box out of curiosity or accidentally touch a high-tension electrical wire. Such injuries have a mortality rate of 3–15% for children who arrive at the hospital for treatment. Survivors have a high rate of morbidity, including major limb amputations. Points of entry of current through the skin and the exit site show characteristic features consistent with current density and heat. The majority of entrance wounds involve the upper extremity, with small exit wounds in the lower extremity. The electrical path, from entrance to exit, takes the shortest distance between the 2 points and may produce injury in any organ or tissue in the path of the current. Multiple exit wounds in some patients attest to the possibility of several electrical pathways in the body, placing virtually any structure in the body at risk (Table 92.9 ). Damage to the abdominal viscera, thoracic structures, and the nervous system (confusion, coma, paralysis) in areas remote from obvious extremity injury occurs and must be sought, particularly in injuries with multiple current pathways or those in which the victim falls from a high pole. Sometimes an ignition occurs and results in concurrent flame burn and clothing fire. Cardiac abnormalities , manifested as ventricular fibrillation or cardiac arrest, are common; patients with high-tension electrical injury need an initial electrocardiogram and cardiac monitoring until they are stable and have been fully assessed. Higher-risk patients have abnormal electrocardiographic findings and a history of loss of consciousness. Renal damage from deep muscle necrosis and subsequent myoglobinuria is another complication; such patients need forced alkaline diuresis to minimize renal damage. Soft tissue (muscle) injury of an extremity may produce a compartment syndrome . Aggressive removal of all dead and devitalized tissue, even with the risk of functional loss, remains the key to effective management of the electrically damaged extremity. Early debridement facilitates early closure of the wound. Damaged major vessels must be isolated and buried in a viable muscle to prevent exposure. Survival depends on immediate intensive care; functional result depends on long-term care and delayed reconstructive surgery.

Table 92.9

Electrical Injury: Clinical Considerations SYSTEM General

Cardiac

Pulmonary

Renal

Neurologic

Cutaneous/oral

CLINICAL MANIFESTATIONS —

MANAGEMENT Extricate the patient. Perform ABCs of resuscitation; immobilize the spine. Obtain history: voltage, type of current. Obtain complete blood count with platelets, electrolytes, BUN, creatinine, and glucose. Dysrhythmias: asystole, ventricular fibrillation, sinus Treat dysrhythmias. tachycardia, sinus bradycardia, premature atrial contractions, Provide cardiac monitor, premature ventricular contractions, conduction defects, atrial electrocardiogram, and fibrillation, ST-T wave changes radiographs with suspected thoracic injury. Perform creatinine phosphokinase with isoenzyme measurements if indicated. Respiratory arrest, acute respiratory distress, aspiration Protect and maintain the syndrome airway. Provide mechanical ventilation if indicated, chest radiograph, and arterial blood gas levels. Acute kidney injury, myoglobinuria Provide aggressive fluid management unless central nervous system injury is present. Maintain adequate urine output, >1 mL/kg/hr. Consider central venous or pulmonary artery pressure monitoring. Measure urine myoglobin; perform urinalysis; measure BUN, creatinine. Immediate: loss of consciousness, motor paralysis, visual Treat seizures. disturbances, amnesia, agitation; intracranial hematoma Provide fluid restriction if indicated. Secondary: pain, paraplegia, brachial plexus injury, syndrome of Consider spine radiographs inappropriate antidiuretic hormone secretion, autonomic and MRI, especially cervical. disturbances, cerebral edema Delayed: paralysis, seizures, headache, peripheral neuropathy Perform CT or MRI scan of the brain if indicated. Oral commissure burns, tongue and dental injuries; skin burns Search for the entrance resulting from ignition of clothes, entrance and exit burns, and and exit wounds. arc burns Treat cutaneous burns; determine patient's

tetanus status. Obtain consultation for plastic surgery of ear, nose, and throat, if indicated. Electrical burns to mouth could include oral commissures and Ensure no entry or exit lips; low-voltage electrical burns secondary to high conductivity wounds and no cardiac of saliva involvement. Confirm all injuries are localized. Management is observation until eschar sloughs off and granulation tissue fills in. Obtain plastic surgeon evaluation after first healing, usually with scar formation. Abdominal Viscus perforation and solid-organ damage; ileus; abdominal Place nasogastric tube if injury rare without visible abdominal burns patient has airway compromise or ileus. Obtain serum ALT, AST, amylase, BUN, and creatinine measurements and CT scans as indicated. Musculoskeletal Compartment syndrome from subcutaneous necrosis limb edema Monitor patient for possible and deep burns compartment syndrome. Long-bone fractures, spine injuries Obtain radiographs and orthopedic/general surgery consultations as indicated. Ocular Visual changes, optic neuritis, cataracts, extraocular muscle Obtain an ophthalmology paresis consultation as indicated.

AST, Aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen. Adapted from Hall ML, Sills RM: Electrical and lightning injuries. In Barkin RM, editor: Pediatric emergency medicine, St Louis, 1997, Mosby, p 484.

Lightning burns occur when a high-voltage current directly strikes a person (most dangerous) or when the current strikes the ground or an adjacent (incontact) object. A step voltage burn is observed when lightning strikes the ground and travels up one leg and down the other (the path of least resistance). Lightning burns depend on the current path, the type of clothing worn, the presence of metal, and cutaneous moisture. Entry, exit, and path lesions are possible; the prognosis is poorest for lesions of the head or legs. Internal organ injury along the path is common and does not relate to the severity of the cutaneous burn. Linear burns, usually 1st or 2nd degree, are in the locations where sweat is present. Feathering, or an arborescent pattern, is characteristic of lightning injury. Lightning may ignite clothing or produce serious cutaneous burns from heated metal in the clothing. Internal complications of lightning burns include cardiac arrest caused by asystole, transient hypertension,

premature ventricular contractions, ventricular fibrillation, and myocardial ischemia. Most severe cardiac complications resolve if the patient is supported with CPR (see Chapter 81 ). CNS complications include cerebral edema, hemorrhage, seizures, mood changes, depression, and paralysis of the lower extremities. Rhabdomyolysis and myoglobinuria (with possible renal failure) also occur. Ocular manifestations include vitreous hemorrhage, iridocyclitis, retinal tearing, or retinal detachment.

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Greene MA. Comparison of the characteristics of fire and nonfire households in the 2004–2005 survey of fire department– attended and unattended fires. Inj Prev . 2012;18:170–175. Hart DW, Wolf SE, Ramzy PI, et al. Anabolic effects of oxandrolone after severe burn. Ann Surg . 2001;233:556–564. Hermanns-Clausen M, Weinmann W, Auwarter V, et al. Drug dosing error with drops: severe clinical course of codeine intoxication in twins. Eur J Pediatr . 2009;168:819–824. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med . 2001;345:1223–1229. Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lancet . 2004;363:1895–1902. Hohlfeld J, de Buys Roessingh A, Hiti-Burri N, et al. Tissue engineered fetal skin constructs for paediatric burns. Lancet . 2006;366:840–842. Jeschke MG, Herndon DN. Burns in children: standard and new treatments. Lancet . 2014;383:1168–1176. Juurlink DN, Buckley NA, Stanbrook MB, et al. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev . 2005;(1) [CD002041]. Kai-Yang L, Zhao-Fan X, Luo-Man Z, et al. Epidemiology of pediatric burns requiring hospitalization in China: a literature review of retrospective studies. Pediatrics . 2008;122:132– 142. Kelly LE, Rieder M, van den Anker J, et al. More codeine fatalities after tonsillectomy in north American children. Pediatrics . 2012;129(5):e1343–e1347. Kraft R, Herndon DN, Al-Mousawi AM, et al. Burn size and survival probability in paediatric patients in modern burn care: a prospective observational cohort study. Lancet . 2012;379:1013–1020. Lowell G, Quinlan K, Gottleib LJ. Preventing unintentional

scald burns: moving beyond tap water. Pediatrics . 2008;122:799–804. Monstrey S, Hoeksema H, Verbelen J, et al. Assessment of burn depth and burn wound healing potential. Burns . 2008;34:761–769. Musgrave MA, Fingland R, Gomez M, et al. The use of inhaled nitric oxide as adjuvant therapy in patients with burn injuries and respiratory failure. J Burn Care Rehabil . 2000;21:551– 557. Niazi ZB, Essex TJ, Papini R, et al. New laser doppler scanner, a valuable adjunct in burn depth assessment. Burns . 1993;19:485–489. Orgill DP. Excision and skin grading of thermal burns. N Engl J Med . 2009;360:893–900. Porter C, Tompkins RG, Finnerty CC, et al. The metabolic stress response to burn trauma: current understanding and therapies. Lancet . 2016;388:1417–1426. Prelack K, Dylewski M, Sheridan RL. Practical guidelines for nutritional management of burn injury and recovery. Burns . 2007;33:14–24. Sanghavi P, Bhalla K, Das V. Fire-related deaths in India in 2001: a retrospective analysis of data. Lancet . 2009;373:1282–1288. Sheridan RL, Hinson M, Liang MH, et al. Long-term outcomes of children surviving massive burns. JAMA . 2000;283:69– 73. Sheridan RL. Fire-related inhalation injury. N Engl J Med . 2016;375(5):464–469. Sheridan RL. Thermal injuries. McInerny TK, Adam HM, Campbell DE. American academy of pediatrics pediatric textbook of pediatric care . American Academy of Pediatrics: Elk Grove Village, IL; 2008. Singer AJ, Dagum AB. Current management of acute cutaneous

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Useful Links www.ameriburn.org . www.cpsc.gov . www.safekids.org .

CHAPTER 93

Cold Injuries Alia Y. Antoon

The involvement of children and youth in snowmobiling, mountain climbing, winter hiking, and skiing places them at risk for cold injury. Cold injury may produce either local tissue damage, with the injury pattern depending on exposure to damp cold (frostnip, immersion foot, or trench foot), dry cold (which leads to local frostbite), or generalized systemic effects (hypothermia).

Pathophysiology Ice crystals may form between or within cells, interfering with the sodium pump, and may lead to rupture of cell membranes. Further damage may result from clumping of red blood cells or platelets, causing microembolism or thrombosis. Blood may be shunted away from an affected area by secondary neurovascular responses to the cold injury; this shunting often further damages an injured part while improving perfusion of other tissues. The spectrum of injury ranges from mild to severe and reflects the result of structural and functional disturbance in small blood vessels, nerves, and skin.

Etiology Body heat may be lost by conduction from wet clothing or contact with metal or other solid conducting objects, convection from wind chill, evaporation, or radiation . Susceptibility to cold injury may be increased by dehydration, alcohol or drug use, impaired consciousness, exhaustion, hunger, anemia, impaired circulation from cardiovascular disease, and sepsis; very young or older persons also are more susceptible. Certain medications may contribute to

hypothermia, whereas others may cause reduced metabolism or clearance during hypothermia (Table 93.1 ).

Table 93.1

Drugs Displaying Reduced Metabolism or Clearance in Hypothermia Atropine Digoxin Fentanyl Gentamicin Lidocaine Phenobarbital Procaine Propranolol Sulfanilamide (AVC cream) Succinylcholine D -Tubocurarine Adapted from Bope ET, Kellerman RD, editors: Conn's current therapy 2014 , Philadelphia, 2014, Elsevier/Saunders (Box 3, p 1135). Hypothermia occurs when the body can no longer sustain normal core temperature by physiologic mechanisms, such as vasoconstriction, shivering, muscle contraction, and nonshivering thermogenesis. When shivering ceases, the body is unable to maintain its core temperature; when the body core temperature falls to 12,000 genes. Information focuses on the relationship between phenotype and genotype. Genetic Testing Registry. A resource that provides information on individual genes, genetic tests, clinical laboratories, and medical conditions. This resource also provides access to GeneReviews, a collection of expert-authored reviews on a variety of genetic disorders. Genetics Home Reference. A resource that provides consumer-friendly information about the effects of genetic variations on human health. National Human Genome Research Institute. A resource for information about human genetics and ethical issues. Human Gene Mutation Database. A searchable index of all described mutations in human genes with phenotypes and references. DECIPHER. A database designed to aid physicians in determining the potential consequences of chromosomal deletions and duplications.

WEB ADDRESS www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov/omim

www.ncbi.nlm.nih.gov/gtr/

www.ghr.nlm.nih.gov www.genome.gov www.hgmd.cf.ac.uk http://decipher.sanger.ac.uk

Database of Genomic Variants. A database of chromosomal alterations seen in normal controls. Gene Letter . An online magazine of genetics. American Society of Human Genetics American College of Medical Genetics

http://dgv.tcag.ca/dgv/app/home www.geneletter.com www.ashg.org www.acmg.net

The Burden of Genetic Disorders in Childhood Medical problems associated with genetic disorders can appear at any age, with the most obvious and serious problems typically manifesting in childhood. It has been estimated that 53/1,000 children and young adults can be expected to have diseases with an important genetic component. If congenital anomalies are included, the rate increases to 79/1,000. In 1978 it was estimated that just over half of admissions to pediatric hospitals were for a genetically determined condition. By 1996, because of changes in healthcare delivery and a greater understanding of the genetic basis of many disorders, that percentage rose to 71%, in one large pediatric hospital in the United States, with 96% of chronic disorders leading to admission having an obvious genetic component or being influenced by genetic susceptibility. Major categories of genetic disorders include single-gene, genomic, chromosomal, and multifactorial conditions. Individually, each single-gene disorder is rare, but collectively they represent an important contribution to childhood disease. The hallmark of a single-gene disorder is that the phenotype is overwhelmingly determined by changes that affect an individual gene. The phenotypes associated with single-gene disorders can vary from one patient to another based on the severity of the change affecting the gene and additional modifications caused by genetic, environmental, and stochastic factors. This feature of genetic disease is termed variable expressivity . Common single-gene disorders include sickle cell anemia and cystic fibrosis. Some identifiable syndromes and diseases can be caused by more than one gene (e.g., Noonan syndrome by RAF1, NF1, NRAS, PTPN11, SOS1, SOS2, KRAS, BRAF, SOC2, LZTR1, and RIT1 ). In addition, mutations affecting a single gene may produce different phenotypes (e.g., SCN5A and Brugada syndrome, long QT syndrome 3, dilated cardiomyopathy, familial atrial fibrillation, and congenital sick sinus syndrome). Single-gene disorders tend to occur when changes in a gene have a profound

effect on the quantity of the gene product produced, either too much or too little, or the function of the gene product, either a loss of function or a harmful gain of function. Single-gene disorders can be caused by de novo sequence changes that are not found in the unaffected parents of the affected individual, or they may be caused by inherited changes. When a single-gene disorder is known to be caused by changes in only 1 gene, or a small number of individual genes, searching for deleterious changes is most often performed by directly sequencing that gene and, in some cases, looking for small deletions and/or duplications. When multiple genes can cause a particular disorder, it is sometimes more efficient and cost-effective to screen large numbers of disease-causing genes using a diseasespecific panel that takes advantage of next-generation sequencing technology than to screen genes individually. When such panels are not available, or when the diagnosis is in question, physicians may consider screening the proteincoding regions of all genes by whole exome sequencing (WES) on a clinical basis. In many circumstances, WES is less expensive than sequencing multiple individual genes. In the future, whole genome sequencing , in which an individual's entire genome is sequenced, may become a valid clinical option as the cost of such tests fall and our ability to interpret the clinical consequences of the thousands of changes identified in such tests improves (see Chapter 94 ). The risk of having a child with a particular single-gene disorder can vary from one population to another. In some cases, this is the result of a founder effect , in which a specific change affecting a disease-causing gene becomes relatively common in a population derived from a small number of founders. This high frequency is maintained when there is relatively little interbreeding with persons outside that population because of social, religious, or physical barriers. This is the case for Tay-Sachs disease in Ashkenazi Jews and French Canadians. Other changes may be subject to positive selection when found in the heterozygous carrier state. In this case, individuals who carry a single copy of a genetic change (heterozygotes ) have a survival advantage over noncarriers. This can occur even when individuals who inherit 2 copies of the change (homozygotes ) have severe medical problems. This type of positive selection is evident among individuals in sub-Saharan Africa who carry a single copy of a hemoglobin mutation that confers relative resistance to malaria but causes sickle cell anemia in homozygotes. Genomic disorders are a group of diseases caused by alterations in the genome, including deletions (copy number loss), duplications (copy number gain), inversions (altered orientation of a genomic region), and chromosomal

rearrangements (altered location of a genomic region). Contiguous gene disorders are caused by changes that affect 2 or more genes that contribute to the clinical phenotype and are located near one other on a chromosome. DiGeorge syndrome, which is caused by deletions of genes located on chromosome 22q11, is a common example. Some genomic disorders are associated with distinctive phenotypes whose pattern can be recognized clinically. Other genomic disorders do not have a distinctive pattern of anomalies but can cause developmental delay, cognitive impairment, structural birth defects, abnormal growth patterns, and changes in physical appearance. Fluorescent in situ hybridization (FISH) can provide information about the copy number and location of a specific genomic region. Array-based copy number detection assays can be used to screen for chromosomal deletions (large and small) and duplications across the genome, but do not provide information about the orientation or location of genomic regions. A chromosome analysis (karyotype ) can detect relatively large chromosomal deletions and duplications and can also be useful in identifying inversions and chromosomal rearrangements even when they are copy number neutral changes that do not result in a deletion or duplication of genomic material. Deletions, duplications, and chromosomal rearrangements that affect whole chromosomes, or large portions of a chromosome, are typically referred to as chromosomal disorders . One of the most common chromosomal disorders is Down syndrome, most often associated with the presence of an extra copy, or trisomy , of an entire chromosome 21. When all or a part of a chromosome is missing, the disorder is referred to as monosomy . Translocations are a type of chromosomal rearrangement in which a genomic region from one chromosome is transferred to a different location on the same chromosome or on a different (nonhomologous) chromosome. Translocations can be balanced, meaning that no genetic material has been lost or gained, or they can be unbalanced, in which some genetic material has been deleted or duplicated. In some cases, only a portion of cells that make up a person's body are affected by a single-gene defect, a genomic disorder, or a chromosomal defect. This is referred to as mosaicism and indicates that the individual's body is made up of 2 or more distinct cell populations. Polygenic disorders are caused by the cumulative effects of changes or variations in more than 1 gene. Multifactorial disorders are caused by the cumulative effects of changes or variations in multiple genes and/or the combined effects of both genetic and environmental factors. Spina bifida and

isolated cleft lip or palate are common birth defects that display multifactorial inheritance patterns. Multifactorial inheritance is seen in many common pediatric disorders, such as asthma and diabetes mellitus. These traits can cluster in families but do not have a mendelian pattern of inheritance (see Chapter 97 ). In these cases the genetic changes or variations that are contributing to a particular disorder are often unknown, and genetic counseling is based on empirical data.

The Changing Paradigm of Genetics in Medicine Genetic testing is increasingly available for a wide variety of both rare and relatively common genetic disorders. Genetic testing is typically used in pediatric medicine to resolve uncertainty regarding the underlying etiology of a child's medical problems and provides a basis for improved genetic counseling and possibly a specific therapy. Even in cases where a specific treatment is not available, identifying a genetic cause can aid physicians in providing individuals and family with accurate prognostic and recurrence risk information and usually helps to relieve unfounded feelings of guilt and stem the tide of misdirected blame. Genetic tests will ultimately come to underlie a high proportion of medical decisions and will be seamlessly incorporated into routine medical care. Although most genetic testing is presently aimed at identifying or confirming a diagnosis, in the future, genetic testing may find wider application as a means of determining if an individual is predisposed to develop a particular disease. Another area in which genetic testing could make a significant impact is on individualized drug treatment. It has long been known that genetic variation in the enzymes involved in drug metabolism underlies differences in the therapeutic effect and toxicity of some drugs. As the genetic changes that underlie these variations are identified, new genetic tests are being developed that allow physicians to tailor treatments based on individual variations in drug metabolism, responsiveness, and susceptibility to toxicity (see Chapter 72 ). It is likely that the expansion of such testing will depend, at least in part, on the extent to which such tests can be linked to strategies to prevent disease or improve outcome (see Chapter 94 ). As such links are made, we will enter into a new era of personalized medical treatment.

Long-standing and highly successful carrier screening programs have existed for disorders such as Tay-Sachs disease and many other rare, single-gene disorders that are prevalent in specific populations. Couples are usually offered screening for a variety of conditions, in part based on ancestry (Tay-Sachs disease, hemoglobinopathies, cystic fibrosis). Couples found to be at increased risk for such disorders can be offered preconception or prenatal testing aimed at detecting specific disease-causing mutations. Prenatal screening is routinely offered for chromosomal disorders such as trisomy 13, trisomy 18, and Down syndrome. An increasing number of pregnancies affected by these and other genetic disorders are being recognized by noninvasive screening tests targeting fetal cell-free DNA in maternal blood and by fetal ultrasound. When genetic disorders are suspected, chorionic villus sampling at 10-12 wk of gestation or amniocentesis at 16-18 wk of gestation can provide material for genetic testing. When a couple are at risk for a specific genetic defect, preimplantation genetic diagnosis can sometimes be used to select unaffected early embryos, which are then implanted as part of an in vitro fertilization procedure. Although prenatally obtained genetic material can be used to identify singlegene disorders, genomic disorders, and chromosomal anomalies, the information obtained on any pregnancy depends on the tests that are ordered. It is important that physicians select the most appropriate prenatal tests, and that couples understand the limitations of these tests. No amount of genetic testing can guarantee the birth of a healthy child. Specific treatments are not available for the majority of genetic disorders, although some important exceptions exist (Chapter 94 ). Inborn errors of metabolism were the first genetic disorders to be recognized, and many are amenable to treatment by dietary manipulation (see Chapter 102 ). These conditions result from genetically determined deficiency of specific enzymes, leading to the buildup of toxic substrates and/or deficiency of critical end products. Individual metabolic disorders tend to be very rare, but their combined impact on the pediatric population is significant. Tandem mass spectrometry has made it relatively inexpensive to screen for a large number of these disorders in the newborn period. Use of this technology not only dramatically increases the number of metabolic disorders identified within a population, but also allows treatment to be initiated at a much earlier stage in development. Another area showing progress in genetic therapies is the treatment of

lysosomal storage disorders (see Chapter 104.4 ). These metabolic diseases are caused by defects in lysosomal function. Lysosomes are cellular organelles that contain specific digestive enzymes. Some of these disorders that were characterized by early lethal or intractable chronic illness can now be treated using specially modified enzymes administered by intravenous infusion. These enzymes are taken up by cells and incorporated into lysosomes. Conditions such as Gaucher disease and Fabry disease are routinely treated using enzyme replacement , and similar therapies are being developed for other lysosomal disorders. Therapeutic advances are also being made in the treatment of nonmetabolic genetic disorders. Improvements in surgical techniques and intensive care medicine are extending the survival of children with life-threatening birth defects such as congenital diaphragmatic hernia and severe cardiac defects. In many cases the life expectancy of children with debilitating genetic disorders is also increasing. For example, in cystic fibrosis, improvements in nutrition and the management of chronic pulmonary disease allow an increasing percentage of affected patients to survive into adulthood, creating a need to transition care from pediatric to adult providers. Gene replacement therapies have long been anticipated and are starting to show some benefit (see Chapter 94 ). Stem cell–based therapies have also been touted as a potential treatment for a number of intractable disorders, but clear evidence that such therapies are effective has yet to materialize.

Ethics Issues As with all medical care, genetic testing, diagnosis, and treatment should be performed confidentially . Nothing is as personal as one's genetic information, and all efforts should be made to avoid any stigma for the patient. Many people worry that results of genetic testing will put them, or their child, at risk for genetic discrimination. Genetic discrimination occurs when people are treated unfairly because of a difference in their DNA that suggests they have a genetic disorder or they are at an increased risk of developing a certain disease. In the United States the Genetic Information Nondiscrimination Act of 2008 protects individuals from genetic discrimination at the hands of health insurers and employers, but does not extend protection against discrimination from providers of life, disability, or long-term care insurance. As in all medical decision-making, the decisions about genetic testing should

be based on a careful evaluation of the potential benefits and risks. In the pediatric setting, these decisions may be more difficult because physicians and parents are often called on to make decisions for a child who cannot directly participate in discussions about testing. Molecular diagnostic tests are often used to diagnose malformation syndromes, cognitive delay, or other disabilities in which there is a clear benefit to the child. In other cases, such as genetic testing for susceptibility to adult-onset diseases, it is appropriate to wait until the child or adolescent is mature enough to weigh the potential risks and benefits and make his or her own decisions about genetic testing. Policies regarding genetic testing of children have been developed collaboratively by the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG; Pediatrics 131[3]:620–622, 2013). These recommendations are outlined next. General Recommendations 1. Decisions about whether to offer genetic testing and screening should be driven by the best interest of the child. 2. Genetic testing is best offered in the context of genetic counseling. Genetic counseling can be performed by clinical geneticists, genetic counselors, or any other health care provider with appropriate training and expertise. AAP and ACMG support the expansion of educational opportunities in human genomics and genetics for medical students, residents, and practicing pediatric primary care providers. Diagnostic Testing 3. In a child with symptoms of a genetic condition, the rationale for genetic testing is similar to that of other medical diagnostic evaluations. Parents or guardians should be informed about the risks and benefits of testing, and their permission should be obtained. Ideally, and when appropriate, the assent of the child should be obtained. 4. When performed for therapeutic purposes, pharmacogenetic testing of children is acceptable, with permission of parents or guardians and, when appropriate, the child's assent. If a pharmacogenetic test result carries implications beyond drug targeting or dose responsiveness, the broader implications should be discussed before testing. Newborn Screening 5. AAP and ACMG support the mandatory offering of newborn screening for all children. After education and counseling about the substantial

benefits of newborn screening, its remote risks, and the next steps in the event of a positive screening result, parents should have the option of refusing the procedure, and an informed refusal should be respected. Carrier Testing 6. AAP and ACMG do not support routine carrier testing in minors when such testing does not provide health benefits in childhood. The AAP and ACMG advise against school-based testing or screening programs, because the school environment is unlikely to be conducive to voluntary participation, thoughtful consent, privacy, confidentiality, or appropriate counseling about test results. 7. For pregnant adolescents or for adolescents considering reproduction, genetic testing and screening should be offered as clinically indicated, and the risks and benefits should be explained clearly. Predictive Genetic Testing 8. Parents or guardians may authorize predictive genetic testing for asymptomatic children at risk of childhood-onset conditions. Ideally, the assent of the child should be obtained. 9. Predictive genetic testing for adult-onset conditions generally should be deferred unless an intervention initiated in childhood may reduce morbidity or mortality. An exception might be made for families for whom diagnostic uncertainty poses a significant psychosocial burden, particularly when an adolescent and the parents concur in their interest in predictive testing. 10. For ethical and legal reasons, healthcare providers should be cautious about providing predictive genetic testing to minors without the involvement of their parents or guardians, even if a minor is mature. Results of such tests may have significant medical, psychological, and social implications, not only for the minor but also for other family members. Histocompatibility Testing 11. Tissue compatibility testing of minors of all ages is permissible to benefit immediate family members but should be conducted only after thorough exploration of the psychosocial, emotional, and physical implications of the minor serving as a potential stem cell donor. A donor advocate or similar mechanism should be in place from the outset to avert coercion and safeguard the interests of the child. Adoption

12. The rationale for genetic testing of children in biological families should apply for adopted children and children awaiting placement for adoption. If a child has a known genetic risk, prospective adoptive parents must be made aware of this possibility. In rare cases, it may be in a child's best interest to undergo predictive genetic testing for a known risk before adoption, to ensure the child's placement with a family capable of and willing to accept the child's potential medical and developmental challenges. In the absence of such indications, genetic testing should not be performed as a condition of adoption. Disclosure 13. At the time of genetic testing, parents or guardians should be encouraged to inform their child of the test results at an appropriate age. Parents or guardians should be advised that, under most circumstances, a request by a mature adolescent for test results should be honored. 14. Results from genetic testing of a child may have implications for the parents and other family members. Healthcare providers have an obligation to inform parents and the child, when appropriate, about these potential implications. Healthcare providers should encourage patients and families to share this information and offer to help explain the results to the extended family or refer them for genetic counseling. 15. Misattributed paternity, use of donor gametes, adoption, or other questions about family relationships may be uncovered “incidentally” whenever genetic testing is performed, particularly when testing multiple family members. This risk should be discussed, and a plan about disclosure or nondisclosure should be in place before testing. Direct-to-Consumer Testing 16. AAP and ACMG strongly discourage the use of direct-to-consumer and home-kit genetic testing of children because of the lack of oversight on test content, accuracy, and interpretation.

Bibliography American Academy of Pediatrics, Committee on Bioethics and Committee on Genetics; American College of Medical Genetics and Genomics, Social, Ethical and Legal Issues Committee. Ethical and policy issues in genetic testing and

screening of children. Pediatrics . 2013;131:620–622. Baird PA, Anderson TW, Newcombe HB, et al. Genetic disorders in children and young adults: a population study. Am J Hum Genet . 1988;42:677–693. Brezina PR, Brezina DS, Kearns WG. Preimplantation genetic testing. BMJ . 2012;345:38–43. Centers for Disease Control and Prevention. CDC Grand rounds: newborn screening and improved outcomes. MMWR Morb Mortal Wkly Rep . 2012;61:390–393. Dauber A, Stoler J, Hechter E, et al. Whole exome sequencing reveals a novel mutation in CUL7 in a patient with an undiagnosed growth disorder. J Pediatr . 2013;162:202–204. Friedman Ross L, Rothstein MA, Wright Clayton E. Mandatory extended searches in all genome sequencing: “incidental findings,” patient autonomy, and shared decision making. JAMA . 2013;310(4):367–368. Greely HT. Banning genetic discrimination. N Engl J Med . 2005;353:865–867. Hahn S, Hösli I, Lapaire O. Non-invasive prenatal diagnostics using next generation sequencing: technical, legal and social challenges. Expert Opin Med Diagn . 2012;6(6):517–528. Hall JG, Powers EK, McLlvaine RT, et al. The frequency and financial burden of genetic disease in a pediatric hospital. Am J Med Genet . 1978;1:417. McCandless SE, Brunger JW, Cassidy SB. The burden of genetic disease on inpatient care in a children's hospital. Am J Hum Genet . 2004;74:121–127. May T, Zusevics KL, Strong KA. On the ethics of clinical whole genome sequencing of children. Pediatrics . 2013;132:207–209. Miller JW. Preliminary results of gene therapy for retinal degeneration. N Engl J Med . 2008;358:2282–2284. Qasim W, Gaspar HB, Thrasher AJ. Update on clinical gene

therapy in childhood. Arch Dis Child . 2007;92:1028–1031. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med . 2010;61:437– 455.

CHAPTER 96

The Human Genome Daryl A. Scott, Brendan Lee

The human genome has approximately 20,000 genes that encode the wide variety of proteins found in the human body. Reproductive or germline cells contain 1 copy (N) of this genetic complement and are haploid , whereas somatic (nongermline) cells contain 2 complete copies (2N) and are diploid . Genes are organized into long segments of deoxyribonucleic acid (DNA ), which, during cell division, are compacted into intricate structures together with proteins to form chromosomes. Each somatic cell has 46 chromosomes: 22 pairs of autosomes , or nonsex chromosomes, and 1 pair of sex chromosomes (XY in a male, XX in a female). Germ cells (ova or sperm) contain 22 autosomes and 1 sex chromosome, for a total of 23. At fertilization, the full diploid chromosome complement of 46 is again realized in the embryo. Most of the genetic material is contained in the cell's nucleus. The mitochondria (the cell's energy-producing organelles) contain their own unique genome. The mitochondrial chromosome consists of a double-stranded circular piece of DNA, which contains 16,568 base pairs (bp) of DNA and is present in multiple copies per cell. The proteins that occupy the mitochondria are produced either in the mitochondria, using information contained in the mitochondrial genome, or are produced outside of the mitochondria, using information contained in the nuclear genome, and then transported into the organelle. Sperm do not usually contribute mitochondria to the developing embryo, so all mitochondria are maternally derived, and a child's mitochondrial genetic makeup derives exclusively from the child's biological mother (see Chapter 106 ).

Fundamentals of Molecular Genetics DNA consists of a pair of chains of a sugar-phosphate backbone linked by

pyrimidine and purine bases to form a double helix (Fig. 96.1 ). The sugar in DNA is deoxyribose. The pyrimidines are cytosine (C) and thymine (T); the purines are guanine (G) and adenine (A). The bases are linked by hydrogen bonds such that A always pairs with T and G with C. Each strand of the double helix has polarity, with a free phosphate at one end (5′) and an unbonded hydroxyl on the sugar at the other end (3′). The 2 strands are oriented in opposite polarity in the double helix.

FIG. 96.1 DNA double helix, with sugar-phosphate backbone and nitrogenous bases. (From Jorde LB, Carey JC, Bamshad MJ, et al, editors: Medical genetics , ed 2, St Louis, 1999, Mosby, p 8.)

The replication of DNA follows the pairing of bases in the parent DNA strand. The original 2 strands unwind by breaking the hydrogen bonds between base pairs. Free nucleotides, consisting of a base attached to a sugar-phosphate chain, form new hydrogen bonds with their complementary bases on the parent strand;

new phosphodiester bonds are created by enzymes called DNA polymerases. Replication of chromosomes begins simultaneously at multiple sites, forming replication bubbles that expand bidirectionally until the entire DNA molecule (chromosome) is replicated. Errors in DNA replication, or mutations induced by environmental mutagens such as irradiation or chemicals, are detected and potentially corrected by DNA repair systems. The central tenet of molecular genetics is that information encoded in DNA, predominantly located in the cell nucleus, is transcribed into messenger ribonucleic acid (mRNA ), which is then transported to the cytoplasm, where it is translated into protein. A prototypical gene consists of a regulatory region, segments called exons that encode the amino acid sequence of a protein, and intervening segments called introns (Fig. 96.2 ).

FIG. 96.2 Flow of information from DNA to RNA to protein for a hypothetical gene with 3 exons and 2 introns. Within the exons, colored regions indicate coding sequences. Steps include transcription, RNA processing and splicing, RNA transport from the nucleus to the cytoplasm, translation, and protein assembly. (From Nussbaum RL, McInnis RR, Willard HF, Hamosh A, editors: Thompson & Thompson genetics in medicine, ed 7, Philadelphia, 2007, Saunders/Elsevier, p 31.)

Transcription is initiated by attachment of ribonucleic acid (RNA ) polymerase to the promoter site upstream of the beginning of the coding sequence. Specific proteins bind to the region to repress or activate transcription by opening up the chromatin , which is a complex of DNA and histone proteins. It is the action of these regulatory proteins (transcription factors ) that determines, in large part, when a gene is turned on or off. Some genes are also turned on and off by methylation of cytosine bases that are adjacent to guanine bases (cytosine-phosphate-guanine bases, CpGs ). Methylation is an example of an epigenetic change, meaning a change that can affect gene expression, and possibly the characteristics of a cell or organism, but that does not involve a change in the underlying genetic sequence. Gene regulation is flexible and responsive, with genes being turned on or off during development and in response to internal and external environmental conditions and stimuli. Transcription proceeds through the entire length of the gene in a 5′ to 3′ direction to form an mRNA transcript whose sequence is complementary to that of one of the DNA strands. RNA, like DNA, is a sugar-phosphate chain with pyrimidines and purines. In RNA the sugar is ribose, and uracil replaces the thymine found in DNA. A “cap” consisting of 7-methylguanosine is added to the 5′ end of the RNA in a 5′-5′ bond and, for most transcripts, several hundred adenine bases are enzymatically added to the 3′ end after transcription. mRNA processing occurs in the nucleus and consists of excision of the introns and splicing together of the exons. Specific sequences at the start and end of introns mark the sites where the splicing machinery will act on the transcript. In some cases, there may be tissue-specific patterns to splicing, so that the same primary transcript can produce multiple distinct proteins. The processed transcript is next exported to the cytoplasm, where it binds to ribosomes, which are complexes of protein and ribosomal RNA (rRNA ). The genetic code is then read in triplets of bases, each triplet corresponding with a specific amino acid or providing a signal that terminates translation . The triplet codons are recognized by transfer RNAs (tRNAs ) that include complementary anticodons and bind the corresponding amino acid, delivering it to the growing peptide. New amino acids are enzymatically attached to the peptide. Each time an amino acid is added, the ribosome moves 1 triplet codon step along the mRNA. Eventually a stop codon is reached, at which point translation ends and the peptide is released. In some proteins, there are posttranslational modifications , such as attachment of sugars (glycosylation ); the protein is then

delivered to its destination within or outside the cell by trafficking mechanisms that recognize portions of the peptide. Another mechanism of genetic regulation is noncoding RNAs, which are RNAs transcribed from DNA but not translated into proteins. Noncoding RNAs function in mediating splicing, the processing of coding RNAs in the nucleus, and the translation of coding mRNAs in ribosomes. The roles of large noncoding RNAs (>200 bp) and short noncoding RNAs (200 repeats) in offspring. With this number of repeats, the FMR1 gene becomes hypermethylated, and protein production is lost. Table 97.2

Diseases Associated With Polynucleotide Repeat Expansions

DISEASE

CATEGORY 1 Huntington disease

PARENT IN WHOM LOCATION REPEAT NORMAL ABNORMAL DESCRIPTION EXPANSION OF SEQUENCE RANGE RANGE USUALLY EXPANSION OCCURS

Loss of motor CAG control, dementia, affective disorder Spinal and bulbar Adult-onset CAG muscular atrophy motor-neuron disease associated with androgen insensitivity Spinocerebellar ataxia Progressive CAG type 1 ataxia, dysarthria,

6-34

36-100 or more

More often Exon through father

11-34

40-62

More often Exon through father

6-39

41-81

More often Exon through father

dysmetria Progressive ataxia, dysarthria Dystonia, distal muscular atrophy, ataxia, external ophthalmoplegia Spinocerebellar ataxia Progressive type 6 ataxia, dysarthria, nystagmus Spinocerebellar ataxia Progressive type 7 ataxia, dysarthria, retinal degeneration Spinocerebellar ataxia Progressive type 17 ataxia, dementia, bradykinesia, dysmetria DentatorubralCerebellar pallidoluysian atrophy, ataxia, atrophy/Haw River myoclonic syndrome epilepsy, choreoathetosis, dementia CATEGORY 2 Pseudoachondroplasia, Short stature, multiple epiphyseal joint laxity, dysplasia degenerative joint disease Oculopharyngeal Proximal limb muscular dystrophy weakness, dysphagia, ptosis Cleidocranial Short stature, dysplasia open skull sutures with bulging calvaria, clavicular hypoplasia, shortened fingers, dental anomalies Synpolydactyly Polydactyly and syndactyly CATEGORY 3 Myotonic dystrophy Muscle loss, (DM1; chromosome cardiac 19) arrhythmia, cataracts, frontal balding Myotonic dystrophy Muscle loss, (DM2; chromosome 3) cardiac arrhythmia, Spinocerebellar ataxia type 2 Spinocerebellar ataxia type 3 (MachadoJoseph disease)

CAG

15-29

35-59

—

CAG

13-36

68-79

More often Exon through father

CAG

4-16

21-27

—

CAG

7-35

38-200

More often — through father

CAG

29-42

47-55

—

CAG

7-25

49-88

More often Exon through father

GAC

5

6-7

—

Exon

GCG

6

7-13

—

Exon

GCG, GCT, GCA

17

27 (expansion — observed in 1 family)

Exon

GCG, GCT, GCA

15

22-25

Exon

CTG

5-37

CCTG

200

5′ untranslated region

CTG

16-37

107-127

More often through mother More often through mother

ATTCT

12-16

800-4,500

CAG

7-28

66-78

12-bp repeat motif

2-3

30-75

Intellectual CGG impairment, large ears and jaws, macroorchidism in males Mild intellectual GCC impairment

Spinocerebellar ataxia Adult-onset type 8 ataxia, dysarthria, nystagmus Spinocerebellar ataxia Ataxia and type 10 seizures Spinocerebellar ataxia Ataxia, eye type 12 movement disorders; variable age at onset Progressive myoclonic Juvenile-onset epilepsy type 1 convulsions, myoclonus, dementia

3′ untranslated region

More often Intron through father — 5′ untranslated region

Autosomal 5′ untranslated recessive region inheritance, so transmitted by both parents

From Jorde LB, Carey JC, Bamshad MJ, et al: Medical genetics , ed 3, St Louis, 2006, Mosby, p 82.

FIG. 97.18 The locations of the trinucleotide repeat expansions and the sequence of each trinucleotide in 5 representative trinucleotide repeat diseases, shown on a schematic of a generic pre–messenger RNA (mRNA). The minimal number of repeats in the DNA sequence of the affected gene associated with the disease is also indicated, as well as the effect of the expansion on the mutant RNA or protein. (From Nussbaum RL, McInnes RR, Willard HF, editors: Thompson & Thompson genetics in medicine, ed 8, Philadelphia, 2016, Elsevier; based partly on an unpublished figure of John A. Phillips III, Vanderbilt University.)

Some triplet expansions associated with other genes can cause disease through a mechanism other than decreased protein production. In Huntington disease the expansion causes the gene product to have a new, toxic effect on the neurons of the basal ganglia. For most triplet repeat disorders, there is a clinical correlation to the size of the expansion, with a greater expansion causing more severe symptoms and having an earlier age of disease onset. The observation of increasing severity of disease and early age at onset in subsequent generations is termed genetic anticipation and is a defining characteristic of many triplet repeat expansion disorders (Fig. 97.19 ).

FIG. 97.19 Myotonic dystrophy pedigree illustrating genetic anticipation. In this case the age at onset for family members affected with an autosomal dominant disease is lower in more recent generations. Black, Affected patients.

Genetic Imprinting The 2 copies of most autosomal genes are functionally equivalent. However, in some cases, only 1 copy of a gene is transcribed and the 2nd copy is silenced. This gene silencing is typically associated with methylation of DNA, which is an epigenetic modification, meaning it does not change the nucleotide sequence of the DNA (Fig. 97.20 ). In imprinting , gene expression depends on the parent of origin of the chromosome (see Chapter 98.8 ). Imprinting disorders result from an imbalance of active copies of a given gene, which can occur for several reasons. Prader-Willi and Angelman syndromes, two distinct disorders associated with developmental impairment, are illustrative. Both can be caused by microdeletions of chromosome 15q11-12. The microdeletion in Prader-Willi syndrome is always on the paternally derived chromosome 15, whereas in Angelman syndrome it is on the maternal copy. UBE3A is the gene responsible for Angelman syndrome. The paternal copy of UBE3A is transcriptionally silenced in the brain, and the maternal copy continues to be transcribed. If an individual has a maternal deletion, an insufficient amount of UBE3A protein is produced in the brain, resulting in the neurologic deficits seen in Angelman syndrome.

FIG. 97.20 Tissue-specific DNA methylation and epigenetic heterogeneity among individuals. A subset of the DNA methylation patterns within a cell is characteristic of that cell type. Cell type–specific and tissue-specific DNA methylation patterns are illustrated by organ-to-organ variations in the clusters of methylated CpGs (cytosinephosphate-guanine bases) within the same individual. Despite overall consistency in tissue-specific DNA methylation patterns, variations in these patterns exist among different individuals. Methylated CpGs are indicated by a filled circle and unmethylated CpGs by an open circle . Single nucleotide polymorphisms (SNPs) are indicated by the corresponding base. (Redrawn from Brena RM, Huang THM, Plass C: Toward a human epigenome, Nat Genet 38:1359–1360, 2006.)

Uniparental disomy (UPD) , the rare occurrence of a child inheriting both copies of a chromosome from the same parent, is another genetic mechanism that can cause Prader-Willi and Angelman syndromes. Inheriting both chromosomes 15 from the mother is functionally the same as deletion of the paternal 15q12 and results in Prader-Willi syndrome. Approximately 30% of cases of Prader-Willi syndrome are caused by maternal UPD15, whereas paternal UPD15 accounts for only 3% of Angelman syndrome (see Chapter 98.8 ). A mutation in an imprinted gene is another cause. Pathologic variants in UBE3A account for almost 11% of patients with Angelman syndrome and also result in familial transmission. The most uncommon cause is a mutation in the imprinting center, which results in an inability to correctly imprint UBE3A . In a woman, inability to reset the imprinting on her paternally inherited chromosome 15 imprint results in a 50% risk of passing on an incorrectly methylated copy of UBE3A to a child, who would then develop Angelman syndrome. Besides 15q12, other imprinted regions of clinical interest include the short arm of chromosome 11, where the genes for Beckwith-Wiedemann syndrome

and nesidioblastosis map, and the long arm of chromosome 7 with maternal UPD of 7q, which has been associated with some cases of idiopathic short stature and Russell-Silver syndrome. Imprinting of a gene can occur during gametogenesis or early embryonic development (reprogramming). Genes can become inactive or active by various mechanisms including DNA methylation or demethylation or histone acetylation or deacetylation, with different patterns of (de)methylation noted on paternal or maternal imprintable chromosome regions. Some genes demonstrate tissuespecific imprinting (see Fig. 97.20 ). Several studies suggest a small but significantly increased incidence of imprinting disorders, specifically BeckwithWiedemann and Angelman syndrome, associated with assisted reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection. However, the overall incidence of these disorders in children conceived using assisted reproductive technologies is likely to be 80 in 10%) Low birthweight Postnatal growth deficiency Microcephaly Seizures Autism

Extremity/Skeletal Short, incurved 5th finger Brachydactyly Kyphosis Joint hyperextensibility Persistent fetal fingertip pads Hypoplastic finger nails

Cardiovascular Multiple forms of congenital heart disease

Other

Nonimmune hydrops Hypothyroidism Precocious puberty Delayed puberty Lymphatic malformations Feeding difficulties

Bibliography Banka S, Lederer D, Benoit V, et al. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clin Genet . 2015;87:252–258. Benjamin JS, Pilarowski GO, Carosso GA, et al. A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. Proc Natl Acad Sci USA . 2017;114(1):125–130. Birney E, Smith GD, Greally JM. Epigenome-wide association studies and the interpretation of disease–omics. PLoS Genet . 2016;12(6):e1006105. Blewitt M, Whitelaw E. The use of mouse models to study epigenetics. Cold Spring Harb Perspect Biol . 2013;5(11):a017939. Chen F, Marquez H, Kim Y-K, et al. Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice. J Clin Invest . 2014;124(2):801–811. Dentici ML, Di Pede A, Lepri FR, et al. Kabuki syndrome: clinical and molecular diagnosis in the first year of life. Arch Dis Child . 2015;100:158–164. Henikoff S, Greally JM. Epigenetics, cellular memory and gene regulation. Curr Biol . 2016;26(14):R644–R648. Janesick AS, Shioda T, Blumberg B. Transgenerational inheritance of prenatal obesogen exposure. Mol Cell Endocrinol . 2014;398(1–2):31–35. Jirtle RL. The Agouti mouse: a biosensor for environmental

epigenomics studies investigating the developmental origins of health and disease. Epigenomics . 2014;6(5):447–450. Lintas C, Persico AM. Unraveling molecular pathways shared by Kabuki and Kabuki-like syndromes. Clin Genet . 2017; 10.1111/cge.12963 [Epub ahead of print]. Michels KB, Binder AM, Dedeurwaerder S, et al. Recommendations for the design and analysis of epigenomewide association studies. Nat Meth . 2013;10(10):949–955. Richmond RC, Sharp GC, Ward ME, et al. DNA methylation and BMI: investigating identified methylation sites at HIF3A in a causal framework. Diabetes . 2016;65(5):1231–1244.

CHAPTER 101

Genetic Approaches to Rare and Undiagnosed Diseases William A. Gahl, David R. Adams, Thomas C. Markello, Camilo Toro, Cynthia J. Tifft

Rare and novel disorders often present in childhood and represent a diagnostic challenge that can be addressed using advanced genetic techniques. In the United States, rare disorders are defined as those affecting 4,000 patient applications to the UDP, prior investigations are recounted in a summary letter from the referring clinician and documented with medical records that include photos, videos, imaging, and histologic slides of biopsy material. Specialty consultants review the records, and the UDP directors determine the next steps. Accepted patients come to the NIH Clinical Center for a week-long inpatient admission. Approximately half the patients with undiagnosed diseases have neurologic disease; cardiovascular, rheumatology, immunology, and pulmonary problems are also common. Approximately 40% of accepted patients are children, who often have congenital anomalies and neurologic disorders.

Clinical Evaluation Patients remain without a definitive diagnosis after an extensive workup in part because every individual has a unique genetic and environmental background, and diseases have variable expression. Undiagnosed conditions include those never before seen, unusual presentations of otherwise recognizable conditions, and combinations of conditions that obfuscate each other's identities. A thorough clinical investigation allows the clinician to broaden the differential diagnosis through research, consultation, and clinical testing. Extensive phenotyping, imaging, and other tests provide better documentation of the presentation and allow for association with diseases not yet discovered, genetic variants, and patient cohorts. A complete history anchors the data and includes prenatal and neonatal findings, developmental milestones, growth pattern, onset and progression of symptoms and signs, precipitating influences, response to medications, and a pedigree to determine which family members are possibly affected. Pertinent

physical findings include dysmorphisms, organomegaly, neurologic impairment, bone involvement, and dermatologic findings. Because many rare and novel disorders are multisystemic, consultants play a critical role in every diagnostic evaluation. Typical studies performed to address possible diagnoses are listed in Table 101.1 ; neurodevelopmental or neurodegenerative phenotypes require even more extensive studies (Table 101.2 ). Table 101.1 Initial Studies to Generate New Diagnostic Hypotheses TEST Electrolytes, lactate, pyruvate Plasma amino acids Urine organic acids Aldolase, creatine phosphokinase Carnitine (free, total, acyl, panel) Cerebrospinal fluid (CSF) analysis Brain MRI/magnetic resonance spectroscopy Mass spectrometry to detect N - and O -linked proteoglycan abnormalities Lysosomal enzyme testing White cell and skin electron microscopy Pathologic evaluation of affected tissues with special stains, DNA hybridization Echocardiogram, electrocardiogram Nerve conduction velocity, electromyogram Fibroblast cell line Single nucleotide polymorphism, exome/genome/karyotype Erythrocyte sedimentation rate, C-reactive protein

RELATED DISORDERS/DISORDER GROUPS Energy metabolism defects, including mitochondrial disorders Renal disorders, amino acid disorders Renal disorders, organic acid disorders, energy metabolism disorders, vitamin deficiencies Muscle disorders Fatty acid oxidation disorders, carnitine metabolism disorders Neurotransmitter disorders, inborn errors of metabolism, select disorders that may present only in the CSF Structural and morphologic clues to disorders affecting central nervous system Congenital disorders of glycosylation Lysosomal storage diseases Lysosomal storage diseases; neuronal lipofuscinoses Any Structural and functional abnormalities of the heart Dysfunction of anterior horn cells, nerves, neuromuscular junction, or muscle Any Any Inflammatory disorders

Table 101.2

Diagnostic Evaluation of the Neurologically Impaired Child Consultations Genetics/genetic counseling Neurology

Ophthalmology Endocrinology Immunology Rheumatology Dermatology Cardiology Neuropsychology Nutrition Rehabilitative medicine Physical therapy Occupational therapy Speech therapy

Procedures Swallow study for aspiration Abdominal ultrasound (hepatosplenomegaly) Skeletal survey (dysostosis) Bone density scan (nonambulatory or growth failure patients) Bone age Electroencephalogram, evoked responses, electroretinogram (ERG) Muscle biopsy for electron transport chain function, histology, immunohistochemistry Neuropsychometric testing Nerve biopsy

Laboratory Evaluations Complete blood count with differential and peripheral smear Comprehensive metabolic panel Prothrombin time/partial thromboplastin time (for anesthesia sedation) Thyroid-stimulating hormone, thyroxine Vitamins A and E, 1,25-dihydroxyvitamin D Lactate, pyruvate Ammonia Amino acids (plasma and urine)

Organic acids (urine) Acylcarnitine profile Total and free carnitine Lysosomal enzyme analysis in leukocytes/fibroblasts White blood cell coenzyme Q Purines and pyrimidines (urine) α-Glucosidase (plasma and urine) Peroxisomal panel Oxysterols Methylmalonic acid and homocysteine (plasma) Copper/ceruloplasmin Transferrin isoelectric focusing N - and O -glycans (plasma) Oligosaccharides and free glycans (urine) Glycosaminoglycans (urine)

Additional Testing if Clinically Indicated Electron microscopy of white blood cell buffy coat for inclusion bodies Electron microscopy of skin biopsy for evidence of storage Stool for ova and parasites, occult blood, fecal fat, or fecal calprotectin Autoimmune antibodies Vaccine response titers C3/C4 Quantitative immunoglobulins T-cell subsets Conjunctival or salivary gland biopsy

Research Specimens Cerebrospinal fluid Serum Plasma Skin biopsy for fibroblasts and/or melanocytes Isolated DNA/RNA Urine

Studies Under Sedation 3T MRI/magnetic resonance spectroscopy of brain (and spine if indicated) Skin biopsy Ophthalmologic exam Brainstem auditory evoked response Electroretinogram Lumbar puncture for biopterin, neopterin, neurotransmitters, folate, and inflammatory markers Dental exam Large blood draws Catheterization for urine Any part of the physical exam difficult to do in an awake child, including dysmorphology measurements and genital and rectal exam Electromyography and nerve conduction studies An inpatient admission allows for close interaction among experts in different fields, informs the evaluation of complex cases, and often leads to new disease discovery. In the last situation, other family members require evaluation to ascertain whether they are affected with the disorder.

Commercial Genetic Studies Once phenotyping is complete, a list of candidate genetic disorders can be compiled. Laboratory testing is available for an increasingly large number of molecular disorders. Examples of genetic panels include those for X-linked cognitive impairment, hereditary spastic paraplegia, spastic paraplegia and gait disorders, spinocerebellar ataxias, dystonias, and mitochondrial disorders. Some of these are expensive and may exceed the cost of exome sequencing . On the other hand, exome and genome sequencing are not useful for detecting diseases caused by many types of genetic disorder, including from DNA repeats. In addition, exome sequencing may provide less certainty for excluding genetic diseases than a disease-specific test panel.

Single Nucleotide Polymorphism Arrays

Single nucleotide polymorphism (SNP ) arrays and next-generation sequencing (NGS) provide valuable genome-wide structural information. The human genome's 3.2 billion bases include many that are polymorphic, customarily defined as differing between any 2 people >1% of the time. In most human populations, about 4 million differences exist between any 2 unrelated individuals (about 1 polymorphism for every 1,000 bases in the genome on average). Within a single ethnic population, about 1 common SNP occurs per 3,000-7,000 bases, where common means a >10% chance that the base will differ between 2 unrelated people. Approximately 1 million of these common SNPs can be included on a DNA hybridization array and examined simultaneously, revealing copy number variants, mosaicism, and regions of identity by descent. These results complement NGS results; one example is the pairing of sequence variants detected by exome or genome sequencing with trans -oriented deletions detected by SNP assay.

Exome Sequencing Technical advances have allowed for massive, inexpensive DNA sequencing, making it feasible to determine the sequence of the coding regions of almost all the human genes. Because this involves 1.9% of the 3.2 billion bases in the human genome, exome sequences comprise approximately 60,000,000 bases. Using current technology, clinical exome sequencing adequately sequences >80% of known genes and >90% of genes that have been associated with human disease. The average exome sequencing produces about 35,000 bases (0.06%) that differ from the “reference” sequence and from any other unrelated human sequence of the same ethnic group. These variants include some laboratory and computational errors. In practice, most variants are inconsequential polymorphisms and minor polynucleotide repeats that occur near intron/exon boundaries. However, each of the 35,000 variants of unknown significance is a potential disease-causing variant, yet only 1 (or 2 for compound heterozygous recessive cases) is the disease-causing mutation for a monogenic disorder (with perhaps 2 or 3 additional loci modifying severity). The clinician and bioinformatician must reduce the number of candidate variants to a tractable number, which is challenging. For instance, a variant causing an adult-onset disease may look just as damaging as a different variant causing congenital-onset disease. However, the likelihood of the presence of the associated diseases is much different in an adult vs a child.

Certain rules are used to separate likely-interesting variants from likelyuninteresting variants. For example, variants that segregate in a family consistent with a given inheritance model (e.g., dominant or recessive) are retained, while those that segregate in an inconsistent manner are set aside. This segregation filter requires careful clinical data collection and experimental design, since it depends on correct assignment of affected vs unaffected statuses in the family and collection of sequencing data for family members besides the proband. A 2nd technique used to evaluate sequence variants is pathogenicity assessment . Bioinformaticians estimate the likelihood that a given DNA sequence variant will have biologic consequences (e.g., change protein function or gene expression). Factors such as nucleotide conservation and differences in coded amino acids are used to create a pathogenicity estimate, or score. Various software programs take different, often overlapping, approaches. PolyPhen-2, SIFT, and MutationTaster rate the pathogenicity of amino acid changes. Computer modeling programs such as CADD, Eigen, and M-CAP, trained on model genetic changes that are already validated, predict effects on gene expression of noncoding variants. These filters are very powerful because of large population datasets that are publically available, including the 1000Genomes project, ExAC, and the UK's 10K genome project. In the next 1 or 2 yr, datasets with genome populations in the 100,000 to 1 million range (e.g., GnomAD database) will further improve these filters and provide better subpopulation frequencies. Ultimately, a multiethnic, graph theory-based alignment should allow successful filtering of variants in currently incomplete genomic regions such as the HLA region. Overall, computational pathogenicity assessment has false-positive and false-negative rates of 10–20%. Some filters compare variants to databases that contain previously measured or asserted properties of variants found in human populations, such as population frequency information (e.g., ExAC), or curated evidence for association with human disease (e.g., CLINVAR). The latter, while potentially useful, is quite incomplete for many genes, but this is improving. One common pitfall of database-derived filters is an inaccurate designation of certain variants as rare. This typically happens when the database is missing information from human populations in whom the variant is seen more often than in the included populations. Several points need to be considered when employing genome-scale sequencing for clinical diagnostics. Positive predictive value gives the likelihood that a positive test is a true positive. This is higher in a population in

whom a disease is common and lower in a population in whom the disease is rare. A person being tested with exome sequencing will show no clinical signs or symptoms of most of the genetic diseases for which the exome sequencing tests. Therefore, many apparently positive findings will be false positives, variants associated with phenotypes that do not match the person being tested. Individual vs family studies are relevant because family data allow for the proband's variants to be substantially filtered. This advantage must be weighed against the financial costs of studying families vs individuals. Furthermore, family studies are useless if an affected person is called unaffected, or vice versa. Therefore, phenotyping family members is critical. For later-onset conditions, younger siblings may not be suitable for inclusion in an exome sequencing study unless their affected status can be determined unambiguously. Datasets with large numbers of young individuals may have many pathologic variants that cause disease in elderly persons and are inappropriate for filtering variants in late-onset adult diseases or for prenatal counseling about late-onset disease inheritance risks. Data revisiting policies must be addressed. Genome-scale sequencing generates data for many genes besides those involved in the current diagnostic effort; these data may be useful in the future care of the patient. Some unreported mutated genes, not currently associated with disease, may be implicated in the future as disease risk factors or even as protective factors. In the current testing environment, time-limited data reuse policies and storage and reuse fees are increasingly common. In fact, the storage of data is now becoming more expensive than the cost of re-generating the data. Early discussion with a genetic specialist is critical. Genetic counseling should be sought before an exome sequencing study is sent. Proper consent for exome sequencing studies is an involved process, including discussions of disease risk factors, unrelated medical conditions, carrier states, and cancer susceptibility. Consented individuals should be asked which types of results they would like to receive. Anticipating findings that are difficult to use clinically is an important part of counseling. Variants of unknown significance (VUS) are problematic, and genome-scale sequencing amplifies the problem by including variable numbers of results that are difficult to use for medical decision-making. Discussing such variants with families can be challenging; counseling families about the likelihood of receiving this type of result before testing is performed can help the family to cope when the report is returned (see Chapter 94 ).

When used as a gene panel, exome sequencing rules in but does not rule out . An exome study is a cost-effective way to test many genes simultaneously, but coverage of any given exon varies. Therefore, exome studies cannot always exclude variants in a panel of genes. With careful analysis involving laboratory validation performed on many similarly processed individuals, the exome coverage of any given gene can be assessed. However, commercial/clinical testing facilities may be unwilling to perform such an analysis when a large set of genes needs to be considered. Therefore, a gene panel can be useful when the index of suspicion is high for a disorder caused by a large group of genes. Cerebellar ataxia and hereditary spastic paraplegia are examples (see Chapters 615.1 and 631 ). Providing information to the testing facility improves the chance of diagnosis. Exome sequencing interpretation benefits substantially from the incorporation of an accurate and detailed phenotype. The more clinical information provided to the testing lab, the more specific and useful will be the clinical report. The role of whole genome sequencing (WGS) is not yet defined in clinical practice but remains a consideration when exome sequencing yields no diagnosis. The fundamental issue is whether the VUS findings in an exome will be more meaningful than any additional variants discovered by WGS, rather than a clinical conclusion that there is no germline genetic/molecular cause for the undiagnosed patient. WGS tools have less confidence because of net lower coverage, take more time to process, and generate variants in noncoding regions of the genome that are much more difficult to filter and interpret.

Gene Function Studies Despite filtering for frequency and predicted deleteriousness, a variant identified by exome or genome sequencing cannot be interpreted as the cause of an individual's disease unless it has been previously demonstrated to cause a disease with a similar phenotype. To prove causality, medical genetics relies on association (the recurrence of mutations within a gene among individuals with a similar phenotype). For rare diseases, there may be too few affected patients to demonstrate a statistically significant association, and other evidence from phenotype ontologies, metabolomics, glycomics, proteomics, and lipidomics may be required. In addition, models (e.g., mice, zebrafish, fruit flies, yeast, cultured cells) can be developed to recapitulate the disease. The variant in

question can also be linked to a biologic process or pathway that is known to cause a similar phenotype when disturbed. Finally, standardized and correlated phenotypic and genomic data are deposited into a database to identify other individuals with a similar phenotype and mutations in the same gene. Physicians may apply their past biases to a group of variants that could be disease causing, but this is often misleading. A standardized computational approach is preferable. For example, the Human Phenotype Ontology standardizes the description of a disease and, because the descriptors have been mapped to other human diseases and to mutant model organisms, identifies possible candidate genes and genetic networks for causing the disease. Similarly, untargeted laboratory screening tests provide an unbiased survey of patient cellular biology and physiology and a more informed prioritization of candidate variants. The ultimate proof of causality is to ameliorate the disease process by correcting the genetic defect; this might be demonstrable in a model system that recapitulates the human disease. Alternatively, a search for other patients with a similar phenotype and mutations in the same gene can be performed using public databases established using strict statistical and biologic standards.

Pediatric Issues Of the UDP's 1st 500 pediatric applications, >10% had more than 1 family member (usually a sibling) similarly affected. The age distribution had peaks at 4-5 yr (reflecting patients with congenital disorders) and at 16-18 yr (representing disorders with symptom onset at early school age). Most applicants had been on a diagnostic odyssey for >5 yr. Of the 200 pediatric cases accepted, 25% received a diagnosis; half were obtained using conventional diagnostic methods, including clinical suspicion, biochemical testing with molecular confirmation, or radiographic interpretation. Otherwise, SNP analysis and NGS yielded the diagnosis; all involved rare diseases. Pediatric medical records require attention to what has and what has not been completed previously. The electronic medical record is an important tool, but “copy forward” functions can perpetuate errors, such as reports of normal testing when in fact the test was recommended or ordered but not performed. Repetitive copying also fosters sloppiness in critical thinking, failure to take an adequate history, and missing the nuances of symptom progression. A history and physical examination should be performed anew and all prior testing results confirmed

through copies of original laboratory reports. Prolonged and painful procedures should be performed under sedation, but the risks associated with sedation must be weighed against the value of information and samples obtained.

Considerations for Families of Undiagnosed Children When a child comes to a genetics clinic for evaluation, the parents ask these questions:

◆ What does my child have? (diagnosis) ◆ Why did it happen? (etiology/inheritance) ◆ What will happen in the future? (natural history; prognosis) ◆ Is there a treatment? (therapy) ◆ Could the same thing happen to other family members? (recurrence risk) The answers all require an accurate diagnosis. The lack of a diagnosis makes both the family and the physician uncomfortable, raises suspicion among relatives and acquaintances, and creates feelings of guilt about not having worked hard enough to obtain a diagnosis. Families often consult more and more specialists, becoming frustrated with the lack of coordination among providers. Families should save copies of every test and every visit from each institution in a binder for travel among institutions. A 2- to 3-page narrative summarizing the child's history, medications, list of healthcare providers with contact information, main medical issues, level of functioning on well days and sick days, and interventions that worked in the past can be invaluable in an emergency room setting. An electronic copy is easily updated. Parents can always be the best advocates for their child, particularly an undiagnosed child. Recommendations to parents of an undiagnosed child are similar to those that apply to any child with chronic illness:

◆ Organize copies of all records, especially original reports from “send-out” laboratories. ◆ Carry an updated emergency letter. ◆ Establish a medical home even if you obtain many second opinions. ◆ Find a physiatrist (rehabilitation medicine physician) to coordinate rehabilitative care. ◆ Strongly advocate with the school system for needed services (see Chapter 48 ), using a legal advocate if necessary; ◆ Explore parent support groups for unknown disorders (Syndromes Without a Name, National Organization for Rare Disorders). ◆ Periodically check with providers (especially geneticists) for new diagnoses reported in the medical literature. ◆ Carve out time for yourselves as caregivers by engaging extended family members or respite care services. ◆ Work at supporting and being attentive to well children in the family. ◆ For the dying child, consider an autopsy to establish a diagnosis, especially when there is a possibility of future pregnancies.

The Diagnostic Spectrum Rare and new genetic disorders can present at any age; a gene's “severe”

mutations may manifest early in life while “mild” mutations present later. Diagnoses of known disorders can have very different bases, such as the extent of recognition of a clinical entity, a molecular confirmation, or biochemical evidence. Some variants identified by SNP and exome sequencing analyses may represent new diseases. One example of the use of these technologies to discover a new diagnosis involves 2 brothers whose parents were first cousins. The brothers had an earlyonset spastic ataxia-neuropathy syndrome, with lower-extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. A homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2 , which encodes a subunit of a mitochondrial protease, was identified by exome sequencing. The AFG3L2 protein can bind to another AFG3L2 molecule or to paraplegin. UDP collaborators in Germany used a yeast model system to demonstrate that the patients' mutation affects the specific amino acid involved in the formation of both these complexes. As a result, the brothers exhibited the signs and symptoms of a known AFG3L2 defect, autosomal dominant spinocerebellar ataxia type 28 (SCA28), and also deficits attributable to a paraplegin defect, hereditary spastic paraplegia type 7 (SPG7). Other features of a mitochondrial disorder (oculomotor apraxia, extrapyramidal dysfunction, myoclonic epilepsy) were also present. The 2 brothers represent the 1st such cases in the world and expand the phenotype of AFG3L2 disease. A 2nd example involves 2 siblings ages 5 and 10 yr with hypotonia, developmental delays, facial dysmorphisms, hearing loss, nystagmus, seizures, and atrophy on brain MRI. In this case the leading clue was biochemical in nature, and genetic analysis confirmed the diagnosis. Urine thin-layer chromatography for oligosaccharides identified a strong band determined by mass spectrometry to consist of a tetrasaccharide containing 3 glucoses and 1 mannose. This suggested a defect of glucosidase I, the 1st enzyme involved in endoplasmic reticulum trimming of N -linked glycoproteins from a highmannose to a complex form. Mutation analysis confirmed compound heterozygous variants in the glucosidase I gene, establishing the diagnosis of congenital disorder of glycosylation IIb. The 2 siblings were the 2nd and 3rd patients in the world with this disorder. Occasionally an autosomal dominant disorder, typically presenting in adulthood, can manifest as a completely different and more severe disorder when pathologic variants in the same gene are inherited from each parent; the child is a

compound heterozygote. This was the case in a 3 yr old child who inherited 2 variants in GARS, the gene causing autosomal dominant Charcot-Marie-Tooth disease (CMT) 2D. The child had severe intrauterine and postnatal growth retardation, microcephaly, developmental delay, optic nerve atrophy and retinal pigment changes, as well as an atrial septal defect. Neither parent was symptomatic at the time the child was evaluated; the parents had normal electromyography and nerve conduction studies. This case emphasizes the need to consent families before any genetic testing as to the possibility of receiving unexpected results in additional family members. In this case, genetic counseling was expanded to include possible CMT2D in the parents.

Bibliography Adams DR, Sincan M, Fuentes Fajardo K, et al. Analysis of DNA sequence variants detected by high-throughput sequencing. Hum Mutat . 2012;33:599–608. Bordini BJ, Stephany A, Kliegman R. Overcoming diagnostic errors in medical practice. J Pediatr . 2017;185:19–25. ClinVar: National Center for Biotechnology Information, US National Library of Medicine. http://www.ncbi.nlm.nih.gov/clinvar/ . Gahl WA. The power of an undiagnosed disease program in a clinical research enterprise. Gallin JI, Ognibene F. Principles and practice of clinical research . Elsevier: Philadelphia; 2012:701–705. Gahl WA, Markello TC, Toro C, et al. The NIH Undiagnosed Diseases Program: insights into rare diseases. Genet Med . 2012;14:51–59. Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA . 2011;305:1904–1905. Gahl W, Wise A, Ashley EA. The Undiagnosed Diseases Network of the NIH: a national extension. JAMA . 2015;314:1797–1798. Garwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced

utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions, Genetics Med E-pub . [November] 2014. Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare mendelian disorders. JAMA . 2014;312:1880–1887. Lu JT, Campeau PM, Lee BH. Genotype-phenotype correlation: promiscuity in the era of next-generation sequencing. N Engl J Med . 2014;371:593–596. Markello TC, Carlson-Donohoe H, Sincan M, et al. Sensitive quantification of mosaicism using high-density SNP arrays and the cumulative distribution function. Mol Genet Metab . 2012;105:665–671. Markello TC, Han T, Carlson-Donohoe H, et al. Recombination mapping using Boolean logic and high-density SNP genotyping for exome sequence filtering. Mol Genet Metab . 2012;105:382–389. Online Mendelian Inheritance in Man (OMIM), McKusickNathans Institute of Genetic Medicine. Johns Hopkins University, Baltimore . http://omim.org/ . Pierson TM, Adams D, Bonn F, et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxianeuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet . 2011;7(10):e1002325. Sincan M, Simeonov D, Adams D, et al. VAR-MD: a tool to analyze whole exome/genome variants in small human pedigrees with mendelian inheritance. Hum Mutat . 2012;33:593–598. Taruscio D, Groft S, Cederroth H, et al. Undiagnosed Diseases Network International (UDNI): white paper for global actions to meet patient needs. Mol Genet Metab . 2015;116:223–225. Yang Y, Muzny DM, Xia F, et al. Molecular findings among

patients referred for clinical whole-exome sequencing. JAMA . 2014;312:1870–1878.

PA R T X

Metabolic Disorders OUTLINE Chapter 102 An Approach to Inborn Errors of Metabolism Chapter 103 Defects in Metabolism of Amino Acids Chapter 104 Defects in Metabolism of Lipids Chapter 105 Defects in Metabolism of Carbohydrates Chapter 106 Mitochondrial Disease Diagnosis Chapter 107 Mucopolysaccharidoses Chapter 108 Disorders of Purine and Pyrimidine Metabolism Chapter 109 Hutchinson-Gilford Progeria Syndrome (Progeria) Chapter 110 The Porphyrias Chapter 111 Hypoglycemia

CHAPTER 102

An Approach to Inborn Errors of Metabolism Oleg A. Shchelochkov, Charles P. Venditti

Many childhood conditions are caused by single-gene mutations that encode specific proteins. These mutations can change primary protein structure or the amount of protein synthesized. The function of a protein, whether it is an enzyme, receptor, transport vehicle, membrane component, transcriptional coregulator, or structural element, may be compromised or abolished. Hereditary diseases that disrupt normal biochemical processes are termed inborn errors of metabolism or inherited metabolic diseases . Most genetic changes are clinically inconsequential and represent benign variants. However, pathogenic variants produce diseases that range in severity of presentation and time of onset. Severe metabolic disorders usually become clinically apparent in the newborn period or shortly thereafter, whereas milder forms may present later in childhood and even in adulthood. With some exceptions, the presenting symptoms of most metabolic conditions lack the specificity to enable a definitive diagnosis without further evaluation. The combination of low specificity of presenting symptoms and low prevalence of metabolic disorders makes determination of the diagnosis difficult. Progressive symptoms, the lack of plausible non-genetic diagnosis after detailed evaluation, history of overlapping symptoms in patient's relatives, or consanguinity should alert a pediatrician to seek a consultation with a geneticist and consider metabolic testing early in the evaluation. Correct diagnosis is often only the beginning of a long medical journey for most families affected by metabolic conditions (see Chapter 95 ). Although each inherited metabolic disorder is individually rare, improved diagnosis and increasing survival of patients with metabolic conditions virtually ensure that a pediatrician will encounter and provide care to affected patients. Pediatricians

can play a critical role in establishing the continuity of care, managing some aspects of treatment, fostering adherence, and delivering routine pediatric interventions such as immunizations, referrals to specialists, and elements of genetic counseling (see Chapter 94.1 ). The greater awareness of metabolic conditions, wider availability of biochemical laboratories, global metabolomic analysis, and routine application of exome sequencing dramatically increased the detection rate of the known disorders and contributed to the discovery of new metabolic disorders. Nonetheless, collection and analysis of family history remains a critical screening test that a healthcare provider can use to identify an infant or child at risk for a metabolic disorder. The identification of consanguinity or a particular ethnic background with an unusually high incidence of inborn errors of metabolism can be important to direct further studies. For example, tyrosinemia type 1 is more common among French-Canadians of Quebec, maple syrup urine disease is seen with higher frequency in the U.S. Amish population, and Canavan disease in patients of the Ashkenazi Jewish ancestry.

Newborn Screening The individual rarity of inborn errors of metabolism, the importance of early diagnosis, and the ensuing genetic counseling ramifications make a strong argument for the universal screening all newborn infants. Tandem mass spectrometry of metabolites and digital microfluidics analysis of enzyme activities form the foundation of newborn screening today. Both methods require a few drops of blood to be placed on a filter paper and delivered to a central laboratory for assay. Many genetic conditions can be identified by these methods, and the list of disorders continues to grow (Tables 102.1 and 102.2 ). Pediatricians need to be aware of the general screening procedure and limitations of screening. As a screening method, a positive result may require a repeat newborn screen or confirmatory testing to secure the diagnosis. Time required to return the results vary from country to country and even within states in the same country. Some metabolic conditions can be severe enough to cause clinical manifestations before the results of the newborn screening become available. Conversely, diagnostic metabolites in milder forms of screened disorders may not reach a set threshold to trigger secondary studies, thus leading to a negative newborn screen results and delayed diagnosis. Therefore, negative newborn screening in a patient with symptoms suggestive of a metabolic disorder

warrants a referral to genetics center for further evaluation.

Table 102.1

Disorders Recommended by the American College of Medical Genetics Task Force for Inclusion in Newborn Screening (“Primary Disorders”)* Disorders of Organic Acid Metabolism Isovaleric acidemia Glutaric aciduria type I 3-Hydroxy-3-methylglutaric aciduria Multiple carboxylase deficiency Methylmalonic acidemia (methylmalonyl-CoA mutase deficiency) Methylmalonic acidemia (cbl A and cbl B defects) Propionic acidemia 3-Methylcrotonyl-CoA carboxylase deficiency β-Ketothiolase deficiency

Disorders of Fatty Acid Metabolism Medium-chain acyl-CoA dehydrogenase deficiency Very-long-chain acyl-CoA dehydrogenase deficiency Long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency Trifunctional protein deficiency Carnitine uptake defect

Disorders of Amino Acid Metabolism Phenylketonuria Maple syrup urine disease Homocystinuria Citrullinemia type 1 Argininosuccinic acidemia

Tyrosinemia type I

Hemoglobinopathies Sickle cell anemia (hemoglobin SS disease) Hemoglobin S/β-thalassemia Hemoglobin S/C disease

Other Disorders Congenital hypothyroidism Biotinidase deficiency Congenital adrenal hyperplasia Galactosemia Hearing loss Cystic fibrosis Severe combined immunodeficiency (SCID) † Critical congenital heart disease † cbl A, Cobalamin A defect; cbl B, cobalamin B defect; CoA, coenzyme A.

* As of November 2014, there is state-to-state variation in newborn screening; a

list of the disorders that are screened for by each state is available at http://genesr-us.uthscsa.edu/sites/genes-r-us/files/nbsdisorders.pdf . † The inclusion of SCID and critical congenital heart disease received support of

the American College of Medical Genetics and Genomics.

Table 102.2

Secondary Conditions Recommended by American College of Medical Genetics* Task Force for Inclusion in Newborn Screening Organic Acid Metabolism Disorders

Methylmalonic acidemia (cbl C and cbl D defects) Malonic acidemia 2-Methyl-3-hydroxybutyric aciduria Isobutyryl-CoA dehydrogenase deficiency 2-Methylbutyryl-CoA dehydrogenase deficiency 3-Methylglutaconic aciduria

Fatty Acid Oxidation Disorders Short-chain acyl-CoA dehydrogenase deficiency Glutaric acidemia type 2 Medium/short-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency Medium-chain ketoacyl-CoA thiolase deficiency Carnitine palmitoyltransferase IA deficiency Carnitine palmitoyltransferase II deficiency Carnitine:acylcarnitine translocase deficiency Dienoyl-CoA reductase deficiency

Amino Acid Metabolism Disorders Hyperphenylalaninemia, benign (not classic phenylketonuria) Tyrosinemia type II Tyrosinemia type III Defects of biopterin cofactor biosynthesis Defects of biopterin cofactor regeneration Argininemia Hypermethioninemia Citrullinemia type II (citrin deficiency)

Hemoglobinopathies Hemoglobin variants (including hemoglobin E)

Others

Galactose epimerase deficiency Galactokinase deficiency cbl C, Cobalamin C defect; cbl D, cobalamin D defect; CoA, coenzyme A.

* The American College of Medical Genetics Newborn Screening Expert Group

(May 2006) recommended reporting, in addition to the primary disorders, 25 disorders (“secondary targets”) that can be detected through screening but that do not meet the criteria for primary disorders (https://www.acmg.net/resources/policies/nbs/NBS_Main_Report_01.pdf ). Universal newborn screening may also identify mild forms of inherited metabolic conditions, some of which may never cause clinical manifestations in the lifetime of the individual. For example, short-chain acyl-CoA dehydrogenase deficiency has been identified with unexpectedly high frequency in screening programs using tandem mass spectrometry, but most of these children have remained asymptomatic. This highlights the need for an ongoing evaluation of metabolite cutoff values and approaches to confirmatory testing to maximize the diagnostic yield and minimize potential psychosocial and economic implications of such findings. Premature infants represent a special patient population in whom the incidence of false-positive or false-negative test results can be especially high. With the advent of genetic therapy for spinal muscular atrophy (SMA) and enzyme replacement therapy for some lysosomal storage diseases (e.g., Pompe disease, Fabry disease, Gaucher disease, and mucopolysaccharidosis type 1), pilot newborn screening programs have demonstrated initial success in identifying SMA or lysosomal storage disorders, often before severe symptoms develop.

Clinical Manifestations of Genetic Metabolic Diseases Physicians and other healthcare providers who care for children should familiarize themselves with early manifestations of genetic metabolic disorders,

because (1) severe forms of some of these conditions may cause symptoms before the results of screening studies become available, and (2) the current screening methods, although quite extensive, identify a small number of all inherited metabolic conditions. In the newborn period, the clinical findings are usually nonspecific and similar to those seen in infants with sepsis. A genetic disorder of metabolism should be considered in the differential diagnosis of a severely ill newborn infant, and special studies should be undertaken if the index of suspicion is high (Fig. 102.1 ).

FIG. 102.1 Initial clinical approach to a full-term newborn infant with a suspected genetic metabolic disorder. This schema is a guide to elucidate some of the metabolic disorders in newborn infants. Although some exceptions to this schema exist, it is appropriate for most cases affected by disorders or intermediate metabolism. CNS, Central nervous system; GI, gastrointestinal; HCO3 − , bicarbonate.

Signs and symptoms such as lethargy, hypotonia, hypothermia, convulsions (Table 102.3 ), poor feeding, and vomiting may develop as early as a few hours after birth. Occasionally, vomiting may be severe enough to suggest the diagnosis of pyloric stenosis, which is usually not present, although it may occur

simultaneously in such infants. Lethargy, poor feeding, seizures, and coma may also be seen in infants with hypoglycemia (Table 102.4 ) (see Chapters 111 and 127 ), hypocalcemia (Chapters 64 and 589 ), and hyperammonemia (Table 102.5 ) (Chapter 103 ). Measurements of blood concentrations of glucose and calcium and response to intravenous injection of glucose or calcium help establish these diagnoses. Every organ system can be affected by metabolic disorders. However, physical examination usually reveals nonspecific findings; most signs are related to the central nervous system such as opisthotonus in the case of maple syrup urine disease (MSUD). Hepatomegaly is a common finding in a variety of inborn errors of metabolism (Table 102.6 ). Cardiomyopathy (Table 102.7 ), dysmorphology (Table 102.8 ), and fetal hydrops (Table 102.9 ) are additional potential manifestations of a metabolic disorder (Table 102.10 ). Occasionally, a peculiar odor may offer an invaluable aid to the diagnosis (Table 102.11 ). Table 102.3 Select Inborn Errors of Metabolism Associated With Neurologic and Laboratory Manifestations in Neonates DETERIORATION IN CONSCIOUSNESS Metabolic Acidosis Organic acidemias Disorders of pyruvate metabolism Fatty acid oxidation defects Fructose-1,6-bisphosphatase deficiency Glycogen storage diseases Mitochondrial respiratory chain defects Disorders of ketone metabolism Hypoglycemia * Fatty acid oxidation defects Disorders of gluconeogenesis Disorders of fructose and galactose metabolism Glycogen storage diseases Disorders of ketogenesis Organic acidemias Hyperinsulinemic hypoglycemias Mitochondrial respiratory chain defects Neonatal intrahepatic cholestasis caused by citrin deficiency

Pyruvate carboxylase deficiency Carbonic anhydrase VA deficiency Hyperammonemia ** Urea cycle disorders Organic acidemias Fatty acid oxidation disorders Disorders of pyruvate metabolism GLUD1 -related hyperinsulinemic hypoglycemia Carbonic anhydrase VA deficiency SEIZURES AND HYPOTONIA Antiquitin deficiency (pyridoxine-dependent epilepsy) Pyridoxamine 5'-phosphate oxidase (PNPO) deficiency (pyridoxal phosphate-responsive epilepsy) Folate metabolism disorders Multiple carboxylase deficiency (holocarboxylase synthetase deficiency and biotinidase deficiency) Urea cycle disorders Organic acidemias Fatty acid oxidation disorders Disorders of creatine biosynthesis and transport Disorders of neurotransmitter metabolism Molybdenum cofactor deficiency and sulfite oxidase deficiency Serine deficiency disorders Glycine encephalopathy Asparagine synthetase deficiency Mitochondrial respiratory chain defects Zellweger spectrum disorders Congenital disorders of glycosylation Purine and pyrimidine metabolism defects NEONATAL APNEA Glycine encephalopathy Asparagine synthetase deficiency Urea cycle disorders Organic acidemias Disorders of pyruvate metabolism Fatty acid oxidation defects Mitochondrial respiratory chain defects *

Refer to Table 102.4 for more details on the metabolic disorders associated with neonatal hypoglycemia.

**

Refer to Table 102.5 for more details on the differential diagnosis of neonatal and infantile hyperammonemia.

Modified from El-Hattab AW: Inborn errors of metabolism, Clin Perinatol 42:413-439, 2015 (Box 1, p 415).

Table 102.4 Select Inborn Errors of Metabolism Associated With Neonatal Hypoglycemia CATEGORY OF DISORDERS Fatty acid oxidation disorders

Disorders of gluconeogenesis Disorders of fructose and galactose metabolism Glycogen storage diseases (GSD)

Disorders of ketogenesis Organic acidemias

Hyperinsulinemic hypoglycemia

Other

DISORDERS Carnitine-acylcarnitine translocase deficiency Carnitine palmitoyltransferase Ia deficiency Carnitine palmitoyltransferase II deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/trifunctional protein deficiency Medium-chain acyl-CoA dehydrogenase deficiency Very-long-chain acyl-CoA dehydrogenase deficiency Multiple acyl-CoA dehydrogenase deficiency Fructose-1,6-diphosphatase deficiency Phosphoenolpyruvate carboxykinase deficiency Hereditary fructose intolerance Classic galactosemia GSD type Ia (glucose-6-phosphatase deficiency) GSD type Ib (impaired glucose-6-phosphate exchanger) GSD type III (glycogen debrancher enzyme deficiency) GSD type VI (liver glycogen phosphorylase deficiency) GSD type IX (phosphorylase kinase deficiencies) 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency Propionic acidemia Methylmalonic acidemia Isovaleric acidemia Maple syrup urine disease Multiple carboxylase deficiency (holocarboxylase synthetase deficiency and biotinidase deficiency) HADH -related disorder (3-alpha-hydroxyacyl-CoA dehydrogenase deficiency) GLUD1 -related disorder (hyperammonemia-hyperinsulinism syndrome, HIHA) Mitochondrial respiratory chain defects Neonatal intrahepatic cholestasis caused by citrin deficiency Pyruvate carboxylase deficiency Carbonic anhydrase VA deficiency

Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.17, p 1605).

Table 102.5 Differential Diagnosis of Hyperammonemia INBORN ERRORS OF METABOLISM Urea Cycle Enzyme Defects N-acetylglutamate synthase (NAGS) deficiency Carbamoyl phosphate synthetase 1 (CPS1) deficiency Ornithine transcarbamylase (OTC) deficiency Argininosuccinate synthetase (ASS) deficiency (citrullinemia type 1) Argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria) Arginase 1 deficiency Transport and Synthesis Defects of Urea Cycle Intermediates Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH syndrome) Citrullinemia type 2 caused by citrin deficiency Lysinuric protein intolerance Ornithine aminotransferase deficiency Carbonic anhydrase VA deficiency Organic Acidemias Propionic acidemia MUT -related methylmalonic acidemia and cobalamin metabolism disorders Isovaleric acidemia Fatty Acid Oxidation Disorders Long-chain fatty acid oxidation defects Systemic primary carnitine deficiency Other Pyruvate carboxylase deficiency GLUD1 -related hyperinsulinemic hypoglycemia Neonatal iron overload disorders (e.g. hereditary hemochromatoses) ACQUIRED DISORDERS Transient Hyperammonemia of the Newborn Diseases of the Liver and Biliary Tract Liver failure Biliary atresia Severe Systemic Neonatal Illness Neonates sepsis Heart failure Medications

Valproic acid Cyclophosphamide 5-Pentanoic acid Asparaginase Other Reye syndrome ANATOMIC VARIANTS Vascular bypass of the liver (e.g. a portosystemic anastomosis) TECHNICAL Inappropriate sample collection (e.g., capillary blood or prolonged placement of a tourniquet) Sample not immediately analyzed

Modified from El-Hattab AW: Inborn errors of metabolism, Clin Perinatol 42:413-439, 2015 (Box 8, p 428).

Table 102.6 Select Metabolic Disorders Associated With Hepatic Dysfunction CATEGORY OF DISORDERS Disorders of amino acid metabolism

DISORDERS Tyrosinemia type I Citrullinemia type II caused by citrin deficiency Disorders of methionine metabolism Urea cycle disorders Biliary tract disorders and disorder of bile See Chapter 383 acid synthesis Disorders of fructose and galactose Hereditary fructose intolerance metabolism Classic galactosemia Epimerase deficiency galactosemia Congenital disorders of glycosylation Multiple types Fatty acid oxidation disorders Carnitine-acylcarnitine translocase deficiency Carnitine palmitoyltransferase Ia deficiency Carnitine palmitoyltransferase II deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/trifunctional protein deficiency Very-long-chain acyl-CoA dehydrogenase deficiency Multiple acyl-CoA dehydrogenase deficiency Glycogen storage disorders (GSD) GSD type III (glycogen debrancher enzyme deficiency) GSD type IV (glycogen branching enzyme deficiency) GSD type VI (liver glycogen phosphorylase deficiency) Peroxisomal disorders Zellweger spectrum disorders Disorders of peroxisomal β-oxidation Mitochondrial respiratory chain (RC) Mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects defects Specific single nucleotide pathogenic variants in mtDNA Large-scale mtDNA re-arrangements (Pearson syndrome)

Lysosomal storage disorders Other

Disorders of mitochondrial translation (e.g., tRNAGlu ) Disorder of protein synthesis of RC complexes Disorders affected the assembly or stabilization of RC complexes (e.g., BCS1L ) Disorders of cofactor biosynthesis (e.g. coenzyme Q10) Disorders of mitochondrial transport and dynamics mtDNA depletion syndromes (e.g., DGUOK, MPV17, POLG, SUCLG1 ) Niemann-Pick disease type C α1 -Antitrypsin deficiency

Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.5, p 1579).

Table 102.7 Select Metabolic Disorders Associated With Cardiomyopathy CATEGORY OF DISORDERS Organic acidemias

DISORDERS

Propionic acidemia Cobalamin C deficiency 3-methylglutaconic acidurias (e.g., Barth syndrome and DCMA syndrome) Lysosomal storage Sphingolipidoses (e.g., Fabry disease) disorders Oligosaccharidoses and mucolipidoses (e.g., I-cell disease) Mucopolysaccharidoses Glycogen storage disorders GSD type II (Pompe disease) (GSD) GSD type III (glycogen debrancher enzyme deficiency) PRKAG2 -related disorders (includes lethal congenital glycogen storage disease of heart) Congenital disorders of Multiple types glycosylation Fatty acid oxidation Carnitine-acylcarnitine translocase deficiency disorders Carnitine palmitoyltransferase II deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/trifunctional protein deficiency ACAD9 -related disorder (mitochondrial acyl-CoA dehydrogenase deficiency) Multiple acyl-CoA dehydrogenase deficiency (includes glutaric aciduria type 2) Very-long-chain acyl-CoA dehydrogenase deficiency Systemic primary carnitine deficiency Mitochondrial respiratory Mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects chain (RC) defects Specific single nucleotide pathogenic variants in mtDNA Large-scale mtDNA deletions Disorders of mitochondrial translation (e.g., tRNALeu ) Disorders of protein synthesis of RC complexes (e.g., MT-ATP6 , MT-ATP8 , NDUFS2, NDUFV2, SDHA, SCO2, COX10, COX15 ) Disorders affecting the assembly or stabilization of RC complexes (e.g., TMEM70 ) Disorders of cofactor biosynthesis (e.g. coenzyme Q10) Disorders of mitochondrial transport and dynamics (e.g., SLC25A3 ) mtDNA depletion syndromes (e.g., SUCLG1 )

Other

Danon disease

Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.4, p 1576).

Table 102.8 Select Inborn Errors of Metabolism Associated With Dysmorphic Features CATEGORY OF DISORDERS Congenital disorders of glycosylation Disorders of cholesterol biosynthesis

Lysosomal storage disorders

Organic acidurias

Peroxisomal disorders Other

DISORDERS N-Glycosylation disorders (e.g., PMM2-CDG and ALG3-CDG) O-Glycosylation disorders (e.g., Walker-Warburg syndrome) Smith-Lemli-Opitz syndrome Desmosterolosis Lathosterolosis EBP -related disorder (includes Conradi-Hunermann syndrome) Sphingolipidoses Oligosaccharidoses and mucolipidoses Mucopolysaccharidoses Multiple acyl-CoA dehydrogenase deficiency (includes glutaric aciduria type 2) Mevalonic aciduria* Zellweger spectrum disorders Disorders of peroxisomal β-oxidation Pyruvate dehydrogenase complex deficiency

* Mevalonic aciduria has been classified as an organic acidemia based on the method used for its

diagnosis, but it can also be classified as a peroxisomal single-enzyme disorder or as a defect in cholesterol biosynthesis because of its intracellular location and function, respectively. Modified from Zinn AB: Inborn errors of metabolism. In Fanaroff & Martin's neonatal-perinatal medicine: diseases of the fetus and infant, ed 10, vol 2, Philadelphia, 2015, Elsevier (Table 99.8, p 1583).

Table 102.9 Select Inborn Errors of Metabolism Associated With Hydrops Fetalis Lysosomal storage disorders Mucopolysaccharidoses types I, IVA, and VII Sphingolipidoses (e.g., Gaucher disease, Farber disease, Niemann-Pick disease A, GM1 gangliosidosis, multiple sulfatase deficiency) Lipid storage diseases (Wolman and Niemann-Pick disease C) Oligosaccharidoses (e.g., sialidosis type I) Mucolipidoses (e.g., I-cell disease) Zellweger spectrum disorders

Glycogen storage disease type IV Congenital disorders of glycosylation Mitochondrial respiratory chain defects Transaldolase deficiency

Modified and adapted from El-Hattab AW: Inborn errors of metabolism, Clin Perinatol 42:413-439, 2015 (Box 6, p 417).

Table 102.10 Pathognomonic Clinical Findings Associated With Inborn Errors of Metabolism (Select Examples) FINDINGS Hepatomegaly

Hepatosplenomegaly

Macrocephaly Microcephaly

Coarse facial features

Macroglossia

Dystonia or extrapyramidal signs

DISORDERS Disorders of fructose and galactose metabolism (e.g., classic galactosemia and hereditary fructose intolerance) Glycogen storage diseases Disorders of gluconeogenesis Disorders of fatty acid oxidation and transport Mitochondrial respiratory chain defects Tyrosinemia type 1 Urea cycle disorders Zellweger spectrum disorders Niemann-Pick disease type C Congenital disorders of glycosylation Mucopolysaccharidoses Niemann-Pick disease types A, B, and C Sphingolipidoses (e.g., GM1 gangliosidosis or Gaucher disease) Wolman disease Farber disease (acid ceramidase deficiency) Glutaric acidemia type 1 Canavan disease Mitochondrial respiratory chain defects Disorders of intracellular cobalamin metabolism (e.g., cbl C deficiency) Mucopolysaccharidoses Oligosaccharidoses and mucolipidoses (e.g., α-mannosidosis) Sphingolipidoses (e.g., GM1 gangliosidosis) Galactosialidosis Glycogen storage disease type II (Pompe disease) Mucopolysaccharidoses Oligosaccharidoses and mucolipidoses Sphingolipidoses Galactosialidosis Gaucher disease type 2 Glutaric acidemia type 1 Methylmalonic acidemia Propionic acidemia

Macular “cherry-red spot”

“Bull eye” maculopathy Retinitis pigmentosa

Optic nerve atrophy or hypoplasia

Corneal clouding or opacities

Cataracts

Dislocated lens Skeletal dysplasias and dysostosis multiplex

Thick skin

Desquamating, eczematous, or vesiculobullous skin lesions

Ichthyosis

Krabbe disease Crigler–Najjar syndrome Disorders of neurotransmitter metabolism Pyruvate dehydrogenase complex deficiency GM1 gangliosidosis Tay-Sachs disease (GM2 gangliosidosis) Farber disease (acid ceramidase deficiency) Galactosialidosis Niemann-Pick disease type A Sialidosis Multiple sulfatase deficiency cbl C deficiency (combined methylmalonic acidemia and homocystinuria, type C) Mitochondrial respiratory chain defects Peroxisomal disorders Abetalipoproteinemia Pyruvate dehydrogenase complex deficiency Mitochondrial respiratory chain defects Peroxisomal disorders Propionic acidemia MUT -related methylmalonic acidemia and cobalamin metabolism disorders Mucolipidoses Mucopolysaccharidoses Steroid sulfatase deficiency Tyrosinemia type II Cystinosis Disorders of galactose metabolism (e.g., classic galactosemia) Congenital disorders of glycosylation Mitochondrial respiratory chain (RC) defects Peroxisomal disorders Lowe oculocerebrorenal syndrome Cystathionine β-synthase deficiency Molybdenum cofactor deficiency and sulfite oxidase deficiency Oligosaccharidoses and mucolipidoses Mucopolysaccharidoses Sphingolipidoses Galactosialidosis Peroxisomal disorders Disorders of cholesterol biosynthesis Congenital disorders of glycosylation Oligosaccharidoses and mucolipidoses Mucopolysaccharidoses Sphingolipidoses Acrodermatitis enteropathica Essential amino acid deficiencies in organic acidemias Hartnup disorder Multiple carboxylase deficiency (holocarboxylase synthetase deficiency and biotinidase deficiency) Porphyrias Gaucher disease type 2 Steroid sulfatase deficiency Refsum disease ELOVL4 -related disorder Serine deficiency disorders

Alopecia

Multiple carboxylase deficiency (holocarboxylase synthetase deficiency and biotinidase deficiency)

Steely or kinky hair Trichorrhexis nodosa Persistent diarrhea

Menkes disease Argininosuccinic aciduria (ASL deficiency) Glucose-galactose malabsorption Congenital lactase deficiency Congenital chloride diarrhea Sucrase-isomaltase deficiency Acrodermatitis enteropathica Abetalipoproteinemia Congenital folate malabsorption Wolman disease Lysinuric protein intolerance Classic galactosemia

Modified from Cederbaum S: Introduction to metabolic and biochemical genetic diseases. In Gleason CA, Juul SE, editors: Avery's diseases of the newborn, ed 10, Philadelphia, 2018, Elsevier (Table 21.1, p 227).

Table 102.11 Inborn Errors of Amino Acid Metabolism Associated With Peculiar Odor INBORN ERROR OF METABOLISM Isovaleric acidemia Glutaric acidemia (type II) Maple syrup urine disease Multiple carboxylase deficiency 3-Methylcrotonyl-CoA carboxylase deficiency 3-Hydroxy-3-methylglutaric aciduria Phenylketonuria Trimethylaminuria Dimethylglycine dehydrogenase deficiency Tyrosinemia type 1 Hypermethioninemia Cystinuria Tyrosinemia type I Hawkinsinuria Oasthouse urine disease

URINE ODOR Sweaty feet, acrid Maple syrup, burnt sugar Cat urine

Mousey or musty Rotten fish Boiled cabbage, rancid butter Boiled cabbage Sulfur “Swimming pool” Hops-like

In an increasing number of patients, a metabolic condition may be recognized months or years after birth. This is more typical in patients carrying milder autosomal recessive pathogenic variants, in mitochondrial disorders, in females affected by X-linked recessive conditions, and specific metabolic conditions that usually present later in life. Clinical manifestations, such as intellectual disability, motor deficits, developmental regression, seizures, psychosis, cardiomyopathy, myopathy, organomegaly, and recurrent emesis, in patients beyond the neonatal period should suggest an inherited metabolic disease (Table

102.12 ). There may be an episodic or intermittent pattern, with episodes of acute clinical manifestations separated by periods of seemingly disease-free states. The episodes are usually triggered by stress or nonspecific catabolic stress such as an infection. The child may die during one of these acute attacks. An inborn error of metabolism should be considered in any child with 1 or more of the following manifestations: unexplained developmental delay; intellectual disability; developmental regression; motor deficits or adventitious movements (e.g., dystonia, choreoathetosis, ataxia); seizures; catatonia; unusual odor (particularly during an acute illness); intermittent episodes of unexplained vomiting, acidosis, mental deterioration, psychosis, or coma; hepatomegaly; renal stones; renal dysfunction, especially Fanconi syndrome or renal tubular acidosis; muscle weakness; and cardiomyopathy (Table 102.12 ). Table 102.12 Clinical Findings That Should Prompt a Metabolic Workup Family history

Sibling(s) who died from unexplained causes or exhibit overlapping symptoms Ethnic groups with high prevalence of metabolic disorders Consanguinity Intrauterine growth retardation, sepsis-like presentation in the neonatal period, nonimmune fetal hydrops Postnatal failure to thrive, microcephaly, macrocephaly, short stature Progressive encephalopathy, lethargy, coma, intractable seizures, developmental delay, developmental regression, intellectual disability, autism spectrum disorder, hypotonia, spasticity, dystonia, strokes, ataxia, psychosis, intracranial calcifications, white matter disease, peripheral neuropathy Hyperventilation, apnea

Perinatal history Growth Central and peripheral nervous systems Respiratory system Cardiovascular Cardiac failure with or without cardiomyopathy, arrhythmia system Musculoskeletal Rhabdomyolysis, myopathy system Osteopenia, early-onset osteoporosis, skeletal dysplasia, epiphyseal abnormalities, bone crises Eye Retinitis pigmentosa, macular dystrophy, cataracts, corneal opacities, nystagmus, cherry-red spot Hearing Sensorineural hearing loss Gastrointestinal Hepatomegaly, splenomegaly, liver failure, Reye syndrome, cholestasis, cirrhosis, chronic system diarrhea, vomiting, acute pancreatitis Kidney Renal dysfunction, renal stones Hematological Anemia, leukopenia, thrombocytopenia, pancytopenia, hemolytic-uremic syndrome system Skin Hair abnormality, alopecia, lipodystrophy, recalcitrant eczema

Diagnosis usually requires a variety of specific laboratory studies. Plasma amino acid analysis, plasma acylcarnitine profile, total and free carnitine profile,

and urine organic acid assay, while not exhaustive in their diagnostic scope, are useful as initial screening tests to evaluate for a suspected inborn error of metabolism. Measurements of plasma ammonia, lactate, bicarbonate, and pH are readily available in hospitals and very helpful initially in differentiating major causes of genetic metabolic disorders (Table 102.13 ; see Fig. 102.1 ). Elevation of blood ammonia is usually caused by defects of urea cycle enzymes, organic acidemias, and disorders of fatty acid oxidation. Infants with elevated blood ammonia levels from urea cycle defects tend to have normal serum pH and bicarbonate values; without measurement of blood ammonia, they may remain undiagnosed and succumb to their disease. In organic acidemias, elevated plasma ammonia is accompanied by severe acidosis caused by accumulation of organic acids, ketone bodies, and lactate in body fluids.

Table 102.13

Laboratory Findings That Should Prompt a Metabolic Workup Hyperammonemia Metabolic acidosis Lactic acidosis Ketosis Hypoglycemia Liver dysfunction Pancytopenia When blood ammonia, pH, and bicarbonate values are normal, other aminoacidopathies (e.g. hyperglycinemia) or galactosemia should be considered. Galactosemic infants may also manifest cataracts, hepatomegaly, ascites, and jaundice.

Treatment The majority of patients with genetic disorders of metabolism respond to one or more of the following treatments: 1. Special diets play an important role in the treatment of affected children.

Dietary changes should be tailored to the pathophysiology of the condition and vary greatly among disorders. 2. Hemodialysis for expeditious removal of accumulated noxious compounds. This is a very effective modality for treatment of the acute phase of the condition. 3. Catabolic states in patients at risk for metabolic crisis can be treated with fluids containing dextrose and electrolytes. 4. Administration of the deficient metabolite. 5. Administration of the cofactor or coenzyme to maximize the residual enzyme activity. 6. Activation of alternate pathways to reduce the noxious compounds accumulated because of the genetic mutation. 7. Administration of the deficient enzyme. 8. Bone marrow transplantation. 9. Liver and kidney transplantation. The organ transplantation modalities may offer the best treatment modality to stabilize a metabolic patient and improve quality of life. To date, replacement of the mutant gene with a normal copy using gene therapy has been successful in only a few diseases. Treatment of genetic disorders of metabolism is complex and requires medical and technical expertise. The therapeutic regimen often needs to be tailored to the individual patient because of large phenotypic variations in the severity of the disease, even within a single family. Providing education and support for the family is the key to successful long-term therapy. Even in patients with poor prognoses, every effort should be made to establish correct diagnoses premortem. Effective treatment is best achieved by a team of specialists— metabolic genetics specialist, nutritionist, neurologist, and psychologist—in a major medical center.

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and lysosomal storage disorders takes advantage of novel therapies. J Pediatr . 2017;190:9–10. Baily MA, Murray TH. Ethics and newborn genetic screening: new technologies, new challenges . Johns Hopkins University Press: Baltimore; 2009. Bennett MJ. Newborn screening for metabolic diseases: saving children's lives and improving outcomes. Clin Biochem . 2014;47:693–694. Landau YE, Lichter-Konecki U, Levy HL. Genomics in newborn screening. J Pediatr . 2014;164:14–19. Plass AMC, van El CG, Pieters T, et al. Neonatal screening for treatable and untreatable disorders: prospective parents’ opinions. Pediatrics . 2010;125:e99–e106. Pollitt RJ. Newborn blood spot screening: new opportunities, old problems. J Inherit Metab Dis . 2009;32:395–399. Shin SY, Fauman EB, Petersen AK, et al. An atlas of genetic influences on human blood metabolites. Nat Genet . 2014;46:543–550. Sokal EM. Treating inborn errors of liver metabolism with stem cells: current clinical development. J Inherit Metab Dis . 2014;37(4):535–539. Stevenson T, Millan MT, Wayman K, et al. Long-term outcome following pediatric liver transplant action for metabolic disorders. Pediatr Transplant . 2010;14:268–275. Taraiol-Graovac M, Shyr C, Ross GA, et al. Exome sequencing and the management of neurometabolic disorders. N Engl J Med . 2016;374(23):2246–2255. Vernon HJ. Inborn errors of metabolism: advances in diagnosis and therapy. JAMA Pediatr . 2015;169(8):778–782.

CHAPTER 103

Defects in Metabolism of Amino Acids 103.1

Phenylalanine Oleg A. Shchelochkov, Charles P. Venditti

Keywords phenylalanine phenylketonuria PKU hyperphenylalaninemia phenylalanine hydroxylase tetrahydrobiopterin BH4 Phenylalanine is an essential amino acid. Dietary phenylalanine not utilized for protein synthesis is normally degraded by way of the tyrosine pathway (Fig. 103.1 ). Deficiency of the enzyme phenylalanine hydroxylase (PAH) or of its cofactor tetrahydrobiopterin (BH4 ) causes accumulation of phenylalanine in body fluids and in the brain.

FIG. 103.1 Pathways of phenylalanine and tyrosine metabolism. Enzyme defects causing genetic conditions are depicted as horizontal bars crossing the reaction arrow(s). Pathways for synthesis of cofactor BH4 are shown in purple. BH4 * refers to defects of BH4 metabolism that affect the phenylalanine, tyrosine, and tryptophan hydroxylases (see Figs. 103.2 and 103.5 ). PKU, Phenylketonuria; NE, nonenzymatic. Enzymes: (1) Phenylalanine hydroxylase, (2) pterin-carbinolamine dehydratase, (3) dihydrobiopterin reductase, (4) guanosine triphosphate (GTP) cyclohydrolase, (5) 6pyruvoyltetrahydropterin synthase, (6) sepiapterin reductase, (7) carbonyl reductase, (8) aldolase reductase, (9) dihydrofolate reductase, (10) tyrosine aminotransferase, (11) 4-hydroxyphenylpyruvate dioxygenase, (12) homogentisic acid dioxygenase, (13) maleylacetoacetate isomerase, (14) fumarylacetoacetate hydrolase.

Elevations of phenylalanine in the plasma depend on the degree of enzyme deficiency. In patients with severe PAH deficiency (previously referred to as classic phenylketonuria ), plasma phenylalanine levels on unrestricted diet usually exceed 20 mg/dL (>1,200 µmol/L). Patients with milder PAH pathogenic variants have plasma phenylalanine levels between 10 mg/dL (600 µmol/L) and 20 mg/dL (1,200 µmol/L). Levels between 2 and 10 mg/dL (120-600 µmol/L) on unrestricted diet are observed in patients with mild hyperphenylalaninemia . In

affected infants with plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate; see Fig. 103.1 ) that are excreted in the urine, giving rise to the term phenylketonuria (PKU). These metabolites have no known role in pathogenesis of central nervous system (CNS) damage in PKU patients; their presence in the body fluids simply signifies the severity of the condition. The brain is the main organ damaged by PKU, but the exact mechanism of injury remains elusive. Both toxic levels of phenylalanine and insufficient tyrosine may play a role. Phenylalanine hydroxylase converts phenylalanine to tyrosine , which is necessary for the production of neurotransmitters such as epinephrine, norepinephrine, and dopamine (Fig. 103.2 ). If the degree of enzymatic block is severe, tyrosine becomes an essential amino acid and may be deficient if intake is not adequate. On the other hand, observations that lower concentration of phenylalanine in plasma and brain tissue are associated with improved neurobehavioral outcomes support the view that toxic levels of phenylalanine are key to the mechanisms of the disease. High blood levels of phenylalanine can saturate the transport system across the blood-brain barrier and cause inhibition of the cerebral uptake of other large neutral amino acids such as branched-chain amino acids, tyrosine, and tryptophan, impairing brain protein synthesis.

FIG. 103.2 Other pathways involving tyrosine metabolism. BH4 * indicates hyperphenylalaninemia caused by tetrahydrobiopterin (BH4 ) deficiency (see Fig. 103.1 ). HVA, Homovanillic acid; VMA, vanillylmandelic acid. Enzymes: (1) Tyrosine hydroxylase (TH), (2) aromatic L -amino acid decarboxylase (AADC), (3) dopamine βhydroxylase (DβH), (4) phenylethanolamine-N -methyltransferase (PNMT), (5) catechol O -methyltransferase (COMT), (6) monoamine oxidase (MAO).

Severe Phenylalanine Hydroxylase Deficiency (Classic Phenylketonuria) Elevations of plasma phenylalanine >20 mg/dL (>1,200 µmol/L), if untreated, invariably result in the development of signs and symptoms of classic PKU, except in uncommon and unpredictable cases.

Clinical Manifestations The affected infant appears normal at birth. Profound intellectual disability develops gradually if the infant remains untreated. Cognitive delay may not be evident for the 1st few months. In untreated patients, 50–70% will have an IQ below 35, and 88–90% will have an IQ below 65. Only 2–5% of untreated patients may have normal intelligence. Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom. Older untreated children become hyperactive with autistic behaviors, including purposeless hand movements, rhythmic rocking, and athetosis. Untreated and undertreated infants are lighter in their complexion than unaffected siblings. Some may have a seborrheic or eczematoid rash, which is usually mild and disappears as the child grows older. These children have an odor of phenylacetic acid, which has been described as musty or “mousey.” Neurologic signs include seizures (approximately 25%), spasticity, hyperreflexia, and tremors; >50% have electroencephalographic (EEG) abnormalities. Microcephaly, prominent maxillae with widely spaced teeth, enamel hypoplasia, and growth retardation are other common findings in untreated children. Low bone mineral density and osteopenia have been reported in affected individuals of all ages. Although inadequate intake of natural proteins seems to be the major culprit, the exact pathogenesis of this sequela remains unclear. Long-term care of patients with PKU is best achieved by a team of experienced professionals (metabolic specialist, nutritionist, and psychologist) in a regional treatment center. The clinical manifestations of classic PKU are rarely seen in countries where neonatal screening programs for the detection of PKU are in effect.

Non-PKU Hyperphenylalaninemia In any screening program for PKU, a group of infants will be identified in whom

initial plasma concentrations of phenylalanine are above normal (i.e., >2 mg/dL, or 120 µmol/L) but 10 mg/dL (600 µmol/L). It is generally accepted that infants with persistent (more than a few days) plasma levels of phenylalanine ≥6 mg/dL (360 µmol/L) should also be treated with a phenylalanine-restricted diet similar to that in classic PKU. The goal of therapy is to reduce phenylalanine levels in the plasma and brain. Formulas free of, or low in, phenylalanine are commercially available. The diet should be started as soon as the diagnosis is established. Because phenylalanine is not synthesized endogenously, the diet should provide phenylalanine to prevent phenylalanine deficiency. Dietary phenylalanine tolerance is determined based on age and severity of the PAH deficiency. Phenylalanine deficiency is manifested by lethargy, failure to thrive, anorexia, anemia, rashes, diarrhea, and even death. Further, tyrosine becomes an essential amino acid in this disorder, and its adequate intake must be ensured. Special food items low in phenylalanine are commercially available for dietary treatment of affected children and adults. There is no firm consensus concerning optimal levels of blood phenylalanine in affected patients either across different countries or among treatment centers in the United States. The current recommendation is to maintain blood phenylalanine levels between 2 and 6 mg/dL (120-360 µmol/L) throughout life. Discontinuation of therapy, even in adulthood, may cause deterioration of IQ and cognitive performance. Lifelong adherence to a low-phenylalanine diet is extremely difficult. Patients who maintain good control as children but discontinue the phenylalanine-restricted diet as teenagers or adults may experience significant difficulties with executive function, concentration, emotional liability, and depression. Executive dysfunction may also occur in early-treated children despite diet treatment. Given the difficulty of maintaining a strict low-phenylalanine diet, there are continuing attempts to find other modalities for treatment of these patients. Administration of large neutral amino acids (LNAAs) is another approach to dietary therapy. LNAAs (tyrosine, tryptophan, leucine, isoleucine, valine, methionine, histidine, and phenylalanine) share the same transporter protein (LNAA type 1 or LAT-1) for transit through the intestinal cell membrane and

blood-brain barrier (BBB). Binding of LNAAs to the transporter protein is a competitive process. The rationale for use of LNAA is that these molecules compete with phenylalanine for transport across the BBB; therefore, large concentrations of other LNAAs in the intestinal lumen and in the blood reduce the uptake of phenylalanine into bloodstream and the brain. Large, controlled clinical trials are necessary to establish the efficacy of this treatment. Oral administration of BH4 , the cofactor for PAH, may result in reduction of plasma levels of phenylalanine in some patients with PAH deficiency. Plasma levels of phenylalanine in these patients may decrease enough to allow for considerable modification of their dietary restriction. In very rare cases the diet may be discontinued because the phenylalanine levels remain under 6 mg/dL (360 µmol/L). The response to BH4 cannot be predicted consistently based on the genotype alone, especially in compound heterozygous patients. Sapropterin dihydrochloride , a synthetic form of BH4 , which acts as a cofactor in patients with residual PAH activity, is approved by the U.S. Food and Drug Administration (FDA) to reduce phenylalanine levels in PKU. A sustained decrease of plasma phenylalanine by at least 30% is consistent with sapropterin responsiveness. Injectable PEGylated recombinant phenylalanine ammonia lyase is in development.

Pregnancy in Women With PAH Deficiency (Maternal Phenylketonuria) Pregnant women with PAH deficiency who are not on a phenylalanine-restricted diet have a very high risk of having offspring with intellectual disability, microcephaly, growth retardation, congenital malformations, and congenital heart disease. These complications are directly correlated with elevated maternal blood phenylalanine levels during pregnancy. Prospective mothers who have been treated for PAH deficiency should be maintained on a phenylalaninerestricted diet before and during pregnancy. The best observed outcomes occur when strict control of maternal blood phenylalanine concentration is instituted before pregnancy. Plasma phenylalanine levels >6 mg/dL (360 µmol/L) after conception are associated with increased incidence of intrauterine growth restriction and congenital malformations, as well as lower IQ. However, there is strong evidence that phenylalanine control instituted after conception results in improved outcomes. The currently recommended phenylalanine concentration is

2-6 mg/dL (120-360 µmol/L) throughout the pregnancy, although some expert groups advocate plasma phenylalanine levels 60% of patients become symptomatic between 3 and 11 mo of age. Infrequently, patients may remain asymptomatic until adolescence. With the addition of 3-HMG-CoA lyase deficiency to the newborn screening using C5OH-carnitine, many infants are identified presymptomatically in the newborn period. Similar to 3-HMG-CoA synthase deficiency, patients affected by 3HMG-CoA lyase deficiency may present with acute hypoketotic hypoglycemia. Episodes of vomiting, severe hypoglycemia, hypotonia, acidosis with mild or no ketosis, and dehydration may rapidly lead to lethargy, ataxia, and coma. These episodes often occur during a catabolic state such as prolonged fasting or an

intercurrent infection. Hepatomegaly is common. These manifestations may be mistaken for Reye syndrome or fatty acid oxidation defects such as mediumchain acyl-CoA dehydrogenase deficiency. Long-term complications can include dilated cardiomyopathy, hepatic steatosis, and pancreatitis. Development can be normal, but intellectual disability and seizures with abnormalities in the white matter seen on MRI have been observed in patients after prolonged episodes of hypoglycemia. Laboratory findings include hypoglycemia, moderate to severe hyperammonemia, and acidosis. There is mild or no ketosis (see Fig. 103.7 ). Urinary excretion of 3-hydroxy-3-methylglutaric acid and other proximal intermediate metabolites of leucine catabolism (3-methylglutaric acid, 3methylglutaconic acid, and 3-hydroxyisovaleric acid) is markedly increased, causing the urine to smell like cat urine . Glutaric and dicarboxylic acids may also be increased in urine during acute attacks. Secondary carnitine deficiency is common. The condition is inherited as an autosomal recessive trait. 3-HMGCoA lyase is encoded by gene HMGCL . Diagnosis may be confirmed by molecular analysis of HMGCL or by enzyme assay in cultured fibroblasts, leukocytes, or liver specimens. Prenatal diagnosis is possible by molecular DNA analysis if the familial pathogenic variants are known or by enzymatic assay of the cultured amniocytes or a chorionic villi biopsy. Treatment of acute episodes includes hydration, infusion of glucose to control hypoglycemia, provision of adequate calories, and administration of bicarbonate to correct acidosis. Hyperammonemia should be treated promptly (see Chapter 103.12 ). Renal replacement therapy may be required in patients with severe recalcitrant hyperammonemia. Restriction of protein and fat intake is recommended for long-term management. Oral administration of L -carnitine (50-100 mg/kg/24 hr) prevents secondary carnitine deficiency. Prolonged fasting should be avoided.

Succinyl-CoA:3-Oxoacid-CoA Transferase Deficiency Succinyl-CoA:3-oxoacid-CoA transferase (SCOT ) deficiency and βketothiolase deficiency collectively are referred to as ketone utilization disorders. SCOT participates in the conversion of ketone bodies (acetoacetate and 3-hydroxybutyrate) generated in liver mitochondria into acetoacetyl-CoA in

the nonhepatic tissues (see Fig. 103.7 ). A deficiency of this enzyme results in the accumulation of ketone bodies, ketoacidosis, increased utilization of glucose, and hypoglycemia. During fasting, patients tend to have a proportional elevation of plasma free fatty acids. More than 30 patients with SCOT deficiency have been reported to date. The condition may not be rare because many cases may be mild and may remain undiagnosed. SCOT deficiency can be distinguished from β-ketothiolase deficiency by the absence of 2-methylacetoacetate, 2-methyl-3hydroxybutyrate, and tiglylglycine, characteristic of the latter disorder. Plasma acylcarnitine profile tends to show no specific abnormalities. A common clinical presentation is an acute episode of severe ketoacidosis in an infant who had been growing and developing normally. About half the patients become symptomatic in the 1st wk of life, and practically all become symptomatic before 2 yr of age. The acute episode is often precipitated by a catabolic state triggered by an infection or prolonged fasting. Without treatment, the ketoacidotic episode can result in death. A chronic subclinical ketosis may persist between the attacks. Development is usually normal, although severe and recurrent episodes of ketoacidosis and hypoglycemia can predispose patients to neurocognitive impairment. Laboratory findings during the acute episode are nonspecific and include metabolic acidosis and ketonuria with high levels of acetoacetate and 3hydroxybutyrate in blood and urine. No other organic acids are found in the blood or in the urine. Blood glucose levels are usually normal, but hypoglycemia has been reported in some affected newborn infants with severe ketoacidosis. Plasma amino acids and plasma acylcarnitine profile are usually normal. Severe SCOT deficiency can be accompanied by ketosis even when patients are clinically stable. This condition should be considered in any infant with unexplained bouts of ketoacidosis. Diagnosis can be established by molecular analysis of OXCT1 or by demonstrating a deficiency of enzyme activity in cultured fibroblasts. The condition is inherited as an autosomal recessive trait. Treatment of acute episodes consists of rehydration with solutions containing dextrose, correction of acidosis, and the provision of a diet adequate in calories. Long-term treatment should include high-carbohydrate diet and avoidance of prolonged fasting and administration of dextrose before anticipated or during established catabolic states.

Mevalonate Kinase Deficiency

Mevalonic acid, an intermediate metabolite of cholesterol synthesis, is converted to 5-phosphomevalonic acid by the action of the enzyme mevalonate kinase (MVK) (see Fig. 103.7 ). Based on clinical manifestations and degree of enzyme deficiency, 2 conditions have been recognized: mevalonic aciduria and hyperimmunoglobulinemia D syndrome. Both disorders are accompanied by recurrent fever, gastrointestinal symptoms, mucocutaneous manifestations, and lymphadenopathy. Patients with mevalonic aciduria also show growth retardation and nervous system involvement. In practice, the 2 disorders represent the 2 ends of the spectrum.

Mevalonic Aciduria Clinical manifestations include failure to thrive, growth retardation, intellectual disability, hypotonia, ataxia, myopathy, hepatosplenomegaly, cataracts, and facial dysmorphisms (dolichocephaly, frontal bossing, low-set ears, downward slanting of eyes, long eyelashes). Most patients experience recurrent crises characterized by fever, vomiting, diarrhea, hepatosplenomegaly, arthralgia, lymphadenopathy, edema, and morbilliform rash. These episodes typically last 2-7 days and recur up to 25 times a year. Death may occur during these crises. Laboratory findings include marked elevation of mevalonic acid in urine; the concentration of urinary mevalonic acid ranges between 500 and 56,000 mmol/mol of creatinine (normal: A, p.Gly170Arg) results in mistargeting of the enzyme to the mitochondria instead of the peroxisomes and loss of in vivo function. Prenatal diagnosis has been achieved by DNA analysis of chorionic villus samples or by the measurement of fetal hepatic enzyme activity obtained by needle biopsy.

Primary Hyperoxaluria Type 2 (l-Glyceric Aciduria)

This rare condition is caused by a deficiency of the glyoxylate reductase– hydroxypyruvate reductase enzyme complex (see Fig. 103.8 ). A deficiency in the activity of this complex results in an accumulation of two intermediate metabolites, hydroxypyruvate (the ketoacid derivative of serine) and glyoxylic acid. Both these compounds are further metabolized by LDH to L -glyceric acid and oxalic acid, respectively. A high prevalence of this disorder is reported in the Saulteaux-Ojibway Indians of Manitoba. Primary hyperoxaluria type 2 results in the deposition of calcium oxalate in the renal parenchyma and urinary tract. Renal stones presenting with renal colic and hematuria may develop before age 2 yr. Renal failure is less common in this condition than in primary hyperoxaluria type 1. Urinary testing reveals large amounts of L -glyceric acid in addition to high levels of oxalate. Urinary L -glyceric acid is considered a pathognomonic finding in primary hyperoxaluria type 2. Urinary excretion of glycolic acid and glyoxylic acid is not increased. The presence of L -glyceric acid without increased levels of glycolic and glyoxylic acids in urine differentiates this type from type 1 hyperoxaluria. Diagnosis can be confirmed by molecular analysis of GRHPR (9p13.2) or by the enzyme assay in liver biopsy. Principles of therapy are similar to those in primary hyperoxaluria type 1. Renal transplant is used in some patients; no experience with kidney-liver transplantation is available at this time.

Primary Hyperoxaluria Type 3 Approximately 10% of patients with primary hyperoxaluria have deficiency of 4-hydroxy-2-oxoglutarate aldolase 1 (HOGA1), the underlying cause of hyperoxaluria type 3. The enzyme is encoded by HOGA1 mapped to chromosome 10q24.2. This mitochondrial enzyme catalyzes the final step in the metabolic pathway of hydroxyproline generating pyruvate and glyoxylate from 4-hydroxy-2-oxoglutarate (HOG; see Figs. 103.8 and 103.9 ). In vitro studies show inhibition of glyoxylate reductase–hydroxypyruvate reductase enzyme activity by high concentration of HOG that accumulates in patients with hyperoxaluria type 3. This inhibition results in a biochemical phenotype similar to hyperoxaluria type 2 (see Fig. 103.8 ). Patients with primary hyperoxaluria type 3 usually presented with calcium oxalate kidney stones in early childhood, but asymptomatic older siblings were also identified. Gradually, renal function may decline, infrequently resulting in

end-stage renal disease. Increased levels of HOG in urine, serum, and liver biopsy samples of these patients is the distinguishing feature of this disorder. Treatment involves high oral fluid intake, management of oral citrate or phosphate intake to prevent calcium oxalate renal stone formation, and avoidance of dehydration to prevent acute kidney injury. In severe forms of this disorder, dialysis and transplantation may be required to address the end-stage renal disease.

Creatine Deficiency Disorders Creatine is synthesized mainly in the liver, pancreas, and kidneys and to a lesser degree in the brain from arginine and glycine and is transported to muscles and the brain, where there is high activity of the enzyme creatine kinase (Fig. 103.10 ). Phosphorylation and dephosphorylation of creatine in conjunction with adenosine triphosphate and diphosphate provide high-energy phosphate transfer reactions in these organs. Creatine is nonenzymatically metabolized to creatinine at a constant daily rate and is excreted in the urine. Three genetic conditions are known to cause creatine deficiency in the brain and other tissues. Two enzymes, arginine:glycine amidinotransferase (AGAT ) and guanidinoacetate methyltransferase (GAMT ; Fig. 103.10 ), are involved in the biosynthesis of creatine. Both conditions may respond to creatine supplementation, especially when the treatment is started in early age. The 3rd condition, an X-linked inherited defect, is caused by deficiency of the creatinine transporter (CRTR) protein mediating uptake of creatine by brain and muscle.

FIG. 103.10 Biosynthesis of serine and creatine. Enzymes: (1) 3-Phosphoglycerate dehydrogenase, (2) 3-phosphoserine aminotransferase, (3) 3-phosphoserine phosphatase, (4) arginine:glycine amidinotransferase (AGAT), (5) guanidinoacetate methyltransferase (GAMT), (6) creatine kinase.

Clinical manifestations of the 3 defects overlap, relate to the brain and muscle, and may appear in the 1st few wk or mo of life. Developmental delay, intellectual disability, speech delay, psychiatric symptoms (autism and psychosis), hypotonia, ataxia, and seizures are common findings. Dystonic movements have been documented in GAMT and CRTR deficiency. Laboratory findings include decreased creatine in plasma in patients with AGAT and GAMT defects. Plasma creatinine level alone is insufficient to diagnose these disorders. Secondary to impaired reabsorption of creatine in kidneys, the urinary ratio of creatine to creatinine is increased in male patients with a CRTR defect but can also be mildly elevated in female carriers. Marked elevations of guanidinoacetate in blood, urine, and especially in CSF, are diagnostic of GAMT defects. In contrast, low levels of guanidinoacetate can be found in body fluids in the AGAT defect. Absence of creatine and creatine phosphate (in all 3 defects) and high levels of guanidinoacetate (in GAMT defect) can be demonstrated in the brain by magnetic resonance spectroscopy (MRS). Brain MRI may show signal hyperintensity in the globus pallidus. Diagnosis of AGAT deficiency or GAMT deficiency may be confirmed by DNA analysis or by measuring of enzymatic activity in cultured fibroblasts (GAMT) or lymphoblasts (AGAT). Diagnosis of CRTR deficiency can be confirmed by DNA analysis or a creatine uptake assay in fibroblasts.

The outcomes of treatment are age-dependent and best with treatment started in the neonatal period or presymptomatically. In AGAT-deficient patients, oral creatine monohydrate (up to 400-800 mg/kg/24 hr) may improve muscle weakness in most and neurocognitive outcomes in some patients. In GAMTdeficient patients, supplementation with oral creatine monohydrate (up to 400800 mg/kg/24 hr), ornithine (up to 400-800 mg/kg/24 hr), and dietary arginine restriction may result in improved muscle tone and neurocognitive development and may alleviate seizures. In CRTR-deficient patients, administration of creatine and its precursors (arginine and glycine) does not restore creatine in the brain, but some patients may experience improvements of seizures and neurocognitive outcomes. AGAT and GAMT defects are inherited as autosomal recessive traits. The gene for AGAT (GATM) is on chromosome 15q21.1 and that for GAMT (GAMT) is on chromosome 19p13.3. CRTR is an X-linked disorder and the gene (SLC6A8) is on Xq28. CRTR defect is the most common cause of creatine deficiency, accounting for up to 1–2% of males with intellectual disability of unknown cause.

Bibliography Bjoraker KJ, Swanson MA, Coughlin IICR, et al. Neurodevelopmental outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated nonketotic hyperglycemia. J Pediatr . 2016;170:234–239. Cheillan D, Joncquel-Chevalier Curt M, Briand G, et al. Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms. Orphanet J Rare Dis . 2012;7:96. Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med . 2013;369:649–658. Coulter-Mackie MB, White CT, Lange D, et al. Primary hyperoxaluria type 1. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2002 [updated 2014] https://www.ncbi.nlm.nih.gov/books/NBK1283/ [1993–

2017]. Dhar SU, Scaglia F, Li FY, et al. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab . 2009;96:38–43. Ellis D, Lieb J. Hyperoxaluria and genitourinary disorders in children ingesting almond milk products. J Pediatr . 2015;167:1155–1158. Menéndez Suso JJ, Del Cerro Marín MJ, Dorao MartínezRomillo P, et al. Nonketotic hyperglycinemia presenting as pulmonary hypertensive vascular disease and fatal pulmonary edema in response to pulmonary vasodilator therapy. J Pediatr . 2012;161:557–559. Mercimek-Mahmutoglu S, Ndika J, Kanhai W, et al. Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. Hum Mutat . 2014;35:462–469. Mercimek-Mahmutoglu S, Salomons GS. Creatine deficiency syndromes. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2009 [updated 2015] https://www.ncbi.nlm.nih.gov/books/NBK3794/ [1993– 2017]. Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S, Salomons GS. Creatine deficiency syndromes. Pagon RA, Adam MP, Ardinger HH, et al. GeneReviews [Internet] . University of Washington: Seattle; 2009 [updated 2011] http://www.ncbi.nlm.nih.gov/books/NBK3794/ [1993–2014]. Milliner DS, Harris PC, Lieske JC. Primary hyperoxaluria type 3. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2015 https://www.ncbi.nlm.nih.gov/books/NBK316514/ [1993– 2017].

Nasrallah F, Feki M, Kaabachi N. Creatine and creatine deficiency syndromes: biochemical and clinical aspects. Pediatr Neurol . 2010;42:163–171. Phillips IR, Shephard EA. Primary trimethylaminuria . https://www.ncbi.nlm.nih.gov/books/NBK1103/ . Rezvani I, Auerbach VH. Primary hyperoxaluria. N Engl J Med . 2013;369:2162–2163. Rumsby G. Primary hyperoxaluria type 2. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2008 [updated 2011] https://www.ncbi.nlm.nih.gov/books/NBK2692/ [1993– 2017]. Sass JO, Fischer K, Wang R, et al. D -Glyceric aciduria is caused by genetic deficiency of D -glycerate kinase (GLYCTK). Hum Mutat . 2010;31:1280–1285. Stockler-Ipsiroglu S, van Karnebeek C, Longo N, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab . 2014;111:16–25. Valayannopoulos V, Boddaert N, Chabli A, et al. Treatment by oral creatine, L -arginine and L -glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis . 2012;35:151–157. Van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet . 2013;50:463–472. Van de Kamp JM, Mancini GM, Salomons GS. X-linked creatine transporter deficiency: clinical aspects and pathophysiology. J Inherit Metab Dis . 2014;37:715–733. Van Hove J, Coughlin C II, Scharer G. Glycine encephalopathy. Pagon RA, Adam MP, Ardinger HH, et al. GeneReviews [Internet] . University of Washington: Seattle; 2002 [updated

2013] http://www.ncbi.nlm.nih.gov/books/NBK1357/ [1993– 2014]. Williams EL, Bockenhauer D, van't Hoff WG, et al. The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. Nephrol Dial Transplant . 2012;27:3191–3195.

103.8

Serine Deficiency Disorders (Serine Biosynthesis and Transport Defects) Oleg A. Shchelochkov, Charles P. Venditti

Keywords serine phosphoglycerate dehydrogenase PHGDH PGDH phosphoserine aminotransferase PSAT PSAT1 3-phosphoserine phosphatase PSP Neu-Laxova syndrome serine transporter ASCT1 SLC1A4

Serine is a nonessential amino acid supplied through dietary sources and through its endogenous synthesis, mainly from glucose and glycine. The endogenous production of serine comprises an important portion of the daily requirement of this amino acid, especially in the synaptic junctions where it contributes to the metabolism of phospholipids as well as D -serine and glycine, both involved in neurotransmission (see Chapter 103.11 ). Consequently, deficiency of any of the enzymes involved in the biosynthesis of serine or its transport causes neurologic manifestations. The clinical spectrum of serine deficiency disorders is wide and varies from Neu-Laxova syndrome on the severe end of spectrum to epilepsy and developmental delay on the milder end. Affected patients respond favorably to oral supplementation with serine and glycine provided that the treatment is initiated very early in life. Figs. 103.8 and 103.10 show the metabolic pathway for synthesis and catabolism of serine.

3-Phosphoglycerate Dehydrogenase Deficiency 3-Phosphoglycerate dehydrogenase (PHGDH ) deficiency has a broad range of symptoms and ages of presentation. Neu-Laxova syndrome type 1 is the most severe manifestation and presents prenatally with intrauterine growth restriction and congenital anomalies, including dysmorphic facial features, microcephaly, CNS malformations, limb deformities, and ichthyosis. Most patients with this form are stillborn or have early neonatal mortality. Infantile-onset PHGDH deficiency presents with feeding problems, failure to thrive, vomiting, irritability, intractable seizures, severe developmental delay, and hypertonia progressing to spastic quadriplegia. Nystagmus, cataracts, hypogonadism, and megaloblastic anemia have been observed in some affected infants. Patients with a milder form of this disorder experience cognitive impairment, behavioral problems, sensorineural polyneuropathy, and childhood-onset seizures. Laboratory findings include low fasting levels of serine and glycine in plasma and very low levels of serine and glycine in CSF. No abnormal organic acid metabolite is found in the urine. MRI of the brain shows cerebral atrophy with enlarged ventricles, significant attenuation of white matter, and impaired myelination. Diagnosis can be confirmed by DNA analysis or by measurement of the enzyme activity in cultured fibroblasts. Treatment with high doses of serine (200-700 mg/kg/24 hr orally) and glycine (200-300 mg/kg/24 hr)

normalizes the serine levels in the blood and CSF. When started postnatally, this treatment may improve seizures, spasticity, and brain myelination. One case report suggests that developmental delay may be prevented if the treatment commences in the 1st days of life or prenatally. The condition is inherited as an autosomal recessive trait. The gene for 3phosphoglycerate dehydrogenase enzyme (PHGDH) has been mapped to chromosome 1p12. If familial pathogenic variants are known, molecular prenatal diagnosis is possible. Administration of serine to the mother carrying an affected fetus was associated with stabilization of the fetal head circumference, as evidenced by ultrasound. Treatment with supplemental serine has continued postnatally; the patient remained normal neurologically at 4 yr of age. The favorable response of this condition to a relatively straightforward treatment makes this diagnosis an important consideration in any child with microcephaly and neurologic defects such as psychomotor delay or a seizure disorder. Measurements of serine and glycine in the CSF are critical for diagnosis because mild decreases of these amino acids in the plasma can be easily overlooked.

Phosphoserine Aminotransferase Deficiency Phosphoserine aminotransferase 1 (PSAT1 ) catalyzes conversion of 3phosphohydroxypyruvate to 3-phosphoserine (see Fig. 103.10 ). Deficiency of this enzyme may present in the neonatal period with poor feeding, cyanotic episodes, and irritability and may progress to intractable, multifocal seizures and microcephaly. Brain imaging may reveal generalized cerebral and cerebellar atrophy. Laboratory studies done on postprandial plasma samples may reveal normal or mildly decreased levels of serine and glycine. Serine and glycine levels are usually more depressed on the CSF amino acid analysis. Treatment with serine and glycine as outlined earlier may result in clinical improvement. The condition is inherited as an autosomal recessive trait, and the gene (PSAT1) is mapped to chromosome 9q21.2.

3-Phosphoserine Phosphatase

Deficiency 3-Phosphoserine phosphatase catalyzes the final step in the L -serine synthesis converting 3-phosphoserine to L -serine. Deficiency of this enzyme results in a rare disorder with clinical and biochemical findings indistinguishable from the PHGDH and PSAT1 deficiencies. The disorder is caused by autosomal recessive pathogenic variants in PSPH mapped to chromosome 7p11.2.

Bibliography Acuna-Hidalgo R, Schanze D, Kariminejad A, et al. NeuLaxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L -serine biosynthesis pathway. Am J Hum Genet . 2014;95(3):285–293. El-Hattab AW. Serine biosynthesis and transport defects. Mol Genet Metab . 2016;118(3):153–159. Tabatabaie L, Klomp LW, Berger R, et al. L -serine synthesis in the central nervous system: a review on serine deficiency disorders. Mol Genet Metab . 2010;99:256–262.

103.9

Proline Oleg A. Shchelochkov, Charles P. Venditti

Keywords proline hydroxyproline hyperprolinemia hyperprolinemia type 1 proline oxidase PRODH hyperprolinemia type 2 aldehyde dehydrogenase 4 ALDH4A1 pyrroline-5-carboxylate P5C prolidase prolidase deficiency PEPD De novo proline synthesis pyrroline-5-carboxylate synthase P5C synthase ALDH18A1 pyrroline-5-carboxylate reductase PYCR1 de Barsy syndrome Proline is a nonessential amino acid synthesized endogenously from glutamic

acid, ornithine, and arginine (see Fig. 103.9 ). Proline and hydroxyproline are found in high concentrations in collagen. Normally, neither of these amino acids is found in large quantities in urine. Excretion of proline and hydroxyproline as iminopeptides (dipeptides and tripeptides containing proline or hydroxyproline) is increased in disorders of accelerated collagen turnover, such as rickets or hyperparathyroidism. Proline is also found in synapses, where it can interact with glycine and glutamate receptors (see Chapter 103.11 ). The catabolic pathway of proline and hydroxyproline produces glyoxylic acid, which can be further metabolized to glycine or oxalic acid (see Fig. 103.8 ). Accumulation of proline in tissues is associated with disorders of hyperprolinemia type 1 and hyperprolinemia type 2. Reduced de novo synthesis of proline causes syndromes manifesting with cutis laxa (see Fig. 678.8 ) with progeroid features or spastic paraplegia . Two types of primary hyperprolinemia have been described.

Hyperprolinemia Type I This rare autosomal recessive condition is caused by deficiency of proline oxidase (proline dehydrogenase; see Fig. 103.9 ). Most patients with hyperprolinemia type 1 appear asymptomatic, although some may present with intellectual disability, seizures, and behavioral problems. Hyperprolinemia may also be a risk factor for autism spectrum disorders and schizophrenia. The nature of such wide phenotypic range in this biochemical condition has not been elucidated. The gene encoding proline oxidase (PRODH) is mapped to 22q11.2 and is located within the critical region for the velocardiofacial syndrome . Laboratory studies reveal high concentrations of proline in plasma, urine, and CSF. Increased urinary excretion of hydroxyproline and glycine is also present, which could be related to saturation of the shared tubular reabsorption mechanism due to massive prolinuria. No effective treatment has yet emerged. Restriction of dietary proline causes modest improvement in plasma proline with no proven clinical benefit.

Hyperprolinemia Type II This is a rare autosomal recessive condition caused by the deficiency of Δ1 pyrroline-5-carboxylate dehydrogenase (aldehyde dehydrogenase 4; see Fig.

103.9 ). Intellectual disability and seizures (usually precipitated by an intercurrent infection) have been reported in affected children, but asymptomatic patients have also been described. The cause for such disparate clinical outcomes is incompletely understood. The gene encoding P5C dehydrogenase (ALDH4A1) is mapped to chromosome 1p36.13. Laboratory studies reveal increased concentrations of proline and Δ1 pyrroline-5-carboxylic acid (P5C) in blood, urine, and CSF. The presence of P5C differentiates this condition from hyperprolinemia type I. Increased level of P5C in body fluids, especially in the CNS, appears to antagonize vitamin B6 and lead to vitamin B6 dependency (see Chapter 103.14 ). Vitamin B6 dependency may be the main cause of seizures and neurologic findings in this condition and may explain the variability in clinical manifestations in different patients. Treatment with high doses of vitamin B6 is recommended.

Prolidase Deficiency During collagen degradation, imidodipeptides are formed and are normally cleaved by tissue prolidase. Deficiency of prolidase, which is inherited as an autosomal recessive trait, results in the accumulation of imidodipeptides in body fluids. Age at onset varies from 6 mo to the 3rd decade of life. The clinical manifestations of this rare condition also vary and include recurrent, severe, and painful skin ulcers, which are typically on hands and legs. Other skin lesions that may precede ulcers by several years may include a scaly erythematous maculopapular rash, purpura, and telangiectasia. Most ulcers become infected. Healing of the ulcers may take months. Other findings include developmental delays, intellectual disability, organomegaly, anemia, thrombocytopenia, and immune dysfunction resulting in increased susceptibility to infections (recurrent otitis media, sinusitis, respiratory infection, splenomegaly). Some patients may have craniofacial abnormalities such as ptosis, ocular proptosis, hypertelorism, small beaked nose, and prominent cranial sutures. Asymptomatic cases have also been reported. Increased incidence of systemic lupus erythematosus has been noted in children. High levels of urinary excretion of imidodipeptides are diagnostic. The gene for prolidase (PEPD) has been mapped to chromosome 19q13.11. The diagnosis can be confirmed using DNA analysis. Enzyme assay may be performed in erythrocytes or cultured skin fibroblasts.

Treatment of prolidase deficiency is supportive. Infectious complications can be fatal and warrant close and proactive antibiotic management. Oral supplementation with proline, ascorbic acid, and manganese and topical proline and glycine have not been found to be consistently effective in all patients.

Disorders of De Novo Proline Synthesis De novo synthesis of proline and ornithine from glutamate appears to be critical in the normal biology of connective tissue and to maintain urea cycle in a repleted state. Correspondingly, clinical manifestations of these disorders encompass connective tissue abnormalities, nervous system abnormalities, and variable biochemical abnormalities reflecting urea cycle dysfunction. This section summarizes clinical and laboratory findings associated with the deficient function of Δ1 -pyrroline-5-carboxylate (P5C) synthase (see Fig. 103.9 ) encoded by ALDH18A1 (mapped to 10q24.1) and PSC reductase encoded by PYCR1 (mapped to 17q25.3). Deficient activity of P5C synthase has been associated with several phenotypes, including de Barsy syndrome , characterized by cataracts, growth retardation, intellectual disability, a prematurely aged appearance (progeroid features), and cutis laxa. Some patients may show pyramidal signs. Skin biopsy may reveal decreased size of elastic fibers and collagen abnormalities. Brain imaging studies show cortical atrophy, ventriculomegaly, and reduced creatine. Laboratory findings include reduced levels of proline, ornithine, citrulline, and arginine as well as mild fasting hyperammonemia. Patients may show only intermittent abnormalities of plasma amino acids, likely related to the time of blood sampling in relation to the last meal. Interestingly, both autosomal recessive and autosomal dominant forms of inheritance have been described. The diagnosis can be suspected in a patient presenting with cutis laxa, developmental delay, mild hyperammonemia, and amino acid abnormalities. The diagnosis can be confirmed using molecular DNA analysis or using the glutamine loading test on skin fibroblasts. Treatment is supportive, although supplementation with citrulline or arginine to address hyperammonemia and cerebral creatine depletion have been proposed. Deleterious mutations in PYCR1 result in the abnormal function of the mitochondrial Δ1 -pyrroline-5-carboxylate reductase, which catalyzes the last step in the synthesis of proline from P5C. The most consistent finding in patients

carrying proven pathogenic variants in PYCR1 include triangular facies, cutis laxa (de Barsy–like syndrome ), joint hypermobility, wrinkled skin, gerodermia osteodysplastica, and progeroid features. Skin biopsy reveals reduction of the elastic fibers and infiltration with inflammatory cells. Some patients may have epilepsy, developmental delays, intellectual disability, cataracts, osteopenia, and failure to thrive. However, many of the affected families are consanguineous, thus confounding the phenotype. Of note, plasma amino acid analysis typically reveals no specific abnormalities. The diagnosis depends on the recognition of the skin findings and can be confirmed using molecular DNA analysis. Available pedigrees of families affected by PYCR1 -related disorder supports the autosomal recessive mode of inheritance.

Bibliography Coutelier M, Goizet C, Durr A, et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain . 2015;138(Pt 8):2191–2205. Dimopoulou A, Fischer B, Gardeitchik T, et al. Genotypephenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Mol Genet Metab . 2013;110(3):352–361. Ferreira C, Wang H. Prolidase Deficiency. 2015 Jun 25. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington, Seattle: Seattle (WA); 1993-2017 [Available from] https://www.ncbi.nlm.nih.gov/books/NBK299584/ . Kurien BT, D'Sousa A, Bruner BF, et al. Prolidase deficiency breaks tolerance to lupus-associated antigens. Int J Rheum Dis . 2013;16:674–680. Martinelli D, Häberle J, Rubio V, et al. Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine. J Inherit Metab Dis . 2012;35(5):761–776. Mitsubuchi H, Nakamura K, Matsumoto S, et al. Inborn errors

of proline metabolism. J Nutr . 2008;138:2016S–2020S. Raux G, Bunsel E, Hecketsweiler B, et al. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum Mol Genet . 2007;16:83–91.

103.10

Glutamic Acid Oleg A. Shchelochkov, Charles P. Venditti

Keywords glutamic acid glutamate γ-glutamylcysteinylglycine glutathione γ-glutamyl cycle glutathione synthetase GSSD 5-oxoprolinase OPLAH glutamate-cysteine ligase γ-glutamylcysteine synthetase GCLC γ-glutamyl transpeptidase GGT glutathionemia hemolytic anemia 5-oxoproline 5-oxoprolinemia

high–anion gap metabolic acidosis 5-oxoprolinuria secondary 5-oxoprolinuria Glutamic acid and its amide derivative glutamine have a wide range of functions in the body. Glutamate plays numerous biologic roles, functioning as a neurotransmitter, an intermediate compound in many fundamental biochemical reactions, and a precursor of an inhibitory neurotransmitter γ-aminobutyric acid (GABA) (see Chapter 103.11 ). Another major product of glutamate is glutathione (γ-glutamylcysteinylglycine). This ubiquitous tripeptide, with its function as the major antioxidant in the body, is synthesized and degraded through a complex cycle called the γ-glutamyl cycle (Fig. 103.11 ). Because of its free sulfhydryl (–SH) group and its abundance in the cell, glutathione protects other sulfhydryl-containing compounds (e.g., enzymes, coenzyme A) from oxidation. It is also involved in the detoxification of peroxides, including hydrogen peroxide, and in keeping the intracellular milieu in a reduced state. In addition, glutathione participates in amino acid transport across the cell membrane through the γ-glutamyl cycle.

FIG. 103.11 The γ-glutamyl cycle and related pathways. Defects of the glutathione (GSH) synthesis and degradation are noted. Enzymes: (1) γ-Glutamyl transpeptidase (GGT), (2) γ-glutamyl cyclotransferase, (3) 5-oxoprolinase, (4) γ-glutamyl-cysteine synthetase, (5) glutathione synthetase, (6) glutamate decarboxylase, (7) γ-aminobutyric acid (GABA) transaminase, (8) succinate-semialdehyde dehydrogenase, (9) glutamine synthetase, (10) dipeptidase.

One of the biochemical manifestations of γ-glutamyl cycle deficiency is increased urinary excretion of 5-oxoproline, which could be the result of both genetic and non-genetic causes. 5-Oxoprolinemia should be routinely considered in the differential diagnosis of high–anion gap metabolic acidosis (HAGMA). Two metabolic disorders can present with massive 5-oxoprolinuria: glutathione synthetase deficiency and 5-oxoprolinase deficiency (Fig. 103.11 ). However, a more common clinical scenario is a transient and mild urinary elevation of 5oxoproline in urine that can be seen in a variety of metabolic and acquired conditions, such as exposure to acetaminophen and some hydrolyzed-protein

formulas, severe burns, Stevens-Johnson syndrome, homocystinuria, urea cycle defects, and tyrosinemia type I.

Glutathione Synthetase Deficiency Three forms of this rare condition have been reported. In the mild form , enzyme deficiency causes glutathione deficiency only in erythrocytes. These patients present with hemolytic anemia without chronic metabolic acidosis and demonstrate high residual activity of glutathione synthetase on enzymatic testing. A moderate form has also been observed in which the hemolytic anemia is associated with variable degrees of metabolic acidosis and 5oxoprolinuria. Its severe form is distinguished by presence of hemolytic anemia accompanied by severe acidosis, massive 5-oxoprolinuria, and neurologic manifestations.

Glutathione Synthetase Deficiency, Severe and Moderate Forms Affected newborn infants with this rare condition usually develop acute symptoms of metabolic acidosis, jaundice, and mild to moderate hemolytic anemia in the 1st few days of life. Chronic acidosis continues after recovery. Similar episodes of life-threatening acidosis may occur during an infection (e.g., gastroenteritis) or after a surgical procedure. Progressive neurologic damage develops with age, manifested by intellectual disability, spastic tetraparesis, ataxia, tremor, dysarthria, and seizures. Susceptibility to infections, presumably because of granulocyte dysfunction, is observed in some patients. Patients with the moderate form of glutathione synthetase deficiency have milder acidosis and less 5-oxoprolinuria than is seen in the severe form, with no neurologic manifestations. Laboratory findings include metabolic acidosis, mild to moderate degrees of hemolytic anemia, and 5-oxoprolinuria. High concentrations of 5-oxoproline are also found in blood. The urinary and blood levels of 5-oxoproline is less pronounced in patients with moderate form of the condition. The glutathione content of erythrocytes is markedly decreased. Increased synthesis of 5oxoproline in this disorder is thought to be the result of the conversion of γglutamylcysteine to 5-oxoproline by the enzyme γ-glutamyl cyclotransferase

(see Fig. 103.11 ). γ-Glutamylcysteine production increases greatly because the normal inhibitory effect of glutathione on the γ-glutamylcysteine synthetase enzyme is removed. Treatment of acute attack includes hydration, correction of acidosis (by infusion of sodium bicarbonate), and measures to correct anemia and hyperbilirubinemia. Chronic administration of alkali is usually needed indefinitely. Supplementation with vitamin C, vitamin E, and selenium is recommended. Drugs and oxidants known to cause hemolysis and stressful catabolic states should be avoided. Oral administration of glutathione analogs has been tried with variable success. Prenatal diagnosis can be achieved by the measurement of 5-oxoproline in amniotic fluid, by enzyme analysis in cultured amniocytes or chronic villus samples, or by DNA analysis. Successful pregnancy in an affected female (moderate form) has been reported, with favorable outcomes for both mother and infant.

Glutathione Synthetase Deficiency, Mild Form The mild form has been reported in only a few patients. Mild to moderate hemolytic anemia has been the only clinical finding. Splenomegaly has been reported in some patients. Cognitive development is normal. Chronic metabolic acidosis typically is not seen. Some patients can have increased concentrations of 5-oxoproline in the urine. Pathogenic variants in the gene for this enzyme (GSSD) appear to decrease the half-life of the enzyme, which causes an increased rate of protein turnover without affecting its catalytic function. The expedited rate of enzyme turnover caused by these pathogenic variants is of little or no consequence for tissues with protein synthetic capability. However, inability of mature erythrocytes to synthesize protein results in glutathione deficiency in the erythrocytes. Treatment is that of hemolytic anemia and avoidance of drugs and oxidants that can trigger the hemolytic process. All forms of glutathione synthetase deficiency are inherited as an autosomal recessive trait. GSSD is located on chromosome 20q11.22. Diagnosis can be confirmed by DNA analysis or enzyme activity in erythrocytes or skin fibroblasts.

5-Oxoprolinase Deficiency

More than 20 patients with 5-oxoprolinuria (4-10 g/day) caused by 5oxoprolinase (see Fig. 103.11 ) deficiency have been described. No specific clinical picture has yet emerged; completely asymptomatic affected individuals have also been identified. It is therefore not clear whether 5-oxoprolinase deficiency is of any clinical consequence. No treatment is currently recommended. The gene for the enzyme (OPLAH) is on chromosome 8q24.3.

γ-Glutamylcysteine Synthetase Deficiency (Glutamate-Cysteine Ligase Deficiency) Only a few patients with this enzyme deficiency have been reported. The most consistent clinical manifestation has been mild chronic hemolytic anemia. Acute attacks of hemolysis have occurred after exposure to sulfonamides. Peripheral neuropathy and progressive spinocerebellar degeneration have been noted in 2 siblings in adulthood. Laboratory findings of chronic hemolytic anemia were present in all patients. Generalized aminoaciduria is also present because the γglutamyl cycle is involved in amino acid transport in cells (see Fig. 103.11 ). Treatment should focus on the management of hemolytic anemia and avoidance of drugs and oxidants that may trigger the hemolytic process. The condition is inherited as an autosomal recessive trait; the gene (GCLC) is mapped to chromosome 6p12.1.

γ-Glutamyl Transpeptidase Deficiency (Glutathionemia) γ-Glutamyl transpeptidase (GGT) is present in any cell that has secretory or absorptive functions. It is especially abundant in the kidneys, pancreas, intestines, and liver. The enzyme is also present in the bile. Measurement of GGT in the blood is frequently performed to evaluate liver and bile duct diseases. GGT deficiency causes elevation in glutathione concentrations in body fluids, but the cellular levels remain normal (see Fig. 103.11 ). Because only a few patients with GGT deficiency have been reported, the scope of clinical manifestations has not yet been defined. Mild to moderate intellectual disability and severe behavioral problems were observed in 3 patients. However, 1 of 2 sisters with this condition had normal intelligence as an adult, and the other had

Prader-Willi syndrome. Laboratory findings include marked elevations in urinary concentrations of glutathione (up to 1 g/day), γ-glutamylcysteine, and cysteine. None of the reported patients has had generalized aminoaciduria, a finding that would have been expected to occur in this enzyme deficiency (see Fig. 103.11 ). Diagnosis can be confirmed by measurement of the enzyme activity in leukocytes or cultured skin fibroblasts. No effective treatment has been proposed. The condition is inherited as an apparent autosomal recessive trait. γGlutamyl transpeptidases represent a large family of enzymes encoded by at least 7 genes.

Genetic Disorders of Metabolism of γAminobutyric Acid See Chapter 103.11 .

Bibliography Almusafri F, Elamin HE, Khalaf TE, et al. Clinical and molecular characterization of 6 children with glutamatecysteine ligase deficiency causing hemolytic anemia. Blood Cells Mol Dis . 2017;65:73–77. Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr . 2001;139(1):79–84. Sass JO, Gemperle-Britschgi C, Tarailo-Graovac M, et al. Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families. Mol Genet Metab . 2016;119(1–2):44–49.

103.11

Genetic Disorders of Neurotransmitters Oleg A. Shchelochkov, Charles P. Venditti

Keywords neurotransmitters tyrosine hydroxylase deficiency autosomal recessive Segawa syndrome aromatic L -amino acid decarboxylase deficiency AADC GTP cyclohydrolase 1 deficiency GCH1 autosomal dominant Segawa syndrome BH4 deficiency hyperphenylalaninemia sepiapterin reductase deficiency SPR dopamine β-hydroxylase deficiency DBH monoamine oxidase deficiency monoamine oxidase A deficiency MAOA MAOB γ-aminobutyric acid transaminase deficiency ABAT succinic semialdehyde dehydrogenase deficiency γ-hydroxybutyric aciduria SSADH ALDH5A1 dopamine transporter protein deficiency

SLC6A3 dopamine-serotonin vesicular transporter disease vesicular monoamine transporter deficiency SLC18A2 vesicular monoamine transporter 2 VMAT2 hyperprolinemia Neurotransmitters are chemical substances released from the axonal end of excited neurons at the synaptic junctions; they mediate initiation and amplification or inhibition of neural impulses. A number of amino acids and their metabolites comprise the bulk of neurotransmitters. Pathogenic variants in genes responsible for the synthesis, transport, or degradation of these substances may cause conditions that manifest neurologic and/or psychiatric abnormalities (Table 103.3 ). Previously, children affected by disorders of neurotransmitters have been given syndromic diagnoses such as cerebral palsy, epilepsy, parkinsonism, dystonia, or autism. Diagnosis, in most cases, requires specialized laboratory studies of the cerebrospinal fluid (CSF), because some of the neurotransmitters generated in the central nervous system (CNS), dopamine and serotonin, do not cross the blood-brain barrier, and their abnormal concentrations are not detected in the serum or urine. A growing number of these conditions are being identified; diseases once thought to be rare are now diagnosed with increasing frequency. Table 103.3

Genetic Disorders of Neurotransmitters in Children TRANSMITTER MONOAMINES Dopamine Serotonin and dopamine

Norepinephrine GABA

SYNTHESIS DEFECTS

DEGRADATION DEFECTS

TH deficiency AADC deficiency BH4 deficiency With and without hyperphenylalaninemia DβH deficiency ?

MAO deficiency MAO deficiency

Histamine HDC deficiency TRANSPORTER PROTEINS

MAO deficiency GABA transaminase deficiency GHB aciduria ?

Dopamine transporter Vesicular monoamine transporter AMINO ACIDS Proline Serine Glycine

DAT deficiency VMAT2 deficiency

? ?

? 3-PGD, PSAT, PSPH deficiencies 3-PDG, PSAT deficiencies

Hyperprolinemia ? NKH

AADC, Aromatic L -amino acid decarboxylase; BH4 , tetrahydrobiopterin; DAT, dopamine transporter; DβH, dopamine β-hydroxylase; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyric acid; HDC, histidine decarboxylase; hyperphe, hyperphenylalaninemia; MAO, monoamine oxidase; NKH, nonketotic hyperglycinemia; 3-PGD, 3-phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, 3-Phosphoserine Phosphatase Deficiency; TH, tyrosine hydroxylase; VMAT2, vesicular monoamine transporter 2.

Tyrosine Hydroxylase Deficiency (Infantile Parkinsonism, Autosomal Recessive Dopa-Responsive Dystonia, Autosomal Recessive Segawa Syndrome) Tyrosine hydroxylase catalyzes the formation of L -dopa from tyrosine. Deficiency of this enzyme results in deficiencies of dopamine and norepinephrine (see Fig. 103.2 ). The differential diagnosis includes a wide range of inherited dystonias, including autosomal dominant dystonia caused by GTP cyclohydrolase 1 deficiency. Clinical manifestations range from mild to very severe. In general, 2 phenotypes have been recognized. In the mild form (dopa-responsive dystonia, or type A ), symptoms of unilateral limb dystonia causing gait incoordination and postural tremor occur in childhood and worsen with age if the condition remains untreated. Diurnal variation of symptoms (worse at the end of the day) may be present. Cognitive development is usually normal. In the severe form of tyrosine hydroxylase deficiency (infantile parkinsonism, infantile encephalopathy, or type B ), the clinical manifestations occur at birth or shortly thereafter and include microcephaly, developmental delay, involuntary movements of the limbs with spasticity, dystonia, ptosis, expressionless face, oculogyric crises (upward eye-rolling movements), and autonomic dysfunction (temperature instability, excessive sweating, hypoglycemia, salivation, tremor,

gastrointestinal reflux, constipation). Brisk reflexes, myoclonus, athetosis, and distal chorea may be present. The patient with the severe form usually shows incomplete response to treatment with L -dopa and is prone to developing L dopa–induced dyskinesia as a side effect. Laboratory findings include reduced levels of dopamine and its metabolite homovanillic acid (HVA) and normal concentrations of tetrahydrobiopterin (BH4 ), neopterin, and 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of serotonin) in the CSF. Serum prolactin levels are usually elevated. These findings are not diagnostic of the condition; diagnosis should be established by molecular gene analysis. Treatment with L -dopa/carbidopa results in significant clinical improvement in most patients, but the severe forms are invariably associated with L -dopa– induced dyskinesias. To minimize the side effects of therapy, the treatment should be started with a low dose and increased very slowly, if needed. Other therapeutic interventions include anticholinergics, serotonergic agents, and monoamine oxidase (MAO) B inhibitors, including amantadine, biperiden, and selegiline. Bilateral subthalamic nucleus deep brain stimulation has shown clinical efficacy in one case. Tyrosine hydroxylase deficiency is inherited as an autosomal-recessive trait. Molecular testing for pathogenic variants in the TH gene is available clinically.

Aromatic l-Amino Acid Decarboxylase Deficiency Aromatic L -amino acid decarboxylase (AADC) is a vitamin B6 –dependent enzyme that catalyzes the decarboxylation of both 5-hydroxytryptophan to form serotonin (see Fig. 103.5 ) and L -dopa to generate dopamine, (see Fig. 103.2 ). Clinical manifestations are related to reduced availability of dopamine and serotonin. Poor feeding, lethargy, hypotension, hypothermia, oculogyric crises, and ptosis have been observed in affected neonates. Clinical findings in infants and older children include developmental delay, truncal hypotonia with hypertonia of limbs, oculogyric crises, extrapyramidal movements (choreoathetosis, dystonia, myoclonus), and autonomic abnormalities (sweating, salivation, irritability, temperature instability, hypotension). Symptoms may have a diurnal variation, becoming worse by the end of the day. Laboratory findings include decreased concentrations of dopamine and

serotonin and their metabolites (HVA, 5-HIAA, norepinephrine, vanillylmandelic acid [VMA]) and increased levels of 5-hydroxytryptophan, L dopa, and its metabolite (3-O -methyldopa) in body fluids, especially in CSF. Elevated serum concentrations of prolactin (a result of dopamine deficiency) have also been observed. MRI of the brain reveals cerebral atrophy with degenerative changes in the white matter. A urine screening program, focused on 3-O -methyl-dopa and VMA, has demonstrated diagnostic promise in highdisease prevalence populations. Treatment with neurotransmitter precursors has produced limited clinical improvement. Dopamine and serotonin have no therapeutic value because of their inability to cross the blood-brain barrier. Dopamine agonists (L dopa/carbidopa, bromocriptine), MAO inhibitors (tranylcypromine), serotonergic agents and high doses of pyridoxine, a cofactor for AADC enzyme, have been tried. Pyridoxine supplementation in patients harboring the p.S250F variant in AADC may be beneficial. The recent demonstration of CNS-directed gene therapy with an adeno-associated viral vector has shown benefit in some patients. Preimplantation genetic diagnosis after in vitro fertilization has been achieved in the high-prevalence Taiwanese population. The gene encoding AADC (DDC ) is on chromosome 7p12.1. The condition is inherited as an autosomal recessive trait.

Tetrahydrobiopterin Deficiency See Chapter 103.1 . BH4 is the cofactor for phenylalanine hydroxylase (see Fig. 103.1 ), tyrosine hydroxylase (see Fig. 103.2 ), tryptophan hydroxylase (see Fig. 103.5 ), and nitric oxide synthase. It is synthesized from GTP in many tissues (see Fig. 103.1 ). Deficiencies of enzymes involved in the biosynthesis of BH4 result in inadequate production of this cofactor, which causes deficiencies of monoamine neurotransmitters with or without concomitant hyperphenylalaninemia.

Tetrahydrobiopterin Deficiency With Hyperphenylalaninemia See Chapter 103.1 .

Tetrahydrobiopterin Deficiency Without Hyperphenylalaninemia GTP Cyclohydrolase 1 Deficiency (Hereditary Progressive Dystonia, Autosomal Dominant Dopa-Responsive Dystonia, Autosomal Dominant Segawa Syndrome) This form of dystonia, caused by guanosine triphosphate (GTP) cyclohydrolase 1 deficiency, is inherited as an autosomal dominant trait and is more common in females than males (4 : 1 ratio) (see Chapter 615.4 ). Clinical manifestations usually start in early childhood with tremor and dystonia of the lower limbs (toe gait ), which may spread to all extremities within a few years. Torticollis, dystonia of the arms, and poor coordination may precede dystonia of the lower limbs. Early development is generally normal. Symptoms have an impressive diurnal variation, becoming worse by the end of the day and improving with sleep. Autonomic instability is not uncommon. Parkinsonism may also be present or develop with advancing age. Late presentation in adult life has also been reported, associated with action dystonia (“writer's cramp”), torticollis, or generalized rigid hypertonia with tremor but without postural dystonia. Additionally, limited data on adults suggest symptoms related to serotonin deficiency (sleep disturbance, cognitive impairment, impulsivity). Laboratory findings show reduced levels of BH4 and neopterin in the CSF without hyperphenylalaninemia (see Chapter 103.1 ). Dopamine and its metabolite (HVA) may also be reduced in CSF. The serotonergic pathway is less affected by this enzyme deficiency; thus concentrations of serotonin and its metabolites are usually normal. Plasma phenylalanine is normal, but an oral phenylalanine loading test (100 mg/kg) produces an abnormally high plasma phenylalanine level with an elevated phenylalanine/tyrosine ratio. The ratio, obtained at the 2-3 hr after the load, in combination with urine neopterin level, has optimal diagnostic specificity and sensitivity. The existence of asymptomatic carriers indicates that other factors or genes may play a role in pathogenesis. The asymptomatic carrier may be identified by the phenylalanine loading test. Diagnosis may be confirmed by reduced levels of BH4 and neopterin in CSF, measurement of the enzyme activity, and molecular genetic analysis (see Chapter 103.1 ). Clinically, the condition should be differentiated from other causes of dystonias and childhood parkinsonism, especially tyrosine hydroxylase, sepiapterin reductase, and aromatic amino acid decarboxylase deficiencies.

Treatment with L -dopa/carbidopa usually produces dramatic clinical improvement. Oral administration of BH4 is also effective but is rarely used. The gene for GTP cyclohydroxylase 1 (GCH1 ) is located on chromosome 14q22.2.

Sepiapterin Reductase Deficiency Sepiapterin reductase is involved in conversion of 6-pyruvoyl-tetrahydropterin to BH4 . It also participates in the salvage pathway of BH4 synthesis (see Fig. 103.1 ). Sepiapterin reductase deficiency results in accumulation of 6-lactoyltetrahydropterin, which can be converted to sepiapterin nonenzymatically. The majority of sepiapterin is metabolized to BH4 through the salvage pathway in peripheral tissues (see Fig. 103.1 ), but because of the low activity of dihydrofolate reductase in brain, the amount of BH4 remains insufficient for proper synthesis of dopamine and serotonin. This explains the absence of hyperphenylalaninemia and the often-delayed diagnosis. Clinical manifestations usually appear within a few months of life. Cardinal manifestations include paroxysmal stiffening, oculogyric crises, and hypotonia. Additional findings include motor and language delays, weakness, limb hypertonia, dystonia, hyperreflexia, and early-onset parkinsonism. The symptoms usually have a diurnal variation. Misdiagnosis as cerebral palsy is common and a wide variability of symptoms have been reported. Diagnosis is established by measurement of CSF neurotransmitters and pterin metabolites, which reveal decreased dopamine, HVA, norepinephrine, and 5-HIAA and marked elevations of sepiapterin and dihydrobiopterin. The serum concentration of prolactin may be elevated. The phenylalanine loading test may have diagnostic utility. Diagnosis may be confirmed by molecular genetic analysis or enzyme assay in fibroblasts. Treatment with slowly increasing doses of Ldopa/carbidopa and 5-hydroxytryptophan usually produces dramatic clinical improvement. The condition is inherited as an autosomal recessive trait; the gene SPR encoding sepiapterin reductase is located on chromosome 2p13.2.

Dopamine β-Hydroxylase Deficiency Dopamine β-hydroxylase catalyzes the conversion of dopamine to norepinephrine (see Fig. 103.2 ). The deficiency of this enzyme results in reduced or absent synthesis of norepinephrine, leading to dysregulation of the

sympathetic function. Infants and children may present with difficulty opening eyes, ptosis, hypotension, hypothermia, hypoglycemia, and nasal stuffiness. Adult patients may present with profound deficits of autonomic regulation, resulting in severe orthostatic hypotension, and sexual dysfunction in males. Presyncopal symptomatology includes dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain; olfactory function remains relatively intact. The diagnosis can be aided by performing autonomic function testing (measurement of the sinus arrhythmia ratio, blood pressure studies during controlled hyperventilation, Valsalva maneuver, cold pressor, handgrip exercise). Laboratory findings include decreased or absent norepinephrine and epinephrine and their metabolites, with elevated levels of dopamine and its metabolite (HVA), in plasma, CSF, and urine. Elevated plasma dopamine may be pathognomonic for this disease. MRI of the brain shows decreased brain volume, consistent with the neurotrophic role of norepinephrine. Treatment with L dihydroxyphenylserine, which is converted to norepinephrine directly in vivo by the action of AADC, leads to significant improvement in orthostatic hypotension and normalizes noradrenaline and its metabolites. The condition is inherited as an autosomal recessive trait; the gene (DBH) encoding dopamine β-hydroxylase resides on chromosome 9q34.2.

Monoamine Oxidase a Deficiency Human genome encodes 2 monoamine oxidase (MAO) isoenzymes: MAO A and MAO B. Both enzymes catalyze oxidative deamination of most biogenic amines in the body, including serotonin (see Fig. 103.5 ), norepinephrine, epinephrine, and dopamine (see Fig. 103.2 ). The genes for both isoenzymes are on the X chromosome (Xp11.3), residing in close proximity. A deletion of both genes can also encompass a neighboring gene, NDP, resulting in a contiguous deletion syndrome, which can present as an atypical Norrie disease (see Chapter 640 ). Male patients with MAO A deficiency manifest borderline intellectual deficiency and impaired impulse control. The consequences of the isolated MAO B deficiency are incompletely understood. Combined MAO A and B deficiency causes severe intellectual disability and behavioral problems and can be associated with pronounced laboratory abnormalities (e.g., 4-6–fold serotonin elevation in physiologic fluids, elevated O -methylated amine metabolites, and reduced deamination products [VMA, HVA]). Dietary intervention (low tyramine, phenylethylamine, and L -dopa/dopamine intake) did not improve

patients' blood serotonin levels. Inheritance of MAO deficiency is X-linked. Treatment of MAO A deficiency is supportive.

Disorders of γ-Aminobutyric Acid (GABA) Metabolism GABA is the main inhibitory neurotransmitter synthesized in the synapses through decarboxylation of glutamic acid by glutamate decarboxylase (GAD). The same pathway is responsible for production of GABA in other organs, especially the kidneys and the β-cells of the pancreas. GAD enzyme requires pyridoxine (vitamin B6 ) as cofactor. Two GAD enzymes, GAD1 (GAD67 ) and GAD2 (GAD65 ) have been identified. GAD1 is the main enzyme in the brain, and GAD2 is the major enzyme in the β-cells. Antibodies against GAD65 and GAD67 have been implicated in the development of type 1 diabetes and stiffperson syndrome , respectively. GABA is catabolized to succinic acid by 2 enzymes, GABA transaminase and succinic semialdehyde dehydrogenase (SSADH) (see Fig. 103.11 ).

γ-Aminobutyric Acid Transaminase Deficiency Clinical manifestations in the 2 index infant siblings included severe psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and increased linear growth likely related to GABA-mediated increased secretion of growth hormone. Increased concentrations of GABA and β-alanine were found in CSF (see Fig. 103.11 ). Evidence of leukodystrophy was noted in the postmortem examination of the brain. A 3rd patient showed severe psychomotor retardation, recurrent episodic lethargy, and intractable seizures with comparable CSF metabolite abnormalities to those of the index probands. GABA transaminase deficiency is demonstrated in brain and lymphocytes. Treatment is symptomatic. Intervention with vitamin B6 , the cofactor for the enzyme, was without therapeutic benefit. The gene (ABAT), maps to chromosome 16p13.2; the condition is inherited as an autosomal recessive trait.

Succinic Semialdehyde Dehydrogenase

Deficiency (γ-Hydroxybutyric Aciduria) Clinical manifestations of SSADH deficiency usually begin in infancy with developmental delays with a disproportionate deficit in expressive language, hypotonia, and ataxia; seizures occur in approximately 50% of patients (see Fig. 103.11 ). Many patients also carry the diagnosis of autism spectrum disorder . Neuropsychiatric comorbidity (especially oppositional defiance, obsessioncompulsion, and hyperactivity) can be disabling, particularly in adolescents and adults. Abnormal EEG findings include background slowing and generalized spike-wave paroxysms, with variable lateralization in hemispheric onset and voltage predominance. Photosensitivity and electrographic status epilepticus of sleep have been reported in combination with difficulties in sleep maintenance and excessive daytime somnolence. MRI of the brain shows an increased T2weighted hyperintensity involving the globus pallidi, cerebellar dentate nuclei, and subthalamic nuclei, usually in a bilaterally symmetric distribution. The biochemical hallmark, γ-hydroxybutyric acid (GHB), is elevated in physiologic fluids (CSF, plasma, urine) in all patients. Increased concentrations of GABA are also found in CSF. Heightened diagnostic suspicion evolves through documentation of elevated urinary GHB, and confirmation is achieved by molecular genetic testing. Treatment remains elusive; vigabatrin (GABA-transaminase inhibitor) has been employed empirically, with mixed outcomes, and there is concern with its use as it further elevates CNS GABA in an already hyper-GABAergic disorder. Additionally, vigabatrin can cause constriction of the visual field and long-term use is contraindicated. The gene for SSADH (ALDH5A1) is located on chromosome 6p22, and inheritance follows an autosomal-recessive pattern. Prenatal diagnosis has been achieved by measurement of GHB in the amniotic fluid, assay of the enzyme activity in the amniocytes, chorionic villus sampling, or DNA analysis.

Defects in Neurotransmitter Transporter Proteins More than 20 different proteins are involved in transporting different neurotransmitters across the neuronal membranes. The main function of most of these transporters is to remove the excess neurotransmitters from the synaptic

junction back into the presynaptic neurons (reuptake). This recycling process not only regulates the precise effect of neurotransmitters at the synaptic junction, but also resupplies the presynaptic neurons with neurotransmitters for future use. A few transporter proteins are involved in shuttling neurotransmitters from the neuronal cytoplasm across the membrane of synaptic vesicles for storage (vesicular transporters). On neuronal stimulation, these vesicles release a bolus of neurotransmitters through exocytosis. As expected, pathogenic variants in transporter proteins interfere with the proper reuptake and storage of neurotransmitters and may result in clinical manifestations similar to those seen in deficiencies of neurotransmitters metabolism. Several conditions caused by pathogenic variants of neurotransmitter protein transporters have been described, including dopamine transporter protein deficiency and dopamine-serotonin vesicular transporter disease.

Dopamine Transporter Protein Deficiency This transporter protein is involved in reuptake of dopamine by the presynaptic neurons, and its deficiency causes depletion of dopamine and thus a dopamine deficiency state. Dopamine transporter protein (DAT) is encoded by SLC6A3 gene on chromosome 5p15.33. Pathogenic variants of this gene has been reported in 13 children. These children presented with symptoms of infantile parkinsonism-dystonia syndrome . Irritability and feeding difficulties started shortly after birth and progressed to hypotonia, lack of head control, parkinsonism, dystonia, and global developmental delay by early infancy. Brain MRI usually shows no abnormalities. CSF examination revealed elevation of HVA and normal level of 5-HIAAs. The urinary level of HVA and serum concentration of prolactin were increased. Diagnosis was established by demonstrating the loss-of-function mutation in the SLC6A3 gene. No effective treatment has been identified; L -dopa/carbidopa did not result in improvements in clinical or biochemical parameters.

Dopamine-Serotonin Vesicular Transporter Disease (Vesicular Monoamine Transporter Deficiency) This autosomal recessive condition, described in 8 children from a consanguineous Saudi Arabian family, is caused by a pathogenic variant in the

SLC18A2 gene. This gene encodes the vesicular monoamine transporter 2 (VMAT2), which is involved in transporting dopamine and serotonin from the cytoplasm into the synaptic storage vesicles located in the axonal terminals of the presynaptic neurons. Most affected children presented in the 1st yr of life with symptoms consistent with deficiencies of dopamine (hypotonia progressing into dystonia, parkinsonism, oculogyric crises), serotonin (sleep and psychiatric disturbances), and norepinephrine-epinephrine (excessive sweating, tremors, temperature instability, postural hypotension, ptosis). Neurocognitive delays become apparent in the 1st yr of life. No diurnal variation of the symptoms was noted. Brain imaging studies were within normal limits. Changes in the levels of CNS neurotransmitters and their metabolites have been inconsistent. The phenotype resembles that seen in AADC and BH4 deficiencies (see earlier). Diagnosis requires molecular analysis of SLC18A2 (located on chromosome 10q25.3). Treatment with L -dopa/carbidopa caused exacerbation of symptoms, whereas pramipexole, a dopamine receptor agonist, resulted in a promising clinical response.

Histidine Decarboxylase Deficiency Decarboxylation of histidine by histidine decarboxylase produces histamine, which functions as a neurotransmitter in the brain. Deficiency of this enzyme (expressed mainly in the posterior hypothalamus) results in deficiency of histamine in the CNS and in one family caused an autosomal dominant form of Tourette syndrome (see Chapter 103.13 ).

Hyperprolinemia Intellectual disability and seizures are common findings in most patients with hyperprolinemia types I and II. Patients with type I hyperprolinemia typically show a benign clinical course but could have an increased risk of developing schizophrenia. The contribution of increased concentration of proline to the mechanisms of schizophrenia, however, remains unclear. The neurologic abnormalities observed in hyperprolinemia type II are mainly caused by development of vitamin B6 dependency in this condition (see Chapter 103.9 ). Dietary intervention in hyperprolinemias type I and II is neither feasible nor recommended.

3-Phosphoglycerate Dehydrogenase Deficiency See Chapter 103.8 .

Phosphoserine Aminotransferase Deficiency See Chapter 103.8 .

Nonketotic Hyperglycinemia See Chapter 103.7 .

Bibliography Acosta MT, Munasinghe J, Pearl PL, et al. Cerebellar atrophy in human and murine succinic semialdehyde dehydrogenase deficiency. J Child Neurol . 2010;25:1457–1461. Blau N, van Spronsen FJ. Disorders of phenylalanine and tetrahydrobiopterin metabolism. Blau N, Duran M, Gibson KM, et al. Physician's guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases . Springer: Heidelberg; 2014:3–21. Clark JF, Cecil KM. Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes. Pediatr Res . 2015;77(3):398–405. Friedman J. Sepiapterin reductase deficiency. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2015 https://www.ncbi.nlm.nih.gov/books/NBK304122/ [1993– 2017]. Furukawa Y. GTP cyclohydrolase 1-deficient dopa-responsive

dystonia. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2002 [updated 2015] https://www.ncbi.nlm.nih.gov/books/NBK1508/ [1993– 2017]. Furukawa Y, Kish S. Tyrosine hydroxylase deficiency. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2008 [updated 2017] https://www.ncbi.nlm.nih.gov/books/NBK1437/ [1993– 2017]. Hwu WL, Muramatsu S, Tseng SH, et al. Gene therapy for aromatic L -amino acid decarboxylase deficiency. Sci Transl Med . 2012;4(134):134ra61. Knerr I, Gibson KM, Murdoch G, et al. Neuropathology in succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol . 2010;42:255–258. Marecos C, Ng J, Kurian MA. What is new for monoamine neurotransmitter disorders? J Inherit Metab Dis . 2014;37(4):619–626. Narboux-Nême N, Sagné C, Doly S, et al. Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences. Neuropsychopharmacology . 2011;36:2538–2550. Ng J, Zhen J, Meyer E, et al. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain . 2014;137:1107–1119. Opladen T, Hoffmann GF, Kühn AA, et al. Pitfalls in phenylalanine loading test in the diagnosis of doparesponsive dystonia. Mol Genet Metab . 2013;108:195–197. Pearl PL. Monoamine neurotransmitter deficiencies. Handb Clin Neurol . 2013;113:1819–1825. Pearl PL, Wiwattanadittakul N, Roullet JB, et al. Succinic

semialdehyde dehydrogenase deficiency. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2004 [updated 2016] https://www.ncbi.nlm.nih.gov/books/NBK1195/ [1993– 2017]. Rilstone JJ, Alkhater RA, Minassian BA. Brain dopamineserotonin vesicular transport disease and its treatment. N Engl J Med . 2013;368:543–550. Robertson D, Garland EM. Dopamine beta-hydroxylase deficiency. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2003 [updated 2015] https://www.ncbi.nlm.nih.gov/books/NBK1474/ [1993– 2017]. Segawa M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev . 2011;33:195–201. Van Hove JLK, Thomas JA. Disorders of glycine, serine, GABA and proline metabolism. Blau N, Duran M, Gibson KM, et al. Physician's guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases . Springer: Heidelberg; 2014:63–84. Vogel KR, Pearl PL, Theodore WH, et al. Thirty years beyond discovery—clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. J Inherit Metab Dis . 2013;36:401–410.

103.12

Urea Cycle and Hyperammonemia (Arginine, Citrulline, Ornithine)

Oleg A. Shchelochkov, Charles P. Venditti

Keywords urea cycle disorder hyperammonemia carbamoyl phosphate synthetase 1 CPS1 ornithine transcarbamylase OTC argininosuccinate synthetase 1 classic citrullinemia ASS1 citrin citrin deficiency SLC25A13 neonatal intrahepatic cholestasis argininosuccinate lyase argininosuccinic aciduria ASL arginase 1 hyperargininemia argininemia ARG1 N -acetylglutamate NAG N -acetylglutamate synthetase NAGS sodium benzoate sodium phenylacetate sodium phenylbutyrate Ammonul ariginine citrulline orotate

orotic acid argininosuccinate argininosuccinic acid acrodermatitis enteropathica valproic acid valproate transient hyperammonemia of the newborn THAN disorders of ornithine metabolism gyrate atrophy of the retina and choroid ornithine aminotransferase OAT hyperammonemia-hyperornithinemia-homocitrullinemia syndrome hyperammonemia-hyperornithinemia-homocitrullinuria syndrome HHH syndrome SLC25A15 congenital glutamine deficiency glutamine synthetase GLUL Catabolism of amino acids results in the production of free ammonia, which in high concentration is toxic to the CNS. Mammals detoxify ammonia to urea through a series of reactions known as the urea cycle (Fig. 103.12 ), which is composed of 5 enzymes: carbamoyl phosphate synthetase 1 (CPS1 ), ornithine transcarbamylase (OTC ), argininosuccinate synthetase (ASS ), argininosuccinate lyase (ASL ), and arginase 1. A 6th enzyme, N acetylglutamate (NAG) synthetase (NAGS ), catalyzes synthesis of NAG, which is an obligatory activator (effector) of the CPS1 enzyme. Individual deficiencies of these enzymes have been observed and, with an overall estimated prevalence of 1 in 35,000 live births, they are the most common genetic causes of hyperammonemia in infants.

FIG. 103.12 Urea cycle: pathways for ammonia disposal and ornithine metabolism. Reactions occurring in the mitochondria are depicted in purple. Reactions shown with interrupted arrows are the alternate pathways for the disposal of ammonia. Enzymes: (1) Carbamyol phosphate synthetase type 1 (CPS1), (2) ornithine transcarbamylase (OTC), (3) argininosuccinate synthetase (ASS), (4) Argininosuccinate lyase (ASL), (5) arginase 1, (6) ornithine aminotransferase, (7) N -acetylglutamate (NAG) synthetase, (8) citrin, (9) ornithine transporter (ORNT1). HHH syndrome, Hyperammonemiahyperornithinemia-homocitrullinemia.

Genetic Causes of Hyperammonemia Hyperammonemia, sometimes severe, occurs in inborn errors of metabolism other than the urea cycle defects (Table 103.4 ; see also Table 102.5 ). The mechanisms of hyperammonemia in some of these conditions are diverse and include accumulation of toxic metabolites (e.g., organic acids), impaired transport of urea cycle intermediates (e.g., HHH syndrome), or depletion of urea cycle intermediates (e.g., lysinuric protein intolerance), leading to compromised function of the urea cycle.

Table 103.4

Inborn Errors of Metabolism Causing Hyperammonemia Deficiencies of the urea cycle enzymes Carbamyl phosphate synthetase 1 Ornithine transcarbamylase Argininosuccinate synthetase Argininosuccinate lyase Arginase 1 N -acetylglutamate synthetase Organic acidemias Propionic acidemia Methylmalonic acidemia Isovaleric acidemia β-Ketothiolase deficiency Multiple carboxylase deficiencies Medium-chain fatty acid acyl-CoA dehydrogenase deficiency Glutaric acidemia type I 3-Hydroxy-3-methylglutaric aciduria Lysinuric protein intolerance Hyperammonemia-hyperornithinemia-homocitrullinemia syndrome Transient hyperammonemia of the newborn Congenital hyperinsulinism with hyperammonemia

Clinical Manifestations of Hyperammonemia In the neonatal period , symptoms and signs are mostly related to brain dysfunction and are similar regardless of the cause of the hyperammonemia. The affected infant appears normal at birth but becomes symptomatic following the introduction of dietary protein. Refusal to eat, vomiting, tachypnea, and lethargy can quickly progress to a deep coma. Seizures are common. Physical examination may reveal hepatomegaly in addition to obtundation. Hyperammonemia can trigger increased intracranial pressure that may be manifested by a bulging fontanelle and dilated pupils.

In infants and older children , acute hyperammonemia is manifested by vomiting and neurologic abnormalities such as ataxia, confusion, agitation, irritability, combativeness, and psychosis. These manifestations may alternate with periods of lethargy and somnolence that may progress to coma. Routine laboratory studies show no specific findings when hyperammonemia is caused by defects of the urea cycle enzymes. Blood urea nitrogen is usually low in these patients. Some patients may initially present with unexplained elevated serum alanine transaminase (ALT) and aspartate transaminase (AST) and even meet the criteria for acute liver failure. In infants with organic acidemias, hyperammonemia is commonly associated with severe acidosis as well as ketonuria . Newborn infants with hyperammonemia are often misdiagnosed as having sepsis; they may succumb without a correct diagnosis. Neuroimaging may reveal cerebral edema. Autopsy may reveal microvesicular steatosis, mild cholestasis, and fibrosis of the liver. Thus, because of the nonspecific presentation or urea cycle disorders, it is imperative to measure plasma ammonia levels in any ill infant with severe sepsis, unexplained liver dysfunction, recurrent emesis, or progressive encephalopathy.

Diagnosis The main criterion for diagnosis is hyperammonemia. Each clinical laboratory should establish its own normal values for blood ammonia. Normal newborn values are higher than those of the older child or adult. Levels as high as 100 µmol/L can occur in healthy term infants. An ill infant usually manifests a blood ammonia level >150 µmol/L. Fig. 103.13 illustrates an approach to the differential diagnosis of hyperammonemia in the newborn infant. Careful inspection of individual plasma amino acids usually reveals abnormalities that may help the diagnosis. In patients with deficiencies of CPS1, OTC, or NAGS, frequent findings include elevations in plasma glutamine and alanine with concurrent decrements in citrulline and arginine. These disorders cannot be differentiated from one another by the plasma amino acid levels alone. A marked increase in urinary orotic acid in patients with OTC deficiency helps differentiate this defect from CPS1 deficiency. Differentiation between the CPS1 deficiency and the NAGS deficiency may require an assay of the respective enzymes or molecular analysis of the relevant genes. Clinical improvement occurring after oral administration of carbamylglutamate, however, may suggest NAGS deficiency. Patients with a deficiency of ASS, ASL, or arginase 1 have marked

increases in the plasma levels of citrulline, argininosuccinic acid, or arginine, respectively. The combination of hyperammonemia and marked hypercitrullinemia or argininosuccinic acidemia is virtually pathognomonic for these disorders. Children with urea cycle defects often self-select a low-protein, high-carbohydrate diet, especially those with late-onset disease or symptomatic females with partial OTC deficiency.

FIG. 103.13 Clinical approach to a newborn infant with symptomatic hyperammonemia. CPS1, Carbamoyl phosphate synthetase 1; HHH syndrome, hyperornithinemia-hyperammonemia-homocitrullinemia; NAGS, N -acetylglutamate synthetase; OTC, ornithine carbamoyltransferase.

Mass screening of newborn infants identifies patients with ASS, ASL, and arginase 1 deficiencies.

Treatment of Acute Hyperammonemia Clinical outcome depends mainly on the severity and the duration of hyperammonemia. Serious neurologic sequelae are likely in newborns with severe elevations in blood ammonia (>300 µmol/L) for more than 12 hr. Thus, acute hyperammonemia should be treated promptly and vigorously. The goal of therapy is to lower the concentration of ammonia. This is accomplished by (1) removal of ammonia from the body in a form other than urea and (2) minimizing endogenous protein breakdown and favoring endogenous protein synthesis by providing adequate calories and essential amino acids (Table 103.5 ). Fluid, electrolytes, glucose (10–15%), and lipids (1-2 g/kg/24 hr) should be infused intravenously, together with minimal amounts of protein (0.25 g/kg/24 hr), preferably including essential amino acids. Oral feeding with a low-protein formula (0.5-1.0 g/kg/24 hr) through a nasogastric tube should be started as soon as sufficient improvement is seen.

Table 103.5

Treatment of Acute Hyperammonemia in an Infant 1. Provide adequate calories, fluid, and electrolytes intravenously (10% glucose, NaCl* and intravenous lipids 1 g/kg/24 hr). Add minimal amounts of protein preferably as a mixture of essential amino acids (0.25 g/kg/24 hr) during the 1st 24 hr of therapy. 2. Give priming doses of the following compounds: (To be added to 20 mL/kg of 10% glucose and infused within 1-2 hr) • Sodium benzoate 250 mg/kg † • Sodium phenylacetate 250 mg/kg † • Arginine hydrochloride 200-600 mg/kg as a 10% solution 3. Continue infusion of sodium benzoate † (250-500 mg/kg/24 hr), sodium phenylacetate † (250-500 mg/kg/24 hr), and arginine (200-600 mg/kg/24 hr ‡ ) following the above priming doses. These compounds should be added to the daily intravenous fluid. 4. Initiate peritoneal dialysis or hemodialysis if above treatment fails to produce an appreciable decrease in plasma ammonia.

* The concentration of sodium chloride should be calculated to be 0.45–0.9%,

including the amount of the sodium in the drugs. † Sodium from these drugs should be included as part of the daily sodium

requirement. ‡ The higher dose is recommended in the treatment of patients with citrullinemia

and argininosuccinic aciduria. Arginine is not recommended in patients with arginase deficiency and in those whose hyperammonemia is secondary to organic acidemia. Sodium benzoate and sodium phenylacetate should be used with caution in patients with organic acidemias. Because the kidneys clear ammonia poorly, its removal from the body must be expedited by formation of compounds with a high renal clearance. An important advance in the treatment of hyperammonemia has been the introduction of acylation therapy by using an exogenous organic acid that is acylated endogenously with nonessential amino acids to form a nontoxic compound with high renal clearance. The main organic acids used for this purpose are sodium salts of benzoic acid and phenylacetic acid. Benzoate forms hippurate with endogenous glycine in the liver (see Fig. 103.12 ). Each mole of benzoate removes 1 mole of ammonia as glycine. Phenylacetate conjugates with glutamine to form phenylacetylglutamine, which is readily excreted in the urine. One mole of phenylacetate removes 2 moles of ammonia as glutamine from the body (see Fig. 103.12 ). Sodium phenylbutyrate, metabolized to phenylacetate, is the primary oral formulation. For intravenous (IV) use, a combined formulation of benzoate and phenylacetate (Ammonul) is commercially available. Another valuable therapeutic adjunct is IV infusion of arginine , which is effective in all patients (except those with arginase deficiency). Arginine administration supplies the urea cycle with ornithine (see Fig. 103.12 ). In patients with citrullinemia, 1 mole of arginine reacts with 1 mole of ammonia (as carbamoyl phosphate) to form citrulline. In patients with argininosuccinic acidemia, 2 moles of ammonia (as carbamoyl phosphate and aspartate) react with arginine to form argininosuccinic acid. Citrulline and argininosuccinate are less toxic than ammonia and more readily excreted by the kidneys. In patients with CPS1 or OTC deficiencies arginine administration is indicated because this amino acid is not produced in sufficient amounts to enable endogenous protein synthesis. For enteral therapy, patients with OTC deficiency benefit from

supplementation with citrulline (200 mg/kg/24 hr) because 1 mole of citrulline reacts with 1 mole of ammonia (through aspartic acid) to form arginine. Administration of arginine or citrulline is contraindicated in patients with arginase deficiency , a rare condition in which the usual presenting clinical picture is spastic diplegia rather than hyperammonemia. Arginine therapy is of no benefit if hyperammonemia is secondary to an organic acidemia. In a newborn infant with an initial episode of hyperammonemia, arginine should be used until the diagnosis is established (see Table 103.5 ). Benzoate, phenylacetate, and arginine may be administered together for maximal therapeutic effect. A priming dose of these compounds is followed by continuous infusion until recovery from the acute state occurs. Both benzoate and phenylacetate are usually supplied as concentrated solutions and should be properly diluted (1–2% solution) for IV use. The recommended therapeutic doses of both compounds deliver a substantial amount of sodium to the patient; this amount should be included in calculation of the daily sodiumn requirement. Benzoate and phenylacetate (or the combined formulation, Ammonul) should be used with caution in newborn infants with hyperbilirubinemia because they may displace bilirubin from albumin; however, there are no documented cases of kernicterus (see Chapter 123.4 ) reported in neonates with hyperammonemia who have received such therapies. In infants at risk, it is advisable to reduce bilirubin to a safe level while considering IV administration of benzoate or phenylacetate. If the initial ammonia level is 500 µmol/L, extracorporeal detoxification is the initial method of ammonia removal. Exchange transfusion has little effect on reducing total body ammonia. It should be used only if dialysis cannot be employed promptly or when the patient is a newborn infant with hyperbilirubinemia (see earlier). Hemodialysis dramatically lowers blood ammonia within a few hours, but if it is unavailable or technically unfeasible, peritoneal dialysis may be used as an alternative. When hyperammonemia is caused by an organic acidemia and hemodialysis is not available, peritoneal dialysis can be used to remove both the offending organic acid and ammonia. Oral administration of neomycin limits growth of intestinal bacteria that can produce ammonia. However, this modality is of limited use in patients (e.g., affected neonates) in whom reduction of hyperammonemia is an urgent priority.

Oral lactulose acidifies the intestinal lumen, thereby reducing the diffusion of ammonia across the intestinal epithelium. This agent is of limited applicability in newborns, who have a high risk of acidemia and dehydration. There has been interest in the use of cooling as a therapeutic adjunct in newborn infants with metabolic encephalopathy such as that caused by hyperammonemia. Clinical studies are in progress to evaluate the efficacy of this approach. There may be considerable lag between the normalization of ammonia level and an improvement in the patient's neurologic status. Several days may be needed before the infant becomes fully alert.

Long-Term Therapy Once the infant is alert, therapy should be tailored to the underlying cause of the hyperammonemia. In general, all patients, regardless of the enzymatic defect, require protein restriction limited to age-adjusted recommended dietary allowance (RDA). In pediatric patients with defects in the urea cycle, chronic administration of sodium benzoate (250 mg/kg/24 hr), sodium phenylbutyrate (250-500 mg/kg/24 hr), and arginine (200-400 mg/kg/24 hr) or citrulline (in patients with OTC deficiency, 200-400 mg/kg/24 hr) is effective in maintaining blood ammonia levels within the normal range (shown doses are for patients who weigh 500 mg/day should be avoided. The pyridoxine dependency and thus the therapy are lifelong. The therapeutic benefit of a lysine-restricted diet is being evaluated.

Glutaric Aciduria Type 1 (Glutaryl-CoA Dehydrogenase Deficiency) Glutaric acid is an intermediate in the degradation of lysine (see Fig. 103.14 ), hydroxylysine, and tryptophan. Glutaric aciduria type 1 , a disorder caused by a deficiency of glutaryl-CoA dehydrogenase, should be differentiated from glutaric aciduria type 2 , a distinct clinical and biochemical disorder caused by defects in the mitochondrial electron transport chain (see Chapter 104.1 ).

Clinical Manifestations Macrocephaly is a common but nonspecific finding in patients with glutaric aciduria type 1. It develops in the 1st yr of life but can also be present at birth and precede the onset of neurologic manifestations. Some affected infants may also show subtle neurologic symptoms, such as delayed onset of motor milestones, irritability, and feeding problems, during this seemingly asymptomatic period. The onset of the condition is usually heralded by acute encephalopathic findings , such as loss of normal developmental milestones (head control, rolling over, or sitting), seizures, generalized rigidity, opisthotonos, choreoathetosis, and dystonia caused by acute striatal injury. These symptoms may occur suddenly in an apparently normal infant after a minor infection. Brain imaging reveals increased extraaxial (particularly frontal) fluid with stretched bridging veins, striatal lesions, dilated lateral ventricles, cortical atrophy (mainly in frontotemporal region), and fibrosis. Recovery from the 1st attack usually occurs slowly, but some residual neurologic abnormalities may persist, especially dystonia and choreoathetosis. Without treatment, additional acute attacks resembling the first can occur during subsequent episodes of intercurrent infections or catabolic states. In some patients these signs and

symptoms may develop gradually in the 1st few yr of life. Hypotonia and choreoathetosis may gradually progress into rigidity and dystonia (insidious form ). Acute episodes of metabolic decompensation with vomiting, ketosis, seizures, and coma also occur in this form after infection or other catabolic states. Without treatment, death may occur in the 1st decade of life during one of these episodes. Affected infants are prone to development of subdural hematoma and retinal hemorrhage following minor falls and head traumas. This can be misdiagnosed as child abuse. The intellectual abilities usually remain relatively normal in most patients.

Laboratory Findings During acute episodes, mild to moderate metabolic acidosis and ketosis may occur. Hypoglycemia, hyperammonemia, and elevations of serum transaminases are seen in some patients. High concentrations of glutaric acid are usually found in urine, blood, and CSF. 3-Hydroxyglutaric acid may also be present in the body fluids. Acylcarnitine profile shows elevated glutarylcarnitine (C5-DC) in blood and urine. Plasma concentrations of amino acids are usually within normal limits. Laboratory findings may be unremarkable between attacks. Glutaric aciduria type 1 can be identified on the newborn screen by measuring glutarylcarnitine levels in blood spots. The sensitivity of this screening method depends on the cutoff value used by a newborn screen program, and some patients can be missed. For example, it can happen in a subset of patients with glutaric aciduria type 1 who may present with normal plasma and urinary levels of glutaric acid and variably elevated plasma glutarylcarnitine. This type of glutaric aciduria type 1 referred to as a “low-excretor” phenotype carries the same risk of developing brain injury as in a “high-excretor” phenotype. In some low-excreting patients, glutaric acid is elevated only in CSF. Urinary glutarylcarnitine appears to be a more sensitive screening method to identify affected low-excreting patients. In any child with progressive dystonia and dyskinesia, activity of the enzyme glutaryl-CoA dehydrogenase and molecular analysis of GCDH should be performed.

Treatment Patients require lysine- and tryptophan-restricted diet while meeting physiologic requirements for protein, micronutrients, and vitamins. Increased dietary

arginine may decrease cellular uptake of lysine and decrease the endogenous formation of glutaryl-CoA. Patients should be routinely evaluated for lysine and tryptophan deficiency by monitoring plasma amino acids and growth. L Carnitine supplementation (50-100 mg/kg/24 hr orally) is recommended in all cases. Emergency treatment during acute illness, including temporary cessation of protein intake for 24 hr, replacement of lost calories using carbohydrates or lipids, IV L -carnitine, IV dextrose, prompt treatment of infection, and control of fever, is critical to decreasing the risk of striatal injury. All patients should be provided with an emergency letter describing the underlying diagnosis, recommended evaluation, and treatment. Early diagnosis through newborn screening with prevention and aggressive treatment of intercurrent catabolic states (infections) can help minimize striatal injury and ensure a more favorable prognosis. Patients with movement disorder and spasticity may require treatment with baclofen, diazepam, trihexyphenidyl, and injectable botulinum toxin A. Glutaric aciduria type 1 is inherited as an autosomal recessive trait. The prevalence is estimated at 1 : 100,000 live births worldwide. The condition is more prevalent in some ethnic populations (Canadian Oji-Cree Indians, Irish Travelers, black South Africans, Swedes, and the Old Order Amish population in the United States). The gene for glutaryl-CoA dehydrogenase (GCDH) is located on chromosome 19p13.2. Molecular analysis of GCDH can aid in identifying patients with a low-excretor phenotype associated with specific pathogenic variants (e.g., p.M405V, p.V400M, p.R227P). High prevalence of known pathogenic variants in specific ethnic populations can enable a cost-effective molecular evaluation and counseling. Prenatal diagnosis can be accomplished by demonstrating increased concentrations of glutaric acid in amniotic fluid, by assay of the enzyme activity in amniocytes or chorionic villus samples, or by identification of the known pathogenic variants in GCDH .

Lysinuric Protein Intolerance (Familial Protein Intolerance) This rare autosomal recessive disorder is caused by a defect in the transport of the cationic amino acids lysine, ornithine, and arginine in both intestine and kidneys. Deficiency of the transporter protein (Y+L amino acid transporter 1) in this condition causes multisystem manifestations, which start initially with

gastrointestinal (GI) symptoms. The transport defect in this condition resides in the basolateral (antiluminal) membrane of enterocytes and renal tubular epithelia. This explains the observation that cationic amino acids are unable to cross these cells even when administered as dipeptides. Lysine in the form of dipeptide crosses the luminal membrane of the enterocytes but hydrolyzes to free lysine molecules in the cytoplasm. Free lysine, unable to cross the basolateral membrane of the cells, diffuses back into the lumen. Refusal to feed, nausea, aversion to protein, vomiting, and mild diarrhea, which may result in failure to thrive, wasting, and hypotonia, may be seen shortly after birth. Breastfed infants usually remain asymptomatic until soon after weaning, possibly because of the low-protein content of breast milk. Episodes of hyperammonemia may occur after ingestion of a high-protein meal. Mild to moderate hepatosplenomegaly, osteoporosis, sparse brittle hair, thin extremities with moderate centripetal adiposity, and growth retardation are common physical findings in patients whose condition has remained undiagnosed. Neurocognitive status is usually normal, but moderate intellectual disability has been observed in some patients. Progressive interstitial pneumonitis with bouts of acute exacerbation often occurs in these patients. This usually progresses to severe alveolar proteinosis. Clinical manifestations include progressive exertional dyspnea, fatigue, cough, diminished breath sound, and inspiratory rales; cyanosis may develop in older patients. Some patients have remained undiagnosed until the appearance of pulmonary manifestations. Radiographic evidence of pulmonary fibrosis has been observed in up to 65% of patients without clinical manifestations of pulmonary involvement. Renal involvement is manifested initially by proteinuria, hematuria, and elevation of serum creatinine, which may progress to end-stage renal failure. Renal tubular involvement with laboratory findings of renal Fanconi syndrome may also be present. Renal biopsy reveals pathologic findings consistent with glomerulonephritis and tubulointerstitial nephritis. Hematologic findings of anemia, leukopenia, thrombocytopenia, and elevated ferritin may also be present. A condition resembling hemophagocytic lymphohistiocytosis/macrophage activation syndrome has also been reported. Immunologic abnormalities (impaired lymphocyte function, abnormalities in immune globulins, hypocomplementemia) and acute pancreatitis are frequent features of lysinuric protein intolerance. Laboratory findings may reveal hyperammonemia and an elevated

concentration of urinary orotic acid, which develop after high-protein feeding. Plasma concentrations of lysine, arginine, and ornithine are usually mildly decreased, but urinary levels of these amino acids, especially lysine, are greatly increased. The pathogenesis of hyperammonemia is likely related to the depletion of urea cycle intermediates caused by poor absorption and the increased renal loss of ornithine and arginine. Plasma concentrations of alanine, glutamine, serine, glycine, and proline are usually increased. Anemia, increased serum levels of ferritin, lactate dehydrogenase (LDH), thyroxine-binding globulin, hypercholesterolemia, and hypertriglyceridemia are common findings. This condition should be differentiated from hyperammonemia caused by urea cycle defects (see Chapter 103.12 ), especially in heterozygous females with OTC deficiency, in whom increased urinary excretion of lysine, ornithine, and arginine is not seen. Treatment with a low-protein diet providing the RDA of protein and supplemented with oral citrulline (50-100 mg/kg/day) can produce biochemical and clinical improvements. Episodes of hyperammonemia should be treated promptly (see Chapter 103.12 ). Supplementation with lysine (10-30 mg/kg/day) given in small and frequent doses helps improve plasma levels. The dose of lysine should be titrated down if patients develop abdominal pain and diarrhea. Treatment with high doses of prednisone has been effective in the management of acute pulmonary complications in some patients. Bronchopulmonary lavage is the treatment of choice for patients with alveolar proteinosis. The condition is more prevalent in Finland and Japan, where the prevalence is 1 : 60,000 and 1 : 57,000 live births, respectively. The gene for lysinuric protein intolerance (SLC7A7) is mapped to chromosome 14q11.2. Pregnancies in affected mothers have been complicated by anemia, thrombocytopenia, toxemia, and bleeding, but offspring have been normal.

Bibliography Basura GJ, Hagland SP, Wiltse AM, et al. Clinical features and the management of pyridoxine-dependent and pyridoxineresponsive seizures: review of 63 North American cases submitted to a patient registry. Eur J Pediatr . 2009;168:697– 704.

Boy N, Haege G, Heringer J, et al. Low lysine diet in glutaric aciduria type I—effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis . 2013;36:525– 533. Gospe SM Jr. Pyridoxine-dependent epilepsy. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2001 [updated 2017] https://www.ncbi.nlm.nih.gov/books/NBK1486/ [1993– 2017]. Jafari P, Braissant O, Bonafé L, et al. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab . 2011;104:425–437. Kölker S, Boy SP, Heringer J, et al. Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I—a decade of experience. Mol Genet Metab . 2012;107:72–80. Kölker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I—revised recommendations. J Inherit Metab Dis . 2011;34:677–694. Nunes J, Loureiro S, Carvalho S, et al. Brain MRI findings as an important diagnostic clue in glutaric aciduria type 1. Neuroradiol J . 2013;26:155–161. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab . 2012;106:12–17. Sebastio G, Nunes V. Lysinuric protein intolerance. Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet] . University of Washington: Seattle; 2006 [updated 2011] https://www.ncbi.nlm.nih.gov/books/NBK1361/ [1993– 2017]. Stockler S, Plecko B, Gospe SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular

characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab . 2011;104:48–60. Strauss KA, Donnelly P, Wintermark M. Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain . 2010;133(Pt 1):76–92. Struys EA, Nota B, Bakkali A, et al. Pyridoxine-dependent epilepsy with elevated urinary α-amino adipic semialdehyde in molybdenum cofactor deficiency. Pediatrics . 2012;130:e1716–e1719. Tort F, Ugarteburu O, Torres MA, et al. Lysine restriction and pyridoxal phosphate administration in a NADK2 patient. Pediatrics . 2016;138(5):e20154534. Tortorelli S, Hahn SH, Cowan TM, et al. The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia type I. Mol Genet Metab . 2005;84(2):137–143. Van Karnebeek CD, Stockler-Ipsiroglu S, Jaggumantri S, et al. Lysine-restricted diet as adjunct therapy for pyridoxinedependent epilepsy: the PDE Consortium Consensus Recommendations. JIMD Rep . 2014;15:1–11. Zinnanti WJ, Lazovic J. Mouse model of encephalopathy and novel treatment strategies with substrate competition in glutaric aciduria type I. Mol Genet Metab . 2010;100(Suppl 1):S88–S91.

103.15

N -Acetylaspartic Acid (Canavan Disease)

Reuben K. Matalon, Joseph M. Trapasso

Keywords Canavan disease atypical Canavan disease N -acetylaspartic acid NAA ASPA aspartoacylase recombinant adeno-associated viruses rAAVs blood-brain barrier leukodystrophy progressive macrocephaly N -Acetylaspartic acid (NAA ), a derivative of aspartic acid, is synthesized in the brain and is found in a high concentration similar to glutamic acid. Studies suggest that NAA has multiple functions, such as serving as an acetate reservoir for myelin synthesis and being an organic osmolyte that helps regulate cerebral osmolality. However, the complete function of NAA is not yet fully understood. Aspartoacylase cleaves the N -acetyl group from NAA. Deficiency of aspartoacylase leads to Canavan disease , a severe leukodystrophy characterized by excessive excretion of NAA and spongy degeneration of the white matter of the brain. Canavan disease is an autosomal recessive disorder and is more prevalent in individuals of Ashkenazi Jewish descent than in other ethnic groups. The defective gene for Canavan disease (ASPA) is located on chromosome 17, and genetic testing can be offered for patients, family members, and at-risk populations.

Etiology and Pathology The deficiency of the enzyme aspartoacylase leads to NAA accumulation in the brain, especially in white matter, and massive urinary excretion of this

compound. Excessive amounts of NAA are also present in the blood and CSF. Brain biopsies of patients with Canavan disease show spongy degeneration of the myelin fibers, astrocytic swelling, and elongated mitochondria. There is striking vacuolization and astrocytic swelling in white matter. Electron microscopy reveals distorted mitochondria. As the disease progresses, the ventricles enlarge because of cerebral atrophy.

Clinical Manifestations The severity of Canavan disease covers a wide spectrum. Infants usually appear normal at birth and may not manifest symptoms of the disease until 3-6 mo of age, when they develop progressive macrocephaly , severe hypotonia, persistent head lag, and delayed milestones. As the disease progresses, there is spasticity, joint stiffness, and contractures. Optic atrophy and seizures develop. Feeding difficulties, poor weight gain, and gastroesophageal reflux may occur in the 1st yr of life; swallowing deteriorates, and nasogastric feeding or permanent gastrostomy may be required. In the past, most patients died in the 1st decade of life, but with the advances in medical technology and improved supportive care, now they often survive to the 2nd or 3rd decade.

Atypical Canavan Disease Juvenile or mild Canavan disease is less common than infantile Canavan disease and is most prevalent in non-Ashkenazi Jews. Affected patients with juvenile Canavan disease usually present with mild speech and motor delay and may have retinitis pigmentosa . The other typical features of Canavan disease are usually not present. These children have moderately increased urinary excretion of NAA, which suggests Canavan disease. Brain MRI demonstrates increased signal intensity in the basal ganglia rather than global white matter disease, sometimes leading to confusion with mitochondrial disease.

Diagnosis In a typical patient with Canavan disease, CT scan and MRI reveal diffuse white matter degeneration, primarily in the cerebral hemispheres, with less involvement of the cerebellum and brainstem (Fig. 103.15 ). Repeated

evaluations may be required. MRS performed at the time of MRI can be done to show the high peak of NAA, suggesting Canavan disease. The diagnosis can also be established by finding elevated amounts of NAA in the urine or blood. NAA is found only in trace amounts (24 ±16 µmol/mmol creatinine) in the urine of unaffected individuals, whereas in patients with Canavan disease its concentration is in the range of 1,440 ±873 µmol/mmol creatinine. High levels of NAA can also be detected in plasma, CSF, and brain tissue. Aspartoacylase in fibroblasts is often used to confirm the diagnosis but is not necessary. The activity of aspartoacylase in the fibroblasts of obligate carriers is half or less the activity found in normal individuals. Genotyping of patients with Canavan disease should always be done and will show mutations of ASPA . The differential diagnosis of Canavan disease should include Alexander disease , which is another leukodystrophy associated with macrocephaly. Alexander disease is caused by a defect in the synthesis of glial fibrillary acidic protein, and the diagnosis can be ruled out by molecular diagnosis on blood lymphocytes.



FIG. 103.15 Axial T-weighted MRI of a 2 yr old patient with Canavan disease. Extensive thickening of the white matter is seen.

There are 2 predominant pathogenic variants leading to Canavan disease in the Ashkenazi Jewish population. The first is an amino acid substitution (E285A) in which glutamic acid is substituted for alanine. This mutation is the most frequent and encompasses 83% of 100 mutant alleles examined in Ashkenazi Jewish patients. The 2nd common pathogenic variant is a change from tyrosine to a nonsense mutation, leading to a stop in the coding sequence (Y231X). This accounts for 13% of mutant alleles. In the non-Jewish population, more diverse pathogenic variants have been observed, and the 2 variants common in Jewish people are rare. A different mutation (A305E), the substitution of alanine for glutamic acid, accounts for 40% of 62 mutant alleles in non-Jewish patients. More than 50 pathogenic variants are described in the non-Jewish population. With Canavan disease, it is important to obtain a molecular diagnosis because this will lead to accurate counseling and prenatal guidance for the family. If the mutations are not known, prenatal diagnosis relies on the NAA level in the amniotic fluid. In Ashkenazi Jewish patients, the carrier frequency can be as high as 1 : 40, which is close to that of Tay-Sachs disease. Carrier screening for Canavan disease is available for Jewish individuals. Genotype phenotype correlation and aspartoacylase expression show that expression studies may aid in understanding the disease. Patients with juvenile or mild forms of Canavan disease have been compound heterozygotes with a mild pathogenic variant on one allele and a severe variant on the other allele. Mild variants include p.Tyr288Cys and p.Arg71His.

Treatment and Prevention No specific treatment is currently available. Recent studies of gene therapy using recombinant adeno-associated viruses (rAAVs ) have shown some positive results in rescuing knockout mice but have yet to be tested in humans. Feeding problems and seizures should be treated on an individual basis. Genetic counseling, carrier testing, and prenatal diagnosis are the only methods of prevention. Gene therapy attempts in children with Canavan disease have shown lack of long-term adverse events, some decrease in the brain elevation of N acetylaspartic acid, improved seizure frequency, and stabilization of overall clinical status.

Bibliography Baslow MH, Guilfoyle DN. Canavan disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical interventions. Biochimie . 2013;95(4):946–956. Gao G, Su Q, Michals-Matalon K, et al. Efficacious and safe gene therapy for Canavan disease: a novel approach. J Inherit Metab Dis . 2011;34(Suppl 3):234. Gessler DJ, Li D, Xu H, et al. Redirecting N -acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease. JCI Insight . 2017 [2.3]. Leone P, Shera D, McPhee SW, et al. Long-term follow-up after gene therapy for Canavan disease. Sci Transl Med . 2012;4:165ra163. Matalon R, Michals K, Sebasta D, et al. Aspartoacylase deficiency and N -acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet . 1988;29:463–471. Matalon R, Michals-Matalon K, Surendran S, et al. Canavan disease: studies on the knockout mouse. Adv Exp Med Biol . 2006;576:77–93. Matalon R, Michals-Matalon K. Canavan disease. Pagon RA, Bird TD, Colan CR, et al. GeneReviews [Internet] . University of Washington: Seattle; 1999 [updated 2011] http://www.ncbi.nlm.nih.gov/books/NBK1234/ [1993–2014]. Michals K, Matalon R. Canavan disease. Raymond GV, Eichler F, Fatemi A, et al. Leukodystrophies . Mac Keith Press: London; 2011:156–169. Sommer A, Sass JO. Expression of aspartoacylase (ASPA) and Canavan disease. Gene . 2012;505(2):206–210. Taylor DL, Davies SE, Obrenovitch TP, et al. Investigation into the role of N -acetylaspartate in cerebral osmoregulation. J

Neurochem . 1995;65:275–281. Zano S, Malik R, Szucs S, et al. Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan disease. Mol Genet Metab . 2011;102:176–180. Zano S, Wijayasinghe YS, Malik R, et al. Relationship between enzyme properties and disease progression in Canavan disease. J Inherit Metab Dis . 2013;36(1):159–160.

CHAPTER 104

Defects in Metabolism of Lipids 104.1

Disorders of Mitochondrial Fatty Acid β-Oxidation Charles A. Stanley, Michael J. Bennett

Keywords fatty acid oxidation defects carnitine cycle newborn screening hypoglycemia medium-chain acyl-CoA dehydrogenase deficiency liver disease cardiomyopathy rhabdomyolysis fasting intolerance mitochondrial metabolism Reye syndrome Mitochondrial β-oxidation of fatty acids is an essential energy-producing pathway. It is particularly important during prolonged periods of starvation and

during periods of reduced caloric intake caused by gastrointestinal illness or increased energy expenditure during febrile illness. Under these conditions, the body switches from using predominantly carbohydrate to predominantly fat as its major fuel. Fatty acids are also important fuels for exercising skeletal muscle and are the preferred substrate for normal cardiac metabolism. In these tissues, fatty acids are completely oxidized to carbon dioxide and water. The end products of hepatic fatty acid oxidation are the ketone bodies β-hydroxybutyrate and acetoacetate. These cannot be oxidized by the liver but are exported to serve as important fuels in peripheral tissues, particularly the brain, where ketone bodies can partially substitute for glucose during periods of fasting. Genetic defects have been identified in almost all the known steps in the fatty acid oxidation pathway; all are recessively inherited (Table 104.1 ). Table 104.1

Mitochondrial Fatty Acid Oxidation Disorders—Clinical and Biochemical Features ENZYME DEFICIENCY Carnitine transporter

GENE OCTN2 SLC22A5

CLINICAL PHENOTYPE

Cardiomyopathy, skeletal myopathy, liver disease, sudden death, endocardial fibroelastosis, prenatal and newborn screening diagnosis reported Long-chain fatty FATP1-6 Rare, acute liver failure in childhood acid transporter requiring liver transplantation Carnitine CPT-IA Liver failure, renal tubulopathy, and sudden palmitoyl death. Prenatal and newborn screening transferase-I diagnosis reported, maternal preeclampsia, HELLP syndrome association described in a few patients. Carnitine CACT Chronic progressive liver failure, persistent ↑ acylcarnitine SLC25A20 NH3 , hypertrophic cardiomyopathy. translocase Newborn screening diagnosis reported. Carnitine CPT-II Early and late onset types. Liver failure, palmitoyl encephalopathy, skeletal myopathy, transferase-II cardiomyopathy, renal cystic changes, newborn screening diagnosis reported. Adult form with acute rhabdomyolysis, myoglobinuria. Short-chain acylSCAD Clinical phenotype unclear. Many individuals CoA ACADS appear to be normal. Others have a variety of dehydrogenase inconsistent signs and symptoms. Subset may have severe manifestations of unclear relationship to biochemical defects. Newborn screening diagnosis reported; significance

LABORATORY FINDINGS ↓ Total and free carnitine, normal acylcarnitines, acylglycine, and organic acids ↓ intracellular C14 -C18 fatty acids, ↓ fatty acid oxidation Normal or ↑ free carnitine, normal acylcarnitines, acylglycine, and organic acids

Normal or ↓ free carnitine, abnormal acylcarnitine profile Normal or ↓ free carnitine, abnormal acylcarnitine profile

Normal or ↓ free carnitine, elevated urine ethylmalonic acid, inconsistently abnormal acylcarnitine profile

Medium-chain acyl-CoA dehydrogenase

MCAD ACADM

Very long-chain acyl-CoA dehydrogenase

VLCAD ACADVL

being questioned. Hypoglycemia, hepatic encephalopathy, sudden death. Newborn screening diagnosis possible, maternal preeclampsia, HELLP syndrome association described rarely, possible long Qt interval. Dilated cardiomyopathy, arrhythmias, hypoglycemia, and hepatic steatosis. Lateonset, stress-induced rhabdomyolysis, episodic myopathy. Prenatal and newborn screening diagnosis possible. Nonketotic fasting hypoglycemia, congenital anomalies, milder forms of liver disease, cardiomyopathy, and skeletal myopathy. Newborn screening diagnosis reported.

ETF dehydrogenase*

ETF-DH

ETF-α*

α-ETF

Nonketotic fasting hypoglycemia, congenital anomalies, liver disease, cardiomyopathy, and skeletal myopathy also described. Newborn screening diagnosis reported.

ETF-β*

β-ETF

Fasting hypoglycemia, congenital anomalies, liver disease, cardiomyopathy, and skeletal myopathy also described. Newborn screening diagnosis reported.

Short-chain L -3hydroxyacylCoA dehydrogenase

SCHAD HAD1

Long-chain L -3- LCHAD hydroxyacylHADH-A CoA dehydrogenase MTP

Long-chain 3ketoacyl-CoA thiolase

Short-chain 2,3enoyl-CoA hydratase

HADH-A, HADH-B

LKAT HADH-B

ECHS1

2,4-Dienoyl-CoA DECR1 reductase

Hyperinsulinemic hypoglycemia, cardiomyopathy, myopathy. Newborn screening diagnosis reported.

Newborn screening diagnosis reported, maternal preeclampsia, HELLP syndrome, and AFLP association described frequently. See also MTP below for clinical manifestations. Severe cardiac and skeletal myopathy, hypoglycemia, acidosis, hyper NH3 , sudden death, elevated liver enzymes, retinopathy. Maternal preeclampsia, HELLP syndrome, and AFLP association described frequently. Severe neonatal presentation, hypoglycemia, acidosis, ↑ creatine kinase, cardiomyopathy, neuropathy, and early death

Leigh disease, lactic acidosis, seizures, cystic degeneration of white matter, microcephaly, metabolic acidosis, extrapyramidal dystonia, dilated cardiomyopathy

Only 1 patient described, hypotonia in the newborn, mainly severe skeletal myopathy

Normal or ↓ free carnitine, ↑ plasma acylglycine, plasma C6 -C10 free fatty acids, ↑ C8 -C10 acyl-carnitine Normal or ↓ free carnitine, ↑ plasma C14:1 , C14 acylcarnitine, ↑ plasma C10 C16 free fatty acids Normal or ↓ free carnitine, increased ratio of acyl:free carnitine, ↑ acylcarnitine, urine organic acid and acylglycines Normal or ↓ free carnitine, increased ratio of acyl:free carnitine, ↑ acylcarnitine, urine organic acid and acylglycines Normal or ↓ free carnitine, increased ratio of acyl:free carnitine, ↑ acylcarnitine, urine organic acid and acylglycines Normal or ↓ free carnitine, elevated free fatty acids, inconsistently abnormal urine organic acid, ↑ 3-OH glutarate, ↑ plasma C4 -OH acylcarnitine Normal or ↓ free carnitine, increased ratio of acyl:free carnitine, ↑ free fatty acids, ↑ C16 -OH and C18 -OH carnitines Normal or ↓ free carnitine, increased ratio of acyl:free carnitine, ↑ free fatty acids, ↑ C16 -OH and C18 -OH carnitines Normal or ↓ free carnitine, increased ratio of acyl:free carnitine, ↑ free fatty acids, ↑ 2-trans , 4-cis decadienoylcarnitine Abnormal organic acids, 2methacrylglycine, 2-methyl2,3 dihydroxybutyrate, also S(2-carboxypropyl)cysteine, S(2-carboxyethyl) cysteamine. Acylcarnitine shows ↑ C4OH (inconsistently). Normal or ↓ free carnitine, ↑ acyl:free carnitine ratio,

and respiratory failure. Hypoglycemia rare. HMG CoA synthetase

HMGCS2

Hypoketosis and hypoglycemia, rarely myopathy

HMG CoA lyase HMGCL

Hypoketosis and hypoglycemia, rarely myopathy

Monocarboxylate SLC16A1 transporter 1 (MCT1)

Severe fasting induced ketoacidosis, rarely hypoglycemia

normal urine organic acids and acylglycines ↑ total plasma fatty acids, enzyme studies in biopsied liver may be diagnostic, genetic testing preferred Normal free carnitine, ↑ C5 OH, and methylglutarylcarnitine, enzymes studies in fibroblasts may be diagnostic Profound ketoacidosis; no specific biomarkers yet identified

*

Also known as glutaric acidemia type II or multiple acyl-CoA dehydrogenase defect (MADD).

AFLP, Acute fatty liver of pregnancy; CoA, coenzyme A; ETF, electron transport flavoprotein; HELLP, hemolysis, elevated liver enzymes, low platelets; MTP, mitochondrial trifunctional protein; NH3 , ammonia. From Shekhawat PS, Matern D, Strauss AW: Fetal fatty oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management, Pediatr Res 57:78R–84R, 2005.

Clinical manifestations characteristically involve tissues with a high βoxidation flux, including liver, skeletal, and cardiac muscle. The most common presentation is an acute episode of life-threatening coma, hepatic encephalopathy, and hypoglycemia induced by a period of fasting resulting from defective hepatic ketogenesis. Other manifestations may include chronic cardiomyopathy and muscle weakness or exercise-induced acute rhabdomyolysis. The fatty acid oxidation defects can often be asymptomatic during periods when there is no fasting stress or increased energy demand. Acutely presenting disease may be misdiagnosed as Reye syndrome or, if fatal, as sudden unexpected infant death . Fatty acid oxidation disorders are easily overlooked because the only specific clue to the diagnosis may be the finding of inappropriately low concentrations of plasma or urinary ketones in an infant who has hypoglycemia, unless specialized metabolic testing is performed. Genetic defects in ketone body utilization may also be overlooked because ketonemia is an expected finding with fasting hypoglycemia. In some circumstances, clinical manifestations appear to arise from toxic effects of fatty acid metabolites rather than inadequate energy production. These circumstances include certain longchain fatty acid oxidation disorders (deficiencies of long-chain 3-hydroxyacyl dehydrogenase [LCHAD ], carnitine palmitoyltransferase-IA [CPT-IA ], or mitochondrial trifunctional protein [MTP ; also known as TFP]) in which the presence of a homozygous affected fetus increases the risk of a life-threatening

illness in the heterozygote mother, resulting in acute fatty liver of pregnancy (AFLP) or preeclampsia with HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. The mechanism of these obstetric complications is likely accumulation of toxic intermediates. Malformations of the brain and kidneys have been described in severe deficiencies of electron transfer flavoprotein (ETF ), ETF dehydrogenase (ETF-DH ), and carnitine palmitoyltransferase-II (CPT-II ), which might reflect in utero toxicity of fatty acid metabolites or a developmental role for these enzymes. Progressive retinal degeneration, peripheral neuropathy, and chronic progressive liver disease have been identified in LCHAD and MTP deficiency. Newborn screening programs using tandem mass spectrometry detect characteristic plasma acylcarnitine profiles in most of these disorders, allowing early and presymptomatic diagnosis. Screening programs have demonstrated that all the fatty acid oxidation disorders combined are among the most common inborn errors of metabolism, at least in predominantly Caucasian populations. Figs. 104.1 and 104.2 outline the steps involved in the oxidation of a typical long-chain fatty acid. In the carnitine cycle , long-chain fatty acids are transported across the barrier of the inner mitochondrial membrane as acylcarnitine esters. (Medium-chain fatty acids, which are commonly provided as medium-chain triglyceride supplementation in infants who are failing to thrive, can bypass the carnitine cycle and enter the mitochondrial β-oxidation cycle directly.) Within the mitochondria, successive turns of the 4-step βoxidation cycle convert the coenzyme A (CoA) –activated fatty acids to acetylCoA units. Two or 3 different specific isoenzymes are needed for each of these β-oxidation steps to accommodate the different chain-length fatty acyl-CoA species. The electrons generated in the first β-oxidation step (acyl-CoA dehydrogenase) are carried by the electron transfer pathway to the electron transport chain at the level of coenzyme Q for adenosine triphosphate production; while electrons generated from the 3rd step (3-hydroxyacyl-CoA dehydrogenase) enter the electron transport chain at the level of complex 1. Most of the acetyl-CoA generated from fatty acid β-oxidation in the liver flows through the pathway of ketogenesis to form β-hydroxybutyrate and acetoacetate, whereas in muscle and heart the fatty acids are completely oxidized to CO2 and water.

FIG. 104.1 Mitochondrial fatty acid oxidation. Carnitine enters the cell through the action of the organic cation/carnitine transporter (OCTN2). Palmitate, a typical 16carbon long-chain fatty acid, is transported across the plasma membrane and can be activated to form a long-chain (LC) fatty acyl coenzyme A (CoA). It then enters into the carnitine cycle, where it is transesterified by carnitine palmitoyltransferase-I (CPT-I), translocated across the inner mitochondrial membrane by carnitine/acylcarnitine translocase (TRANS), and then reconverted into a long-chain fatty acyl-CoA by carnitine palmitoyltransferase-II (CPT-II) to undergo β-oxidation. Very-long-chain acylCoA dehydrogenase (VLCAD/LCAD) leads to the production of (C16 -C10 ) 2,3-enoyl CoA. Mitochondrial trifunctional protein (MTP) contains the activities of enoyl CoA hydratase (hydratase), 3-OH-hydroxyacyl-CoA dehydrogenase (3-OH-ACD), and β-ketothiolase (thiolase). Acetyl-CoA, reduced form of flavin adenine dinucleotide (FADH), and reduced form of nicotinamide adenine dinucleotide (NADH) are produced. Medium- and short-chain fatty acids (C8-4) can enter the mitochondrial matrix independent of the carnitine cycle. Medium-chain acyl-CoA dehydrogenase (MCAD), short-chain acyl-CoA dehydrogenase (SCAD), and short-chain hydroxy acyl-CoA dehydrogenase (SCHAD) are required. Acetyl-CoA can then enter the Krebs (TCA) cycle. Electrons are transported from FADH to the respiratory chain via the electron transfer flavoprotein (ETF) and the electron transfer flavoprotein dehydrogenase (ETF-DH). NADH enters the electron transport chain through complex I. In liver, acetyl-CoA can be converted into hydroxymethylglutaryl (HMG) CoA by β-hydroxy-β-methylglutaryl-CoA synthase (HMG CoA synthase) and then the ketone body acetoacetate by the action of β-hydroxy-βmethylglutaryl-CoA lyase (HMG-CoA lyase).

FIG. 104.2 Pathway of mitochondrial oxidation of palmitate, a typical 16-carbon longchain fatty acid. Enzyme steps include carnitine palmitoyltransferase (CPT) 1 and 2, carnitine/acylcarnitine translocase (TRANS), electron transfer flavoprotein (ETF), ETF dehydrogenase (ETF-DH), acyl-CoA dehydrogenase (ACD), enoyl CoA hydratase (hydratase), 3-hydroxy-acyl-CoA dehydrogenase (3-OH-ACD), β-ketothiolase (thiolase),

β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) synthase, and lyase.

Defects in the β-Oxidation Cycle Medium-Chain Acyl-CoA Dehydrogenase Deficiency Medium-chain acyl-CoA dehydrogenase (MCAD ) deficiency is the most common fatty acid oxidation disorder. The disorder shows a strong founder effect; most patients have a northwestern European ancestry, and the majority of these patients are homozygous for a single common MCAD missense mutation, an A-G transition at cDNA position 985 (c.985A>G) that changes a lysine to glutamic acid at residue 329 (p.K329E).

Clinical Manifestations Previously undiagnosed affected patients usually present in the 1st 3 mo to 5 yr of life with episodes of acute illness triggered by prolonged fasting (>12-16 hr). Signs and symptoms include vomiting and lethargy, which rapidly progress to coma or seizures and cardiorespiratory collapse. Sudden unexpected infant death may occur. The liver may be slightly enlarged with fat deposition. Attacks are rare until the infant is beyond the 1st few mo of life, presumably because of more frequent feedings at a younger age. Affected older infants are at higher risk of illness as they begin to fast through the night or are exposed to fasting stress during an intercurrent childhood illness. Presentation in the 1st days of life with neonatal hypoglycemia has been reported in newborns who were fasted inadvertently or were being breastfed. Diagnosis of MCAD has occasionally been documented in previously healthy teenage and adult individuals, indicating that even patients who have been asymptomatic in infancy are still at risk for metabolic decompensation if exposed to sufficient periods of fasting. An unknown number of patients may remain asymptomatic. Prior to routine newborn screening testing, as many as 25% of MCAD-deficient patients died or suffered severe brain damage from their first episode. Most patients are now diagnosed in the newborn period by blood spot acylcarnitine screening , allowing the initiation of early treatment and prevention of many of the severe signs and symptoms. In some reports, newborns with MCAD deficiency presented acutely before newborn screening results were obtained; neonates who

are exclusively breastfed are at higher risk because of early poor caloric intake.

Laboratory Findings During acute episodes, hypoglycemia is usually present. Plasma and urinary ketone concentrations are inappropriately low (hypoketotic hypoglycemia ). Because of the hypoketonemia, there is little or no metabolic acidosis, which is expected to be present in many children with hypoglycemia. Liver function tests (LFTs) are abnormal, with elevations of liver enzymes (alanine transaminase, aspartate transaminase), elevated blood ammonia, and prolonged prothrombin and partial thromboplastin times. Liver biopsy at times of acute illness shows microvesicular or macrovesicular steatosis from triglyceride accumulation. During fasting stress or acute illness, urinary organic acid profiles by gas chromatography/mass spectrometry show inappropriately low concentrations of ketones and elevated levels of medium-chain dicarboxylic acids (adipic, suberic, and sebacic acids) that derive from microsomal and peroxisomal omega oxidation of accumulated medium-chain fatty acids. Plasma and tissue concentrations of total carnitine are reduced to 25–50% of normal, and the fraction of total esterified carnitine is increased. This pattern of secondary carnitine deficiency is seen in most fatty acid oxidation defects and reflects competition between increased acylcarnitine levels and free carnitine for transport at the renal tubular plasma membrane. Significant exceptions to this rule are the plasma membrane carnitine transporter, CPT-IA, and β-hydroxy-βmethylglutaryl-CoA (HMG-CoA) synthase deficiencies, which do not manifest secondary carnitine deficiency. Diagnostic metabolite patterns for MCAD deficiency include increased plasma C6:0 , C8:0 , C10:0 , and C10:1 acylcarnitine species and increased urinary acylglycines, including hexanoylglycine, suberylglycine, and 3phenylpropionylglycine. Newborn screening, which almost all babies born in the United States receive, can detect presymptomatic MCAD deficiency based on these abnormal acylcarnitines in filter paper blood spots. The diagnosis can be confirmed by finding the common A985G mutation or sequencing the MCAD gene. A 2nd common variant, T199C, has been detected in infants identified by newborn screening. Interestingly, this allele has not been seen to date in symptomatic MCAD patients; it may represent a milder mutation.

Treatment

Acute illnesses should be promptly treated with intravenous (IV) fluids containing 10% dextrose to correct or prevent hypoglycemia and to suppress lipolysis as rapidly as possible (see Chapter 111 ). Chronic therapy consists of avoiding fasting. This usually requires simply adjusting the diet to ensure that overnight fasting periods are limited to 10-12 hr. Continuous intragastric feeding is useful in some patients.

Short-Chain Acyl-CoA Dehydrogenase Deficiency A small number of patients with 2 null mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene have been described with variable phenotype. Most individuals classified as being SCAD deficient actually have polymorphic DNA changes in the SCAD gene; for example, 2 common polymorphisms are G185S and R147W, which are homozygously present in 7% of the population. Some investigators argue that these variants may be susceptibility factors, which require a 2nd, as yet unknown, genetic mutation to express a clinical phenotype; many other investigators believe that SCAD deficiency is a harmless biochemical condition. This autosomal recessive disorder presents with neonatal hypoglycemia and may have normal levels of ketone bodies. The diagnosis is indicated by elevated levels of butyrylcarnitine (C4-carnitine) on newborn blood spots or plasma and increased excretion of urinary ethylmalonic acid and butyrylglycine. These metabolic abnormalities are most pronounced in patients with null mutations and are variably present in patients who are homozygous for the common polymorphisms. The need for treatment in SCAD deficiency has not yet been established. It has been proposed that long-term evaluation of asymptomatic individuals is necessary to determine whether this is or is not a real disease. Most individuals with SCAD deficiency remain asymptomatic throughout life, but there may be a subset of individuals with severe manifestations , including dysmorphic facial features, feeding difficulties/failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy.

Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase/Mitochondrial Trifunctional Protein Deficiency The LCHAD enzyme is part of the MTP, which also contains 2 other steps in βoxidation: long-chain 2,3-enoyl CoA hydratase and long-chain β-ketothiolase. MTP is a hetero-octameric protein composed of 4 α and 4 β chains derived from distinct contiguous genes sharing a common promoter region. In some patients, only the LCHAD activity of the MTP is affected (LCHAD deficiency ), whereas others have deficiencies of all 3 activities (MTP deficiency ). Clinical manifestations include attacks of acute hypoketotic hypoglycemia similar to MCAD deficiency; however, patients often show evidence of more severe disease, including cardiomyopathy, muscle cramps and weakness, and abnormal liver function (cholestasis). Toxic effects of fatty acid metabolites may produce pigmented retinopathy leading to blindness, progressive liver failure, peripheral neuropathy, and rhabdomyolysis. Life-threatening obstetric complications (AFLP, HELLP syndrome) have been observed in heterozygous mothers carrying homozygous fetuses affected with LCHAD/MTP deficiency. Sudden unexpected infant death may occur. The diagnosis is indicated by elevated levels of blood spot or plasma 3-hydroxy acylcarnitines of chain lengths C16 -C18 . Urinary organic acid profile in patients may show increased levels of 3-hydroxydicarboxylic acids of chain lengths C6 -C14 . Secondary carnitine deficiency is common. A common mutation in the α subunit, E474Q, is seen in more than 60% of LCHAD-deficient patients. This mutation in the fetus is especially associated with the obstetric complications, but other mutations in either subunit may also be linked to maternal illness. Treatment is similar to that for MCAD or VLCAD deficiency; that is, avoiding fasting stress. Some investigators have suggested that dietary supplements with medium-chain triglyceride oil to bypass the defect in longchain fatty acid oxidation and docosahexaenoic acid (for protection against the retinal changes) may be useful. Liver transplantation has been attempted in patients with severe liver failure, but does not ameliorate the metabolic abnormalities or prevent the myopathic or retinal complications.

Short-Chain 3-Hydroxyacyl-CoA Dehydrogenase

Deficiency Only 14 patients with proven mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD ) have been reported. Most cases with recessive mutations of the SCHAD gene have presented with episodes of hypoketotic hypoglycemia that was caused by hyperinsulinism. In contrast to those with other forms of fatty acid oxidation disorders, these patients required specific therapy with diazoxide for hyperinsulinism to avoid recurrent hypoglycemia. A single patient with compound heterozygous mutations presented with fulminant hepatic failure at age 10 mo. The SCHAD protein has a nonenzymatic function in which it directly interacts with glutamate dehydrogenase (GDH) to inhibit its activity. In the absence of SCHAD protein, this inhibition is removed, leading to upregulation of GDH enzyme activity, a recognized cause of hyperinsulinism usually from activating mutations of the GDH gene. Severe deficiency of SCHAD protein often presents predominantly as protein-sensitive hypoglycemia rather than as fasting hypoglycemia. It appears that if SCHAD protein is present, inhibition of GDH is maintained even when there is no SCHAD enzyme activity; these patients may present with a more traditional fatty acid oxidation defect. Specific metabolic markers for SCHAD deficiency include elevated plasma C4hydroxy acylcarnitine and urine 3-hydroxyglutaric acid. Successful newborn screening for SCHAD deficiency has been recorded, but the sensitivity of the process has not yet been established. Treatment of SCHAD-deficient patients with hyperinsulinism is with diazoxide. There is insufficient experience with the nonhyperinsulinemic form of SCHAD deficiency at present to recommend treatment modalities, but prevention of fasting seems advisable.

Short-Chain 2,3-Enoyl-CoA Hydratase Deficiency This disorder, resulting from mutations in the ECHS1 gene, has only recently been defined. Many patients were identified through exome sequencing, and currently there are approximately 20 cases in the literature. The disorder affects a shared pathway of short-chain fatty acid and valine metabolism. The clinical phenotypes are more characteristic of mitochondrial disorders of pyruvate metabolism with predominantly a Leigh-like disease (see Chapter 616.2 ) with profound and often-fatal lactic acidosis. Currently, no treatment modalities or specific biomarkers have been established. Several patients were found to

excrete increased levels of methacrylylglycine, a highly reactive and potentially toxic intermediate; 2-methyl-2.3 dihydroxybutyrate; S -(2-carboxypropyl) cysteine; and S -(2-carboxpropyl) cysteamine.

Defects in the Carnitine Cycle Plasma Membrane Carnitine Transport Defect (Primary Carnitine Deficiency) Primary carnitine deficiency is the only genetic defect in which carnitine deficiency is the cause, rather than the consequence, of impaired fatty acid oxidation. The most common presentation is progressive cardiomyopathy with or without skeletal muscle weakness beginning at age 1-4 yr. A smaller number of patients may present with fasting hypoketotic hypoglycemia in the 1st yr of life, before the cardiomyopathy becomes symptomatic. The underlying defect involves the plasma membrane sodium gradient–dependent carnitine transporter that is present in heart, muscle, and kidney. This transporter is responsible both for maintaining intracellular carnitine concentrations 20-50–fold higher than plasma concentrations and for renal conservation of carnitine. Diagnosis of the carnitine transporter defect is aided by patients having extremely reduced carnitine levels in plasma and muscle (1–2% of normal). Heterozygote parents have plasma carnitine levels approximately 50% of normal. Fasting ketogenesis may be normal because liver carnitine transport is normal, but it may become impaired if dietary carnitine intake is interrupted. The fasting urinary organic acid profile may show a hypoketotic dicarboxylic aciduria pattern if hepatic fatty acid oxidation is impaired, but is otherwise unremarkable. The defect in carnitine transport can be demonstrated clinically by the severe reduction in renal carnitine threshold or by in vitro assay of carnitine uptake using cultured fibroblasts or lymphoblasts. Mutations in the organic cation/carnitine transporter (OCTN2) underlie this disorder. Treatment with pharmacologic doses of oral carnitine (100-200 mg/kg/day) is highly effective in correcting the cardiomyopathy and muscle weakness, as well as any impairment in fasting ketogenesis. Muscle total carnitine concentrations remain t, p.P479L) has been identified in individuals of Inuit background in the United States, Canada, and Greenland. This variant is associated with an increased risk for sudden infant death syndrome (SIDS) in the Inuit population. The variant can be detected by newborn screening; enzyme activity is reduced by 80%, and regulation by malonyl-CoA is lost. It has not been established whether CPT-IA (c.1436C>t, p.P479L) is a pathologic enzyme variant or an adaptation to ancient Inuit high-fat diets. Treatment for the severe form of CPTIA deficiency that is found in non-Inuit populations is similar to that for MCAD deficiency, with avoidance of situations where fasting ketogenesis is necessary. The need for treatment of the Inuit variant has not yet been determined.

Carnitine:Acylcarnitine Translocase Deficiency This defect of the inner mitochondrial membrane carrier protein for long-chain acylcarnitines blocks the entry of long-chain fatty acids into the mitochondria for oxidation. The clinical phenotype of this disorder is characterized by a severe and generalized impairment of fatty acid oxidation. Most newborn patients present with attacks of fasting-induced hypoglycemia, hyperammonemia, and cardiorespiratory collapse. All symptomatic newborns have had evidence of cardiomyopathy and muscle weakness. Several patients with a partial translocase deficiency and milder disease without cardiac involvement have also been

identified. No distinctive urinary or plasma organic acids are noted, although increased levels of plasma long-chain acylcarnitines of chain lengths C16 -C18 are reported. Diagnosis can be confirmed using genetic analysis. Functional carnitine:acylcarnitine translocase activity can be measured in cultured fibroblasts or lymphoblasts. Treatment is similar to that of other long-chain fatty acid oxidation disorders.

Carnitine Palmitoyltransferase-II Deficiency Three forms of CPT-II deficiency have been described. A severe neonatal lethal presentation associated with a profound enzyme deficiency and early death has been reported in several newborns in association with dysplastic kidneys, cerebral malformations, and mild facial anomalies. A milder defect is associated with an adult presentation of episodic rhabdomyolysis. The first episode usually does not occur until late childhood or early adulthood. Attacks are frequently precipitated by prolonged exercise. There is aching muscle pain and myoglobinuria that may be severe enough to cause renal failure. Serum levels of creatine kinase are elevated to 5,000-100,000 units/L. Hypoglycemia has not been described, but fasting may contribute to attacks of myoglobinuria. Muscle biopsy shows increased deposition of neutral fat. This adult myopathic presentation of CPT-II deficiency is associated with a common mutation, c.338C>T, p.S113L. This mutation produces a heat-labile protein that is unstable to increased muscle temperature during exercise resulting in the myopathic presentation. The 3rd, intermediate form of CPT-II deficiency presents in infancy or early childhood with fasting-induced hepatic failure, cardiomyopathy, and skeletal myopathy with hypoketotic hypoglycemia, but is not associated with the severe developmental changes seen in the neonatal lethal presentation. This pattern of illness is similar to that seen in VLCAD deficiency, and management is identical. Diagnosis of all forms of CPT-II deficiency can be made by a combination of molecular genetic analysis and demonstrating deficient enzyme activity in muscle or other tissues and in cultured fibroblasts.

Defects in the Electron Transfer Pathway Electron Transfer Flavoprotein and Electron

Transfer Flavoprotein Dehydrogenase Deficiencies (Glutaric Acidemia Type 2, Multiple Acyl-CoA Dehydrogenation Defects) ETF and ETF-DH function to transfer electrons into the mitochondrial electron transport chain from dehydrogenation reactions catalyzed by VLCAD, MCAD, and SCAD, as well as by glutaryl-CoA dehydrogenase and 4 enzymes involved in branched-chain amino acid (BCAA) oxidation. Deficiencies of ETF or ETFDH produce illness that combines the features of impaired fatty acid oxidation and impaired oxidation of several amino acids. Complete deficiencies of either protein are associated with severe illness in the newborn period, characterized by acidosis, hypoketotic hypoglycemia, coma, hypotonia, cardiomyopathy, and an unusual odor of sweaty feet caused by isovaleryl-CoA dehydrogenase inhibition. Some affected neonates have had congenital facial dysmorphism and polycystic kidneys similar to that seen in severe CPT-II deficiency, which suggests that toxic effects of accumulated metabolites may occur in utero. Diagnosis can be made from the newborn blood spot acylcarnitine profile and urinary organic acids; both tests show abnormalities corresponding to blocks in the oxidation of fatty acids (ethylmalonate and C6 -C10 dicarboxylic acids), lysine (glutarate), and BCAAs (isovaleryl-, isobutyryl-, and α-methylbutyrylglycine). The diagnosis can be confirmed by genetic testing for ETF (2 genes, A and B) and ETF dehydrogenase. Most severely affected infants do not survive the neonatal period. Partial deficiencies of ETF and ETF-DH produce a disorder that may mimic MCAD deficiency or other milder fatty acid oxidation defects. These patients have attacks of fasting hypoketotic coma. The urinary organic acid profile reveals primarily elevations of dicarboxylic acids and ethylmalonate, derived from short-chain fatty acid intermediates. Secondary carnitine deficiency is present. Some patients with mild forms of ETF/ETF-DH deficiency may benefit from treatment with high doses of riboflavin, a precursor of the various flavoproteins involved in electron transfer.

Defects in the Ketone Synthesis Pathway The final steps in production of ketones from mitochondrial fatty acid βoxidation convert acetyl-CoA to acetoacetate through 2 enzymes of the HMG-

CoA pathway (Fig. 104.2 ).

β-Hydroxy-β-Methylglutaryl-CoA Synthase Deficiency See Chapter 103.6 . HMG-CoA synthase is the rate-limiting step in the conversion of acetyl-CoA derived from fatty acid β-oxidation in the liver to ketones. Several patients with this defect have been identified. The presentation is one of fasting hypoketotic hypoglycemia without evidence of impaired cardiac or skeletal muscle function. Urinary organic acid profile shows only a nonspecific hypoketotic dicarboxylic aciduria. Plasma and tissue carnitine levels are normal, in contrast to all the other disorders of fatty acid oxidation. A separate synthase enzyme, present in cytosol for cholesterol biosynthesis, is not affected. The HMG-CoA synthase defect is expressed only in the liver (and kidney) and cannot be demonstrated in cultured fibroblasts. The diagnosis can be made by genetic mutation analysis. Avoiding fasting is usually a successful treatment.

β-Hydroxy-β-Methylglutaryl-CoA Lyase Deficiency (3 Hydroxy-3-Methylgutaric Aciduria) See Chapter 103.6 .

Defects in Ketone Body Utilization The ketone bodies, β-hydroxybutyrate and acetoacetate, are the end products of hepatic fatty acid oxidation and are important metabolic fuels for the brain during fasting. Three defects in utilization of ketones in brain and other peripheral tissues present as episodes of hyperketotic coma , with or without hypoglycemia.

Monocarboxylate Transporter-1 Deficiency About 10 patients have been described with recurrent episodes of potentially lethal ketoacidosis, with or without hypoglycemia, caused by deficiency of monocarboxylate transporter 1 (MCT1), a plasma membrane carrier encoded by

SLC16A1 that is required to transport ketones into tissues from plasma. Although the first cases identified were homozygous for inactivating mutations of MCT1, heterozygous carriers can also be affected. Affected patients developed severe ketoacidosis provoked by fasting or infections in their 1st years of life; hypoglycemia was not always present. The differential includes ketotic hypoglycemia associated with milder forms of glycogen storage disease, such as phosphorylase or phosphorylase kinase deficiency (see Chapter 105 ). Treatment for acute episodes includes IV dextrose to suppress lipolysis and inhibit ongoing ketogenesis. Long-term treatment includes avoidance of prolonged fasting stress. The diagnosis can be suspected by unusually severe ketosis and delayed suppression of ketones after starting treatment with dextrose. There are no specific metabolic markers or newborn screening methods. The diagnosis can be established by genetic sequencing of SLC16A1 .

Succinyl-CoA:3-Ketoacid-CoA Transferase Deficiency See Chapter 103.6 . Several patients with succinyl-CoA:3-ketoacid-CoA transferase (SCOT ) deficiency have been reported. The characteristic presentation is an infant with recurrent episodes of severe ketoacidosis induced by fasting. Plasma acylcarnitine and urine organic acid abnormalities do not distinguish SCOT deficiency from other causes of ketoacidosis. Treatment of episodes requires infusion of glucose and large amounts of bicarbonate until metabolically stable. Patients usually exhibit inappropriate hyperketonemia even between episodes of illness. SCOT is responsible for activating acetoacetate in peripheral tissues, using succinyl CoA as a donor to form acetoacetyl-CoA. Deficient enzyme activity can be demonstrated in the brain, muscle, and fibroblasts from affected patients. The gene has been cloned, and numerous mutations have been characterized.

β-Ketothiolase Deficiency See Chapter 103.6 .

Bibliography

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104.2

Disorders of Very-Long-Chain Fatty Acids and Other Peroxisomal Functions Michael F. Wangler, Gerald V. Raymond

Keywords very-long-chain fatty acids VLCFAs peroxisome Zellweger syndrome adrenoleukodystrophy

Peroxisomal Disorders Disorders of very-long-chain fatty acids (VLCFAs) fall within the broader group of peroxisomal diseases. The peroxisomal diseases are genetically determined disorders caused either by the failure to form or maintain the peroxisome or by a defect in the function of a single protein that is normally located in this organelle. These disorders cause serious disability in childhood and occur more frequently and present a wider range of phenotypes than recognized in the past. Many, but not all, peroxisomal disorders are associated with elevations of VLCFAs. This discussion addresses the broader group of peroxisomal disorders with a focus on pediatric presentations.

Etiology Peroxisomal disorders are subdivided into two major categories (Table 104.2 ). In the peroxisomal biogenesis disorders (PBDs) the basic defect is the failure to import 1 or more proteins into the organelle. In the other group, defects affect a single peroxisomal protein (single-enzyme defects ). The peroxisome is present in all cells except mature erythrocytes and is a subcellular organelle surrounded by a single membrane; >50 peroxisomal enzymes are identified. Some enzymes are involved in production and decomposition of hydrogen peroxide and others in lipid and amino acid metabolism. Most peroxisomal enzymes are first synthesized in their mature form on free polyribosomes and enter the cytoplasm. Proteins that are destined for the peroxisome contain specific peroxisome targeting sequences (PTSs). Most peroxisomal matrix proteins contain PTS1 , a 3-amino acid sequence at the carboxyl terminus. PTS2 is an aminoterminal sequence that is critical for the import of enzymes involved in plasmalogen and branched-chain fatty acid metabolism. Import of proteins

involves a complex series of reactions that involves at least 23 distinct proteins. These proteins, referred to as peroxins, are encoded by PEX genes. Table 104.2

Classification of Peroxisomal Disorders PEROXISOMAL BIOGENESIS DISORDERS Zellweger spectrum disorder Zellweger syndrome Neonatal adrenoleukodystrophy (ALD) Infantile Refsum disease Rhizomelic chondrodysplasia punctata (RCDP) and other PEX7 conditions

SINGLE-ENZYME DEFECTS X-linked adrenoleukodystrophy Acyl-CoA oxidase deficiency Bifunctional enzyme deficiency 2-Methylacyl-CoA racemase deficiency DHAP acyltransferase deficiency Alkyl-DHAP synthase deficiency Adult Refsum disease

Epidemiology Except for X-linked adrenoleukodystrophy (ALD) , all the peroxisomal disorders listed in Table 104.2 are autosomal recessive diseases . ALD is the most common peroxisomal disorder, with an estimated incidence of 1 in 17,000 live births. The combined incidence of the other peroxisomal disorders is estimated to be 1 in 50,000 live births, although with broader newborn screening it is expected that the actual incidences of all of the disorders of very-long-chain fatty acids will be more accurately established.

Pathology Absence or reduction in the number of peroxisomes is pathognomonic for disorders of peroxisome biogenesis. In most disorders, membranous sacs contain peroxisomal integral membrane proteins, which lack the normal complement of matrix proteins; these are peroxisome “ghosts.” Pathologic changes are observed in most organs and include profound and characteristic defects in neuronal migration, micronodular cirrhosis of the liver, renal cysts, chondrodysplasia punctata, sensorineural hearing loss, retinopathy, congenital heart disease, and dysmorphic features.

Pathogenesis

All pathologic changes likely are secondary to the peroxisome defect. Multiple peroxisomal enzymes fail to function in the PBDs (Table 104.3 ). The enzymes that are diminished or absent are synthesized but are degraded abnormally fast because they may be unprotected outside the peroxisome. It is not clear how defective peroxisome functions lead to the widespread pathologic manifestations.

Table 104.3

Abnormal Laboratory Findings Common to Zellweger Spectrum Disorders Peroxisomes absent to reduced in number Catalase in cytosol Deficient synthesis and reduced tissue levels of plasmalogens Defective oxidation and abnormal accumulation of very-long-chain fatty acids Deficient oxidation and age-dependent accumulation of phytanic acid Defects in certain steps of bile acid formation and accumulation of bile acid intermediates Defects in oxidation and accumulation of L -pipecolic acid Increased urinary excretion of dicarboxylic acids Mutations in 12 different PEX genes have been identified in PBDs. The pattern and severity of pathologic features vary with the nature of the import defects and the degree of import impairment. These gene defects lead to disorders that were named before their relationship to the peroxisome was recognized, namely, Zellweger syndrome, neonatal ALD, infantile Refsum disease, and rhizomelic chondrodysplasia punctata (RCDP ). The first 3 disorders are considered to form a clinical continuum , with Zellweger syndrome the most severe, infantile Refsum disease the least severe, and neonatal ALD intermediate. They can be caused by mutations in any of the 11 genes involved in peroxisome assembly. The specific gene defects cannot be distinguished by clinical features. The clinical severity varies with the degree to which protein import is impaired. Mutations that abolish import completely are often associated with the Zellweger syndrome phenotype, whereas a missense mutation, in which some degree of import function is retained, leads to the

somewhat milder phenotypes. A defect in PEX7, which involves the import of proteins that utilize PTS2, is associated with RCDP. PEX7 defects that leave import partially intact are associated with milder phenotypes, some of which resemble classic (adult) Refsum disease. The genetic disorders that involve single peroxisomal enzymes usually have clinical manifestations that are more restricted and relate to the single biochemical defect. The primary adrenal insufficiency of ALD is caused by accumulation of VLCFAs in the adrenal cortex, and the peripheral neuropathy in adult Refsum disease is caused by the accumulation of phytanic acid in Schwann cells and myelin.

Zellweger Spectrum Disorder Newborn infants with Zellweger syndrome show striking and consistent recognizable abnormalities. Of central diagnostic importance are the typical facial appearance (high forehead, unslanting palpebral fissures, hypoplastic supraorbital ridges, and epicanthal folds; Fig. 104.3 ), severe weakness and hypotonia, neonatal seizures, and eye abnormalities. Because of the hypotonia and craniofacial appearance, Down syndrome may be suspected. Infants with Zellweger syndrome rarely live more than a few months. More than 90% show postnatal growth failure. Table 104.4 lists the main clinical abnormalities.

FIG. 104.3 Zellweger syndrome. Three affected neonates. Note the hypotonia, high forehead with shallow supraorbital ridges, anteverted nares, and mild micrognathia, as well as the talipes equinovarus and contractures at the knees. (From Shaheen R, AlDirbashi OY, Al-Hassnan ZN, et al: Clinical, biochemical and molecular characterization of peroxisomal diseases in Arabs, Clin Genet 79(1):60–70, 2011.)

Table 104.4

Main Clinical Abnormalities in Zellweger Syndrome ABNORMAL FEATURE High forehead Flat occiput Large fontanelle(s), wide sutures

PATIENTS IN WHOM THE FEATURE WAS PRESENT Number % 58 97 13 81 55 96

Shallow orbital ridges Low/broad nasal bridge Epicanthus High-arched palate External ear deformity Micrognathia Redundant skin fold of neck Brushfield spots Cataract/cloudy cornea Glaucoma Abnormal retinal pigmentation Optic disc pallor Severe hypotonia Abnormal Moro response Hyporeflexia or areflexia Poor sucking Gavage feeding Epileptic seizures Psychomotor retardation Impaired hearing Nystagmus

33 23 33 35 39 18 13 5 30 7 6 17 94 26 56 74 26 56 45 9 30

100 100 92 95 97 100 100 83 86 58 40 74 99 100 98 96 100 92 100 40 81

From Heymans HAS: Cerebro-hepato-renal (Zellweger) syndrome: clinical and biochemical consequences of peroxisomal dysfunctions, Thesis, University of Amsterdam, 1984.

Patients with neonatal ALD show fewer, less prominent craniofacial features. Neonatal seizures occur frequently. Some degree of psychomotor developmental delay is present; function remains in the range of severe intellectual disability, and development may regress after 3-5 yr of age, probably from a progressive leukodystrophy. Hepatomegaly, impaired liver function, pigmentary degeneration of the retina, and severely impaired hearing are invariably present. Adrenocortical function is usually impaired and may require adrenal hormone replacement. Chondrodysplasia punctata and renal cysts are absent. Patients with infantile Refsum disease have survived to adulthood. They can walk, although gait may be ataxic and broad based. Cognitive function is generally impaired, but accurate assessment is limited, usually by the presence of both vision and hearing impairment. Almost all have some degree of sensorineural hearing loss and pigmentary degeneration of the retina. They have moderately dysmorphic features that may include epicanthal folds, a flat nose bridge, and low-set ears. Early hypotonia and hepatomegaly with impaired function are common. Levels of plasma cholesterol and high-density and lowdensity lipoprotein are often moderately reduced. Chondrodysplasia punctata and renal cortical cysts are absent. Postmortem study in infantile Refsum disease reveals micronodular liver cirrhosis and small, hypoplastic adrenals. The brain shows no malformations, except for severe hypoplasia of the cerebellar granule

layer and ectopic locations of the Purkinje cells in the molecular layer. The mode of inheritance is autosomal recessive. Some patients with PBDs have milder and atypical phenotypes. They may present with peripheral neuropathy or with retinopathy, impaired vision, or cataracts in childhood, adolescence, or adulthood and have been diagnosed to have Charcot-Marie-Tooth disease or Usher syndrome . Some patients have survived to the fifth decade. Defects in PEX7, which most frequently lead to the RCDP phenotype, may also lead to a milder phenotype with clinical manifestations similar to those of adult Refsum disease.

Rhizomelic Chondrodysplasia Punctata RCDP is characterized by the presence of stippled foci of calcification within the hyaline cartilage and is associated with dwarfing, cataracts (72%), and multiple malformations caused by contractures. Vertebral bodies have a coronal cleft filled by cartilage that is a result of an embryonic arrest. Disproportionate short stature affects the proximal parts of the extremities (Fig. 104.4A ). Radiologic abnormalities consist of shortening of the proximal limb bones, metaphyseal cupping, and disturbed ossification (Fig. 104.4B ). Height, weight, and head circumference are less than the 3rd percentile, and these children have a severe intellectual disability. Skin changes such as those observed in ichthyosiform erythroderma are present in approximately 25% of patients.

FIG. 104.4 A, Newborn infant with rhizomelic chondrodysplasia punctata. Note the severe shortening of the proximal limbs, the depressed bridge of the nose, hypertelorism, and widespread scaling skin lesions. B, Note the marked shortening of the humerus and epiphyseal stippling at the shoulder and elbow joints. (Courtesy of John P. Dorst, MD.)

Isolated Defects of Peroxisomal Fatty Acid Oxidation In the group of single-enzyme defects, acyl-CoA oxidase and bifunctional enzyme deficiency involve a single enzymatic step in peroxisomal fatty acid oxidation. Defects of bifunctional enzyme are common and are found in approximately 15% of patients who are initially suspected of having Zellweger spectrum disorder. Patients with isolated acyl-CoA oxidase deficiency have a somewhat milder phenotype that resembles, and comes to attention because of the development of, an early childhood leukodystrophy.

Isolated Defects of Plasmalogen Synthesis Plasmalogens are lipids in which the first carbon of glycerol is linked to an alcohol rather than a fatty acid. They are synthesized through a complex series of reactions, the first 2 steps of which are catalyzed by the peroxisomal enzymes dihydroxyacetone phosphate alkyl transferase (DHAPT) and synthase. Deficiency of either of these enzymes leads to a phenotype that is clinically

indistinguishable from the peroxisomal import disorder RCDP. This latter disorder is caused by a defect in PEX7, the receptor for PTS2. RCDP shares the severe deficiency of plasmalogens with these single-enzyme disorders but also has defects of phytanic oxidation. The fact that these single genetic disorders are associated with the full phenotype of RCDP suggests that a deficiency of plasmalogens is sufficient to produce it.

Adult (Classic) Refsum Disease The defective enzyme (phytanoyl-CoA hydroxylase) is localized to the peroxisome. The manifestation of Refsum disease includes impaired vision from retinitis pigmentosa, anosmia, ichthyosis, peripheral neuropathy, ataxia, and occasionally cardiac arrhythmias. In contrast to infantile Refsum disease, cognitive function is normal, and there are no congenital malformations. Refsum disease often does not manifest until young adulthood, but visual disturbances such as night blindness, ichthyosis, and peripheral neuropathy may already be present in childhood and adolescence. Early diagnosis is important because institution of a phytanic acid–restricted diet can reverse the peripheral neuropathy and prevent the progression of the visual and central nervous system (CNS) manifestations. The adult Refsum disease phenotype may also be caused by defects in PEX7.

2-Methylacyl-CoA Racemase Deficiency (AMACR) This disorder is caused by an enzyme defect that leads to the accumulation of the branched-chain fatty acids (phytanic and pristanic acid) and bile acids. Individuals present with typically an adult-onset peripheral neuropathy and may also have pigmentary degeneration of the retina.

Laboratory Findings Diagnosis of a peroxisomal disorder often follows from a biochemical determination of an abnormality and then is confirmed through further genetic testing. The biochemical characterization of peroxisomal disorders uses the generally available testing listed in Table 104.5 . Measurement of plasma VLCFA levels is the most common assay. It must be emphasized that although plasma VLCFA levels are elevated in many patients with peroxisomal disorders, this is not always the case. The most important exception is RCDP, in which VLCFA levels

are normal, but plasma phytanic acid levels are increased and red blood cell (RBC) plasmalogen levels are reduced. In other peroxisomal disorders, the biochemical abnormalities are still more restricted. Therefore, a panel of tests is recommended and includes plasma levels of VLCFAs and phytanic, pristanic, and pipecolic acids and RBC levels of plasmalogens. Tandem mass spectrometry techniques also permit convenient quantitation of bile acids in plasma and urine. This panel of tests can be performed on very small amounts of venous blood and permits detection of most peroxisomal disorders. Furthermore, normal results make the presence of the typical peroxisomal disorder unlikely. Biochemical findings combined with the clinical presentation are often sufficient to arrive at a clinical diagnosis. Methods using dried blood spots of filter paper have been developed and are being incorporated into newborn screening assays. Table 104.5

Diagnostic Biochemical Abnormalities in Peroxisomal Disorders DISORDER ZSD RCDP ALD ACoX Bifunctional enzyme deficiency AMACR Refsum disease

VLCFA ↑↑ Nl ↑ ↑ ↑ Nl Nl

PHYTANIC ACID PRISTANIC ACID ↑* ↑* ↑ Nl Nl Nl Nl Nl ↑ ↑ ↑ ↑ ↑ ↑

PLASMALOGENS ↓ ↓↓ Nl Nl Nl Nl Nl

* Phytanic acid and pristanic acid accumulation is age dependent, and normal (Nl) levels may be

seen in infants and young children. VLCFA, Very-long-chain fatty acids; ZSD, Zellweger spectrum disorder; RCDP, rhizomelic chondroplasia punctata; ALD, adrenoleukodystrophy; ACoX, acyl-CoA oxidase deficiency; AMACR, 2-methylacyl-CoA racemase deficiency.

The next step in diagnosis is generally to proceed to molecular DNA diagnosis, and many clinical laboratories provide a peroxisomal panel using next-generation technology. In some circumstances the diagnosis has been revealed through whole exome sequencing and the pathogenic nature of the alteration then confirmed through biochemical means. Definition of the molecular defect in the proband is essential for carrier detection and speeds prenatal diagnosis . Characterization of the mutation may be of prognostic value in patients with PEX1 defects. This defect is present in approximately 60% of PBD patients, and about half the PEX1 defects have the

G843D allele, which is associated with a significantly milder phenotype than found in other mutations.

Diagnosis Several noninvasive laboratory tests permit precise and early diagnosis of peroxisomal disorders (see Table 104.5 ). The challenge in PBDs is to differentiate them from the large variety of other conditions that can cause hypotonia, seizures, failure to thrive, or dysmorphic features. Experienced clinicians readily recognize classic Zellweger syndrome by its clinical manifestations. However, more mildly affected PBD patients often do not show the full clinical spectrum of disease and may be identifiable only by laboratory assays. Clinical features that warrant diagnostic assay include intellectual disability; weakness and hypotonia; dysmorphic features; neonatal seizures; retinopathy, glaucoma, or cataracts; hearing deficits; enlarged liver and impaired liver function; and chondrodysplasia punctata. The presence of 1 or more of these abnormalities increases the likelihood of this diagnosis. Atypical milder forms presenting as peripheral neuropathy have also been described. Some patients with the isolated defects of peroxisomal fatty acid oxidation resemble those with Zellweger spectrum disorder and can be detected by the demonstration of abnormally high levels of VLCFAs. Patients with RCDP must be distinguished from patients with other causes of chondrodysplasia punctata. RCDP is suspected clinically because of the shortness of limbs, developmental delays, and ichthyosis. The most decisive laboratory test is the demonstration of abnormally low plasmalogen levels in RBCs and an alteration in PEX7 .

Complications Patients with Zellweger syndrome have multiple disabilities involving muscle tone, swallowing, cardiac abnormalities, liver disease, and seizures. These conditions are treated symptomatically, but the prognosis is poor, and most patients succumb in the 1st yr of life. Similarly, individuals with RCDP have multiple systemic and neurologic issues. In addition, they may develop quadriparesis from compression at the base of the brain.

Treatment

The most effective therapy is the dietary treatment of adult Refsum disease with a phytanic acid–restricted diet. However, this only applies to this specific condition. For patients with the somewhat milder variants of the peroxisome import disorders, success has been achieved with multidisciplinary early intervention, including physical and occupational therapy, hearing aids or cochlear implants, augmentative and alternative communication, nutrition, and support for the families. Although most patients continue to function in the impaired range, some make significant gains in self-help skills, and several are in stable condition in their teens or even early 20s. Attempts to mitigate some of the secondary biochemical abnormalities include the oral administration of docosahexaenoic acid (DHA). DHA level is greatly reduced in patients with disorders of peroxisome biogenesis, and this therapy normalizes DHA plasma levels. Although there were anecdotal reports of clinical improvement with DHA therapy, a randomized placebo-controlled study failed to find benefit.

Genetic Counseling All the discussed peroxisomal disorders can be diagnosed prenatally. Prenatal testing using chorionic villi sampling or amniocentesis will usually rely on genetic testing when the alteration is known, but biochemical measurements may be made using the same tests as described for postnatal diagnosis (see Table 104.5 ). Because of the 25% recurrence risk, couples with an affected child should be advised about the availability of prenatal diagnosis.

Adrenoleukodystrophy ALD is an X-linked disorder associated with the accumulation of saturated VLCFAs and a progressive dysfunction of the adrenal cortex and nervous system. It is the most common peroxisomal disorder.

Etiology The key biochemical abnormality in ALD is the tissue accumulation of saturated VLCFAs, with a carbon chain length of 24 or more. Excess hexacosanoic acid (C26:0 ) is the most striking and characteristic feature. This accumulation of fatty

acids is caused by genetically deficient peroxisomal degradation of fatty acid. The defective gene (ABCD1) codes for a peroxisomal membrane protein (ALDP, the ALD protein). Many alterations in ABCD1 have been determined to be pathogenic, with over half these being private or unique to the kindred. A curated database of mutations is maintained (www.x-ald.nl ). The mechanism by which the ALDP defect leads to VLCFA accumulation appears to be a disruption of transport of saturated fatty acids into the peroxisome, with resultant continued elongation of progressively longer fatty acids.

Epidemiology The minimum incidence of ALD in males is 1 in 21,000, and the combined incidence of ALD males and heterozygous females in the general population is estimated to be 1 in 17,000. All races are affected. The various phenotypes often occur in members of the same kindred. Increased implementation of newborn screening in the United States and other countries is expected to improve the accuracy of these incidence estimates.

Pathology Characteristic lamellar cytoplasmic inclusions can be demonstrated on electron microscopy in adrenocortical cells, testicular Leydig cells, and nervous system macrophages. These inclusions probably consist of cholesterol esterified with VLCFA. They are most prominent in cells of the zona fasciculata of the adrenal cortex, which at first are distended with lipid and later atrophy. The nervous system displays 2 types of ALD lesions. In the severe cerebral form, demyelination is associated with an inflammatory response manifested by the accumulation of perivascular lymphocytes that is most intense in the involved region. In the slowly progressive adult form, adrenomyeloneuropathy , the main finding is a distal axonopathy that affects the long tracts in the spinal cord. In this form the inflammatory response is mild or absent.

Pathogenesis The adrenal dysfunction is probably a direct consequence of the accumulation of VLCFAs. The cells in the adrenal zona fasciculata are distended with abnormal lipids. Cholesterol esterified with VLCFA is relatively resistant to

adrenocorticotropic hormone (ACTH)–stimulated cholesterol ester hydrolases, and this limits the capacity to convert cholesterol to active steroids. In addition, C26:0 excess increases the viscosity of the plasma membrane, which may interfere with receptor and other cellular functions. There is no correlation between the neurologic phenotype and the nature of the mutation or the severity of the biochemical defect as assessed by plasma VLCFA levels or between the degree of adrenal involvement and nervous system involvement. The severity of the illness and rate of progression correlate with the intensity of the inflammatory response . The inflammatory response may be partially cytokine mediated and may involve an autoimmune response triggered in an unknown way by the excess of VLCFAs. Mitochondrial damage and oxidative stress also appear to contribute. Approximately half the patients do not experience the inflammatory response; this difference is not understood.

Clinical Manifestations There are 5 relatively distinct ALD phenotypes, 3 of which are present in childhood with symptoms and signs. In all the phenotypes, development is usually normal in the 1st 3-4 yr of life. In the childhood cerebral form of ALD, symptoms most often are first noted between ages 4 and 8 yr. The most common initial manifestations are hyperactivity, inattention, and worsening school performance in a child who had previously been a good student. Auditory discrimination is often impaired, although tone perception is preserved. This may be evidenced by difficulty in using the telephone and greatly impaired performance on intelligence tests in items that are presented verbally. Spatial orientation is often impaired. Other initial symptoms are disturbances of vision, ataxia, poor handwriting, seizures, and strabismus. Visual disturbances are often caused by involvement of the parietooccipital cortex rather than eye or optic tract abnormalities, which leads to variable and seemingly inconsistent visual capacity. Seizures occur in nearly all patients and may represent the first manifestation of the disease. Some patients present with increased intracranial pressure. Impaired cortisol response to ACTH stimulation is present in 85% of patients, and mild hyperpigmentation is noted. In most patients with this phenotype, adrenal dysfunction is recognized only after the condition is diagnosed because of the cerebral symptoms. Cerebral childhood ALD tends to progress rapidly with increasing spasticity and paralysis, visual and hearing loss, and loss of ability to speak or swallow. The

mean interval between the first neurologic symptom and an apparently vegetative state is 1.9 yr. Patients may continue in this apparently vegetative state for ≥10 yr. Adolescent ALD designates patients who experience neurologic symptoms between ages 10 and 21 yr. The manifestations resemble those of childhood cerebral ALD except that progression is slower. Approximately 10% of patients present acutely with status epilepticus, adrenal crisis, acute encephalopathy, or coma. Adrenomyeloneuropathy first manifests in late adolescence or adulthood as a progressive paraparesis caused by long tract degeneration in the spinal cord. Approximately half the affected men also have involvement of the cerebral white matter. The Addison-only phenotype is an important condition. Of male patients with Addison disease, 25% may have the biochemical defect of ALD. Many of these patients have intact neurologic systems, whereas others have subtle neurologic signs. Many acquire adrenomyeloneuropathy in adulthood. The term asymptomatic ALD is applied to persons who have the biochemical defect of ALD but are free of neurologic or endocrinal disturbances. Almost all persons with the gene defect eventually become neurologically symptomatic. Approximately 50% of female heterozygotes acquire a syndrome that resembles adrenomyeloneuropathy but is milder and of later onset. Adrenal insufficiency and cerebral disease are rare. Cases of typical ALD have occurred in relatives of those with adrenomyeloneuropathy. One of the most difficult problems in the management of ALD is the common observation that affected individuals in the same family may have quite different clinical courses. For example, in one family, an affected boy may have severe classic ALD culminating in death by age 10 yr, and another brother will have the later-onset adrenomyeloneuropathy.

Laboratory and Radiographic Findings The most specific and important laboratory finding is the demonstration of abnormally high levels of VLCFAs in plasma, RBCs, or cultured skin fibroblasts. Positive results are obtained in all male patients with ALD and in approximately 85% of female carriers of ALD. Mutation analysis is the most reliable method for the identification of carriers. Simply finding a variation in ABCD1 is not adequate for making the diagnosis of ALD. It must be shown to

segregate with elevated VLCFA levels.

Neuroimaging Patients with childhood cerebral or adolescent ALD have characteristic white matter lesions on MRI. In 80% of patients the lesions are symmetric and involve the splenium of the corpus callosum and periventricular white matter in the posterior parietal and occipital lobes. Many will show a garland of contrast enhancement adjacent and anterior to the posterior hypodense lesions (Fig. 104.5 ). This zone corresponds to the zones of intense perivascular lymphocytic infiltration where the blood-brain barrier breaks down. In 10–15% of patients, the initial lesions are frontal. Unilateral lesions that produce a mass effect suggestive of a brain tumor may occur rarely. MRI provides a clearer delineation of normal and abnormal white matter than does CT and is the preferred imaging modality.

FIG. 104.5 Characteristic MRI findings in cerebral adrenoleukodystrophy. A, Symmetric T2-weighted MRI abnormalities involve the posterior white matter, including the corpus callosum. B, Contrast administration reveals a garland of enhancement.

Impaired Adrenal Function More than 85% of patients with the childhood form of ALD have elevated levels of ACTH in plasma and a subnormal rise of cortisol levels in plasma after IV injection of 250 µg of ACTH (Cortrosyn).

Diagnosis and Differential Diagnosis Diagnosis of asymptomatic males has become available by newborn screening

that has been added to the recommended uniform screening panel. After diagnosis, confirmatory testing and genetic counseling should be provided. Males then enter a program of surveillance for adrenal insufficiency and early detection of potential cerebral disease. Females identified through these programs should also have confirmatory testing, genetic counseling for the family, and screening of other at-risk males. Females do not generally require any other monitoring in childhood. The earliest manifestations of childhood cerebral ALD are difficult to distinguish from the more common attention-deficit disorders or learning disabilities of school-age children. Rapid progression, signs of dementia, or difficulty in auditory discrimination suggest ALD. Even in early stages, neuroimaging shows abnormal changes. Other leukodystrophies or multiple sclerosis may sometimes mimic these radiographic findings, although early ALD has more of a predilection for the posterior brain than its mimics. Definitive diagnosis depends on demonstration of VLCFA excess, which occurs only in ALD and the other peroxisomal disorders. Cerebral forms of ALD, especially if asymmetric, may be misdiagnosed as gliomas or other mass lesion. Individuals have received brain biopsy and rarely other therapies before the correct diagnosis was made. Measurement of VLCFAs in plasma is the most reliable differentiating test. Adolescent or adult cerebral ALD can be confused with psychiatric disorders, dementing disorders, multiple sclerosis, or epilepsy. The first clue to the diagnosis of ALD may be the demonstration of characteristic white matter lesions by neuroimaging; VLCFA assays are confirmatory. ALD cannot be distinguished clinically from other forms of Addison disease; it is recommended that assays of VLCFA levels be performed in all male patients with Addison disease. ALD patients do not usually have antibodies to adrenal tissue in their plasma.

Complications An avoidable complication is the occurrence of adrenal insufficiency . The most difficult neurologic problems are those related to bed rest, contracture, coma, and swallowing disturbances. Other complications involve behavioral disturbances and injuries associated with defects of spatial orientation, impaired vision and hearing, and seizures.

Treatment Corticosteroid replacement for adrenal insufficiency or adrenocortical hypofunction is effective. It may be lifesaving and may increase general strength and well-being, but it does not alter the course of the neurologic disability.

Bone Marrow Transplantation Bone marrow transplantation (BMT) or hematopoietic stem cell therapy benefits patients who show early evidence of the inflammatory demyelination characteristic of the rapidly progressive neurologic disability in boys and adolescents with the cerebral ALD phenotype. BMT carries risk, and patients must be evaluated and selected with care. The mechanism of the beneficial effect is incompletely understood. Bone marrow–derived cells do express ALDP, the protein that is deficient in ALD; approximately 50% of brain microglial cells are bone marrow derived. The favorable effect may be caused by modification of the brain inflammatory response. Follow-up of boys and adolescents who had early cerebral involvement has shown stabilization. On the other hand, BMT does not arrest the course in those who already had severe brain involvement and may accelerate disease progression under these circumstances. The ALD MRI score and the use of performance measures on IQ testing have shown some predictive ability for boys likely to benefit from this procedure. Transplant is not recommended in patients with performance IQ significantly 160 mg/dL, drug therapy should be considered.

Familial Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Familial dysbetalipoproteinemia (FDBL) is caused by mutations in the gene for apoE, which when exposed to environmental influences (e.g., high-fat highcaloric diet, excessive alcohol intake) results in a mixed type of hyperlipidemia. Patients tend to have elevated plasma cholesterol and triglycerides to a relatively similar degree. HDL-C is typically normal, in contrast to other causes of hypertriglyceridemia associated with low HDL. This rare disorder affects approximately 1 in 10,000 persons. ApoE mediates removal of chylomicron and VLDL remnants from the circulation by binding to hepatic surface receptors. The polymorphic APOE gene expresses in 3 isoforms: apoE3, apoE2, and apoE4. E4 is the “normal” allele present in the majority of the population. The apoE2 isoform has lower affinity for the LDL receptor, and its frequency is approximately 7%. Approximately 1% of the population is homozygous for apoE2/E2, the most common mutation associated with FDBL, but only a minority expresses the disease. Expression requires precipitating illnesses such as diabetes, obesity, renal disease, or hypothyroidism. Individuals homozygous for apoE4/E4 are at risk for late-onset Alzheimer disease and dementia from repeated sports-related head injuries. Most patients with FDBL present in adulthood with distinctive xanthomas. Tuberoeruptive xanthomas resemble small, grapelike clusters on the knees,

buttocks, and elbows. Prominent orange-yellow discoloration of the creases of the hands (palmar xanthomas) is also typically present. Atherosclerosis, often presenting with peripheral vascular disease, usually occurs in the 4th or 5th decade. Children may present with a less distinctive rash and generally have precipitating illnesses. The diagnosis of FDBL is established by lipoprotein electrophoresis, which demonstrates a broad beta band containing remnant lipoproteins. Direct measurement of VLDL by ultracentrifugation can be performed in specialized lipid laboratories. A VLDL/total triglyceride ratio >0.30 supports the diagnosis. APOE genotyping for apoE2 homozygosity can be performed, confirming the diagnosis in the presence of the distinctive physical findings. A negative result does not necessarily rule out the disease as other mutations in APOE may cause even more serious manifestations. Pharmacologic treatment of FDBL is necessary to decrease the likelihood of symptomatic atherosclerosis in adults. HMG-CoA reductase inhibitors, nicotinic acid, and fibrates are all effective. FDBL is quite responsive to recommended dietary restriction.

Hypertriglyceridemias The familial disorders of triglyceride-rich lipoproteins include both common and rare variants of the Frederickson classification system. These include familial chylomicronemia (type I), familial hypertriglyceridemia (type IV), and the more severe combined hypertriglyceridemia and chylomicronemia (type V). Hepatic lipase deficiency also results in a similar combined hyperlipidemia.

Familial Chylomicronemia (Type I Hyperlipidemia) This rare single-gene defect, like FH, is caused by mutations affecting clearance of apoB-containing lipoproteins. Deficiency or absence of LPL or its cofactor apoC-II, which facilitates lipolysis by LPL, causes severe elevation of triglyceride-rich plasma chylomicrons. HDL-C levels are decreased. Clearance of these particles is greatly delayed, so the plasma is noted to have a turbid appearance even after prolonged fasting (Fig. 104.13 ). Chylomicronemia caused by LPL deficiency is associated with modest elevation in triglycerides, whereas this is not the case when the cause is deficient or absent apoC-II. Both are autosomal recessive conditions with a frequency of approximately 1 in 1 million population. The disease usually presents during childhood with acute

pancreatitis. Eruptive xanthomas on the arms, knees, and buttocks may be present, and there may be hepatosplenomegaly. The diagnosis is established by assaying triglyceride lipolytic activity. Treatment of chylomicronemia is by vigorous dietary fat restriction supplemented by fat-soluble vitamins. Mediumchain triglycerides that are adsorbed into the portal venous system may augment total fat intake, and administration of fish oils may also be beneficial.

FIG. 104.13 Milky plasma from patient with acute abdominal pain. (From Durrington P: Dyslipidaemia, Lancet 362:717–731, 2003.)

Familial Hypertriglyceridemia (Type IV Hyperlipidemia) Familial hypertriglyceridemia (FHTG) is an autosomal dominant disorder of unknown etiology that occurs in approximately 1 in 500 individuals. It is characterized by elevation of plasma triglycerides >90th percentile (250-1,000

mg/dL range), often accompanied by slight elevation in plasma cholesterol and low HDL. FHTG does not usually manifest until adulthood, although it is expressed in approximately 20% of affected children. In contrast to FCHL, FHTG is not thought to be highly atherogenic. It is most likely caused by defective breakdown of VLDL, or less often by overproduction of this class of lipoproteins. The diagnosis should include the presence of at least 1 first-degree relative with hypertriglyceridemia. FHTG should be distinguished from FCHL and FDBL, which require more vigorous treatment to prevent coronary or peripheral vascular disease. The differentiation is usually possible on clinical grounds, in that lower LDL-C levels accompany FHTG, but measurement of normal apoB levels in FHTG may be helpful in ambiguous situations. A more severe hypertriglyceridemia characterized by increased levels of chylomicrons as well as VLDL particles (Frederickson type V ) may occasionally be encountered. Triglyceride levels are often >1,000 mg/dL. The disease is rarely seen in children. In contrast to chylomicronemia (Frederickson type I ), LPL or apoC-II deficiency is not present. These patients often develop eruptive xanthomas in adulthood, whereas type IV hypertriglyceridemia individuals do not. Acute pancreatitis may be the presenting illness. As with other hypertriglyceridemias, excessive alcohol consumption and estrogen therapy can exacerbate the disease. Secondary causes of transient hypertriglyceridemia should be ruled out before making a diagnosis of FHTG. A diet high in simple sugars and carbohydrates or excessive alcohol consumption, as well as estrogen therapy, may exacerbate hypertriglyceridemia. Adolescents and adults should be questioned about excessive consumption of soda and other sweetened drinks, as it is common to encounter people who drink supersized drinks or multiple 12 oz cans of sweetened drinks daily. Cessation of this practice often results in dramatic fall in triglyceride levels as well as weight among those who are obese. HDL-C levels will tend to rise as BMI stabilizes. Pediatric diseases associated with hyperlipidemia include hypothyroidism, nephrotic syndrome, biliary atresia, glycogen storage disease, Niemann-Pick disease, Tay-Sachs disease, systemic lupus erythematosus, hepatitis, and anorexia nervosa (Table 104.10 ). Certain medications exacerbate hyperlipidemia, including isotretinoin (Accutane), thiazide diuretics, secondgeneration antipsychotic agents, oral contraceptives, corticosteroids, β blockers, immunosuppressants, and protease inhibitors used in HIV treatment.

Table 104.10

Secondary Causes of Hyperlipidemia Hypercholesterolemia Hypothyroidism Nephrotic syndrome Cholestasis Anorexia nervosa Drugs: progesterone, thiazides, carbamazepine (Tegretol), cyclosporine

Hypertriglyceridemia Obesity Type 2 diabetes Alcohol Renal failure Sepsis Stress Cushing syndrome Pregnancy Hepatitis AIDS, protease inhibitors Drugs: anabolic steroids, β-blockers, estrogen, thiazides

Reduced High-Density Lipoprotein Smoking Obesity Type 2 diabetes Malnutrition Drugs: β-blockers, anabolic steroids Treatment of hypertriglyceridemia in children rarely requires medication unless levels >1,000 mg/dL persist after dietary restriction of fats, sugars, and

carbohydrates, accompanied by increased physical activity. In such patients the aim is to prevent episodes of pancreatitis. The common use of fibrates (fenofibric acid) and niacin in adults with hypertriglyceridemia is not recommended in children. HMG-CoA reductase inhibitors are variably effective in lowering triglyceride levels, and there is considerably more experience documenting the safety and efficacy of this class of lipid-lowering medications in children. In adults, the U.S. Food and Drug Administration (FDA) has approved prescription (Lovaza, Vascepa) and nonprescription fish oils as adjuncts to diet in the treatment of severe hypertriglyceridemias.

Hepatic Lipase Deficiency Hepatic lipase deficiency is a very rare autosomal recessive condition causing elevation in both plasma cholesterol and triglycerides. Hepatic lipase hydrolyzes triglycerides and phospholipids in VLDL remnants and IDL, preventing their conversion to LDL. HDL-C levels tend to be increased rather than decreased, suggesting the diagnosis. Laboratory confirmation is established by measuring hepatic lipase activity in heparinized plasma.

Disorders of High-Density Lipoprotein Metabolism Primary Hypoalphalipoproteinemia Isolated low HDL cholesterol is a familial condition that often follows a pattern suggestive of autosomal dominant inheritance but may occur independent of family history. It is the most common disorder of HDL metabolism. It is defined as HDL-C 20 yr of age have proteinuria. Many also have hypertension, renal stones, nephrocalcinosis, and altered creatinine clearance. Glomerular hyperfiltration, increased renal plasma flow, and microalbuminuria are often found in the early stages of renal dysfunction and can occur before the onset of proteinuria. In younger patients, hyperfiltration and hyperperfusion may be the only signs of renal abnormalities. With the advancement of renal disease, focal segmental glomerulosclerosis and interstitial fibrosis become evident. In some patients, renal function has deteriorated and progressed to failure, requiring dialysis and transplantation. Other renal abnormalities include amyloidosis, a Fanconi-like syndrome, hypocitraturia, hypercalciuria, and a distal renal tubular acidification defect. Patients with GSD Ib can have additional features of recurrent bacterial infections from neutropenia and impaired neutrophil function. Oral involvement including recurrent mucosal ulceration, gingivitis, and rapidly progressive periodontal disease may occur in type Ib. Intestinal mucosa ulceration culminating in GSD enterocolitis is also common. Type 1b is also associated with a chronic inflammatory bowel disease (IBD)–like picture involving the colon that may be associated with neutropenia and/or neutrophil dysfunction; it may resemble ulcerative colitis or Crohn disease.

Diagnosis The clinical presentation and laboratory findings of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia lead to a suspected diagnosis of type I GSD. Neutropenia is noted in GSD Ib patients, typically before 1 yr of age. Neutropenia has also been noted in some patients with GSD Ia, especially

those with the p.G188A variant. Administration of glucagon or epinephrine leads to a negligible increase, if any, in blood glucose levels, but the lactate level rises significantly. Before the availability of genetic testing, a definitive diagnosis required a liver biopsy. Gene-based variant analysis by single-gene sequencing or gene panels provides a noninvasive way to diagnose most patients with GSD types Ia and Ib.

Treatment Treatment focuses on maintaining normal blood glucose levels and is achieved by continuous nasogastric (NG) infusion of glucose or oral administration of uncooked cornstarch. In infancy, overnight NG drip feeding may be needed to maintain normoglycemia. NG feedings can consist of an elemental enteral formula or only glucose or a glucose polymer to provide sufficient glucose to maintain euglycemia. During the day, frequent feedings with high-carbohydrate content are typically sufficient. Uncooked cornstarch acts as a slow-release form of glucose and can be introduced at a dose of 1.6 g/kg every 4 hr for children 2 cm) that are rapidly increasing in size and/or number may necessitate partial hepatic resection. Smaller adenomas (5% and presence of at least 1 missense variant are associated with a nonlethal hepatic cirrhosis phenotype and, in some situations, a lack of progressive liver disease.

Clinical Manifestations There is a high degree of clinical variability associated with type IV GSD. The most common and classic form is characterized by progressive cirrhosis of the liver and manifests in the 1st 18 mo of life as hepatosplenomegaly and failure to thrive. Cirrhosis may present with portal hypertension, ascites, and esophageal varices and may progress to liver failure, usually leading to death by 5 yr of age. Rare patients survive without progression of liver disease; they have a milder hepatic form and do not require a liver transplant. Extrahepatic involvement in some patients with GSD IV consists of musculoskeletal involvement, particularly cardiac and skeletal muscles, as well as central nervous system (CNS) involvement. A neuromuscular form of type IV GSD has been reported, with 4 main variants recognized based on age at presentation. The perinatal form is characterized by a fetal akinesia deformation sequence (FADS) and death in the perinatal period. The congenital form presents at birth with severe hypotonia, muscle atrophy, and neuronal involvement, with death in the neonatal period; some patients have cardiomyopathy. The childhood form presents primarily with myopathy or cardiomyopathy. The adult form, adult polyglucosan body disease (APBD), presents as an isolated myopathy or with diffuse CNS and peripheral nervous system dysfunction, accompanied by accumulation of polyglucosan material in the nervous system. Symptoms of neuronal involvement include peripheral neuropathy, neurogenic bladder, and leukodystrophy, as well as mild cognitive decline in some patients. For APBD, a leukocyte or nerve biopsy is needed to establish the diagnosis because branching

enzyme deficiency is limited to those tissues.

Diagnosis Deposition of amylopectin-like materials can be demonstrated in liver, heart, muscle, skin, intestine, brain, spinal cord, and peripheral nerve in type IV GSD. Liver histology shows micronodular cirrhosis and faintly stained basophilic inclusions in the hepatocytes. The inclusions are composed of coarsely clumped, stored material that is PAS positive and partially resistant to diastase digestion. Electron microscopy (EM) shows, in addition to the conventional α and β glycogen particles, accumulation of the fibrillar aggregations that are typical of amylopectin. The distinct staining properties of the cytoplasmic inclusions, as well as EM findings, could be diagnostic. However, polysaccharides with histologic features reminiscent of type IV disease, but without enzymatic correlation, have been observed. The definitive diagnosis rests on the demonstration of the deficient branching enzyme activity in liver, muscle, cultured skin fibroblasts, or leukocytes, or on the identification of pathogenic variants in the GBE gene. Prenatal diagnosis is possible by measuring enzyme activity in cultured amniocytes, chorionic villi, or DNA-based methodologies.

Treatment There is no specific treatment for type IV GSD. Nervous system involvement, such as gait problems and bladder involvement, requires supportive, symptomatic management. Unlike patients with the other liver GSDs (I, III, VI, IX), those with GSD IV do not have hypoglycemia, which is only seen when there is overt liver cirrhosis. Liver transplantation has been performed for patients with progressive liver disease, but patients must be carefully selected as this is a multisystem disease, and in some patients, extrahepatic involvement may manifest after transplant. The long-term success of liver transplantation is unknown. Individuals with significant diffuse reticuloendothelial involvement may have greater risk for morbidity and mortality, which may impact the success rate for liver transplant.

Type VI Glycogen Storage Disease (Liver Phosphorylase Deficiency, Hers Disease) Type VI GSD is caused by deficiency of liver glycogen phosphorylase .

Relatively few patients are documented, likely because of underreporting of this disease. Patients usually present with hepatomegaly and growth retardation in early childhood. Hypoglycemia, hyperlipidemia, and hyperketosis are of variable severity. Ketotic hypoglycemia may present after overnight or prolonged fasting. Lactic acid and uric acid levels are normal. Type VI GSD presents within a broad spectrum of involvement, some with a more severe clinical presentation. Patients with severe hepatomegaly, recurrent severe hypoglycemia, hyperketosis, and postprandial lactic acidosis have been reported. Focal nodular hyperplasia of liver and hepatocellular adenoma with malignant transformation into carcinoma is reported in some patients. While cardiac muscle was thought to be unaffected, recently mild cardiomyopathy has been reported in a patient with GSD VI. Treatment is symptomatic and aims to prevent hypoglycemia while ensuring adequate nutrition. A high-carbohydrate, high-protein diet and frequent feeding are effective in preventing hypoglycemia. Blood glucose and ketones should be monitored routinely, especially during periods of increased activity/illness. Long-term follow-up of these patients is needed to expand the understanding of the natural history of this disorder. GSD VI is an autosomal recessive disease. Diagnosis can be confirmed through molecular testing of the liver phosphorylase gene (PYGL), which is found on chromosome 14q21-22 and has 20 exons. Many pathogenic variants are known in this gene; a splice-site variant in intron 13 has been identified in the Mennonite population. A liver biopsy showing elevated glycogen content and decreased hepatic phosphorylase enzyme activity can also be used to make a diagnosis. However, with the availability of DNA analysis and next-generation sequencing panels, liver biopsies are considered unnecessary.

Type IX Glycogen Storage Disease (Phosphorylase Kinase Deficiency) Type IX GSD represents a heterogeneous group of glycogenoses. It results from deficiency of the enzyme phosphorylase kinase (PhK), which is involved in the rate-limiting step of glycogenolysis. This enzyme has 4 subunits (α, β, γ, δ), each encoded by different genes on different chromosomes and differentially expressed in various tissues. Pathogenic variants in the PHKA1 gene cause muscle PhK deficiency; pathogenic variants in the PHKA2 and PHKG2 genes cause liver PhK deficiency; pathogenic variants in the PHKB gene cause PhK deficiency in liver and muscle. Pathogenic variants in the PHKG1 gene have not

been identified. Defects in subunits α, β, and γ are responsible for liver presentation. Clinical manifestations of liver PhK deficiency are usually recognizable within the 1st 2 yr of life and include short stature and abdominal distention from moderate to marked hepatomegaly. The clinical severity of liver PhK deficiency varies considerably. Hyperketotic hypoglycemia, if present, can be mild but may be severe in some cases. Ketosis may occur even when glucose levels are normal. Some children may have mild delays in gross motor development and hypotonia. It is becoming increasingly clear that GSD IX is not a benign condition. Severe phenotypes are reported, with liver fibrosis progressing to cirrhosis and HCC, particularly in patients with PHKG2 variants. Progressive splenomegaly and portal hypertension are reported secondary to cirrhosis. Mild cardiomyopathy has been reported in a patient with GSD IX (PHKB variant). Cognitive and speech delays have been reported in a few individuals, but it is not clear whether these delays are caused by PhK deficiency or coincidental. Renal tubular acidosis has been reported in rare cases. Unlike in GSD I, lactic acidosis, bleeding tendency, and loose bowel movements are not characteristic. Although growth is retarded during childhood, normal height and complete sexual development are eventually achieved. As with debrancher deficiency, abdominal distention and hepatomegaly usually decrease with age and may disappear by adolescence. Most adults with liver PhK deficiency are asymptomatic, although further long-term studies are needed to fully assess the impact of this disorder in adults. Phenotypic variability within each subtype is being uncovered with the availability of molecular testing. The incidence of all subtypes of PhK deficiency is approximately 1 : 100,000 live births.

X-Linked Liver Phosphorylase Kinase Deficiency (From PHKA2 Variants) X-linked liver PhK deficiency is one of the most common forms of liver glycogenosis in males. In addition to liver, enzyme activity can also be deficient in erythrocytes, leukocytes, and fibroblasts; it is normal in muscle. Typically, a 1-5 yr old boy presents with growth retardation, an incidental finding of hepatomegaly, and a slight delay in motor development. Cholesterol, triglycerides, and liver enzymes are mildly elevated. Ketosis may occur after fasting. Lactate and uric acid levels are normal. Hypoglycemia is typically mild, if present, but can be severe. The response in blood glucose to glucagon is

normal. Hepatomegaly and abnormal blood chemistries gradually improve and can normalize with age. Most adults achieve a normal final height and are usually asymptomatic despite a persistent PhK deficiency. It is increasingly being recognized that this disorder is not benign as previously thought, and there are patients with severe disease and long-term hepatic sequelae. In rare cases, liver fibrosis can occur and progress to cirrhosis. Liver histology shows glycogen-distended hepatocytes, steatosis, and potentially mild periportal fibrosis. The accumulated glycogen (β particles, rosette form) has a frayed or burst appearance and is less compact than the glycogen seen in type I or III GSD. Fibrous septal formation and low-grade inflammatory changes may be seen. The gene for the common liver isoform of the PhK α subunit, PHKA2, is located on the X chromosome (αL at Xp22.2). Mutations in the PHKA2 gene account for 75% of all PhK cases. X-linked liver PhK deficiency is further subdivided into 2 biochemical subtypes: XLG1, with measurable deficiency of PhK activity in both blood cells and liver, and XLG2, with normal in vitro PhK activity in blood cells and variable activity in liver. It is suspected that XLG2 may be caused by missense variants that affect enzyme regulation, whereas nonsense variants affecting the amount of protein result in XLG1. Female carriers are unaffected.

Autosomal Liver and Muscle Phosphorylase Kinase Deficiency (From PHKB Variants) PhK deficiency in liver and blood cells with an autosomal recessive mode of inheritance has been reported. Similar to the X-linked form, chief symptoms in early childhood include hepatomegaly and growth retardation. Some patients also exhibit muscle hypotonia. In a few cases where enzyme activity has been measured, reduced PhK activity has been demonstrated in muscle. Mutations are found in PHKB (chromosome 16q12-q13), which encodes the β subunit, and result in liver and muscle PhK deficiency. Several nonsense variants, a singlebase insertion, a splice-site mutation, and a large intragenic mutation have been identified. In addition, a missense variant was discovered in an atypical patient with normal blood cell PhK activity.

Autosomal Liver Phosphorylase Kinase Deficiency (From PHKG2 Variants)

This form of PhK deficiency is caused by pathogenic variants in the testis/liver isoform (TL) of the γ subunit gene (PHKG2). In contrast to X-linked PhK deficiency, patients with variants in PHKG2 typically have more severe phenotypes, with recurrent hypoglycemia, prominent hepatomegaly, significant liver fibrosis, and progressive cirrhosis. Liver involvement may present with cholestasis, bile duct proliferation, esophageal varices, and splenomegaly. Other reported presentations include delayed motor milestones, muscle weakness, and renal tubular damage. The spectrum of involvement continues to evolve as more cases are recognized. PHKG2 maps to chromosome 16p12.1-p11.2; many pathogenic variants are known for this gene.

Phosphorylase Kinase Deficiency Limited to Heart These patients have been reported with cardiomyopathy in infancy and rapidly progress to heart failure and death. Recent studies have shown that this is not a case of cardiac-specific primary PhK deficiency as suspected previously, but rather linked to the γ2 subunit of adenosine monophosphate (AMP)–activated protein kinase (see later). The γ2 subunit is encoded by the PRKAG2 gene.

Diagnosis PhK deficiency may be diagnosed by demonstration of the enzymatic defect in affected tissues. PhK can be measured in leukocytes and erythrocytes, but because the enzyme has many isozymes, the diagnosis can be easily missed without studies of liver, muscle, or heart. Individuals with liver PhK deficiency also usually have elevated transaminases, mildly elevated triglycerides and cholesterol, normal uric acid and lactic acid concentrations, and normal glucagon responses. Gene sequencing is used for diagnostic confirmation and subtyping of GSD IX. The PHKA2 gene encoding the α subunit is most frequently involved, followed by the PHKB gene encoding the β subunit. Variants in the PHKG2 gene underlying γ-subunit deficiency are typically associated with severe liver involvement with recurrent hypoglycemia and liver fibrosis.

Treatment and Prognosis The treatment for liver PhK deficiency is symptomatic. It includes a diet high in complex carbohydrates and proteins and small, frequent feedings to prevent hypoglycemia. Cornstarch can be administered with symptom-dependent dosage

and timing (0.6-2.5 g/kg every 6 hr). Oral intake of glucose, if tolerated, should be used to treat hypoglycemia. If not, IV glucose should be given. Prognosis for the X-linked and certain autosomal forms is typically good; however, long term complications are being recognized. Patients with mutations in the γ subunit typically have a more severe clinical course with progressive liver disease. Liver involvement needs to be monitored in all patients with GSD IX by periodic imaging (abdominal ultrasound or MRI every 6-12 mo) and serial hepatic function tests.

Liver Glycogen Synthase Deficiency Liver glycogen synthase deficiency type 0 (GSD 0 ) is caused by deficiency of hepatic glycogen synthase (GYS2) activity, leading to a marked decrease of glycogen stored in the liver. The gene GYS2 is located at 12p12.2. Several pathogenic variants have been identified in patients with GSD 0. The disease appears to be rare in humans, and in the true sense, this is not a type of GSD because the deficiency of the enzyme leads to decreased glycogen stores. Patients present in infancy with early-morning (prebreakfast) drowsiness, pallor, emesis, and fatigue and sometimes convulsions associated with hypoglycemia and hyperketonemia. Blood lactate and alanine levels are low, and there is no hyperlipidemia or hepatomegaly. Prolonged hyperglycemia , glycosuria, lactic acidosis, and hyperalaninemia, with normal insulin levels after administration of glucose or a meal, suggest a deficiency of glycogen synthase. Definitive diagnosis may be by a liver biopsy to measure the enzyme activity or identification of pathogenic variants in GYS2 . Treatment consists of frequent meals, rich in protein and nighttime supplementation with uncooked cornstarch to prevent hypoglycemia and hyperketonemia. Most children with GSD 0 are cognitively and developmentally normal. Short stature and osteopenia are common features. The prognosis seems good for patients who survive to adulthood, including resolution of hypoglycemia, except during pregnancy.

Hepatic Glycogenosis With Renal Fanconi Syndrome (Fanconi-Bickel Syndrome) Fanconi-Bickel Syndrome is a rare autosomal recessive disorder is caused by defects in the facilitative glucose transporter 2 (GLUT-2), which transports

glucose in and out of hepatocytes, pancreatic β cells, and the basolateral membranes of intestinal and renal epithelial cells. The disease is characterized by proximal renal tubular dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in liver and kidney. The affected child typically presents in the 1st yr of life with failure to thrive, rickets, and a protuberant abdomen from hepatomegaly and nephromegaly. The disease may be confused with GSD I because a Fanconi-like syndrome can also develop in type I patients. Adults typically present with short stature, dwarfism, and excess fat in the abdomen and shoulders. Patients are more susceptible to fractures because of early-onset generalized osteopenia. In addition, intestinal malabsorption and diarrhea may occur. Laboratory findings include glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting, hypophosphatemia, increased serum alkaline phosphatase levels, and radiologic findings of rickets. Mild fasting hypoglycemia and hyperlipidemia may be present. Liver transaminase, plasma lactate, and uric acid levels are usually normal. Oral galactose or glucose tolerance tests show intolerance, which could be explained by the functional loss of GLUT-2 preventing liver uptake of these sugars. Tissue biopsy results show marked accumulation of glycogen in hepatocytes and proximal renal tubular cells, presumably from the altered glucose transport out of these organs. Diffuse glomerular mesangial expansion along with glomerular hyperfiltration and microalbuminuria similar to nephropathy in GSD Ia and diabetes have been reported. This condition is rare, and 70% of patients with Fanconi-Bickel syndrome have consanguineous parents. Most patients have homozygous pathogenic variants; some patients are compound heterozygotes. The majority of variants detected thus far predict a premature termination of translation. The resulting loss of the C-terminal end of the GLUT-2 protein predicts a nonfunctioning glucose transporter with an inward-facing substrate-binding site. There is no specific treatment. Symptom-dependent treatment with phosphate and bicarbonate can result in growth improvement. Growth may also improve with symptomatic replacement of water, electrolytes, and vitamin D; restriction of galactose intake; and a diet similar to that used for diabetes mellitus, with small, frequent meals and adequate caloric intake.

Muscle Glycogenoses

The role of glycogen in muscle is to provide substrates for the generation of ATP for muscle contraction. The muscle GSDs are broadly divided into 2 groups. The first group is characterized by hypertrophic cardiomyopathy, progressive skeletal muscle weakness and atrophy, or both, and includes deficiencies of acid αglucosidase , a lysosomal glycogen-degrading enzyme (type II GSD), lysosomal-associated membrane protein 2 (LAMP2 ), and AMP-activated protein kinase γ2 (PRKAG2 ). The 2nd group comprises muscle energy disorders characterized by muscle pain, exercise intolerance, myoglobinuria, and susceptibility to fatigue. This group includes myophosphorylase deficiency (McArdle disease, type V GSD) and deficiencies of phosphofructokinase (type VII ), phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, and muscle-specific phosphorylase kinase. Some of these latter enzyme deficiencies can also be associated with compensated hemolysis , suggesting a more generalized defect in glucose metabolism.

Type II Glycogen Storage Disease (Lysosomal Acid α-1,4-Glucosidase Deficiency, Pompe Disease) Pompe disease, also referred to as GSD type II or acid maltase deficiency , is caused by a deficiency of acid α-1,4-glucosidase (acid maltase), an enzyme responsible for the degradation of glycogen in lysosomes. This enzyme defect results in lysosomal glycogen accumulation in multiple tissues and cell types, predominantly affecting cardiac, skeletal, and smooth muscle cells. In Pompe disease, glycogen typically accumulates within lysosomes, as opposed to its accumulation in cytoplasm in the other glycogenoses. However, as the disease progresses, lysosomal rupture and leakage lead to the presence of cytoplasmic glycogen as well. Pompe disease is an autosomal recessive disorder. The incidence was thought to be approximately 1 in 40,000 live births in Caucasians and 1 in 18,000 live births in Han Chinese. Newborn screening for Pompe disease in the United States suggests that the prevalence is much higher than previously thought (between 1 in 9,132 and 1 in 24,188). The gene for acid α-glucosidase (GAA) is on chromosome 17q25.2. More than 500 pathogenic variants have been identified that could be helpful in delineating the phenotypes. A splice-site variant (IVS1-13T→G; c.-32-13T>G) is commonly seen in late-onset Caucasian

patients.

Clinical Manifestations Pompe disease is broadly classified into infantile and late-onset forms. Infantile Pompe disease (IPD) is uniformly lethal without enzyme replacement therapy (ERT) with alglucosidase alfa. Affected infants present in the 1st day to weeks of life with hypotonia, generalized muscle weakness with a floppy infant appearance, neuropathic bulbar weakness, feeding difficulties, macroglossia, hepatomegaly, and hypertrophic cardiomyopathy, which if untreated leads to death from cardiorespiratory failure or respiratory infection, usually by 1 yr of age. Late-onset Pompe disease (LOPD; juvenile-, childhood-, and adult-onset disease) is characterized by proximal limb girdle muscle weakness and early involvement of respiratory muscles, especially the diaphragm. Cardiac involvement ranges from cardiac rhythm disturbances to cardiomyopathy and a less severe, short-term prognosis. Symptoms related to progressive dysfunction of skeletal muscles can start as early as within 1 yr of age to as late as the 6th decade of life. The clinical picture is dominated by slowly progressive proximal muscle weakness with truncal involvement and greater involvement of the lower limbs than the upper limbs. The pelvic girdle, paraspinal muscles, and diaphragm are the muscle groups most seriously affected in patients with LOPD. Other symptoms may include lingual weakness, ptosis, and dilation of blood vessels (e.g., basilar artery, ascending aorta). With disease progression, patients become confined to a wheelchair and require artificial ventilation. The initial symptoms in some patients may be respiratory insufficiency manifested by somnolence, morning headache, orthopnea, and exertional dyspnea, which eventually lead to sleep-disordered breathing and respiratory failure. Respiratory failure is the cause of significant morbidity and mortality in LOPD. Basilar artery aneurysms with rupture also contribute to mortality in some cases. Smallfiber neuropathy presenting as painful paresthesia has been identified in some LOPD patients. Gastrointestinal disturbances such as postprandial bloating, dysphagia, early satiety, diarrhea, chronic constipation, and irritable bowel disease have been reported. Genitourinary tract involvement is not uncommon and may present as bladder and bowel incontinence, weak urine stream or dribbling. If untreated, the age of death varies from early childhood to late adulthood, depending on the rate of disease progression and the extent of respiratory muscle involvement. With the advent of ERT, a new natural history is

emerging for both survivors of infantile and LOPD.

Laboratory Findings These include elevated levels of serum creatine kinase (CK), aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH). Urine glucose tetrasaccharide, a glycogen breakdown metabolite, is a reliable biomarker for disease severity and treatment response. In the infantile form a chest x-ray film showing massive cardiomegaly is frequently the first symptom detected. Electrocardiographic findings include a high-voltage QRS complex, Wolff-Parkinson-White (WPW) syndrome, and a shortened PR interval. Echocardiography reveals thickening of both ventricles and/or the intraventricular septum and/or left ventricular outflow tract obstruction. Muscle biopsy shows the presence of vacuoles that stain positively for glycogen; acid phosphatase is increased, presumably from a compensatory increase of lysosomal enzymes. EM reveals glycogen accumulation within a membranous sac and in the cytoplasm. Electromyography reveals myopathic features with excessive electrical irritability of muscle fibers and pseudomyotonic discharges. Serum CK is not always elevated in adult patients. Depending on the muscle sampled or tested, the muscle histologic appearance and electromyography may not be abnormal. Some patients with infantile Pompe disease who had peripheral nerve biopsies demonstrated glycogen accumulation in the neurons and Schwann cells.

Diagnosis Diagnosis of Pompe disease can be made by enzyme assay in dried blood spots, leukocytes, blood mononuclear cells, muscle, or cultured skin fibroblasts demonstrating deficient acid α-glucosidase activity. Gene sequencing showing 2 pathogenic variants in the GAA gene is confirmatory. The enzyme assay should be done in a laboratory with experience using maltose, glycogen, or 4methylumbelliferyl-α-D -glucopyranoside (4MUG) as a substrate. The infantile form has a more severe enzyme deficiency than the late-onset forms. Detection of percent residual enzyme activity is captured in skin fibroblasts and muscle. Blood-based assays, especially dried blood spots, have the advantage of a rapid turnaround time and are being increasingly used as the first-line tissue to make a diagnosis. A muscle biopsy is often done with suspected muscle disease and a broad differential; it yields faster results and provides additional information

about glycogen content and site of glycogen storage within and outside the lysosomes of muscle cells. However, a normal muscle biopsy does not exclude a diagnosis of Pompe disease. Late-onset patients show variability in glycogen accumulation in different muscles and within muscle fibers; muscle histology and glycogen content can vary depending on the site of muscle biopsy. There is also a high risk from anesthesia in infantile patients. An electrocardiogram can be helpful in making the diagnosis in suspected cases of the infantile form and should be done for patients suspected of having Pompe disease before any procedure requiring anesthesia, including muscle biopsy, is performed. Urinary glucose tetrasaccharides can be elevated in the urine of affected patients, and levels are extremely high in infantile patients. Availability of next-generation sequencing panels and whole exome sequencing allows for identification of additional patients with Pompe disease, especially when the diagnosis is ambiguous. Prenatal diagnosis using amniocytes or chorionic villi is available.

Treatment Enzyme replacement therapy with recombinant human acid α-glucosidase (alglucosidase alfa) is available for treatment of Pompe disease. Recombinant acid α-glucosidase is capable of preventing deterioration or reversing abnormal cardiac and skeletal muscle functions (Fig. 105.3 ). ERT should be initiated as soon as possible across the disease spectrum, especially for babies with the infantile form, because the disease is rapidly progressive. Infants who are negative for cross-reacting immunologic material (CRIM) develop a high-titer antibody against the infused enzyme and respond to the ERT less favorably. Treatment using immunomodulating agents such as methotrexate, rituximab, and intravenous immune globulin (IVIG) have demonstrated efficacy in preventing the development of an immune response to ERT and immune tolerance. Nocturnal ventilatory support, when indicated, should be used; it has been shown to improve the quality of life and is particularly beneficial during a period of respiratory decompensation.

FIG. 105.3 Chest radiograph and muscle histology findings of an infantileonset Pompe disease patient before (A ) and after (B ) enzyme replacement therapy. Note the decrease in heart size and muscle glycogen with the therapy. (Modified from Amalfitano A, Bengur AR, Morse RP, et al: Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial, Genet Med 3:132–138, 2001.)

In addition to ERT, other adjunctive therapies have demonstrated benefit in Pompe patients. For patients with the late-onset disease, a high-protein diet may be beneficial. Respiratory muscle strength training has demonstrated improvements in respiratory parameters when combined with ERT. Submaximal exercise regimens are of assistance to improve muscle strength, pain, and fatigue. Other approaches are under clinical development to improve the safety and efficacy of enzyme delivery to affected tissues. These include use of chaperone molecules to enhance rhGAA delivery, and neoGAA, which is a second-generation ERT with a high number of mannose-6-phosphate (M6P) tags that enhances M6P receptor targeting and enzyme uptake. Gene therapy studies to correct the endogenous enzyme production pathways have shown promise. Early diagnosis and treatment are necessary for optimal outcomes. Newborn

screening using blood-based assays in Taiwan has resulted in early identification of Pompe cases and thus improved disease outcomes through the early initiation of ERT.

Glycogen Storage Diseases Mimicking Hypertrophic Cardiomyopathy (Danon Disease) Danon disease is caused by pathogenic variants in the LAMP2 gene, which leads to a deficiency of lysosomal-associated membrane protein 2 (LAMP2). This leads to accumulation of glycogen in the heart and skeletal muscle, which presents primarily with hypertrophic cardiomyopathy and skeletal muscle weakness. Danon disease can be distinguished from the usual causes of hypertrophic cardiomyopathy (defects in sarcomere-protein genes) by their electrophysiologic abnormalities, particularly ventricular preexcitation and conduction defects. Patients present with cardiac symptoms, including chest pain, palpitations, syncope, and cardiac arrest, usually between ages 8 and 15 yr. Other clinical manifestations in Danon disease include peripheral pigmentary retinopathy, lens changes, and abnormal electroretinograms. This disorder is inherited in an X-linked dominant pattern. Diagnosis can be done by genetic testing for the LAMP2 gene. The prognosis for LAMP2 deficiency is poor, with progressive end-stage heart failure early in adulthood. Treatment is directed toward management of symptoms in affected individuals, including management of cardiomyopathy, correction of arrhythmias, and physical therapy for muscle weakness. Cardiac transplantation has been tried successfully in some patients.

Adenosine Monophosphate–Activated Protein Kinase γ2 Deficiency (PRKAG2 Deficiency) AMP-activated protein kinase γ2 (PRKAG2) deficiency is caused by pathogenic variants in the PRKAG2 gene mapped to chromosome 7q36. PRKAG2 is required for the synthesis of the enzyme AMP-activated protein kinase (AMPK), which regulates cellular pathways involved in ATP metabolism. Common presentations include hypertrophic cardiomyopathy and electrophysiologic abnormalities such as WPW syndrome, atrial fibrillation, and progressive atrioventricular block. Cardiac involvement is variable and includes supraventricular tachycardia, sinus bradycardia, left ventricular dysfunction, and

even sudden cardiac death in some cases. In addition to cardiac involvement, there is a broad spectrum of phenotypic presentations including myalgia, myopathy, and seizures. Cardiomyopathy caused by PRKAG2 variants usually allows for long-term survival, although a rare congenital form presenting in early infancy is associated with a rapidly fatal course. Cardiomyopathy in PRKAG2 syndrome often mimics that in other conditions, especially Pompe disease, and should be considered as a differential diagnosis in infants presenting with severe hypertrophic cardiomyopathy. Treatment is primarily symptomatic, including management of cardiac failure and correction of conduction defects.

Muscle Glycogen Synthase Deficiency This GSD results from muscle glycogen synthase (glycogen synthase I , GYS1) deficiency. The gene GYS1 has been localized to chromosome 19q13.3. In the true sense, this is not a type of GSD because the deficiency of the enzyme leads to decreased glycogen stores. The disease is extremely rare and has been reported in 3 children of consanguineous parents of Syrian origin. Muscle biopsies showed lack of glycogen, predominantly oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal. Molecular study revealed a homozygous stop mutation (R462→ter) in the muscle glycogen synthase gene. The phenotype was variable in the 3 siblings and ranged from sudden cardiac arrest, muscle fatigability, hypertrophic cardiomyopathy, an abnormal heart rate, and hypotension while exercising, to mildly impaired cardiac function at rest.

Late-Onset Polyglucosan Body Myopathy (From GYG1 Variants) Late-onset polyglucosan body myopathy is an autosomal recessive, slowly progressive skeletal myopathy caused by pathogenic variants in the GYG1 gene blocking glycogenin-1 biosynthesis. There is a reduced or complete absence of glyogenin-1, which is a precursor necessary for glycogen formation. Polyglucosan accumulation in skeletal muscles causes adult-onset proximal muscle weakness, prominently affecting hip and shoulder girdles. Cardiac involvement is not seen. Compared with GSD IV–APBD, nervous system involvement is uncommon, although polyglucosan deposition is seen in both disorders. GYG1 is mapped to chromosome 3q24. Muscle biopsies show PAS-

positive storage material in 30–40% of muscle fibers. EM reveals the typical polyglucosan structure, consisting of ovoid form composed of partly filamentous material.

Type V Glycogen Storage Disease (Muscle Phosphorylase Deficiency, McArdle Disease) GSD type V is caused by deficiency of myophosphorylase activity. Lack of this enzyme limits muscle ATP generation by glycogenolysis, resulting in muscle glycogen accumulation, and is the prototype of muscle energy disorders. A deficiency of myophosphorylase impairs the cleavage of glucosyl molecules from the straight chain of glycogen.

Clinical Manifestations Symptoms usually first develop in late childhood or in the 2nd decade of life. Clinical heterogeneity is uncommon, but cases suggesting otherwise have been documented. Studies have shown that McArdle disease can manifest in individuals as old as 74, as well as in infancy in a fatal, early-onset form characterized by hypotonia, generalized muscle weakness, and respiratory complication. Symptoms are generally characterized by exercise intolerance with muscle cramps and pain. Symptoms are precipitated by 2 types of activity: brief, high-intensity exercise, such as sprinting or carrying heavy loads, and less intense but sustained activity, such as climbing stairs or walking uphill. Most patients can perform moderate exercise, such as walking on level ground, for long periods. Many patients experience a characteristic “second wind” phenomenon, with relief of muscle pain and fatigue after a brief period of rest. As a result of the underlying myopathy, these patients may be at risk for statininduced myopathy and rhabdomyolysis. While patients typically experience episodic muscle pain and cramping from exercise, 35% of patients with McArdle disease report permanent pain that has a serious impact on sleep and other activities. Studies also suggest that there may also be a link between GSD V and variable cognitive impairment. Approximately 50% of patients report burgundy-colored urine after exercise as a result of exercise-induced myoglobinuria secondary to rhabdomyolysis . Excessive myoglobinuria after intense exercise may precipitate acute renal failure.

Lab findings show elevated levels of serum CK at rest, which further increases after exercise. Exercise also elevates the levels of blood ammonia, inosine, hypoxanthine, and uric acid, which may be attributed to accelerated recycling of muscle purine nucleotides caused by insufficient ATP production. Type V GSD is an autosomal recessive disorder. The gene for muscle phosphorylase (PYGM) has been mapped to chromosome 11q13.

Diagnosis The standard diagnosis for GSD V includes a muscle biopsy to measure glycogen content as well as enzyme and sequencing of PYGM . An ischemic exercise test offers a rapid diagnostic screening for patients with a metabolic myopathy. Lack of an increase in blood lactate levels and exaggerated blood ammonia elevations indicate muscle glycogenosis and suggest a defect in the conversion of muscle glycogen or glucose to lactate. The abnormal ischemic exercise response is not limited to type V GSD. Other muscle defects in glycogenolysis or glycolysis produce similar results (deficiencies of muscle phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, or LDH). An ischemic exercise test was once used to be a rapid diagnostic screening for suspected patients but was associated with severe complications and false-positive results. A nonischemic forearm exercise test with high sensitivity that is easy to perform and cost-effective has been determined to be indicative of muscle glycogenosis. However, as with the ischemic test, it cannot differentiate between abnormal exercise responses due to type V disease versus other defects in glycogenolysis or glycolysis or debranching enzyme (noted when the test is done after fasting). The diagnosis is confirmed by molecular genetic testing of PYGM. A common nonsense variant, p.R49X in exon 1, is found in 90% of Caucasian patients, and a deletion of a single codon in exon 17 is found in 61% of Japanese patients. The p.R49X variant represents 55% of alleles in Spanish patients, whereas the p.W797R variant represents 14% and the p.G204S 9% of pathogenic alleles in the Spanish population. There seems to be an association between clinical severity of GSD V and presence of the D allele of the ACE insertion/deletion polymorphism. This may help explain the spectrum of phenotypic variability manifested in this disorder.

Treatment

Avoidance of strenuous exercise prevents the symptoms; regular and moderate exercise is recommended to improve exercise capacity. Glucose or sucrose given before exercise or injection of glucagon can greatly improve tolerance in these patients. A high-protein diet may increase muscle endurance, and low-dose creatine supplement has been shown to improve muscle function in some patients. The clinical response to creatine is dose dependent; muscle pain may increase on high doses of creatine supplementation. Vitamin B6 supplementation reduces exercise intolerance and muscle cramps. Longevity is not generally affected.

Type VII Glycogen Storage Disease (Muscle Phosphofructokinase Deficiency, Tarui Disease) Type VII GSD is caused by pathogenic variants in the PFKM gene, located on chromosome 12q13.1, which results in a deficiency of muscle phosphofructokinase enzyme. This enzyme is a key regulatory enzyme of glycolysis and is necessary for the ATP-dependent conversion of fructose-6phosphate to fructose-1,6-diphosphate. Phosphofructokinase is composed of 3 isoenzyme subunits according to the tissue type and are encoded by different genes: (PFKM [M: muscle], PFKL [L: liver], and PFKP [P: platelet]). Skeletal muscle has only the M subunit, whereas red blood cells (RBCs) express a hybrid of L and M forms. In type VII GSD the M isoenzyme is defective, resulting in complete deficiency of enzyme activity in muscle and a partial deficiency in RBCs. Type VII GSD is an autosomal recessive disorder with increased prevalence in individuals of Japanese ancestry and Ashkenazi Jews. A splicing defect and a nucleotide deletion in PFKM account for 95% of pathogenic variants in Ashkenazi Jews. Diagnosis based on molecular testing for the common variants is thus possible in this population.

Clinical Manifestations Although the clinical picture is similar to that of type V GSD, the following features of type VII GSD are distinctive: 1. Exercise intolerance, which usually commences in childhood, is more severe than in type V disease and may be associated with nausea,

vomiting, and severe muscle pain; vigorous exercise causes severe muscle cramps and myoglobinuria. 2. Compensatory hemolysis occurs, as indicated by an increased level of serum bilirubin and an elevated reticulocyte count. 3. Hyperuricemia is common and exaggerated by muscle exercise to a greater degree than that observed in type V or III GSD. 4. An abnormal polysaccharide is present in muscle fibers; it is PAS positive but resistant to diastase digestion. 5. Exercise intolerance is especially worse after carbohydrate-rich meals because the ingested glucose prevents lipolysis, thereby depriving muscle of fatty acid and ketone substrates. This is in contrast to patients with type V disease, who can metabolize blood borne glucose derived from either endogenous liver glycogenolysis or exogenous glucose; indeed, glucose infusion improves exercise tolerance in type V patients. 6. The “second wind” phenomenon is absent because of the inability to break down blood glucose. Several rare type VII variants occur. One variant presents in infancy with hypotonia and limb weakness and proceeds to a rapidly progressive myopathy that leads to death by 4 yr of age. A 2nd variant occurs in infancy and results in congenital myopathy and arthrogryposis with a fatal outcome. A 3rd variant presents in infancy with hypotonia, mild developmental delay, and seizures. An additional presentation is hereditary nonspherocytic hemolytic anemia . Although these patients do not experience muscle symptoms, it remains unclear whether these symptoms will develop later in life. One variant presents in adults and is characterized by a slowly progressive, fixed muscle weakness rather than cramps and myoglobinuria. It may also cause mitral valve thickening from glycogen buildup.

Diagnosis To establish a diagnosis, a biochemical or histochemical demonstration of the enzymatic defect in the muscle is required. The absence of the M isoenzyme of phosphofructokinase can also be demonstrated in muscle, blood cells, and fibroblasts. Gene sequencing can identify pathogenic variants for the phosphofructokinase gene.

Treatment There is no specific treatment. Strenuous exercise should be avoided to prevent acute episodes of muscle cramps and myoglobinuria. Consuming simple carbohydrates before strenuous exercise may benefit by improving exercise tolerance. A ketogenic diet has been reported to show clinical improvement in a patient with infantile GSD VII. Drugs such as statins should be avoided. Precautionary measures should be taken to avoid hyperthermia while undergoing anesthesia. Carbohydrate meals and glucose infusions have demonstrated worsening symptoms because of the body's inability to utilize glucose. The administered glucose tends to lower the levels of fatty acids in the blood, a primary source of muscle fuel.

Muscle-Specific Phosphorylase Kinase Deficiency (From PHKA1 Variants) A few cases of PhK deficiency restricted to muscle are known. Patients, both male and female, present either with muscle cramps and myoglobinuria with exercise or with progressive muscle weakness and atrophy. PhK activity is decreased in muscle but normal in liver and blood cells. There is no hepatomegaly or cardiomegaly. This is inherited in an X-linked or autosomal recessive manner. The gene for the muscle-specific form α subunit (αM) is located at Xq12. Pathogenic variants of the gene have been found in some male patients with this disorder. The gene for muscle γ subunit (γM, PHKG1 ) is on chromosome 7p12. No pathogenic variants in this gene have been reported so far.

Other Muscle Glycogenoses With Muscle Energy Impairment Six additional defects in enzymes—phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, fructose-1,6-bisphosphate aldolase A, muscle pyruvate kinase, and β-enolase in the pathway of the terminal glycolysis—cause symptoms and signs of muscle energy impairment similar to those of types V and VII GSD. The failure of blood lactate to increase in response to exercise is a useful diagnostic test and can be used to differentiate muscle glycogenoses from disorders of lipid metabolism, such as carnitine palmitoyltransferase II

deficiency and very-long-chain acyl-CoA dehydrogenase deficiency, which also cause muscle cramps and myoglobinuria. Muscle glycogen levels can be normal in the disorders affecting terminal glycolysis, and assaying the muscle enzyme activity is needed to make a definitive diagnosis. There is no specific treatment (see preceding Treatment section).

Bibliography Akman HO, Aykit Y, Amuk OC, et al. Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1 . Neuromuscul Disord . 2016;26(1):16–20. Byrne BJ, Falk DJ, Pacel CA, et al. Pompe disease gene therapy. Hum Mol Genet . 2011;20:R61–R68. Case LE, Beckemeyer AA, Kishnani PS. Infantile Pompe disease on ERT—update on clinical presentation, musculoskeletal management, and exercise considerations. Am J Med Genet C Semin Med Genet . 2012;160C:69–79. Chiang SC, Hwu WL, Lee NC, et al. Algorithm for Pompe disease newborn screening: results from the Taiwan screening program. Mol Genet Metab . 2012;106(3):281–286. Chien YH, Lee NC, Huang HJ, et al. Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. J Pediatr . 2011;158:1023–1027. D'Souza R, Levandowski C, Slavov D, et al. Danon disease: clinical features, evaluation, and management. Circ Heart Fail . 2014;7(5):843–849. DiMauro S, Spiegel R. Progress and problems in muscle glycogenoses. Acta Myol . 2011;30(2):96–102. Elder ME, Nayak S, Collins SW, et al. B-cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alphaglucosidase in infantile-onset Pompe disease. J Pediatr . 2013;163:847–854.

Hopkins PV, Campbell C1, Klug T, et al. Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri. J Pediatr . 2015;166(1):172–177. Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med . 2014;16(11):e1. Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med . 2010;12(7):446–463. Kronn DF, Day-Salvatore D, Hwu WL, et al. Management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics . 2016;140(1):e20160280. Maga JA, Zhou J, Kambampati R, et al. Glycosylationindependent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in Pompe mice. J Biol Chem . 2013;288(3):1428–1438. Miteff F, Potter HC, Allen J, et al. Clinical and laboratory features of patients with myophosphorylase deficiency (McArdle disease). J Clin Neurosci . 2011;18(8):1055–1058. Poelman E, Hoogeveen-Westerveld M, Kross-de Haan MA, et al. High sustained antibody titers in patients with classic infantile Pompe disease following immunomodulation at start of enzyme replacement therapy. J Pediatr . 2018;195:236– 243. Porto A, Brun F, Severini G, et al. Clinical spectrum of PRKAG2 syndrome. Circ Arrhythm Electrophysiol . 2016;9(1):e003121. Rimoin DL, Connor JM, Pyeritz RE, et al. Emery and Rimoin's principles and practice of medical genetics . Churchill Livingstone Elsevier: New York; 2011.

Roscher A, Patel J, Hewson S, et al. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Mol Genet Metab . 2014;113(3):171–176. Valayannopoulos V, Bajolle F, Arnoux JB, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III with D ,L -3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res . 2011;70:638–641. Valle D, Beaudet AL, Vogelstein B, et al. Online metabolic and molecular bases of inherited disease . [updated 2011] http://www.ommbid.com ; 2006. Wang DQ, Fiske LM, Carreras CT, et al. Natural history of hepatocellular adenoma formation in glycogen storage disease type 1. J Pediatr . 2011;159:442–446. Yang CF, Yang CC, Liao HC, et al. Very early treatment for infantile-onset Pompe disease contributes to better outcomes. J Pediatr . 2016;169:174–180.

105.2

Defects in Galactose Metabolism Priya S. Kishnani, Yuan-Tsong Chen

Keywords galactose lactose galactosemia transferase

galactokinase epimerase reducing substance Milk and dairy products contain lactose , the major dietary source of galactose. The metabolism of galactose produces fuel for cellular metabolism through its conversion to glucose-1-phosphate (see Table 105.1 ). Galactose also plays an important role in the formation of galactosides, which include glycoproteins, glycolipids, and glycosaminoglycans. Galactosemia denotes the elevated level of galactose in the blood and is found in 3 distinct inborn errors of galactose metabolism in 1 of the following enzymes: galactose-1-phosphate uridyl transferase, galactokinase, and uridine diphosphate galactose-4-epimerase. The term galactosemia, although adequate for the deficiencies in any of these disorders, generally designates the transferase deficiency.

Galactose-1-Phosphate Uridyl Transferase Deficiency Galactosemia Two forms of the deficiency exist: infants with complete or near-complete deficiency of the enzyme (classic galactosemia) and those with partial transferase deficiency. Classic galactosemia is a serious disease with onset of symptoms typically by the 2nd half of the 1st wk of life. The incidence is predicted to be 1 in 60,000 live births. The newborn infant receives high amounts of lactose (up to 40% in breast milk and certain formulas), which consists of equal parts of glucose and galactose. Without the transferase enzyme, the infant is unable to metabolize galactose-1-phosphate, the accumulation of which results in injury to kidney, liver, and brain. This injury may begin prenatally in the affected fetus by transplacental galactose derived from the diet of the heterozygous mother or by endogenous production of galactose in the fetus.

Clinical Manifestations The diagnosis of uridyl transferase deficiency should be considered in newborn or young infants with any of the following features within a few days or weeks after birth: jaundice, hepatomegaly, vomiting, hypoglycemia, seizures, lethargy,

irritability, feeding difficulties, poor weight gain or failure to regain birthweight, and aminoaciduria. Untreated children may show nuclear cataracts, vitreous hemorrhage, hepatic failure, cirrhosis, ascites, splenomegaly, or intellectual disability. Patients with galactosemia are at increased risk for Escherichia coli neonatal sepsis; the onset of sepsis often precedes the diagnosis of galactosemia. Pseudotumor cerebri can occur and cause a bulging fontanel. Complete withdrawal of lactose from the diet results in improvement of the acute symptoms. If untreated, death from liver and kidney failure and sepsis may follow within days. When the diagnosis is not made at birth, damage to the liver (cirrhosis) and brain (intellectual disability) becomes increasingly severe and irreversible. Partial transferase deficiency is generally asymptomatic. It is more common than classic galactosemia and is diagnosed in newborn screening because of moderately elevated blood galactose and/or low transferase activity. Galactosemia should be considered for the newborn or young infant who is not thriving or who has any of the preceding findings. Light and electron microscopy of hepatic tissue reveals fatty infiltration, the formation of pseudoacini, and eventual macronodular cirrhosis. These changes are consistent with a metabolic disease but do not indicate the precise enzymatic defect.

Diagnosis The initial diagnosis of galactosemia is done by demonstration of a reducing substance in several urine specimens collected while the patient is on a diet containing human milk, cow's milk, or any other formula containing lactose. The reducing substance detected in urine by Clinitest (e.g., glucose, galactose) can be identified by chromatography or an enzymatic test specific for galactose. Galactose can be detected in urine, provided the milk feeding was within the last few hours and the child is not vomiting excessively. Clinistix urine test results are usually negative because the test relies on the action of glucose oxidase, which is specific for glucose but is nonreactive with galactose. Amino acids may be detected in urine since they are excreted together with glucose because of a proximal renal tubular syndrome. Since galactose is injurious to persons with galactosemia, diagnostic challenge tests dependent on administering galactose orally or intravenously should not be used. Direct enzyme assay using erythrocytes establishes the diagnosis. The clinician needs to confirm that the patient did not receive a blood transfusion before the collection of the blood

sample, because a diagnosis could be missed. A novel method utilizes nonradioactive ultraviolet (UV) light and high-performance liquid chromatography (HPLC) to accurately detect levels of galactose-1-phosphate uridyl transferase in erythrocytes.

Genetics Transferase deficiency is an autosomal recessive disorder. Based on newborn screening in the United States, the frequency of the disease is approximately 1 in 47,000 live births. There are several enzymatic variants of galactosemia. The Duarte variant, a single– amino acid substitution (p.N314D), has diminished RBC enzyme activity (50% of normal), but usually is of no clinical significance. This variant is the most common, with a carrier frequency of 12% in the general population. Those who are heterozygous for the Duarte variant of galactosemia typically have 25% of normal galactose activity, few symptoms, elevated metabolites, and no need for intervention. Other similar variants expressing little enzyme activity typically require no intervention. Some black patients have milder symptoms despite the absence of measurable transferase activity in erythrocytes; these patients retain 10% enzyme activity in liver and intestinal mucosa, whereas most white patients have no detectable activity in any of these tissues. More than 230 identifiable pathogenic variants have been associated with transferase deficiency. In blacks, 62% of alleles are represented by the p.S135L variant, a variant that is responsible for a milder disease course. In the white population, 70% of alleles are represented by the p.Q188R and p.K285N missense variants and are associated with severe disease. Carrier testing and prenatal diagnosis can be performed by direct enzyme analysis of amniocytes or chorionic villi; testing can also be DNA based.

Treatment and Prognosis With the availability of newborn screening for galactosemia, it is possible to identify and treat patients earlier than before. All galactose-containing foods should be removed from the diet on initial suspicion of galactosemia. Various non–lactose-containing milk substitutes are available (casein hydrolysates, soybean-based formula). Elimination of galactose from the diet along with adequate calcium supplementation reverses growth failure and renal and hepatic dysfunction. Cataracts regress, and most patients have no impairment of vision.

Early diagnosis and treatment have improved the prognosis of galactosemia. On long-term follow-up, however, patients still manifest ovarian failure with primary or secondary amenorrhea, decreased bone mineral density, developmental delay, and learning disabilities that increase in severity with age. Hypergonadotropic hypogonadism is reported in 80% to >90% of female patients with classic galactosemia. Although most women with classic galactosemia are infertile when they reach childbearing age, a small number have given birth. Most patients manifest speech disorders, whereas a smaller number demonstrate poor growth and impaired motor function and balance (with or without overt ataxia). The relative control of galactose-1-phosphate levels does not always correlate with long-term outcome, leading to the belief that other factors, such as elevated galactitol, decreased uridine diphosphate galactose (a donor for galactolipids and proteins), and endogenous galactose production may be responsible.

Galactokinase Deficiency The deficient enzyme is galactokinase , which normally catalyzes the phosphorylation of galactose. The principal metabolites accumulated are galactose and galactitol. Two genes are reported to encode galactokinase: GK1 on chromosome 17q24 and GK2 on chromosome 15. Cataracts are usually the sole manifestation of galactokinase deficiency; pseudotumor cerebri is a rare complication. The affected infant is otherwise asymptomatic. Heterozygous carriers may be at risk for presenile cataracts. Lab findings show an increased concentration of blood galactose levels, provided the infant has been fed a lactose-containing formula. The diagnosis is made by demonstrating an absence of galactokinase activity in erythrocytes or fibroblasts. Transferase activity is normal. Treatment is dietary restriction of galactose.

Uridine Diphosphate Galactose-4Epimerase Deficiency There are 2 distinct forms of epimerase deficiency. The first is a benign form that is diagnosed incidentally through newborn screening programs. Affected individuals are asymptomatic because the enzyme deficiency is limited to leukocytes and erythrocytes. This form does not require treatment. The second

variety is severe because the epimerase deficiency is more generalized. Clinical manifestations resemble transferase deficiency, with the additional symptoms of hypotonia and nerve deafness. Clinical symptoms improve with restriction of galactose in diet. Although the severe form of galactosemia is rare, it must be considered in a symptomatic patient with measurable galactose-1-phosphate who has normal transferase activity. The abnormally accumulated metabolites are similar to those in transferase deficiency; however, there is also an increase in cellular uridine diphosphate (UDP) galactose. Diagnosis is confirmed by the assay of epimerase in erythrocytes. Patients with the severe form of epimerase deficiency cannot synthesize UDP galactose from UDP glucose and are galactose dependent. Because galactose is an essential component of many nervous system structural proteins, patients are placed on a galactose-restricted diet rather than a galactose-free diet. Infants with the mild form of epimerase deficiency have not required treatment. It is advisable to follow urine specimens for reducing substances and exclude aminoaciduria within a few weeks of diagnosis while the infant is still on lactose-containing formula. The gene for UDP galactose-4-epimerase (GALE) is located on chromosome 1 at 1p36. Carrier detection is possible by measurement of epimerase activity in the erythrocytes. Prenatal diagnosis for the severe form of epimerase deficiency can be done using an enzyme assay of cultured amniotic fluid cells.

Bibliography Fridovich-Keil JL, Walter JH. Galactosemia. The online metabolic & molecular bases of inherited disease . McGrawHill: New York; 2009 http://www.ommbid.com . Potter NL, Nievergelt Y, Shriberg LD. Motor and speech disorders in classic galactosemia. JIMD Rep . 2013;11:31–41. Rimoin DL, Connor JM, Pyeritz RE, et al. Emery and Rimoin's principles and practice of medical genetics . Churchill Livingstone Elsevier: New York; 2011. Waisbren SE, Potter NL, Gordon CM, et al. The adult galactosemic phenotype. J Inherit Metab Dis . 2012;35(2):279–286.

105.3

Defects in Fructose Metabolism Priya S. Kishnani, Yuan-Tsong Chen

Keywords fructose fructosuria hereditary fructose intolerance fructokinase aldolase hypoglycemia Two inborn errors are known in the specialized pathway of fructose metabolism: benign or essential fructosuria and hereditary fructose intolerance. Fructose-1,6bisphosphatase deficiency, although strictly speaking not a defect of the specialized fructose pathway, is discussed in Chapter 105.4 .

Deficiency of Fructokinase (Essential or Benign Fructosuria) Deficiency of fructokinase is not associated with any clinical manifestations. Fructosuria is an accidental finding usually made because the asymptomatic patient's urine contains a reducing substance. No treatment is necessary, and the prognosis is excellent. Inheritance is autosomal recessive with an incidence of 1 in 120,000 live births. The gene encoding fructokinase (KHK) is located on chromosome 2p23.3. Fructokinase catalyzes the first step of metabolism of dietary fructose: conversion of fructose to fructose-1-phosphate (see Fig. 105.1 ). Without this enzyme, ingested fructose is not metabolized; its level is increased in the blood,

and it is excreted in urine because practically no renal threshold exists for fructose. Clinitest results reveal the urinary reducing substance, which can be identified as fructose by chromatography.

Deficiency of Fructose-1,6-Bisphosphate Aldolase (Aldolase B, Hereditary Fructose Intolerance) Deficiency of fructose-1,6-bisphosphate aldolase (aldolase-B ) is a severe condition of infants caused by a deficiency of aldolase B activity in the liver, kidney, and intestine. This enzyme catalyzes the hydrolysis of fructose-1,6bisphosphate into triose phosphate and glyceraldehyde phosphate. The same enzyme also hydrolyzes fructose-1-phosphate. In the absence of enzyme activity, there is a rapid accumulation of fructose-1-phosphate, which presents with severe symptoms when fructose-containing food is ingested.

Epidemiology and Genetics The exact incidence of hereditary fructose intolerance (HFI) is unknown but is estimated to be as high as 1 in every 26,000 live births. HFI is inherited in an autosomal recessive manner. The ALDOB gene is mapped to chromosome 9q22.3. At least 40 pathogenic variants causing HFI are known. The most common pathogenic variant identified in northern Europeans is a single missense variant, a G→C transversion in exon 5 resulting in the normal alanine at position 149 being replaced by proline. This variant, along with 2 other missense variants (p.A174D and p.N334K), account for 80–85% of HFI in Europe and the United States. Diagnosis of HFI can be made by direct DNA analysis for the common variants and phosphorus magnetic resonance spectroscopy.

Clinical Manifestations Affected individuals remain asymptomatic until fructose or sucrose (table sugar) is introduced in diet (usually from fruit, fruit juice, or sweetened cereal). Signs and symptoms typically manifest in infancy when foods or formulas containing these sugars are introduced. Certain patients are very sensitive to fructose, whereas others can tolerate moderate intakes (up to 250 mg/kg/day). The

average intake of fructose in Western societies is 1-2 g/kg/day. Early clinical manifestations resemble galactosemia and include jaundice, hepatomegaly, vomiting, lethargy, irritability, and convulsions. There may also be a higher incidence of celiac disease in HFI patients (>10%) than in the general population (1–3%). As they grow older, patients usually develop an aversion to fructosecontaining foods due to associated symptoms of nausea, vomiting, and abdominal pain. Characteristic lab findings include lactic acidosis, hypophosphatemia, hyperuricemia, and hypermagnesemia. A prolonged clotting time, hypoalbuminemia, elevation of bilirubin and transaminase levels, and proximal tubular dysfunction are also seen. Acute fructose ingestion produces symptomatic hypoglycemia; the higher the intake, the more severe the clinical picture. Chronic ingestion results in failure to thrive and hepatic disease. If the intake of fructose persists, hypoglycemic episodes recur, leading to progressive renal and hepatic failure and eventually death.

Diagnosis The presence of a reducing substance in urine during an acute episode raises the possibility of HFI. Oral fructose challenge is no longer considered a diagnostic approach because of high risk to the patient, who can become acutely ill after the test. Definitive diagnosis is made by demonstration of 2 pathogenic variants in ALDOB on molecular genetic testing. A common pathogenic variant (substitution of Pro for Ala at position 149) accounts for 53% of HFI alleles worldwide. An alternative is to show deficient hepatic fructose 1-phosphate aldolase (aldolase B) activity on liver biopsy.

Treatment Acute episodes are managed symptomatically by correcting hypoglycemia with IV glucose (dextrose) administration, providing supportive treatment of hepatic insufficiency, and correcting metabolic acidosis. Complete elimination of fructose usually rapidly reverses symptoms and results in normalization of related metabolic disturbances. The cornerstone of long-term treatment is the complete restriction of all sources of sucrose, fructose, and sorbitol from the diet. It may be difficult because these sugars are widely used additives, found even in most medicinal preparations. With treatment, liver and kidney

dysfunction improves, and catch-up in growth is common. Intellectual development is usually unimpaired. As the patient matures, symptoms become milder even after fructose ingestion; the long-term prognosis is good. Because of voluntary dietary avoidance of sucrose, affected patients have few dental caries. Care should be taken to avoid fructose-containing IV fluids during hospitalizations.

Bibliography Bouteldja N, Timson DJ. The biochemical basis of hereditary fructose intolerance. J Inherit Metab Dis . 2010;33(2):105– 112. Rimoin DL, Connor JM, Pyeritz RE, et al. Emery and Rimoin's principles and practice of medical genetics . Churchill Livingstone Elsevier: New York; 2011. Steinmann B, Gitzemann R, van den Berghe G. Disorders of fructose metabolism. The online metabolic and molecular bases of inherited disease–OMMBID . McGraw-Hill: New York; 2009 http://www.ommbid.com .

105.4

Defects in Intermediary Carbohydrate Metabolism Associated With Lactic Acidosis Priya S. Kishnani, Yuan-Tsong Chen

Keywords pyruvate lactic acidosis lactate biotin mitochondria respiratory chain Leigh disease oxidation, retinopathy Lactic acidosis (type B3 ) occurs with defects of carbohydrate metabolism that interfere with the conversion of pyruvate to glucose via the pathway of gluconeogenesis or to carbon dioxide and water via the mitochondrial enzymes of the Krebs cycle. Fig. 105.4 depicts the relevant metabolic pathways. Type I GSD, fructose-1,6-diphosphatase deficiency, and phosphoenolpyruvate carboxylase deficiency are disorders of gluconeogenesis associated with lactic acidosis. Pyruvate dehydrogenase complex deficiency, respiratory chain defects, and pyruvate carboxylase deficiency are disorders in the pathway of pyruvate metabolism causing lactic acidosis. Lactic acidosis (type B3) can also occur in defects of fatty acid oxidation, organic acidurias (see Chapters 103.6 , 103.10 , and 104.1 ), or biotin utilization diseases (type B3) (Table 105.2 ). These disorders are easily distinguishable by the presence of abnormal acyl carnitine profiles, amino acids in the blood, and unusual organic acids in the urine. Blood lactate, pyruvate, and acyl carnitine profiles, and the presence of these unusual urine organic acids should be determined in infants and children with unexplained acidosis, especially if there is an increase of anion gap.

FIG. 105.4 Enzymatic reactions of carbohydrate metabolism, deficiencies of which can give rise to lactic acidosis, pyruvate elevations, or hypoglycemia. The pyruvate dehydrogenase complex comprises, in addition to E1 , E2 , and E3 , an extra lipoate-containing protein (not shown), called protein X, and pyruvate dehydrogenase phosphatase.

Table 105.2

Causes of Type B Lactic Acidosis Type B1—Underlying Diseases Renal failure Hepatic failure Diabetes mellitus Malignancy Systemic inflammatory response syndrome Human immunodeficiency virus

Type B2—Drugs and Toxins Acetaminophen Alcohols—ethanol, methanol, diethylene glycol, isopropanol, and propylene glycol Antiretroviral nucleoside analogs—zidovudine, didanosine, and lamivudine β-Adrenergic agonists—epinephrine, ritodrine, and terbutaline Biguanides—phenformin and metformin

Cocaine, methamphetamine Cyanogenic compounds—cyanide, aliphatic nitriles, and nitroprusside Diethyl ether Fluorouracil Halothane Iron Isoniazid Linezolid Nalidixic acid Niacin Propopol Salicylates Strychnine Sugars and sugar alcohols—fructose, sorbitol, and xylitol Sulfasalazine Total parenteral nutrition Valproic acid Vitamin deficiencies—thiamine and biotin

Type B3—Inborn Errors of Metabolism Glucose-6-phosphatase deficiency (von Gierke disease) Fructose-1,6-diphosphatase deficiency Phosphoenolpyruvate carboxykinase deficiency Pyruvate carboxylase deficiency Pyruvate dehydrogenase complex (PDHC) deficiency Krebs cycle defects Methylmalonic aciduria and other organic acidemias Kearns-Sayre syndrome Pearson syndrome Barth syndrome Mitochondrial DNA depletion syndromes Nuclear DNA respiratory chain defects Mitochondrial DNA respiratory defects Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Myoclonic epilepsy with ragged red fibers (MERRF)

Adapted from Vernon C, LeTourneau JL: Lactic acidosis: recognition, kinetics, and associated prognosis, Crit Care Clin 26:255–283, 2010 (Box 1, p 264). Lactic acidosis unrelated to an enzymatic defect occurs in hypoxemia (type A lactic acidosis). In this case, as well as in defects in the respiratory chain, the serum pyruvate concentration may remain normal (5 mM) Dilated cardiomyopathy with muscle weakness Wolff-Parkinson-White arrhythmia

Ophthalmologic Retinal degeneration with signs of night blindness, color vision deficits, decreased visual acuity, or pigmentary retinopathy Ophthalmoplegia/paresis Fluctuating, dysconjugate eye movements Ptosis Sudden- or insidious-onset optic neuropathy/atrophy

Gastroenterologic Unexplained or valproate-induced liver failure Severe dysmotility Pseudoobstructive episodes

Other A newborn, infant, or young child with unexplained hypotonia, weakness,

failure to thrive, and a metabolic acidosis (particularly lactic acidosis) Exercise intolerance that is not in proportion to weakness Hypersensitivity to general anesthesia Episodes of acute rhabdomyolysis Elevated GDF-15 level MRI, Magnetic resonance imaging, MRS, magnetic resonance spectroscopy; GDF, growth and differentiation factor. From Haas RH, Parikh S, Falk MJ, et al: Mitochondrial disease: a practical approach for primary care physicians, Pediatrics 120:1326–1333, 2007 (Table 1, p 1327). The majority of mitochondrial disorders are caused by nuclear genes involved in mitochondrial function, and >300 genes have been included in nuclear gene panels for mitochondrial disorder diagnosis. However, pathogenic variants can be identified in 50% or fewer of patients diagnosed clinically with a mitochondrial disorder. An important consideration is that many genetic and multifactorial conditions have been associated with defects in 1 or more of the 4 complexes assayed in mitochondrial oxidative phosphorylation testing. These latter conditions feature so-called secondary mitochondrial dysfunction, because the conditions are not considered to be mitochondrial disorders per se. Treatment remains largely symptomatic and does not significantly alter the outcome of disease. Some patients appear to respond to cofactor supplements, typically coenzyme Q10 ± L -carnitine at pharmacologic doses. The addition of creatine monohydrate and α-lipoic acid supplementation may add a significant benefit. EPI-743 is a parobenzoquinone like agent that has protective activity against oxidative injury; it is a promising agent in the treatment of mitochondrial disorders, including Leigh syndrome.

Leigh Disease (Subacute Necrotizing Encephalomyelopathy) Leigh disease is a heterogeneous neurologic disease characterized by demyelination, gliosis, necrosis, relative neuronal sparing, and capillary proliferation in specific brain regions (see Chapter 616.2 ). Patients with Leigh

disease frequently present with feeding and swallowing problems, failure to thrive, and developmental delay. The presentation is highly variable and may include seizures, altered consciousness, pericardial effusion, and dilated cardiomyopathy. Diagnosis is usually confirmed by radiologic or pathologic evidence of symmetric lesions affecting the basal ganglia, brainstem, and subthalamic nuclei. Patients with Leigh disease have defects in several enzyme complexes. Dysfunction in cytochrome-c oxidase (complex IV) is the most commonly reported defect, followed by NADH–coenzyme Q reductase (complex I), PDHC, and pyruvate carboxylase (see Chapter 106 ). Pathogenic variants in the nuclear SURF1 gene, which encodes a factor involved in the biogenesis of cytochrome-c oxidase and mitochondrial DNA variants in the adenosine triphosphatase 6 coding region, have been reported in patients with Leigh disease in association with complex IV deficiency. The most common mitochondrial DNA variant in Leigh disease is the T8993G variant in MT-ATP6 . The prognosis for Leigh syndrome is poor. In a study of 14 cases, there were 7 fatalities before age 1.5 yr. Lactic acidosis, hypoglycemia, and encephalopathy have also been reported in patients with thiamine transporter deficiency and with pyridoxine-dependent epilepsy. Both disorders should improve by the provision of thiamine and pyridoxine, respectively.

Bibliography Barnerias C, Saudubray JM, Touti G, et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol . 2010;52(2):1–9. Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology . 2016;86:2010–2015. Fassone E, Rahman S. Complex I deficiency: clinical features, biochemistry, and molecular genetics. J Med Genet . 2012;49(9):578–590. Ghaddhab C, Morin C, Brunel-Guitton C, et al. Premature ovarian failure in French Canadian Leigh syndrome. J

Pediatr . 2017;184:227–229. Koopman WJH, Distelmaier F, Smeitink JA, et al. OXPHOS mutations and neurodegeneration. EMBO J . 2013;32(1):9– 29. Koopman WJH, Willema PHGM, Smeitink JAM. Monogenic mitochondrial disorders. N Engl J Med . 2012;366:1132– 1140. Mercimek-Mahmutoglu S, Horvath GA, Coulter-Mackie M, et al. Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy. Pediatrics . 2012;129:e1368–e1372. Montero R, Yubero D, Villarroya J, et al. GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. PLoS ONE . 2016;11(2):e0148709. Pèrez-Dueñas B, Serrano M, Rebollo M, et al. Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency. Pediatrics . 2013;131:e1670–e1675. Rimoin DL, Connor JM, Pyeritz RE, et al. Emery and Rimoin's principles and practice of medical genetics . Churchill Livingstone Elsevier: New York; 2011. Steinmann B, Gitzemann R, van den Berghe G. Disorders of fructose metabolism. The online metabolic and molecular bases of inherited disease–OMMBID . McGraw-Hill: New York; 2009 http://www.ommbid.com . Vernon C, LeTourneau JL. Lactic acidosis: recognition, kinetics, and associated prognosis. Crit Care Clin . 2010;26:255–283. Vernon HJ. Inborn errors of metabolism: advances in diagnosis and therapy. JAMA Pediatr . 2015;169(8):778–782. Wallace DC. Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen . 2010;51(5):440–450.

105.5

Defects in Pentose Metabolism Priya S. Kishnani, Yuan-Tsong Chen

Keywords hexose monophosphate pentosuria xylulose transaldolase ribose urine reducing substance Approximately 90% of glucose metabolism in the body is via the glycolytic pathway, with the remaining 10% via the hexose monophosphate pathway. The hexose monophosphate shunt leads to formation of pentoses, as well as providing NADH. One of the metabolites is ribose-5-phosphate, which is used in the biosynthesis of ribonucleotides and deoxyribonucleotides. Through the transketolase and transaldolase reactions, the pentose phosphates can be converted back to fructose-6-phosphate and glucose-6-phosphate.

Essential Pentosuria Essential pentosuria is a benign disorder encountered principally in Ashkenazi Jews and is an autosomal recessive trait. The urine contains L -xylulose , which is excreted in increased amounts because of a block in the conversion of L xylulose to xylitol as a result of xylitol dehydrogenase deficiency . The condition is usually discovered accidentally in a urine test for reducing substances. No treatment is required.

Transaldolase Deficiency Few patients have reported symptoms that include liver cirrhosis, hepatosplenomegaly, severe neonatal hepatopathy, and cardiomyopathy. Biochemical abnormalities revealed elevated levels of arabitol, ribitol, and erythritol in the urine. Erythronic acid has been identified by urine nuclear magnetic resonance spectroscopy as another hallmark metabolite. Enzyme assay in the lymphoblasts and fibroblasts demonstrated low transaldolase activity, which was confirmed by pathogenic variants in the transaldolase gene. In addition, measurement of transaldolase activity in fibroblasts, lymphoblasts, or liver tissue, as well as assessing urinary concentrations of polyols, also can be used to confirm the diagnosis.

Ribose-5-Phosphate Isomerase Deficiency Only one case of this disorder has been reported. The affected male had psychomotor delay from early in life and developed epilepsy at 4 yr of age. Thereafter, a slow neurologic regression developed, with prominent cerebellar ataxia, some spasticity, optic atrophy, and a mild sensorimotor neuropathy. MRI of the brain at ages 11 and 14 yr showed extensive abnormalities of the cerebral white matter. Proton magnetic resonance spectroscopy (MRS) of the brain revealed elevated levels of ribitol and D -arabitol. These pentitols were also increased in urine and plasma similar to the patient found in transaldolase deficiency. Enzyme assays in cultured fibroblasts showed deficient ribose-5phosphate isomerase activity, which was confirmed by a molecular study. These results, combined with a study of ribose-5-phosphate isomerase–deficient mice, demonstrated that the specific genetic pairing of a null allele with an allele coding for a form of the enzyme that is only partly active, allowing for cell type– dependent expression deficits, is a contributing factor to the rarity of the disease. Ribose-5-phosphate isomerase deficiency may represent an example of a singlegene disease that appears seldom because of its complex molecular etiology.

Bibliography Copeland WC. Defects of mitochondrial DNA replication. J

Child Neurol . 2014;29(9):1216–1224. Pierce SB, Spurrell CH, Mandell JB, et al. Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria. Proc Natl Acad Sci USA . 2011;108(45):18313–18317. Rimoin DL, Connor JM, Pyeritz RE, et al. Emery and Rimoin's principles and practice of medical genetics . Churchill Livingstone Elsevier: New York; 2011. Valle D, Beaudet AL, Vogelstein B, et al. Online metabolic and molecular bases of inherited disease . [updated 2011] http://www.ommbid.com ; 2006. Wamelink MMC, Struys EA, Jakobs C. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J Inherit Metab Dis . 2008;31:703–717.

105.6

Disorders of Glycoprotein Degradation and Structure Margaret M. McGovern, Robert J. Desnick

The disorders of glycoprotein degradation and structure include several lysosomal storage diseases that result from defects in glycoprotein degradation, and the congenital disorders of glycosylation (see Chapter 105.7 ). Glycoproteins are macromolecules composed of oligosaccharide chains linked to a peptide backbone. They are synthesized by 2 pathways: the glycosyltransferase pathway, which synthesizes oligosaccharides linked O -glycosidically to serine or threonine residues; and the dolichol, lipid-linked pathway, which synthesizes oligosaccharides linked N -glycosidically to asparagine.

The glycoprotein lysosomal storage diseases result from the deficiency of the enzymes that normally participate in the degradation of oligosaccharides and include sialidosis, galactosialidosis, aspartylglucosaminuria, and αmannosidosis. In some instances the underlying abnormality that leads to glycoprotein accumulation also results in abnormal degradation of other classes of macromolecules that contain similar oligosaccharide linkages, such as certain glycolipids and proteoglycans. In these cases the underlying enzymatic deficiency results in the accumulation of both glycoproteins and glycolipids. The classification of these types of disorders as lipidoses or glycoproteinoses depends on the nature of the predominantly stored substance. In general, the glycoprotein disorders are characterized by autosomal recessive inheritance and a progressive disease course with clinical features that resemble those seen in the mucopolysaccharidoses.

Sialidosis and Galactosialidosis Sialidosis is an autosomal recessive disorder that results from the primary deficiency of neuraminidase because of mutations in the gene (NEU1 ) that encodes this protein, located on chromosome 6p21.33. In contrast, galactosialidosis is caused by the deficiency of 2 lysosomal enzymes— neuraminidase and β-galactosidase. The loss of these enzymatic activities results from mutations in a single gene, CTSA, located on chromosome 20q13.12, that encodes the protective protein cathepsin A, which functions to stabilize these enzymatic activities. Neuraminidase normally cleaves terminal sialyl linkages of several oligosaccharides and glycoproteins. Its deficiency results in the accumulation of oligosaccharides, and the urinary excretion of sialic acid terminal oligosaccharides and sialylglycopeptides. Examination of tissues from affected individuals reveals pathologic storage of substrate in many tissues, including liver, bone marrow, and brain. The clinical phenotype associated with neuraminidase deficiency is variable and includes type I sialidosis, which usually presents in the 2nd decade of life with myoclonus and cherry-red spots in the macula. These patients typically present secondary to gait disturbances, myoclonus, or visual complaints. In contrast, type II sialidosis occurs at several ages of onset (congenital, infantile, and juvenile), depending on the severity of the gene mutation. The congenital and infantile forms result from isolated neuraminidase deficiency, whereas the juvenile form results from both neuraminidase and β-galactosidase deficiency.

The congenital type II disease is characterized by hydrops fetalis, neonatal ascites, hepatosplenomegaly, stippling of the epiphyses, periosteal cloaking, and stillbirth or death in infancy. The type II infantile form presents in the 1st yr of life with dysostosis multiplex, moderate global developmental delays, visceromegaly, corneal clouding, cherry-red maculae, and seizures. The juvenile type II form of sialidosis, which is sometimes designated galactosialidosis, has a variable age of onset ranging from infancy to adulthood. In infancy, the phenotype is similar to that of GM1 gangliosidosis, with edema, ascites, skeletal dysplasia, and cherry-red spots. Patients with later-onset disease have dysostosis multiplex, visceromegaly, intellectual disability, dysmorphism, corneal clouding, progressive neurologic deterioration, and cherry-red spots. No specific therapy exists for any form of the disease, although studies in animal models have demonstrated improvement in the phenotype after bone marrow transplantation. The diagnosis of sialidosis and galactosialidosis is achieved by the demonstration of the specific enzymatic deficiency or by mutations in the responsible gene. Prenatal diagnosis using cultured amniotic cells or chorionic villi is available by demonstrating the enzyme defect and/or specific gene mutations.

Aspartylglucosaminuria This is a rare autosomal recessive lysosomal storage disorder, except in Finland, where the carrier frequency is estimated at 1 in 36 adults, the high frequency due to a founder gene. The disorder results from the deficient activity of aspartylglycosaminidase and the subsequent accumulation of aspartylglycosamine, particularly in the liver, spleen, and thyroid. The gene for the enzyme (AGA) has been localized to chromosome 4q32-33, and the DNA and gene have been isolated and sequenced. In the Finnish population, a single AGA mutation encoding p.C163S accounts for most mutant alleles, whereas outside of Finland, a large number of private mutations have been described. Affected individuals with aspartylglucosaminuria typically present in the 1st yr of life with recurrent infections, diarrhea, and umbilical hernias. Coarsening of the facies and short stature usually develop later. Other features include joint laxity, macroglossia, hoarse voice, crystal-like lens opacities, hypotonia, and spasticity. Psychomotor development is usually near normal until age 5 yr, when a decline is noted. Behavioral abnormalities are typically seen, and IQ values in

affected adults are usually140 gene mutations have been reported. Affected patients display clinical heterogeneity. There is a severe infantile form, or type I disease, and a milder juvenile variant, type II disease. All patients have psychomotor retardation, facial coarsening, and dysostosis multiplex. The infantile form of the disorder, however, is characterized by more rapid cognitive deterioration, with death occurring between ages 3 and 10 yr. Patients with the infantile form also have more severe skeletal involvement and hepatosplenomegaly. The juvenile disorder is characterized by onset of symptoms in early childhood or adolescence, with milder somatic features and survival to adulthood. Hearing loss, destructive synovitis, pancytopenia, and spastic paraplegia have been reported in type II patients. The diagnosis is made by the demonstration of the marked deficiency of α-mannosidase activity in white blood cells or cultured fibroblasts. Clinical trials of ERT with recombinant human α-mannosidase are underway. Prenatal diagnosis can be made by demonstrating the enzyme defect and/or the specific gene mutations in cultured amniocytes or chorionic villi.

Bibliography Arvio M, Mononen I. Aspartylglycosaminuria: a review. Orphanet J Rare Dis . 2016;11:162–172.

Borgwardt L, Stensland HM, Olsen KJ, et al. Alphamannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localization. Orphanet J Rare Dis . 2015;10:70–86. Freeze HH, Eklund EA, Ng BG, et al. Neurological aspects of human glycosylation disorders. Annu Rev Neurosci . 2015;38:105–125. Stroobants S, Damme M, Van der Jeugd A, et al. Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immunetolerant alpha-mannosidosis mice. Neurobiol Dis . 2017;106:255–268. Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med . 2014;370:533–542.

105.7

Congenital Disorders of Glycosylation Eva Morava, Peter Witters

Keywords glycosylation deglycosylation glycans transferrin isoelectric focusing TIEF cerebro-ocular dysplasia–muscular dystrophy

phosphomannomutase-2 deficiency PMM2-CDG mannosephosphoisomerase deficiency MPI-CDG mannose therapy glucosyltransferase-1 deficiency ALG6-CDG UDP-GlcNAc:Dol-P-GlcNAc-P transferase deficiency DPAGT1-CDG muscle-eye-brain disease hyperphosphatasia PIGA-CDG steroid 5α-reductase deficiency SRD5A3-CDG cutis laxa Golgi-α1-2 mannosidase-1 deficiency MAN1B1-CDG phosphoglucomutase-1 deficiency PGM1-CDG D -galactose Golgi homeostasis manganese transporter defect SLC39A8-CDG N -glycanase-1 deficiency NGLY1 Glycosylation is the complex multistep metabolic process of adding (oligo)saccharides to proteins and lipids. The classification of disorders of hypoglycosylation is based on biochemical structures: (1) defects in protein N linked glycosylation, (2) defects in protein O -linked glycosylation, (3) defects in glycosphingolipid and in glycosylphosphatidylinositol-anchor glycosylation, and (4) defects in multiple glycosylation pathways and in other pathways (Fig. 105.7 ). No disorders are known to result from abnormal C -linked glycosylation. Congenital disorders of glycosylation are labeled based on their genetic defect (CDG) .

FIG. 105.7 Schematic of different types of glycosylation. Left to right, Glycosphingolipids, glycophospholipid anchor (GPI anchor), O -linked membrane protein glycosylation, N -linked membrane glycosylation, and secretory N -linked glycan.

Protein glycosylation is an essential pathway. Most functional proteins are glycosylated, including serum proteins (e.g., transferrin, ceruloplasmin, TBG), hormones (e.g., TSH, FSH, FH, ACTH, IGFBP3), and clotting and anticoagulation factors (e.g., factors IX and XI, antithrombin). Membrane proteins are also highly glycosylated. Important intracellular glycoproteins include enzymes such as glycosyltransferases or lysosomal enzymes. N -glycans are linked to the amide group of asparagine. They are synthetized in a complicated process throughout the cytoplasm, endoplasmic reticulum (ER), and Golgi complex, starting with sugar activation and nucleotide sugar synthesis, then oligosaccharide assembly, and finally glycan processing (Fig. 105.8 ). The majority of the pediatric disorders are N -glycosylation disorders. O -glycans are linked to the hydroxyl group of serine or threonine. These diverse glycoproteins are mostly formed in the Golgi complex; their defects can involve xylosylation, fucosylation, mannosylation, or other modifications. An important focus is O -

mannosylation defects because of their relevance for dystroglycanopathies.

FIG. 105.8 Overview of different cell compartments involved in N -linked protein glycosylation. Activation of nucleotide sugars in the cytoplasm is followed by step-bystep dolichol-linked synthesis of glycans associated with the endoplasmic reticulum. Transfer of the glycan from the lipid arm to the protein is followed by transport to the Golgi for further modifications.

Lipid glycosylation is an essential process for the synthesis of ceramide and ganglioside synthesis. Glycosylphosphatidylinositols (GPIs) are very special glycolipids that link various proteins to the plasma membrane, as complex lipidsugar anchors (GPI anchors, see Fig. 105.7 ).

Congenital disorders of glycosylation (CDG) are predominantly multisystem diseases, caused by >140 different genetic defects in glycoprotein and glycolipid glycan synthesis. This rapidly growing group is one of the newest and largest metabolic disorder groups. Most patients described with CDG have N -glycosylation defects, followed by the fastest-growing group of CDGs, involving multiple glycosylation pathways and dolicholphosphate synthesis. Smaller groups are O -glycosylation disorders and disorders of glycosylphosphatidylinositol. The “oldest” CDG is PMM2-CDG, in which the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme that catalyzes the conversion of mannose-6-phosphate into mannose-1phosphate. The majority of CDGs have an autosomal recessive inheritance. Only 2 N -linked CDGs are autosomal dominant, GANAB-CDG and PRKCSH-CDG. The dominantly inherited O -linked CDGs include EXT1/EXT2-CDG, POFUT1-CDG, and POGLUT1-CDG. X-linked CDGs include ALG13-CDG, SSR4-CDG, PIGA-CDG, SLC35A2-CDG, ATP6AP2-CDG and ATP6AP1CDG. Some CDGs are lethal; 20% of PMM2-CDG patients die in the 1st 2 yr of life. Some patients, however, stabilize throughout young adulthood. Almost any clinical phenotype can be present in a patient with CDG. It can affect any organ or organ system and most often includes the central nervous system (CNS). The most common clinical features include developmental and speech delay, seizures, ataxia, spasticity, peripheral neuropathy, hypotonia, strabismus, abnormal fat distribution, visual loss, cardiomyopathy, feeding difficulties, liver dysfunction, endocrine abnormalities, bleeding diathesis, and thrombosis (Fig. 105.9 and Table 105.6 ). Single-organ presentations are rare in CDGs (e.g., TUSC3-CDG and ST3GAL3-CDG: brain; DHDDS-CDG: retina; ALG14-CDG: neuromuscular junction; POFUT1-CDG and POGLUT1-CDG: skin; SEC23BCDG: red cell lineage; EXT1/EXT2-CDG: cartilage; TMEM199-CDG: liver). Many CDGs are recognizable syndromes. CDG should be considered in any patient with a developmental disability or an unexplained clinical condition, especially in multisystem disease with neurologic involvement.

FIG. 105.9 Patients with phosphomannomutase-2 deficiency (PMM2-CDG) and recognizable clinical features. A, Inverted nipples. B and C, Abnormal fat distribution. D, Muscle atrophy caused by peripheral neuropathy after puberty. E, Characteristic facial features with strabismus, short nose, anteverted nares, long philtrum, and large ears. F, MRI of brain with T1-weighted sagittal image showing cerebellar vermis hypoplasia (arrow) and brain atrophy.

Table 105.6

Clinical and Laboratory Features in Common Congenital Disorders of Glycosylation (CDGs), with Clinically Recognizable Phenotype and Abnormal Glycosylation, Detectable by Serum Transferrin Isoform Analysis (TIEF) DEFECTIVE MOST FREQUENT GENE CLINICAL FEATURES

SUGGESTIVE FEATURES

PMM2

Inverted nipples and/or abnormal fat pads, stroke-like episodes

Strabismus, nystagmus, smooth philtrum, large ears, vomiting, diarrhea, FTT, axial hypotonia, cerebellar vermis hypoplasia, ataxia, psychomotor disability,

OTHER LABORATORY BIOCHEMICAL ABNORMALITIES ANOMALIES Elevated serum Type 1 serum transaminases, TIEF, decreased hypoalbuminemia, PMM activity in decreased factor IX, leukocytes and XI and AT activity, fibroblasts low serum

PMI

ALG6

seizures, spasticity, neuropathy, pigmentary retinitis Cholestasis, hepatomegaly, feeding difficulties, recurrent vomiting, chronic diarrhea, ascites, recurrent thrombosis, gastrointestinal bleeding

Hypotonia, muscle weakness, seizures, ataxia, intellectual disability, behavioral abnormalities

ceruloplasmin and TBG levels Hyperinsulinism, protein losing enteropathy Normal intelligence and absence of neurologic features (Distal limb malformations)

Elevated transaminases, hypoalbuminemia, hypoglycemia, decreased factor IX, XI, and AT-III activity

Elevated serum transaminases; hypoalbuminemia; decreased factor IX, XI, and AT activity; low serum IgG level DPAGT1 Microcephaly, brain Congenital Decreased AT, malformations, hypotonia, myasthenia protein C, and protein severe psychomotor disability, phenotype S activity; increased seizures, spasticity, proximal In multisystem creatine kinase; weakness, failure to thrive, phenotype: hypoalbuminemia; joint contractures cataract normal creatine kinase in myasthenia SRD5A3 Developmental delay, Congenital cataract, Low anticoagulation hypotonia, ataxia, cerebellar retinal and iridic factors (AT, protein vermis hypoplasia, intellectual coloboma, glaucoma, C, and protein S disability, speech delay, visual optic nerve dysplasia, activity), increased loss ichthyosis serum transaminases ATP6V0A2 Generalized cutis laxa, Cobblestone-like Mild coagulation hypotonia, strabismus, brain dysgenesis abnormalities, characteristic facial features, increased serum joint laxity, seizures, motor transaminase levels ATP6V1A and and language developmental Cardiovascular Mild coagulation delay, spontaneous ATP6V1E1 anomalies abnormalities and improvement of cutis laxa by increased serum aging transaminase levels, hypercholesterolemia

PGM1

Pierre Robin sequence, cholestasis, short stature, dilated cardiomyopathy,

Cleft palate, hyperinsulinism, normal intelligence

MAN1B1

Developmental delay, speech delay, intellectual disability, muscle weakness

Obesity, autistic Increased serum features, inverted transaminase levels, nipples, characteristic low AT face

TMEM199

Cholestasis, hepatomegaly,

Normal intelligence

Hypoglycemia, increased serum transaminase levels, decreased AT

Decreased serum

Type 1 serum TIEF, decreased PMI activity in leukocytes and fibroblasts

Type 1 serum TIEF, abnormal LLO results in fibroblasts

Type 1 serum TIEF

Type 1 serum TIEF but reported false-negative TIEF Type 2 serum TIEF but reported false-negative TIEF Abnormal apoC-III IEF, characteristic MALDI TOF profile (Note abnormal skin histology) Mixed type 1/ 2 serum TIEF, decreased fibroblast PGM1 activity Type 2 serum TIEF, abnormal apoC-III IEF, diagnostic MALDI TOF profile Type 2 serum

liver steatosis, liver fibrosis, CCDC115 ATP6AP1 and liver failure, spontaneous bleedings, motor ATP6AP2 developmental delay

Hepatomegaly Immune deficiency

SLC39A8

Dwarfism, craniosynostosis, rhizomelia, Leigh disease

Seizures, hypsarrhythmia, hypotonia, developmental and speech delay, FTT

ceruloplasmin, increased serum transaminase levels, hypercholesterolemia, high AP Decreased serum manganese, high serum transaminases, abnormal coagulation

TIEF, abnormal apoC-III IEF, characteristic MALDI TOF profile Type 2 serum TIEF, abnormal apoC-III, characteristic MALDI TOF profile

AP, Alkaline phosphatase; AT, antithrombin; apoC-III: apolipoprotein C-III; FTT, failure to thrive; LLO, lipid-linked oligosaccharides; MALDI-TOF, matrix-assisted laser desorption/ionization time of flight; TBG, thyroxine-binding globulin; TIEF, transferrin isoelectric focusing.

There are also congenital disorders of deglycosylation , including known lysosomal disorders and a severe neurologic condition caused by defective N glycanase function (NGLY1 defect). Laboratory evaluations in most N -linked CDGs rely on a primary screening method called serum transferrin isoelectric focusing (TIEF) . Transferrin isoforms, which are hyposialylated (missing terminal sialic acid residues), show different cathodal shifts depending on either missing glycan chains or truncated glycans. A type 1 pattern suggests an early metabolic defect in the cytosolicER–related glycan synthesis and assembly. A type 2 pattern suggests Golgirelated glycan-processing defects (Fig. 105.10 ).

FIG. 105.10 Diagnostic flow chart of glycosylation disorders affecting Nlinked glycosylation. *Instead of TIEF, mass spectrometry methods can be used as well. IGFBP3, Insulin-like growth factor–binding protein 3; TBG, thyroxine-binding globulin; CDG, congenital disorders of glycosylation; PMM, phosphomannomutase; MPI, mannosephosphoisomerase, LLO, lipid-linked oligosaccharides; TIEF, transferrin isoelectric focusing; IEF, isoelectric focusing; MALDI-TOF, matrix-assisted laser desorption/ionization time of flight.

Isoelectric focusing of apolipoprotein C-III (IEF apoC-III) , a serum mucine type O -glycosylated protein, can detect some O -glycosylation disorders (combined N - and O -linked glycosylation defects). Mass spectrometry in serum for type 1 defects is highly sensitive for mild glycosylation abnormalities. Glycomics by matrix-assisted laser desorption/ionization time of flight (MALDI-TOF ) can be diagnostic in specific types of CDG (mostly Golgi related with a type 2 pattern). Dolichol-linked glycan or lipid-linked oligosaccharide (LLO) analysis is a complicated but sensitive method to detect ER-related N -glycan assembly (CDG type 1) defects in patient fibroblasts. GPIanchor defects can be suspected based on recurrent elevation of alkaline phosphatase levels in blood.

Dystroglycanopathies can be confirmed based on abnormal immunohistochemistry in muscle biopsy. Fluorescence-activated cell sorting (FACS ) analysis of the membrane-anchored markers CD16 and CD24 in leukocytes is highly suggestive for a GPI-anchor abnormality, especially when alkaline phosphatase in blood is significantly elevated. Enzyme analysis in blood is only available for a few, more common CDGs (PMM2-CDG, MPI-CDG, PGM1-CDG); it is more reliable in fibroblasts. With an abnormal TIEF pattern result or clinical suspicion of any type of CDG, most metabolic centers use a direct CDG gene panel analysis or nextgeneration sequencing (NGS; whole exome sequencing) (see Fig. 105.10 ).

Congenital Disorders of Protein N Glycosylation Phosphomannomutase-2 Deficiency (PMM2CDG) Clinical Manifestations PMM2-CDG is the most common and easily recognizable CDG. Most patients have alternating strabismus, characteristic facial features (short nose, long philtrum, large ears) (Fig. 105.9E ), inverted nipples and/or abnormal fat pads (Fig. 105.9A -C ), feeding difficulties, axial hypotonia, and decreased reflexes, already in the 1st few mo of life. Nystagmus (caused by pontocerebellar and vermis hypoplasia; Fig. 105.9F ) is also common. Psychomotor disability is present in most patients, but normal intellectual development has been described in a few patients. Most patients develop a multisystem disease, and A; R141H) is present in 75% of patients of Caucasian origin. The exact incidence of PMM2CDG is not known, but it is estimated to be as high as 1 in 40,000-80,000 in Europe. Prenatal diagnosis is only reliable by genetic testing.

Treatment

The therapy in PMM2-CDG relies on supportive treatment. Even with the best treatment, mortality is about 20% in the 1st 2 yr of life, mostly from cardiac or kidney involvement and severe infections. Current recommended therapy includes adequate nutrition, diet or tube feeding if needed, cardiac support, hormone supplements, physical and occupational therapy, speech therapy, seizure management, and strabismus surgery. Therapeutic developments include targeted mannose-phosphate treatment, and chaperone therapy; these are only in preclinical trial phases.

Mannosephosphoisomerase Deficiency (MPICDG) Clinical Manifestations MPI deficiency is a recognizable and treatable CDG. Most patients show early symptoms of liver disease (cholestasis, elevated transaminases) and feeding difficulties, with recurrent vomiting and chronic diarrhea, most frequently with protein-losing enteropathy. Life-threatening episodes might appear as early as the 1st few mo of life with recurrent thrombosis and severe gastrointestinal bleeding because of severe coagulation abnormalities. Hypoglycemia is usually caused by hyperinsulinism. Hypoalbuminemia can be severe; patients might develop visible abdominal distention from a combination of ascites and hepatomegaly. Patients with MPI-CDG have no other organ involvement, and the CNS is not affected. There are no dysmorphic features. The liver disease frequently progresses to fibrosis or cirrhosis.

Pathophysiology Mannosephosphoisomerase (MPI) catalyzes the conversion of fructose-6phosphate to mannose-6-phosphate, 1 step before PMM2, therefore blocking the formation of activated mannose units (GDP mannose) for oligosaccharide synthesis. Hypoglycosylation leads to abnormal glycoprotein function the same as in PMM2-CDG, especially coagulation and anticoagulation factors, liver function, and hormone receptors.

Diagnosis The primary screening method in a suspected MPI-CDG patient is serum transferrin isoform analysis by TIEF (see Fig. 105.10 ) or MS analysis. MPI

deficiency leads to a type 1 pattern, as seen in PMM2 deficiency. MPI enzyme analysis is available in leukocytes and fibroblasts. The presence of elevated serum transaminases, hypoalbuminemia, decreased factor IX and XI and antithrombin activity, hyperinsulinism, and nonketotic hypoglycemia are highly suggestive for MPI-CDG. MPI-CDG is autosomal recessive. Genetic testing is mostly performed by direct sequencing. The exact incidence of MPI-CDG is not known, but it is estimated at 1 : 800 000 in Europe. Prenatal diagnosis is only reliable by genetic testing. Although this is a rare CDG, early diagnosis is imperative because it is treatable.

Treatment MPI-CDG is the first CDG type treatable by dietary therapy. Mannose therapy is clinically effective by both IV and oral supplementation of 1 g/kg/day divided into 3-4 doses. A known side effect is hemolysis. The treatment uses an alternative pathway: mannose can be phosphorylated by hexokinases to mannose 6-phosphate, bypassing the MPI defect. The clinical symptoms improve rapidly, but liver function might further deteriorate. Liver fibrosis and cirrhosis might necessitate liver transplantation, which will resolve the metabolic disease. The oldest patient known with MPI-CDG has survived into her late 30s.

Glucosyltransferase-1 Deficiency (ALG6-CDG) Clinical Manifestations ALG6-CDG is the 2nd most common CDG. Most patients have hypotonia, muscle weakness, seizures, and ataxia. To date, no patient with ALG6-CDG has normal intelligence. Speech delay and nystagmus are common neurologic signs. Brachydactyly, skeletal abnormalities, and transverse limb defects have been observed. Strabismus and characteristic facial dysmorphism are rare (hypertelorism, oval face, short nose). Inverted nipples and/or abnormal fat pads are exceptional in ALG6-CDG. The most severe ALG6-CDG patients show a multisystem phenotype in the 1st few mo of life, including severe infections, protein-losing enteropathy, hypoalbuminemia, anemia, and failure to thrive. Autistic behavior and mood changes have been observed in several patients. The oldest patient to date is almost 45 yr.

Pathophysiology The metabolic problem is caused by defective binding of the 1st of 3 glucoses to the lipid-linked oligosaccharide in the ER. This glucose binding is essential for attachment of the oligosaccharyltransferase enzyme complex to the newly built oligosaccharide chain and the ability to transfer it to the protein. This leads to protein hypoglycosylation and abnormal glycoprotein function similar to PMM2-CDG and MPI-CDG. Laboratory abnormalities are also similar, including abnormalities in coagulation and anticoagulation factors, liver function, thyroid hormones, and immunoglobulins (IgG).

Diagnosis The primary screening method in a suspected ALG6-CDG patient is serum transferrin glycoform analysis by TIEF or MS analysis. ALG6 deficiency leads to a type 1 pattern (see Fig. 105.10 ), as seen in PMM2 and MPI deficiency. There is no available enzyme analysis, although lipid-linked oligosaccharides could be evaluated in patient fibroblasts. ALG6-CDG is autosomal recessive. Genetic testing is mostly performed by direct sequencing. The most common mutations are p.A333V and p.I299Del. Prenatal diagnosis is only reliable by genetic testing. The exact incidence of ALG6-CDG is not known.

Treatment The current therapy in ALG6-CDG relies on supportive treatment. Mortality is about 10% in the 1st years of life, mostly from protein-losing enteropathy and severe infections.

UDP-GlcNAc:Dol-P-GlcNAc-P Transferase Deficiency (DPAGT1-CDG) Clinical Manifestations DPAGT1 deficiency is a recognizable and potentially treatable CDG. About one third of patients show the congenital myasthenia phenotype, indistinguishable from other genetic congenital myasthenias. Creatine kinase (CK) levels are normal. These patients have a relatively good prognosis, especially with early myasthenia therapy. The other patients show a multisystem phenotype with

microcephaly, brain malformations, hypotonia, severe psychomotor disability, seizures, spasticity, failure to thrive, joint contractures, and cataracts.

Pathophysiology DPAGT1 defect leads to very early arrest of glycan synthesis outside the ER membrane, by slowing down the addition of the 2nd GlcNAc sugar to the phosphorylated dolichol arm. Abnormal receptor glycosylation in the neuromuscular junction leads to myasthenia. Hypoglycosylation in the multisystem type leads to abnormal glycoprotein function similar to that in PMM2-CDG, especially involving the anticoagulation factors, and interestingly leading to high serum CK (in contrast to the congenital myasthenia phenotype) and hypoalbuminemia.

Diagnosis The primary screening method is serum transferrin glycoform analysis or MS analysis. Most patients show a type 1 pattern (see Fig. 105.10 ), but patients with the congenital myasthenia phenotype can show normal screening. There is no clinically available enzyme analysis. DPAGT1-CDG is autosomal recessive. Genetic testing is mostly performed by direct sequencing. The exact incidence is not known. Prenatal diagnosis is only reliable by genetic testing. Because of the false-negative TIEF results in several patients with the myasthenic phenotype, congenital myasthenia panel testing is suggested in suspected cases, especially for determining the potential therapy.

Treatment The congenital myasthenia phenotype is frequently treatable by high-dose pyridostigmine, eventually enhanced with salbutamol. In the multisystem phenotype of DPAGT1-CDG, treatment is supportive.

Congenital Disorders of Protein O Glycosylation Cerebro-Ocular Dysplasia–Muscular Dystrophy and Muscle-Eye-Brain Disease

Spectrum (POMT1-CDG, POMT2-CDG, POMGNT1-CDG) From isolated muscular dystrophy to Walker Warburg syndrome , this group of O -linked glycosylation disorders presents with severe muscle weakness, congenital eye malformations, and neuronal migration defects. Pachygyria, cobblestone dysgenesis, hydrocephalus, polymicrogyria, heterotopias, and corpus callosum agenesis are variably present. Eye malformations include anophthalmia, microphthalmia, congenital cataract, or colobomas. Congenital muscular dystrophy is associated with significant CK level elevations. There is severe psychomotor disability. The underlying metabolic defect is the abnormal synthesis of the Omannosylglycan core, which is essential for the proper glycosylation of αdystroglycan. The α-dystroglycan is heavily O -glycosylated with mannose residues and is expressed in both muscle and brain. Defective mannosylation of α-dystroglycan leads to muscle degeneration and migration defects. Muscle biopsy shows abnormal α-dystroglycan staining on immunohistochemistry. Transferrin isoelectric focusing is normal in patients with isolated O mannosylation defects. There is also no clinically available enzyme analysis. Diagnosis is based on histology (muscle biopsy) and genetic analysis. POMT1-CDG, POMT2-CDG, POMGNT1-CDG are the most common autosomal recessive α-dystroglycanopathies. Additional gene defects occur in the pathway; POMK, FKTN, FKRP, LARGE, B4GAT1, TMEM5, and ISPD have been described in association with human disease. The exact incidence of αdystroglycanopathies is not known. In α-dystroglycanopathies the treatment is supportive.

Defects in Lipid Glycosylation and in Glycosylphosphatidylinositol Anchor Biosynthesis Hyperphosphatasia–Intellectual Disability Syndromes: PIGA Deficiency (PIGA-CDG) This clinically recognizable syndrome is an epilepsy syndrome with intellectual

disability, hypotonia, dysmorphic facial features, skin anomalies, congenital brain malformations, and behavioral abnormalities, including autism. Other organ malformations, including cardiac and renal defects, have also been reported. (Note that somatic mutations with PIGA defect can also lead to paroxysmal nocturnal hemoglobinuria.) N -acetylglucosamine (GlcNAc) cannot be efficiently transferred to phosphatidylinositol for glycophosphatidylinositol synthesis. Abnormal anchoring of alkaline phosphatase leads to hyperphosphatasemia in blood and loss of specific surface antigens on blood cells. Transferrin isoform analysis is normal in GPI-anchor defects. FACS analysis of the membrane-anchored markers CD16 and CD24 in leukocytes is highly suggestive for a GPI-anchor abnormality, especially in association with increased levels of serum alkaline phosphatase. Mutation analysis confirms the defect. PIGA-CDG is X-linked. The exact incidence is not known. A similar phenotype has been described in PIGO, PIGV, PIGY, PIG, PGAP2, and PGAP3 defects. In PIGA-CDG the treatment is supportive.

Defects in Multiple Glycosylation Pathways and in Other Pathways, Including Dolicholphosphate Biosynthesis Defects Steroid 5α-Reductase Deficiency (SRD5A3CDG) Clinical Manifestations SRD5A3 deficiency is a clinically recognizable CDG, originally described as a multiple–congenital malformation syndrome. About 20 patients have been diagnosed at different ages, including one at 45 yr. Patients have hypotonia, ataxia, and eye abnormalities, including congenital cataract, retinal and iridic colobomas, glaucoma, optic nerve dysplasia, and visual loss. Cerebellar vermis hypoplasia can be variable. Intellectual disability has been described in all

affected patients thus far. About one third of patients have severe congenital ichthyosis . Hypertrichosis and dysmorphic facial features are common, including squared face, high forehead, large ears, and coarsening. Some children with SRD5A3-CDG have a severe autism spectrum disorder. Skeletal abnormalities (scoliosis) and cardiac malformations are less common.

Pathophysiology SRD5A3 deficiency leads to abnormal dolichol synthesis affecting early glycan synthesis outside the ER membrane and affects O -mannosylation and GPIanchor synthesis. Hypoglycosylation affects anticoagulation factors and leads to increased serum transaminases.

Diagnosis The primary screening method in a suspected SRD5A3-CDG patient is serum transferrin glycoform analysis or MS analysis. Most patients show a type 1 pattern (see Fig. 105.10 ), but several false-negative cases have been described. There is no clinically available enzyme analysis. SRD5A3-CDG is autosomal recessive. Genetic testing is mostly performed by direct sequencing. The exact incidence is not known.

Treatment In SRD5A3-CDG the treatment is supportive.

Autosomal Recessive Cutis Laxa Type 2 (ARCL2A or ATP6V0A2-CDG, ATP6V1A-CDG and ATP6V1E1-CDG) Clinical Manifestations ATP6V02-CDG is a multiple-malformation syndrome originally described as cutis laxa syndrome and recently discovered to be a combined N - and O -linked glycosylation disorder. Patients show generalized cutis laxa with inelastic, sagging skin at birth, hypotonia, strabismus, myopia, characteristic facial features, and joint laxity. The facial features include hypertelorism, short nose, long philtrum, down-slanting palpebral fissures with sagging eyelids, and sagging cheeks. Cardiovascular involvement is rare, and there is variable CNS

involvement. Seizures and motor and language developmental disability are common, but normal intelligence has been described as well. Sensorineural hearing loss is sometimes observed. Some patients have vermis hypoplasia, and several children have been described with cobblestone like dysgenesis and partial pachygyria on brain MRI. Skeletal abnormalities and short stature are common, as well as late-closing fontanels, and/or brachydactyly and scoliosis. There is frequently enamel dysplasia. The skin features spontaneously improve with age. ATP6V1A-CDG and ATP6V1E1-CDG show a highly overlapping phenotype with associated cardiovascular symptoms and hypercholesterolemia.

Pathophysiology ATP6V0A2 is a membrane subunit of the proton pump of the vesicular adenosine triphosphatase (V-ATPase) complex. Abnormal function of the VATPase complex alters the pH gradient in the secretory pathway and affects the maturation and transport of several glycosyltransferases and elastic fibers (e.g., elastin). ATP6V1A and ATP6V1E1 are other complex subunits affecting ATP6V0A2 function and cause secondary ATPase deficiency. Both N - and O linked glycosylation are affected. There are mild coagulation abnormalities and high serum transaminase levels in some patients.

Diagnosis The primary screening method in a suspected ATP6V0A2-CDG patient is serum transferrin glycoform analysis or MS analysis. Most patients show a type 2 pattern (see Fig. 105.10 ), but false-negative cases have been described before age 6 wk. Apolipoprotein III-C (apoC-III) is a mucin-type secretory glycoprotein that is only O -glycosylated. ApoC-III IEF shows a hypoglycosylation pattern in patients, even when the TIEF is falsely negative. Skin biopsy in patients show classic histologic changes of cutis laxa with diminished, short, abnormal, and fuzzy elastic fibers. ATP6V0A2-CDG is autosomal recessive. Genetic testing is mostly performed by direct sequencing. The exact incidence is not known. ATP6V1A and ATP6V1E1 defects have been recently described.

Treatment In autosomal recessive cutis laxa type 2, the treatment is supportive. There is continuous and spontaneous improvement of skin symptoms throughout the

disease course, especially in ATP6V0A2-CDG.

Golgi-α1-2 Mannosidase-1 Deficiency (MAN1B1CDG) Clinical Manifestations MAN1B1 defect was originally described as an intellectual disability syndrome in association with dysmorphic features. Additional patients were recognized with psychomotor disability, muscle hypotonia, and inverted nipples in association with truncal obesity. The degree of intellectual disability is quite variable. Autistic behaviors, eating disorders, and aggressive behavior are frequent features. More than 30 patients have been reported.

Pathophysiology MAN1B1 codes for a Golgi mannosidase, which is essential for the final “trimming” of mannose units during the glycan processing in the Golgi. Hypermannosylation leads to abnormal, truncated glycans and CDG-II. The glycosylation abnormality in serum is relatively mild. Increased serum transaminases and abnormal coagulation are uncommon.

Diagnosis Most patients show a mild type 2 pattern by TIEF, but false-negative cases have been described. MALDI-TOF analysis shows characteristic, hybrid glycans in serum. In suspected cases, direct sequence analysis is recommended, even if the TIEF is normal. MAN1B1-CDG is autosomal recessive. The exact incidence is unknown; several adult patients are known.

Treatment Only supportive treatment is available.

Phosphoglucomutase-1 Deficiency (PGM1-CDG) Clinical Manifestations PGM1-CDG is a disorder presenting with midline malformations (cleft palate,

Pierre Robin sequence, bifid uvula), liver dysfunction, hypoglycemia, and short stature in almost all patients. Hypoglycemia is usually caused by hyperinsulinism in the 1st years of life. It can resolve with aging; ketotic hypoglycemia has also been observed. Cholestasis, liver fibrosis, and even cirrhosis have been described in a few patients. About one third of patients also show proximal muscle weakness and dilated cardiomyopathy; the latter led to mortality in at least 7 reported cases. Other malformations, including cardiac and skeletal anomalies, have also been described. Wound healing is frequently abnormal, and there is a very high risk for bleeding during surgery. Intelligence is normal.

Pathophysiology Phosphoglucomutase 1 (PGM1) is an essential enzyme for glycogenolysis and glycolysis. It also provides substrates for nucleotide sugars needed for normal glycosylation. PGM1 regulates the bidirectional conversion of glucose-1phosphate and glucose-6-phosphate. During fasting it leads to a glycogenosislike phenotype (also called GSD XIV, MIM 614921). PGM1-CDG affects both the ER- and Golgi-related glycosylation and causes a mixed type 1/type 2 hypoglycosylation pattern. Abnormal serum proteins include coagulation and anticoagulation factors, insulin-like growth factor–binding protein 3 (IGFBP3), TBG, and thyroid-stimulating hormone (TSH), in addition to serum transaminases, hypoglycemia, and elevated CK.

Diagnosis The primary screening method in a suspected PGM1-CDG is serum transferrin glycoform analysis or MS analysis. Patients show a mixed type 1/type 2 pattern. PGM1-CDG is autosomal recessive. It is among the relatively common CDGs; >40 patients have been described. Enzyme testing is possible in blood, but is more reliable in fibroblasts. Direct sequencing is available for testing.

Treatment PGM1-CDG seems to be the 2nd treatable CDG besides MPI-CDG. D Galactose is hypothesized to restore the balance in the availability of different nucleotide sugars. Adding 1 g/kg/day D -galactose for a few weeks to the diet improves glycosylation significantly, although the TIEF pattern does not fully normalize. This treatment improves liver transaminases and antithrombin levels and in some patients the hormonal status. The effect of D -galactose on

hypoglycemic episodes and the myopathy is not yet clear. Larger, long-term dietary trials are ongoing.

Disorders of Golgi Homeostasis: TMEM199-, CCDC115-, ATP6AP2-CDG, and ATP6AP1-CDG Clinical Manifestations These 4 disorders are clinically and biochemically indistinguishable. They have been described with liver function anomalies, cholestasis, fibrosis, and cirrhosis with liver failure, necessitating liver transplantation in a few patients. The phenotype resembles Wilson disease , especially because of low serum ceruloplasmin and copper levels, but there is no Kayser-Fleischer ring. In CCDC115-CDG there are frequently also neurologic features. The intellectual outcome is variable. Additional abnormalities include hypercholesterolemia and elevated alkaline phosphatase. In ATP6AP1-CDG there is also immunologic involvement.

Pathophysiology TMEM199-, CCDC115-, ATP6AP1-CDG, and ATP6AP2-CDG are important for Golgi homeostasis. The exact pathologic mechanism is not yet known, but it is hypothesized that the secondary Golgi dysfunction affects and delays the normal glycosylation process.

Diagnosis The primary screening method in a patient with suspected PGM1-CDG is serum transferrin glycoform analysis or MS analysis. Patients show a type 2 pattern (see Fig. 105.10 ). ApoC-III IEF is abnormal. Glycomics results by MALDITOF analysis are characteristic but cannot discriminate between the 3 defects. Final diagnosis requires mutation analysis. TMEM199-CDG and CCDC115-CDG are autosomal recessive, whereas ATP6AP1-CDG, and ATP6AP2-CDG are X-linked.

Treatment Treatment is supportive; 2 patients successfully underwent liver transplantation.

Manganese Transporter Defect: SLC39A8-CDG Clinical Manifestations This intriguing disorder was originally described as a neurologic disease with hypotonia, seizures (hypsarrhythmia), and developmental disability. Some of the later-described patients had severe skeletal dysplasia with rhizomelic chondrodysplasia, craniosynostosis, and dwarfism. Mitochondrial dysfunction (Leigh disease, cerebral lactic acidemia, dystonia) may also be present.

Pathophysiology SLC39A8 is a membrane transporter, responsible for the manganese (Mn) transmembrane transport. SLC39A8 deficiency affects all Mn-dependent enzymes and therefore different parts of the metabolism. Since several glycosyltransferases (e.g. β-1,4-galactosyltransferase) are Mn dependent, a secondary Golgi glycosylation occurs with a type 2 glycosylation defect. Low serum Mn levels are suggestive but not always present in patients.

Diagnosis The primary screening method in a suspected SLC39A8-CDG is serum transferrin glycoform analysis or MS analysis. Patients show a type 2 pattern (see Fig. 105.10 ). MALDI-TOF analysis is suggestive, but not discriminative. Final diagnosis requires mutation analysis. SLC39A8-CDG is an autosomal recessive disease. Its incidence is unknown.

Treatment Besides supportive treatment, a few patients showed biochemical and clinical improvement (better seizure control) with oral D -galactose (1-3 g/kg/day) therapy.

Congenital Disorders of Deglycosylation N-Glycanase 1 Deficiency (NGLY1 Defect) Clinical Manifestations Patients with NGLY1 deficiency do have a glycosylation disorder, but not from the deficient synthesis; rather, it is caused by deficient breakdown of

glycoproteins. The phenotype comprises severe CNS involvement, microcephaly, intellectual disability, seizures, neuropathy, movement disorders, and hypotonia. The presence of alacrimia , hypolacrimia, or chalazion is highly suggestive for the diagnosis, but not all patients have problems with tearing. Other features include failure to thrive, intrauterine growth restriction, and liver involvement. Some patients have a recognizable oval face with a short nose, flat profile, and hypertelorism. Masklike face also occurs, imitating the phenotype of mitochondrial disorders, especially when serum lactic acid levels are also elevated.

Pathophysiology N -glycanase is responsible for the deglycosylation of misfolded N -linked glycoproteins. The enzyme is essential for cutting off the glycans before the proteins are degraded in the ER. The increased abundance of misfolded N glycans increases ER stress, which has been suggested as a possible reason for lactate elevation in several patients. Serum transaminase and α-fetoprotein levels are also frequently increased.

Diagnosis Serum transferrin isoform analysis shows a normal pattern. Final diagnosis requires mutation analysis. NGLY1-CDG is an autosomal recessive disease. The most common mutation is c.1201A>T/p.R401X. The exact incidence of the condition is unknown, but >20 patients have been reported in a few years since the discovery of the disease.

Treatment Only supportive treatment is available for the patient with NGLY1 deficiency.

Therapeutic Summary Most CDGs are only treatable with supportive therapy. The initially discovered oral mannose treatment in MPI-CDG (1 g/kg/day) has proved to be efficient for coagulation problems and protein-losing enteropathy but cannot prevent liver fibrosis in all patients. Liver transplantation in MPI-CDG has been successful in a few patients. Oral D-galactose in PGM1-CDG (1g/kg/day) improves serum transaminases and coagulation, and has a positive effect on endocrine function,

but cannot restore glycosylation fully. Seizure frequency improved in patients with SLC39A8-CDG receiving oral D -galactose treatment (1 g/kg/day) and oral Mn intake. The congenital myasthenic syndrome in DPAGT1-CDG, GFPT1CDG and GMPPB-CDG has been successfully treated with high dose of cholinesterase inhibitors. Several CDG have been positively controlled by transplantation; including DOLK-CDG (DK1-CDG; heart transplantation) PGM3-CDG (hematopoietic stem cell transplantation), CCDC155-CDG (liver transplantation). Additional CDG treatment options are available for disorders not described in this chapter. Patients with CAD-CDG show significant clinical improvement on receiving oral uridine therapy, especially with seizure control. Two children with SLC35C1-CDG–defective immune function improved on oral fucose therapy. GNE-CDG patients showed significant improvement in muscle strength on N acetylmannoseamin therapy. Several dietary trials are currently ongoing in different CDG.

Bibliography De Lonlay P, Seta N. The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib. Biochim Biophys Acta . 2009;1792(9):841–843. Freeze HH, Chong JX, Bamshad MJ, Ng BG. Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet . 2014;94:161–175. Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol . 2012;11:453–466. Funke S, Gardeitchik T, Kouwenberg D, et al. Perinatal and early infantile symptoms in congenital disorders of glycosylation. Am J Med Genet . 2013;161A:578–584. Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change!. Biochim Biophys Acta . 2009;1792:825– 826. Jaeken J, et al. Sialic acid-deficient serum and cerebrospinal

fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta . 1984;144:245–247. Lam C, Ferreira C, Krasnewich D, et al. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet Med . 2017;19(2):160–168. Lefeber DJ, Morava E, Jaeken J. How to find and diagnose a CDG due to defective N -glycosylation. J Inherit Metab Dis . 2011;34(4):849–852. Mohamed M, Kouwenberg D, Gardeitchik T, et al. Metabolic cutis laxa syndromes. J Inherit Metab Dis . 2011;34:907–916. Morava E. Galactose supplementation in 1 phosphoglucomutase-1 deficiency: review and outlook for a novel treatable CDG. Mol Genet Metab . 2014;112:275–279. Morava E, Tiemes V, Thiel C, et al. ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. J Inherit Metab Dis . 2016;39(5):713–723. Morava E, Wevers RA, Cantagrel V, et al. A novel cerebelloocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain . 2010;133:3210–3220. Pérez-Cerdá C, Girás ML, Serrano M, et al. A population-based study on congenital disorders of protein N - and combined with O -glycosylation: experience in clinical and genetic diagnosis. J Pediatr . 2017;183:170–177. Rymen D, Winter J, van Hasselt PM, et al. Key features and clinical variability of COG6-CDG. Mol Genet Metab . 2015;116(3):163–170. Scott K, Gadomski T, Kozicz T, Morava E. Congenital disorders of glycosylation: new defects and still counting. J Inherit Metab Dis . 2014;37:609–617. Wong SY, Beamer LJ, Gadomski T, et al. Defining the phenotype and assessing severity in phosphoglucomutase-1

deficiency. J Pediatr . 2016;175:130–136.e8.

CHAPTER 106

Mitochondrial Disease Diagnosis Marni J. Falk

See also Chapter 105.4 .

Overview of Mitochondrial Disease Mitochondrial diseases are multisystemic energy failure states with extensive clinical and genetic heterogeneity. Their common basis is best understood through recognition that mitochondria function as biologic “fuel cells” or “batteries,” producing chemical energy in the form of adenosine triphosphate (ATP) by aerobic metabolism of nutrient-derived reducing equivalents, through the integrated function of the 5-complex mitochondrial respiratory chain (RC) (Fig. 106.1 ). Mitochondria also play other essential roles that can be variably disrupted in disease states, such as regulating calcium homeostasis, diverse aspects of intermediary nutrient metabolism, nucleotide metabolism, and oxidative stress. Primary mitochondrial disease results from deficient RC function, which can be caused by mutations in genes that encode RC subunits, assembly factors or cofactors, components of mitochondrial DNA (mtDNA) metabolism and maintenance, or a host of other basic metabolic processes ongoing within mitochondria. Approximately 1,500 proteins exist within the mitochondrial proteome of different tissues, with variants in more than 350 unique genes across both the nuclear and the mitochondrial genomes already implicated as causal in human mitochondrial disease.

FIG. 106.1 Electron transport chain. The electron transport chain consists of 4 protein complexes (I-IV) coupled to a 5th (V), unlinked complex, ATP synthase. Together, these 5 complexes are known as the respiratory chain and are the site where oxidative phosporylation (OXPHOS) occurs to generate energy. The transport chain accepts electrons from NADH (complex I) or FADH2 (complex II) that have been produced by glycolysis, the formation of acetyl–coenzyme A, and the TCA cycle (green arrows). Electrons flow from one complex to another (red arrows) because of the redox potential of each complex and lose a small amount of energy as they move through the chain. Three of the 4 complexes act as pumps, driven by electron flow, moving H+ ions from the matrix to the intermembrane space (blue arrows) . This pumping builds a concentration gradient and creates an electrochemical force that is used by ATP synthase to produce ATP. Under normal conditions, this machinery provides almost all (90%) of the ATP in a cell. However, a small proportion of electrons escape the electron transport chain even under normal conditions and can react with oxygen and complexes I and III to form superoxide (O2 − ). ADP, Adenosine diphosphate; ATP, adenosine triphosphate; Cyt c, cytochrome c ; Q, coenzyme Q; NADH, nicotinamide dinucleotide; Pi, inorganic phosphate; TCA, tricarboxylic acid cycle; FADH2, 1,5dihydro-flavin adenine dinucleotide. (Adapted from Hagberg H, Mallard C, Rousset CI, Thornton C: Mitochondria: hub of injury responses in the developing brain, Lancet Neurol 13(2):217–232, 2014.)

Collectively recognized as the most common group of inherited metabolic diseases, primary (genetic-based) mitochondrial disease has a combined minimal prevalence of 1 in 4,300 individuals across all ages. In addition, secondary mitochondrial dysfunction is broadly implicated in the pathogenesis of a host of complex diseases, ranging from metabolic syndrome to ischemia-

reperfusion injury after stroke, to neurodegenerative diseases. Failure of highenergy demand organs in mitochondrial diseases may clinically present as severe neurodevelopmental, cardiac, myopathic, renal, hepatic, endocrine, immune, gastrointestinal, hearing, and vision disabilities, as well as global metabolic instability with lactic acidosis (Fig. 106.2 ) (see Tables 105.2 and 105.3 ). In most mitochondrial disorders, the phenotype may vary depending on the patient's age or the specific gene or genetic variant. Particularly common mitochondrial disease clinical syndromes that present in children include Leigh syndrome (for which there are more than 90 causal genes), mtDNA depletion syndrome (MDS, for which there are dozens of causal genes), mtDNA deletion syndromes (Pearson, Kearns Sayre), primary lactic acidosis, and pyruvate dehydrogenase deficiency. Common clinical features in children present in at least 90 percent of patients include fatigue, exercise intolerance, weakness, gastrointestinal problems, ataxia, and developmental delay. Thus, mitochondrial diseases present to and must be considered by clinicians across every medical specialty.

FIG. 106.2 Mitochondrial disease subject cohort, experienced symptoms. Frequency of experienced symptoms as reported by the RDCRN selfreported cohort revealed muscle weakness, chronic fatigue, exercise

intolerance, imbalance, and gastrointestinal problems to be the top 5 common symptoms. (Modified from Zolkipli-Cunningham Z, Xiao R, Stoddart A, et al: Mitochondrial disease patient motivations and barriers to participate in clinical trials. PLoS ONE 13(5):e0197513 [Fig. 2].)

Patients with suspected mitochondrial disease may frequently experience a diagnostic odyssey , both clinically and genetically. Their extensive phenotypic heterogeneity without a common biomarker (GDF-15 may be one screening test that may be elevated in some mitochondrial myopathies particularly involving mtDNA deletions or depletion, along with lactic acidosis) presents a challenge to the readily available and accurate clinical diagnosis of mitochondrial disorders in many medical settings. Similarly, their extensive genetic heterogeneity involving known etiologies in >300 nuclear genes and all 37 mitochondrial DNA (mtDNA) genes, with likely dozens to hundreds more causative nuclear disease genes awaiting discovery, can make the accurate genetic diagnosis of an individual patient challenging. The diagnostic uncertainty can be further compounded by poor genotype-phenotype correlations and variable clinical presentations of individual gene disorders, high locus heterogeneity (i.e., multiple different causal disease genes) for similar clinical phenotypes, incomplete penetrance for some gene disorders, variable life stressors or environmental exposures that may exacerbate a given child's disease, and the unique biologic aspects of maternal inheritance for the subset of mitochondrial diseases caused by mtDNA gene mutations.

When to Suspect Mitochondrial Disease Because of failure in the ability to generate cellular energy, mitochondrial diseases can involve any organ system at any age (see Fig. 106.2 ). Mitochondrial disease should be suspected when classic symptoms are present or if unexplained symptoms occur in 3 or more apparently unrelated organs. Individuals may present with a vast array of symptoms, including fatigue, muscle weakness, exercise intolerance, metabolic strokes, seizures, cardiomyopathy, arrhythmias, developmental or cognitive disabilities, autism, diabetes mellitus, other endocrinopathies (adrenal, thyroid), dysautonomia, and autoimmune disorders, as well as impairment of hearing, vision, growth, liver, gastrointestinal (GI), or kidney function. Although individuals may have just one or a few symptoms and a fluctuating disease course in terms of symptom severity, most patients with primary mitochondrial disease tend to develop

progressive symptoms over time. A study of patients with mitochondrial diseases showed an average of 16 different clinically significant symptoms per patient, with a range of 7-35. When considering the diagnosis, it is helpful to recognize that most symptoms of mitochondrial disease involve functional, rather than structural, problems. When mitochondrial disease is considered in the differential diagnosis, it is often helpful to obtain several laboratory screening studies for common biochemical features of mitochondrial disease and overlapping disorders, both at baseline and if unrevealing, during an acute illness or period of decompensation. Blood-based metabolic screening studies include comprehensive chemistry panel, complete blood count with differential, plasma amino acid quantitative analysis, carnitine analysis (total, free, acyl-carnitine profile), ammonia, creatine kinase, and testing for common secondary manifestations of mitochondrial disease (e.g., thyroid screen, lipoprotein profile, hemoglobin A1c ). Urine-based metabolic screening studies include urinalysis, urine organic acid quantitative analysis, and urine amino acid quantitative analysis. Consideration should also be given for screening for congenital disorders of glycosylation or vitamin deficiencies, which may have overlapping clinical features in some cases with mitochondrial disease. Lactic acidemia is neither highly sensitive nor specific for primary mitochondrial disease, but laboratory findings suggestive of primary mitochondrial disease include elevations of blood lactate, pyruvate, lactate:pyruvate ratio, alanine, ratios of alanine to lysine (>3) and alanine to sum of phenylalanine and tyrosine (>4), and anion gap. Biochemical alterations further suggestive of mitochondrial disease may include secondary impairment of fatty acid oxidation with elevation of dicarboxylic acids on acyl-carnitine profile, increased branched-chain amino acids and proline on plasma amino acid analysis, increased tricarboxylic acid cycle intermediates and lactate excretion on urine organic acid analysis, and generalized aminoaciduria on urine amino acid analysis. Growth and differentiation factor 15 (GDF-15 ) may be a useful screening test for mitochondrial depletion based myopathies. Similarly, when mitochondrial disease is considered in the differential diagnosis, obtaining additional clinical evaluations to carefully phenotype the patient for prevalent or highly morbid and potentially modifiable features of mitochondrial disease is important. Because many individuals with mitochondrial disease develop problems with their vision (reduced visual acuity not correctable with glasses, photophobia or nyctalopia with reduced peripheral vision associated with retinal disease or optic atrophy, ophthalmoplegia, ptosis),

hearing (high-frequency sensorineural hearing loss), and heart (arrhythmia, conduction block, cardiomyopathy), carefully evaluating for involvement of these high-energy systems is indicated. Neurologic evaluation is essential because many mitochondrial disease patients experience a range of central (metabolic stroke in cortical or deep gray matter including basal ganglia, midbrain, and/or brainstem, white matter changes, seizures, ataxia, movement disorder, migraine, cognitive changes), peripheral (axonal sensorimotor neuropathy), or autonomic nervous system dysfunction; brain imaging (MRI), spectroscopy (MRS), and on occasion electromyogram or nerve conduction velocity (EMG/NCV) studies can be helpful to support the diagnosis. Formal exercise physiology evaluation can also be useful to quantify and advise patients on their exercise capacity and safety, with some specific features (e.g., reduced V̇O 2 maximal capacity) suggestive of quantifiable mitochondrial dysfunction. Sleep study may be useful for individuals with sleep dysfunction because sleep disorders may mimic mitochondrial disease symptoms, and sleep problems are common and potentially treatable in mitochondrial disease. Gastrointestinal symptoms are common and underrecognized in mitochondrial disease patients, usually involving dysmotility of any portion of the GI tract with reflux, swallowing dysfunction, delayed gastric emptying, feeding and/or growth problems, pseudoobstruction, malabsorption, and constipation. Endocrine abnormalities are also common but underappreciated in many patients, including pituitary, adrenal, thyroid, and pancreatic dysfunction. Such careful phenotyping of patients with suspected mitochondrial disease can thus provide reassurance that the common, and potentially treatable, clinical aspects of mitochondrial disease are not present although they may develop over time, or conversely if identified, increase diagnostic suspicion and direct further diagnostic evaluation.

Mitochondrial Disease Inheritance Primary mitochondrial disease may result from variants in either nuclear genes or mtDNA genes, which may be inherited from a parent or occur de novo in an affected individual. Thus, all mendelian (autosomal recessive, autosomal dominant, X-linked) or maternal (mtDNA) inheritance patterns can be consistent with mitochondrial diseases (Table 106.1 ). Obtaining a detailed, threegeneration pedigree is important to potentially highlight the specific inheritance pattern in a given family. Individuals with inherited mtDNA disorders may

report family members related through their maternal lineage (both males and females may be affected, but only affected individuals will be connected through the female germline), with a range of functional problems in different organs, such as migraines, fatigue, exercise intolerance, stroke, diabetes mellitus, thyroid dysfunction, irritable bowel spectrum, mood disorder, or vision and hearing problems. Inherited X-linked disorders typically present with symptoms only, or more severely, in males related through unaffected or minimally affected females. Autosomal recessive disorders are common in pediatric mitochondrial disease, particularly in consanguineous pedigrees, where a rare variant in the general population becomes enriched and passed down through both maternal and paternal lineages to become homozygous in the affected proband and also affect multiple individuals in a given generation without having affected individuals in earlier generations. Autosomal dominant variants may occur de novo or are passed on from either parent to their child, although many disorders may have reduced penetrance, which may make the genetic disorder appear to skip a generation. Identifying a likely inheritance pattern through pedigree analysis can inform accurate interpretation of large-scale genetic diagnostic evaluations, such as multigene sequencing and deletion/duplication analysis panels and exome or genome sequencing. Establishing a correct genetic diagnosis for mitochondrial disease in an affected individual is essential to enable reliable recurrence risk counseling and testing options in a given family, whether in a future pregnancy by chorionic villus sampling (CVS, typically performed at 10-12 weeks’ gestation) or amniocentesis (typically performed at 16-20 weeks’ gestation) or in the in vitro fertilization (IVF) setting with preimplantation genetic diagnosis (PGD) for a specific disease-causing variant. Table 106.1

Major Molecular Categories of Mitochondrial Genes CAUSAL DISEASE GENE MUTATION EFFECTS GENOME EXAMPLES Electron Nuclear or Decreased functioning of electron transport chain complex Complex I transport chain mtDNA deficiency enzyme subunits Complex II deficiency Electron Nuclear Decreased assembly of electron transport chain enzyme Complex III transport chain complex deficiency assembly factors Complex IV deficiency Complex V COMPONENT

Electron transport chain cofactors

mtDNA translation mtDNA maintenance

Mitochondrial membrane fission and fusion

deficiency Coenzyme Q10 deficiency Iron sulfur cluster defect Lipoyltransferase deficiency Nuclear or Decreased translation of protein-coding mitochondrial Combined oxidative mtDNA DNA genes leading to decreased functioning of electron phosphorylation transport chain enzymes complexes deficiency Nuclear Increased errors in mitochondrial DNA leading to increased Mitochondrial presence of point mutations and deletions, resulting in DNA depletion decreased translation of electron transport chain subunits syndromes Mitochondrial DNA multiple deletion disorders Nuclear Increased mtDNA point mutations and deletions; clumped OPA1 -related and fragmented mitochondria conditions MFN2 -related conditions Nuclear

Decreased functioning of electron transport chain

From McCormick EM, Muraresku CC, Falk MJ: Mitochondrial genomics: a complex field now coming of age. Curr Genet Med Rep 6:52–61, 2018 (Table 1, p. 57).

Special mention is warranted to consider the unique aspects of maternal inheritance that typify mtDNA disorders. More than 300 disease-causing mtDNA variants have been identified, with extensive variation in disease manifestations and features. Most disease-causing variants are present in only a portion of an individual's mtDNA genomes, a concept known as heteroplasmy . For heteroplasmic mtDNA variants, the precise mutation level (percent) can vary between an individual's different tissues and can change over time, with symptom severity corresponding to different threshold mutation levels that can be difficult to define and that typically vary between organs. An individual's mtDNA genome background set of fixed sequence variants, known as a haplogroup , can also influence the penetrance or severity of a mtDNA disease. When a novel or rare mtDNA variant is identified in a given individual, it may be useful to use highly sensitive sequencing methods to test the levels of that mutation (which may be accurate to detect 1% mutation levels) in their different tissues (blood, urine, buccal, skin cells, muscle), as well as tissues from their mother or maternal relatives, to accurately determine whether it may be causal of disease in that family. Research-based functional testing may also be necessary to characterize fully the effects of a newly recognized mtDNA variant. When it is not known whether an mtDNA variant is maternally inherited or occurs de novo, the recurrence risk to future offspring of their asymptomatic parent is empirically estimated at 1 in 25 (4%), although the empirical recurrence risk

rises to 1 in 2 (50%) when the mother is symptomatic.

Diagnostic Testing for Mitochondrial Disease The diagnosis of mitochondrial disease relies foremost on genetic testing (genomic analysis), with biochemical screens useful in blood or urine and invasive tissue testing often seen as secondary, or sometimes not required at all (Fig. 106.3 ).

FIG. 106.3 Diagnostic algorithm for suspected mitochondrial disease. (From Muraresku CC, McCormick EM, Flak MJ: Mitochondrial disease: advances in clinical diagnosis, management, therapeutic development, and preventative strategies. Curr Genet Med Rep 6:62–72, 2018.)

When the clinical evaluation—medical history; detailed review of systems; careful physical, neurologic, and dysmorphic examinations; pedigree-, blood-, and urine-based biochemical screening studies; and additional phenotyping

clinical evaluations—is suggestive of mitochondrial disease, a range of clinical diagnostic testing options can be pursued. Absent a known molecular etiology in an affected family member, first-line genetic diagnostic testing may involve a focused panel of hundreds to thousands of known nuclear genes and the mtDNA genome using next-generation sequencing (NGS) methodologies that will detect both single-nucleotide variants and larger-scale gene deletions and duplications. If such testing is unrevealing, clinically based whole exome sequencing (WES) may be pursued. The standard of care is moving to pursue initial diagnostic testing by WES, which is more comprehensive for genes known not only to cause mitochondrial disease, but also to cause all human genetic diseases. The rationale for this evolution in diagnostic testing approach includes the following factors: 1. An increasingly similar cost and turnaround-time for panel-based and WES-based massively parallel NGS studies. 2. The common genetic diagnostic laboratory practice of generating WES data for all tests ordered, but only evaluating and reporting variants in specific gene subsets when panel-based testing is requested, leaving the remaining genes uninterpreted. 3. The mtDNA genome sequence is often included at no extra cost when clinical WES is ordered in blood, but may need to be repeated in a symptomatic tissue (e.g., muscle, liver) to detect heteroplasmic mtDNA variants that may not be present in blood. 4. The utility of performing concurrent proband and both parental sample sequencing (trio-based testing), as usually pursued with WES but not panel-based testing, thereby allowing concurrent segregation analysis of a suspected pathogenic variants as well as ready identification of de novo dominant variants in the proband. 5. The improved diagnostic yield of exome relative to panel-based testing increasingly being reported by clinical diagnostic laboratories, given the highly heterogeneous nature of mitochondrial disease, rapid rate of change in the recognition of new gene diagnoses making prior established gene panels obsolete, and the extensive phenotypic overlap with non-mitochondrial diseases. 6. The ability to utilize WES raw data (either on a research basis or for reanalysis at a later date by the clinical diagnostic laboratory) to highlight and/or identify “novel” gene disorders not previously

recognized or associated with human disease. A mitochondrial disease community resource to centrally curate all mitochondrial disease, gene, and variant knowledge across both genomes is publicly accessible at www.mseqdr.org . Exome sequencing including mtDNA is estimated to identify the definitive genetic etiology for mitochondrial disease in at least 60% of patients in whom it is strongly suspected, reducing the diagnostic odyssey in many patients from decades or years to months. Tissue-based diagnostic testing has decreased in frequency as a front-line test in all patients with suspected mitochondrial disease, although it still has clinical utility in some cases. These include (1) in the setting of rapidly deteriorating clinical status when genetic testing results may not be available in a timely fashion; (2) when a variant of uncertain significance identified on genomic testing has unclear biochemical consequences; and (3) when uninformative genomic sequencing in blood in an individual with myopathy or muscle symptoms raises concern for other disease processes that may be evident on histology, electron microscopy, immunohistochemistry or enzymatic tissue testing. In addition, some mitochondrial diseases are only evident by tissuebased diagnostic testing. These include mtDNA deletion disorders (typically involving several-thousand nucleotides) not present in blood that cause chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) spectrum disorder, as well as different tissue (muscle or liver)-specific mtDNA depletion disorders (e.g., reduced mtDNA tissue content) that confirm a mitochondrial pathophysiology in a given patient and highlight a likely underlying nuclear gene cause for their disease, since mtDNA maintenance requires a host of nuclear-encoded proteins. Muscle analysis for integrated RC oxidative phosphorylation capacity assessment requires analysis of a fresh muscle biopsy only available at a very limited number of sites worldwide, whereas electron transport chain enzyme activity analyses are the accepted gold standard to evaluate for mitochondrial dysfunction in a previously frozen tissue sample, often shipped elsewhere for diagnostic analysis. Skin biopsies are useful to establish fibroblast cell lines in which these same studies of mitochondrial function can be clinically performed. If detected, abnormalities can be revealing of a specific type of mitochondrial disorder, although not all mitochondrial diseases may be expressed or detectable in skin analysis. Thus, if fibroblast testing is unrevealing, more invasive tissue studies may subsequently need to be pursued. Fibroblast cell lines, and occasionally blood-based

lymphoblastoid cell lines, also provide a minimally invasive cell source to allow other clinical enzymatic analyses to be performed, as well as novel disease gene validation and research-based therapeutic modeling.

Treatment Principles for Mitochondrial Disease Effective therapies for both primary and secondary mitochondrial diseases are lacking, because little has been known about the biochemical and physiologic abnormalities that contribute to their diverse clinical manifestations. Clinical complexity and imprecisely defined or understood biochemical phenotypes of different mitochondrial disease subtypes have made it difficult for clinicians to effectively apply or monitor targeted therapies for RC disease. Mitochondrial cocktails of vitamins and supplements variably include vitamins (B1 , B2 , C), antioxidants (CoQ10 , lipoic acid, vitamin E), and metabolic modifiers (creatine, L -carnitine, L -arginine, folinic acid). Although the efficacy, toxicity, and optimal dose of these drugs are not known and have not been objectively assessed in human RC disease patients, they continue to be empirically prescribed in hopes of enhancing residual RC enzymatic function or quenching toxic metabolites theorized to accumulate in RC dysfunction, and because of patient-based reports of improved well-being. However, provision of these therapies has often adopted a one-size-fits-all approach, ignoring the inherent variation in primary mitochondrial disease subtypes, the tissue-specific manifestations, and the major pathogenic factors, such as the predominant downstream metabolic and signaling alterations that occur in different disease subclasses. Although no cure or U.S. Food and Drug Administration (FDA)–approved therapy yet exists for any mitochondrial disease, improved molecular delineation has enabled selected therapies to advance from the theoretical, empirical, and largely ineffective stage to a promising horizon of rational, personalized, and effective interventions. An increasing number of mitochondrial disease diagnoses have interventions involving the initiation or avoidance of specific medications (corticosteroids, valproic acid, phenytoin, barbiturates, propofol for prolonged duration beyond 30-60 min, certain anesthetics, statins, β-blocking agents, amiodarone, nucleoside reverse transcriptase inhibitors), provision of cofactors or diets, and screening regimens for progressive clinical involvement

of modifiable manifestations. General therapies for Leigh syndrome such as L arginine and citrulline may prevent or reverse neurodevelopmental sequelae from a metabolic stroke. Nutritional therapies in these disorders are tailored to specific disease genes, such as thiamine and biotin for SLC19A3 disease, ubiquinol for PDSS2 (CoQ10 deficiency) disease, and thiamine and the ketogenic diet for PDHA1 (pyruvate dehydrogenase) deficiency. Establishing the precise molecular diagnosis can further be lifesaving by avoiding fasting and mitochondrial-toxic medicines or general anesthetics in specific mitochondrial disease subsets, improving recurrence risk counseling and prevention, enabling targeted screening for reported medical complications, and in some cases providing necessary cofactors or vitamins that may not otherwise have been considered. In addition, reproductive methodologies emerging in some countries for mitochondrial disease prevention, such as mitochondrial replacement technologies (MRTs), are only appropriate to consider in the setting of known pathogenic, inherited mtDNA variants. Finally, the ability to molecularly identify primary mitochondrial disease patients has enabled the design of an increasing number of clinical treatment trials now being planned or underway for a diverse range of symptoms that occur in primary mitochondrial diseases (see www.clinicaltrials.gov ).

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CHAPTER 107

Mucopolysaccharidoses Jürgen W. Spranger

Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid mucopolysaccharides). Glycosaminoglycans (GAGs) are long-chain complex carbohydrates composed of uronic acids, amino sugars, and neutral sugars. The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. These substances are synthesized and, with the exception of hyaluronan, linked to proteins to form proteoglycans, major constituents of the ground substance of connective tissue and of nuclear and cell membranes. Degradation of proteoglycans starts with the proteolytic removal of the protein core, followed by the stepwise degradation of the GAG moiety. Failure of this degradation because of absent or grossly reduced activity of mutated lysosomal enzymes results in the intralysosomal accumulation of GAG fragments (Fig. 107.1 ). Distended lysosomes accumulate in the cell, interfere with cell function, and lead to characteristic patterns of clinical, radiologic, and biochemical abnormalities (Table 107.1 and Fig. 107.2 ). Within these patterns, specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products (Table 107.2 ). As a general rule, the impaired degradation of heparan sulfate is more closely associated with mental deficiency , and that of dermatan, chondroitin, and keratan sulfate with mesenchymal abnormalities . Variable expression within a given entity results from allelic mutations and varying residual activity of mutated enzymes. For instance, allelic mutations of the gene encoding L -iduronidase may result in severe Hurler disease (Hurler syndrome) with early death or in mild Scheie disease (Scheie syndrome) manifesting only with limited joint mobility, mild skeletal abnormalities, and corneal opacities.

FIG. 107.1 Degradation of heparan sulfate and mucopolysaccharidoses resulting from the deficiency of individual enzymes. Some of the enzymes are also involved in the degradation of other glycosaminoglycans (not shown).

Table 107.1

Recognition Pattern of Mucopolysaccharidoses MANIFESTATIONS Intellectual disability Coarse facial features Corneal clouding Visceromegaly Short stature Joint contractures Dysostosis multiplex Leucocyte inclusions Mucopolysacchariduria

MUCOPOLYSACCHARIDOSIS (MPS) TYPE I-H I-S II III IV + − ± + − + (+) + + − + + − − (+) + (+) + (+) − + (+) + − + + + + − − + (+) + (+) + + (+) + + − + + + + +

VI − + + + + + + + +

VII ± ± ± + + + + + +

I-H, Hurler syndrome; I-S, Scheie syndrome; II, Hunter syndrome; III, Sanfilippo syndrome; IV, Morquio syndrome; VI, Maroteaux-Lamy syndrome; VII, Sly syndrome. +, Presence of manifestation, −, absence of manifestation; ±, possible presence of manifestation; (+), mild manifestation.

FIG. 107.2 Patients with various types of mucopolysaccharidoses. MPS-I: Hurler syndrome, age 3 yr; MPS-II: Hunter syndrome, 12 yr; MPS-III: Sanfilippo syndrome, 4 yr; MPS-IV: Morquio syndrome, 10 yr; MPS-VI: Maroteaux-Lamy syndrome, 15 yr.

Table 107.2

Mucopolysaccharidoses: Clinical, Molecular, and Biochemical Aspects

MPS EPONYM TYPE

INHERITANCE

I-H

(Pfaundler-) Hurler

AR

I-S

Scheie

AR

I-HS

Hurler-Scheie AR

II

Hunter

XLR

IIIA

Sanfilippo A

AR

IIIB

Sanfilippo B

AR

IIIC

Sanfilippo C

AR

IIID

Sanfilippo D

AR

IVA

Morquio A

AR

MAIN GENE CLINICAL CHROMOSOME FEATURES IDUA Severe Hurler 4p16.3 phenotype, mental deficiency, corneal clouding, death usually before age 14 yr IDUA Stiff joints, 4p16.4 corneal clouding, aortic valve disease, normal intelligence, survive to adulthood IDUA Phenotype 4p16.4 intermediate between I-H and I-S IDS Severe Xq27.3-28 course: similar to I-H but clear corneas Mild course: less pronounced features, later manifestation, survival to adulthood with mild or without mental deficiency SGSH Behavioral 17q25.3 problems, sleeping NAGLU disorder, 17q21 aggression, HGSNAT progressive 8p11.21 dementia, mild GNS dysmorphism, 12q14 coarse hair, clear corneas Survival to adulthood possible GALNS 16q24.3

Short-trunk dwarfism, fine corneal opacities,

DEFECTIVE ENZYME

ASSAY

α-L -iduronidase

L, F, Ac, Cv

α-L -iduronidase

L, F, Ac, Cv

α-L -iduronidase

L, F, Ac, Cv

Iduronate sulfate sulfatase

S, F, Af, Ac, Cv

Heparan-Ssulfamidase

L, F, Ac, Cv

N -Acetyl-α-D glucosaminidase Acetyl-CoAglucosaminide N acetyltransferase N Acetylglucosamine– 6-sulfate sulfatase

S, F, Ac, Cv F, Ac

F, Ac

N L, F, Acetylgalactosamine- Ac 6-sulfate sulfatase

IVB

Morquio B

AR

GLB1 3p21.33

VI

MaroteauxLamy

AR

ARSB 5q11-q13

VII

Sly

AR

GUSB 7q21.11

IX

Hyaluronidase AR deficiency

MPSPS MPS plus syndrome

AR

HYAL1 3p21.3 VPS33A

characteristic bone dysplasia; final height 120 cm Hurler phenotype with marked corneal clouding but normal intelligence; mild, moderate, and severe expression in different families Varying from fetal hydrops to mild dysmorphism; dense inclusions in granulocytes Periarticular masses, no Hurler phenotype Mild Hurler phenotype, cognitive deficiency, organomegaly, skeletal dysplasia, pancytopenia, renal insufficiency, optic atrophy, early death

β-Galactosidase

L, F, Ac, Cv

N L, F, Acetylgalactosamine- Ac α-4-sulfate sulfatase (arylsulfatase B)

β-Glucuronidase

S, F, Ac, Cv

Hyaluronidase 1

S

No lysosomal enzyme deficiency

AR, Autosomal recessive; XLR, X-linked recessive; L, Leukocytes; S, serum; F, cultured fibroblasts; Ac, cultured amniotic cells; Af, amniotic fluid; Cv, chorionic villus sampling; MIM, Mendelian Inheritance in Man Catalogue.

Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease (Hunter syndrome), which is X-linked recessive. Their birth prevalence varies between 1.2 per 100,000 births (United States) and 16.9 per 100,000 births (Saudi Arabia). In the United States the most common subtype is MPS-III, followed by MPS-I and MPS-II.

Disease Entities Mucopolysaccharidosis I Mucopolysaccharidosis I (MPS-I) is caused by mutations of the IUA gene on

chromosome 4p16.3 encoding α-L -iduronidase. Mutation analysis has revealed 2 major alleles, W402X and Q70X, which account for more than half the MPS-I alleles in the white population. The mutations that introduce stop codons with ensuing absence of functional enzyme (null alleles), and in homozygosity or compound heterozygosity, give rise to Hurler syndrome. Other mutations occur in only one or a few individuals. Deficiency of α-L -iduronidase results in a wide range of clinical involvement, from severe Hurler syndrome to mild Scheie syndrome, which are ends of a broad clinical spectrum. Homozygous nonsense mutations result in severe forms of MPS-I, whereas missense mutations are more likely to preserve some residual enzyme activity associated with a milder form of the syndrome.

Hurler Syndrome The Hurler form of MPS-I (MPS I-H ) is a severe, progressive disorder with involvement of multiple organs and tissues that results in premature death, usually by 10 yr of age. An infant with Hurler syndrome appears normal at birth, but inguinal hernias and failed neonatal hearing tests may be early signs. Diagnosis is usually made at 6-24 mo, with evidence of hepatosplenomegaly, coarse facial features, corneal clouding, large tongue, enlarged head circumference, joint stiffness, short stature, and skeletal dysplasia. Acute cardiomyopathy has been found in some infants 70 have improved long-term outcome. Transplantation does not significantly improve the neuropsychological outcome of MPS patients with impaired cognition at transplantation. Early transplantation in the MPS-II patient may have the same effect. Transplantation in the MPS-VI patient stabilizes or improves cardiac manifestations, posture, and joint mobility. Stem cell transplantation does not correct skeletal or ocular anomalies. Table 107.4

Therapies Aimed at Proximate Causes of Mucopolysaccharidoses HEMATOPOIETIC MPS STEM CELL TYPE TRANSPLANTATION I Yes

ENZYME REPLACEMENT THERAPY Laronidase (Aldurazyme) Idursulfase (Elaprase) No

II

Yes

III

No

IV

Yes

Elosulfase (Vimizim)

VI

Yes

VII

Yes

Galsulfase (Naglazyme) rhGUS

REMARKS Developmental trajectory dependent on time of transplantation. Little effect on connective tissue manifestations. Enzyme replacement immediately after diagnosis. Experimental intrathecal application of recombinant heparin-N -sulfatase in MPS-IIIA. Improved daily activities. No effect on growth or skeletal dysplasia. Improved daily activities. Improved growth. No effect on skeletal dysplasia. Phase 3 study by Ultragenyx, 2016. Limited experience because of rarity of condition.

Enzyme replacement therapy (ERT) using recombinant α-L -iduronidase has been approved for patients with MPS-I (Table 107.4 ). It reduces organomegaly and ameliorates rate of growth, improves joint mobility, and reduces the number

of episodes of sleep apnea and urinary GAG excretion. The enzyme does not cross the blood-brain barrier and does not prevent deterioration of neurocognitive function. Consequently, ERT is appropriate for patients with mild CNS involvement or to stabilize extraneural manifestations in young patients before stem cell transplantation. Recombinant iduronate-2-sulfatase is the treatment of choice for MPS-II to ameliorate nonneural manifestations. ERT with recombinant human GALNS improves physical endurance, respiratory function, and daily living activity of patients with MPS-IV. Similar effects produce recombinant N -acetylgalactosamine-4-sulfatase in patients with MPSVI. Symptomatic therapy focuses on respiratory and cardiovascular complications, hearing loss, carpal tunnel syndrome, spinal cord compression, hydrocephalus, and other problems (Table 107.5 ). The multisystem involvement and progressive nature of MPS syndromes usually requires the complex care provided by medical centers. Table 107.5

Symptomatic Management of Mucopolysaccharidoses PROBLEM

PREDOMINANTLY MANAGEMENT IN

NEUROLOGIC Hydrocephalus MPS I, II, VI, VII Chronic headaches All Behavioral MPS-III disturbance Disturbed sleep– MPS-III wake cycle Seizures MPS I, II, III Atlantoaxial MPS IV instability Spinal cord All compression OPHTHALMOLOGIC Corneal opacity MPS I, VI, VII Glaucoma Retinal degeneration EARS, AIRWAYS Recurrent otitis media Impaired hearing Obstruction

Funduscopy, CT scan Ventriculoperitoneal shunting Behavioral medication, sometimes CT scan, ventriculoperitoneal shunting Melatonin EEG, anticonvulsants Cervical MRI, upper cervical fusion Laminectomy, dural excision

Corneal transplant

MPS I, VI, VII MPS I, II

Medication, surgery Night-light

MPS I, II, VI, VII

Ventilating tubes

All except MPS-IV All except MPS-III

Audiometry, hearing aids Adenotomy, tonsillectomy, bronchodilator therapy, CPAP at night,

laser excision of tracheal lesions, tracheotomy CARDIAC Cardiac valve MPS I, II, VI, VII disease Coronary MPS I, II, VI, VII insufficiency Arrhythmias MPS I, II, VI, VII ORAL, GASTROINTESTINAL Hypertrophic gums, MPS I, II, VI, VII poor teeth Chronic diarrhea MPS-II MUSCULOSKELETAL Joint stiffness All except MPS IV Weakness All Gross long-bone All malalignment Carpal tunnel MPS I, II, VI, VII syndrome ANESTHESIA All except III

Endocarditis prevention, valve replacement Medical therapy Antiarrhythmic medication, pacemaker Dental care Diet modification, loperamide Physical therapy Physical therapy, wheelchair Corrective osteotomies Electromyography, surgical decompression Avoid atlantoaxial dislocation; use angulated video intubation laryngoscope and small endotracheal tubes.

CT, Computed tomography; CPAP, continuous positive airway pressure; EEG, electroencephalogram; MRI, magnetic resonance imaging.

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CHAPTER 108

Disorders of Purine and Pyrimidine Metabolism James C. Harris

The inherited disorders of purine and pyrimidine metabolism cover a broad spectrum of illnesses with various presentations. These include hyperuricemia, acute renal failure, renal stones, gout, unexplained neurologic deficits (seizures, muscle weakness, choreoathetoid and dystonic movements), intellectual and developmental disabilities, acrofacial dysostosis, compulsive self-injury and aggression, autistic-like behavior, unexplained anemia, failure to thrive, susceptibility to recurrent infection (immune deficiency), and deafness. When identified, all family members should be screened. Purines and pyrimidines form the basis of nucleotides and nucleic acids (DNA and RNA) and thus are involved in all biologic processes. Metabolically active nucleotides are formed from heterocyclic nitrogen-containing purine bases (guanine and adenine) and pyrimidine bases (cytosine, uridine, and thymine): all cells require a balanced supply of nucleotides for growth and survival. Purines provide the primary source of cellular energy through adenosine triphosphate (ATP) and the basic coenzymes (nicotinamide adenine dinucleotide and its reduced form) for metabolic regulation and play a major role in signal transduction (guanosine triphosphate [GTP], cyclic adenosine monophosphate, cyclic guanosine monophosphate). Fig. 108.1 shows the early steps in the biosynthesis of the purine ring. Purines are primarily produced from endogenous sources, and in usual circumstances, dietary purines have a small role. The end product of purine metabolism in humans is uric acid (2,6,8-trioxypurine).

FIG. 108.1 Early steps in the biosynthesis of the purine ring.

Uric acid is not a specific disease marker, so the cause of its elevation must be determined. The serum level of uric acid present at any time depends on the size of the purine nucleotide pool, which is derived from de novo purine synthesis, catabolism of tissue nucleic acids, and increased turnover of preformed purines. Uric acid is poorly soluble and must be excreted continuously to avoid toxic accumulation in the body. Baseline serum uric acid is established by the balancing of activity between secretory and absorptive urate transporters in both kidney and intestine. Urate secretion and absorption are mediated by separate, opposing groups of transporters. The majority of the genes involved in the variation in uric acid blood level encode urate transporters or associated regulatory proteins. Thus the fraction of uric acid excreted by the kidney is the result of a complex interplay between secretion and reabsorption by specific and nonspecific uric acid transporters in the proximal tubule, and this sets the level of uric acid in the plasma. Because renal tubule excretion is greater in children than in adults, serum uric acid levels are a less reliable indicator of uric acid production in children than in adults, and therefore measurement of the level in urine may be required to determine excessive production. Clearance of a smaller portion of uric acid is through the gastrointestinal (GI) tract (biliary and intestinal secretion). Because of poor solubility of uric acid under normal circumstances,

uric acid is near the maximal tolerable limits, and small alterations in production or solubility or changes in secretion may lead to hyperuricemia and can result in precipitation monosodium urate crystals in extremities (e.g., fingers or toes), which defines clinical gout . In renal insufficiency, urate excretion is increased by residual nephrons and the GI tract. Increased production of uric acid is found in malignancy, Reye syndrome, Down syndrome, psoriasis, sickle cell anemia, cyanotic congenital heart disease, pancreatic enzyme replacement, glycogen storage disease (types I, III, IV, and V), hereditary fructose intolerance, and acylcoenzyme A dehydrogenase deficiency. The metabolism of both purines and pyrimidines can be divided into biosynthetic, salvage, and catabolic pathways. The first, the de novo pathway, involves a multistep biosynthesis of phosphorylated ring structures from precursors such as CO2 , glycine, and glutamine. Purine and pyrimidine nucleotides are produced from ribose-5-phosphate or carbamyl phosphate, respectively. The second, a single-step salvage pathway, recovers purine bases and pyrimidine nucleosides derived from either dietary intake or the catabolic pathway (Figs. 108.2 and 108.3 ). In the de novo pathway, the nucleosides guanosine, adenosine, cytidine, uridine, and thymidine are formed by the addition of ribose-1-phosphate to the purine bases guanine or adenine and to the pyrimidine bases cytosine, uracil, and thymine, respectively. The phosphorylation of these nucleosides produces monophosphate, diphosphate, and triphosphate nucleotides, as well as the deoxy-nucleotides that are utilized for DNA formation. Under usual circumstances, the salvage pathway predominates over the biosynthetic pathway because nucleotide salvage saves energy for cells. Only a small fraction of the nucleotides turned over by the body each day are degraded and excreted. Synthesis of nucleotides is most active in tissues with high rates of cellular turnover, such as gut epithelium, skin, and bone marrow. The third pathway is catabolism. The end product of the catabolic pathway of the purines in humans is uric acid, whereas catabolism of pyrimidines produces citric acid cycle intermediates.

FIG. 108.2 Pathways in purine metabolism and salvage.

FIG. 108.3 Pathways in pyrimidine biosynthesis.

Inborn errors in the synthesis of purine nucleotides comprise the

phosphoribosylpyrophosphate synthetase spectrum of disorders, including deficiency and superactivity, adenylosuccinate lyase deficiency, and 5-amino-4imizolecarboxamide (AICA) riboside deficiency (AICA-ribosiduria). Disorders resulting from abnormalities in purine catabolism comprise muscle adenosine monophosphate (AMP) deaminase deficiency, adenosine deaminase deficiency, purine nucleoside phosphorylase deficiency, and xanthine oxidoreductase deficiency. Disorders resulting from the purine salvage pathway include hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and adenine phosphoribosyltransferase (APRT) deficiency. Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is an inborn error of pyrimidine synthesis that leads to an excessive excretion of orotic acid in urine. Dihydrorotate dehydrogenase deficiency (Miller syndrome), also a disorder of de novo pyrimidine synthesis, paradoxically may lead to orotic aciduria. Other pyrimidine disorders lead to abnormalities in pyrimidine catabolism , including dihydropyrimidine dehydrogenase (DPD) deficiency, dihydropyrimidinase (DPH) deficiency, β-ureidopropionase deficiency, pyrimidine 5′-nucleotidase deficiency, and thymidine phosphorylase deficiency. A disorder resulting from the pyrimidine salvage is thymidine kinase-2 deficiency.

Gout Gout presents with hyperuricemia, uric acid nephrolithiasis, and acute inflammatory arthritis. Gouty arthritis is caused by monosodium urate crystal deposits that result in inflammation in joints and surrounding tissues. The presentation is most commonly monoarticular, typically in the metatarsophalangeal joint of the big toe. Tophi, deposits of monosodium urate crystals, may occur over points of insertion of tendons at the elbows, knees, and feet or over the helix of the ears. Primary gout usually occurs in middle-aged males and results mainly from decreased renal excretion of uric acid, or purine overconsumption, or high intake of alcohol or fructose, or a combination of these factors. Gout occurs in any condition that leads to reduced clearance of uric acid: during therapy for malignancy or with dehydration, lactic acidosis, ketoacidosis, starvation, diuretic therapy, and renal failure. Excessive purine, alcohol, or fructose ingestion may increase uric acid levels. The biochemical etiology of gout is unknown for most patients, and it is considered to have a basis in genetic polymorphisms, predominantly in uric acid transporters. Purine overproduction

is a rare cause of primary gout and is associated with several genetic disorders discussed later. Secondary gout is either the result of another disorder with rapid tissue breakdown or cellular turnover, leading to increased production or decreased excretion of uric acid, or the result of some types of drug treatment; for example, diuretics cause plasma volume reduction and can precipitate a gouty attack. Gout resulting from endogenous purine overproduction is associated with hereditary disorders of 3 different enzymes that result in hyperuricemia. These include the HPRT deficiency spectrum (ranging from severe deficiency or Lesch-Nyhan syndrome to partial HPRT deficiency), 2 forms of superactivity of PP-ribose-P synthetase, and glycogen storage disease type I (glucose-6phosphatase deficiency). In the first 2 disorders, the basis of hyperuricemia is purine nucleotide and uric acid overproduction, whereas in the 3rd disorder it is both excessive uric acid production and diminished renal excretion of urate. Glycogen storage disease types III, V, and VII are associated with exerciseinduced hyperuricemia, the consequence of rapid ATP utilization and failure to regenerate it effectively during exercise (see Chapter 105.1 ). Juvenile gout results from purine underexcretion. The earlier terminology juvenile hyperuricemic nephropathy has been replaced by the newer term (autosomal dominant) tubulointerstitial kidney disease (ADTKD). The term ADTKD-UMOD (uromodulin-associated kidney disease) is used for medullary cystic kidney disease type 2 and maps to chromosome 16p11.2. It results from uromodulin mutations. Other genes classified as forms of familial juvenile hyperuricemic nephropathy include those for renin and hepatic nuclear factor-1β. Unlike the 3 inherited purine disorders that are X-linked and the recessively inherited glycogen storage disease, these are autosomal dominant conditions. Familial juvenile hyperuricemic nephropathy is associated with a reduced fractional excretion of uric acid. Although it typically presents from puberty up to the 3rd decade, it has been reported in early childhood. It is characterized by early onset, hyperuricemia, gout, familial renal disease, and low urate clearance relative to glomerular filtration rate. It occurs in both males and females and is frequently associated with a rapid decline in renal function that may lead to death unless diagnosed and treated early. Once familial juvenile hyperuricemic nephropathy is recognized, presymptomatic detection is of critical importance to identify asymptomatic family members with hyperuricemia and to begin treatment, when indicated, to prevent nephropathy.

Genetics Familial juvenile hyperuricemic nephropathy-2 (HNFJ2; 613092) is caused by mutation in the renin gene (REN ; 179820) on chromosome 1q32. HNFJ3 (614227) has been mapped to chromosome 2p22.1-p21. ADTKD involves mutations of the mucin (MUC1) gene. The mutation of uromodulin has been traced to chromosome 16.

Treatment Treatment of hyperuricemia involves the combination of allopurinol or febuxostat (xanthine oxidase inhibitors) to decrease uric acid production, probenecid to increase uric acid clearance in those with normal renal function, and increased fluid intake to reduce the concentration of uric acid. A low-purine diet, weight reduction, and reduced alcohol and fructose intake (fructose both reduces urate clearance and accelerates ATP breakdown to uric acid) are recommended.

Abnormalities in Purine Salvage Hypoxanthine-Guanine Phosphoribosyltransferase (HPRT) Deficiency Lesch-Nyhan disease (LND) is a rare X-linked disorder of purine metabolism that results from HPRT deficiency. This enzyme is normally present in each cell in the body, but its highest concentration is in the brain, especially in the basal ganglia. Clinical manifestations include hyperuricemia, intellectual disability, dystonic movement disorder that may be accompanied by choreoathetosis and spasticity, dysarthric speech, and compulsive self-biting, usually beginning with the eruption of teeth. There is a spectrum of severity for the clinical presentations. HPRT levels are related to the extent of motor symptoms, to the presence or absence of selfinjury, and possibly to the level of cognitive function. Purine overproduction is present. The majority of individuals with classic LND have low or undetectable levels of the HPRT enzyme. Partial deficiency in HPRT (Kelley-Seegmiller syndrome ) with >1.5–2.0% enzyme is associated with purine overproduction

and variable neurologic dysfunction (neurologic HPRT deficiency). HPRT deficiency with activity levels >8% of normal still shows purine (and uric acid) overproduction but apparently normal cerebral functioning (HPRT-related hyperuricemia), although cognitive deficits may occur. Qualitatively similar cognitive deficit profiles have been reported in both LND and variant cases. Variants produced scores intermediate between those of patients with LND and normal controls on almost every neuropsychological measure tested.

Genetics The HPRT gene has been localized to the long arm of the X chromosome (q26q27). The complete amino acid sequence for HPRT is known and is encoded by the HPRT1 gene (approximately 44 kb; 9 exons). The disorder appears in males; occurrence in females is extremely rare and ascribed to nonrandom inactivation of the normal X chromosome. Absence of HPRT activity results in a failure to salvage hypoxanthine, which is degraded to uric acid. Failure to consume phosphoribosylpyrophosphate in the salvage reaction results in an increase in this metabolite, which drives de novo purine synthesis, leading to the overproduction of uric acid. Excessive uric acid production manifests as gout, necessitating specific drug treatment (allopurinol). Because of the enzyme deficiency, hypoxanthine accumulates in the cerebrospinal fluid (CSF), but uric acid does not; uric acid is not produced in the brain and does not cross the bloodbrain barrier. The behavior disorder is not caused by hyperuricemia or excess hypoxanthine because patients with partial HPRT deficiency, the variants with hyperuricemia, do not self-injure, and infants with isolated hyperuricemia from birth do not develop self-injurious behavior. The prevalence of the classic LND has been estimated at 1 in 100,000 to 1 in 380,000 persons based on the number of known cases in the United States. The incidence of partial variants is not known. Those with the classic syndrome rarely survive the 3rd decade because of renal or respiratory compromise. The life span may be normal for patients with partial HPRT deficiency without severe renal involvement.

Pathology No specific brain abnormality is documented after detailed histopathology and electron microscopy of affected brain regions. MRI has documented reductions in the volume of basal ganglia nuclei. Abnormalities in neurotransmitter

metabolism have been identified in 3 autopsied cases. All 3 patients had very low HPRT levels (A as predictors of severe fluoropyrimidineassociated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol . 2015;16(16):1639– 1650. Teh LK, Hamzah S, Hashim H, et al. Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients. Ther Drug Monit . 2013;35(5):624–630. Van Staveren MC, Guchelaar HJ, van Kuilenburg AB, et al. Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmacogenomics J . 2013;13(5):389–395.

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CHAPTER 109

Hutchinson-Gilford Progeria Syndrome (Progeria) Leslie B. Gordon

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is a rare, fatal, autosomal dominant segmental premature aging disease. With an estimated incidence of 1 in 4 million live births and prevalence of 1 in 20 million living individuals, there are an estimated total of 400 children living with progeria in 2018 worldwide. There is no gender, ethnic, or regional bias. Progeria is caused by a single-base mutation in the LMNA gene, which results in the production of a mutant lamin A protein called progerin . Lamin A is an intermediate filament inner nuclear membrane protein found in most differentiated cells of the body. Without progerin-specific treatment, children with progeria develop premature progressive atherosclerosis and die of heart failure, usually between ages 5 and 20 yr. Progerin is found in increased concentration in skin and the vascular wall of normal older individuals compared to younger individuals, suggesting a role in normal aging.

Clinical Manifestations Children develop the appearance of accelerated aging, but both clinical and biologic overlaps with aging are segmental, or partial. Physical appearance changes dramatically each year that they age (Fig. 109.1 ). The descriptions discussed next are roughly in order of clinical appearance.

FIG. 109.1 Distinguishing clinical features and radiographic findings in HutchinsonGilford progeria syndrome. A, Alopecia, prominent scalp veins, narrowed nasal bridge, retrognathia; B, generalized lipoatrophy leaves muscular prominence; C, skin tightening and mottling; D, flat umbilicus with scarred-over appearance; E, skin bulging; F, digital joint contractures; G, nail dystrophy with spooning; H, knee joint contractures, lipodystrophy; I, coxa valga of the hip; J, clavicular osteolysis; K, acroosteolysis in a thumb. (Photos courtesy of The Progeria Research Foundation and Boston Children's Hospital.)

Dermatologic Changes Skin findings are often apparent as initial signs of progeria. These are variable in severity and include areas of discoloration, stippled pigmentation, tightened areas that can restrict movement, and areas of the trunk or legs where small (1-2 cm), soft, bulging skin is present. Although usually born with normal hair presence, cranial hair is lost within the first few years, leaving soft, downy, sparse immature hair on the scalp, no eyebrows, and scant eyelashes. Nail dystrophy occurs later in life.

Failure to Thrive Children with progeria experience apparently normal fetal and early postnatal development. Between several months and 1 yr of age, abnormalities in growth and body composition are readily apparent. Severe failure to thrive ensues, heralding generalized lipoatrophy, with apparent wasting of limbs, circumoral

cyanosis, and prominent veins around the scalp, neck, and trunk. The mean weight percentile is usually normal at birth, but decreases to below the 3rd percentile despite adequate caloric intake for normal growth and normal resting energy expenditure. A review of 35 children showed an average weight increase of only 0.44 kg/yr, beginning at 24 mo of age and persisting through life. There is interpatient variation in weight gain, but the projected weight gain over time in individual patients is constant, linear, and very predictable; this sharply contrasts with the parabolic growth pattern for normal age- and gender-matched children. Children reach an average final height of approximately 1 meter and weight of approximately 15 kg. Head circumference is normal. The weight deficit is more pronounced than the height deficit and, associated with the loss of subcutaneous fat, results in the emaciated appearance characteristic of progeria. Clinical problems caused by the lack of subcutaneous fat include sensitivity to cold temperatures and foot discomfort caused by lack of fat cushioning. Overt diabetes is very unusual in progeria, but about 30–40% of children have insulin resistance.

Ocular Abnormalities Ophthalmic signs and symptoms are caused in part by tightened skin and a paucity of subcutaneous fat around the eyes. Children often experience hyperopia and signs of ocular surface disease from nocturnal lagophthalmos and exposure keratopathy, which in turn may lead to corneal ulceration and scarring. Some degree of photophobia is common. Most patients have relatively good acuity; however, advanced ophthalmic disease can be associated with reduced acuity. Children with progeria should have an ophthalmic evaluation at diagnosis and at least yearly thereafter. Aggressive ocular surface lubrication is recommended, including the use of tape tarsorrhaphy at night.

Craniofacial and Dental Phenotypes Children develop craniofacial disproportion, with micrognathia and retrognathia caused by mandibular hypoplasia. Typical oral and dental manifestations include hypodontia, delayed tooth eruption, severe dental crowding, ogival palatal arch, ankyloglossia, presence of median sagittal palatal fissure, and generalized gingival recession. Eruption may be delayed for many months, and primary teeth may persist for the duration of life. Secondary teeth are present but may or may

not erupt. They sometimes erupt on the lingual and palatal surfaces of the mandibular and maxillary alveolar ridges, rather than in place of the primary incisors. In some, but not all cases, extracting primary teeth promotes movement of secondary teeth into place.

Bone and Cartilaginous Abnormalities Development of bone structure and bone density represents a unique skeletal dysplasia that is not based in malnutrition. Acroosteolysis of the distal phalanges, distal clavicular resorption, and thin, tapered ribs are early signs of progeria (as early as 3 mo of age). Facial disproportion a narrowed nasal bridge and retrognathia makes intubation extremely difficult, and fiberoptic intubation is recommended. A pyriform chest structure and small clavicles can lead to reducible glenohumeral joint instability. Growth of the spine and bony pelvis are normal. However, dysplastic growth of the femoral head and neck axis result in coxa valgus (i.e., straightening of the femoral head-neck axis >125 degrees) and coxa magna, where the diameter of the femoral head is disproportionately large for the acetabulum, resulting in hip instability. The resulting hip dysplasia can be progressive and may result in osteoarthritis, avascular necrosis, hip dislocation, and inability to bear weight. Other changes to the appendicular skeleton include flaring of the humeral and femoral metaphyses and constriction of the radial neck. Growth plate morphology is generally normal but can be variable within a single radiograph. The appearance of ossification centers used to define bone age is normal. Bone structure assessed by peripheral quantitative computed tomography (pQCT) of the radius demonstrates distinct and severe abnormalities in bone structural geometry, consistent with progeria representing a skeletal dysplasia. Areal bone mineral density (aBMD) z scores measured by dual-energy X-ray absorptiometry (DXA) adjusted for height-age, and true (volumetric) BMD assessed by pQCT are normal to mildly reduced, refuting the assumption that patients with progeria are osteoporotic. Fracture rates in progeria are normal and not associated with fragility fractures observed in other pediatric metabolic bone diseases, such as osteogenesis imperfecta. Contractures in multiple joints (e.g., fingers, elbows, hips, knees, ankles) may be present at birth and may progress with age because of changes in the laxity of the surrounding soft tissue structures (joint capsule, ligament, skin). Along with irregularities in the congruency of articulating joint surfaces, these changes serve to limit joint motion and affect the pattern of gait. Physical therapy is

recommended routinely and throughout life to maximize joint function.

Hearing Low-tone conductive hearing loss is pervasive in progeria and indicative of a stiff tympanic membrane and/or deficits in the middle ear bony and ligamentous structures. Overall, this does not affect ability to hear the usual spoken tones, but preferential classroom seating is recommended, with annual hearing examinations.

Cardiovascular Disease Approximately 80% of progeria deaths are caused by heart failure, possibly precipitated by events such as superimposed respiratory infection or surgical intervention. Progeria is a primary vasculopathy characterized by pervasive accelerated vascular stiffening, followed by large- and small-vessel occlusive disease from atherosclerotic plaque formation, with valvular and cardiac insufficiency in later years. Hypertension, angina, cardiomegaly, metabolic syndrome, and congestive heart failure are common end-stage events. A study of transthoracic echocardiography in treatment-naïve patients revealed diastolic left ventricular dysfunction associated with age-related decline in lateral and septal early (E′) diastolic tissue Doppler velocity z scores and an increase in the ratio of mitral inflow (E) to lateral and septal E’ velocity z scores. Other echocardiographic findings included left ventricular hypertrophy, left ventricular systolic dysfunction, and mitral or aortic valve disease. These tend to appear later in life. Routine carotid ultrasound for plaque monitoring, carotidfemoral pulse wave velocity (PWVcf ) measures for vascular stiffening, and echocardiography are recommended.

Cerebrovascular Arteriopathy and Stroke Cerebral infarction may occur while the child exhibits a normal electrocardiogram. The earliest incidence of stroke occurred at age 0.4 yr. More often strokes occur in the later years. Over the life span, MRI evidence of infarction can be found in 60% of progeria patients, with half of these clinically silent. Both large- and small-vessel disease is found; collateral vessel formation is extensive. Carotid artery blockages are well documented, but infarction can

occur even in their absence. A propensity for strokes and an underlying stiff vasculature make maintaining adequate blood pressure through hydration (habitually drinking well) a priority in progeria patients; special care should be taken when considering maintenance of consistent blood pressure during general anesthesia, airplane trips, and hot weather. In addition, 15% of deaths in children with progeria occur from head injury or trauma, including subdural hematoma. This implies an underlying susceptibility to subdural hematoma.

Sexual Development Females with progeria can develop Tanner Stage II secondary sexual characteristics, including signs of early breast development and sparse pubic hair. They do not achieve Tanner Stage III. Despite minimal to no physical signs of pubertal development and minimal body fat, over half of females experience spontaneous menarche at a median age of 14 yr. Those experiencing menarche vs nonmenstruating females have similar body mass indices, percentage body fat, and serum leptin levels, all of which are vastly below the healthy adolescent population. If bleeding becomes severe, the complete blood count may be decreased, and an oral contraceptive may be used to decrease bleeding severity. Secondary sexual characteristics in males have not been studied. There are no documented cases of reproductive capacity in females or males with progeria.

Normally Functioning Systems Liver, kidney, thyroid, immune, gastrointestinal, and neurologic systems (other than stroke related) remain intact. Intellect is normal for age, possibly in part from downregulation of progerin expression in the brain by a brain-specific micro-RNA, miRNA-9.

Laboratory Findings The most consistent laboratory findings are low serum leptin below detectable levels (>90%) and insulin resistance (60%). Platelet count is often moderately high. High-density lipoprotein (HDL) cholesterol and adiponectin concentrations decrease with increasing age to values significantly below normal. Otherwise, lipid panels, high-sensitivity C-reactive protein, blood chemistries, liver and kidney function tests, endocrine test, and coagulation tests are generally normal.

Molecular Pathogenesis Mutations in the LMNA gene cause progeria. The normal LMNA/C gene encodes the proteins lamins A and C, of which only lamin A is associated with human diseases. The lamin proteins are the principal proteins of the nuclear lamina, a complex molecular interface located between the inner membrane of the nuclear envelope and chromatin. The integrity of the lamina is central to many cellular functions, creating and maintaining structural integrity of the nuclear scaffold, DNA replication, RNA transcription, organization of the nucleus, nuclear pore assembly, chromatin function, cell cycling, senescence, and apoptosis. Progeria is almost always a sporadic autosomal dominant disease. There are 2 documented sibling occurrences, both presumably stemming from parental mosaicism, where 1 phenotypically normal parent has germline mosaicism. It is caused by the accelerated use of an alternative, internal splice site that results in the deletion of 150 base pairs in the 3′ portion of exon 11 of the LMNA gene. In about 90% of cases, this results from a single C to T transition at nucleotide 1824 that is silent (Gly608Gly) but optimizes an internal splice site within exon 11. The remaining 10% of cases possess 1 of several single-base mutations within the intron 11 splice donor site, thus reducing specificity for this site and altering the splicing balance in favor of the internal splice. Subsequent to all these mutations, translation followed by posttranslational processing of the altered mRNA produces progerin, a shortened abnormal lamin A protein with a 50–amino acid deletion near its C-terminal end. An understanding of the posttranslational processing pathway and how it is altered to create progerin has led to a number of treatment prospects for the disease (Fig. 109.2 ).

FIG. 109.2 Posttranslational processing pathways producing lamin A and progerin, including the target site for lonafarnib. A, Prelamin A polypeptide chain, showing its central α-helical rod domain and C-terminal −CAAX box, representing cysteine (C), aliphatic amino acids (AA), and any amino acid (X). The α-helical rod domain is divided into segments that assist in displaying the progerin defect. Posttranslational processing consists of 4 steps: 1, a farnesyl group is attached to the cysteine residue of the −CAAX box by farnesyltransferase; 2, the last 3 residues are proteolytically cleaved by the zinc metalloprotease Zmpste24 or Ras-converting enzyme (RCE1); 3, carboxy-methylation by isoprenyl-cysteine carboxyl methyltransferase (ICMT); and 4, the terminal 15 C-terminal residues, including the farnesylated and carboxymethylated cysteine, are cleaved off by Zmpste24. B, A 50–amino acid deletion in prelamin A (represented by black segment of the lamin A rod) is the result of a mutation that activates a cryptic splice site within exon 11 of the LMNA gene. This deletion leaves progerin without an attachment site for the last processing step—cleavage of the farnesylation and carboxymethylated terminal 15 amino acid residues. Thus, progerin remains farnesylated and intercalated within the inner nuclear membrane, where it causes much of its cellular damage.

Both lamin A and progerin possess a methylated farnesyl side group attached during posttranslational processing. This is a lipophilic moiety that facilitates intercalation of proteins into the inner nuclear membrane, where most of the lamin and progerin functions are performed. For normal lamin A, loss of the methylated farnesyl anchor releases prelamin from the nuclear membrane, rendering it soluble for autophagic degradation. However, progerin retains its farnesyl moiety. It remains anchored to the membrane, binding other proteins, causing blebbing of the nucleus, disrupting mitosis, and altering gene expression. Progerin also retains a methyl moiety.

Disease in progeria is produced by a dominant negative mechanism; the action of progerin, not the diminution of lamin A, causes the disease phenotype. The severity of disease is determined in part by progerin levels, which are regulated by the particular mutation, tissue type, or other factors influencing use of the internal splice site.

Diagnosis and Differential Diagnosis Overall, the constellation of small body habitus, bone, hair, subcutaneous fat, and skin changes results in the marked physical resemblance among patients with progeria (Fig. 109.3 ). For this reason, clinical diagnosis can be achieved or excluded with relative confidence even at young ages, even though there have been a few cases of low–progerin-expressing patients with extremely mild signs. Clinical suspicion should be followed by LMNA genetic sequence testing. The disorders that resemble progeria are those grouped as the senile-like syndromes and include Wiedmann-Rautenstrauch syndrome, Werner syndrome, Cockayne syndrome, Rothmund-Thomson syndrome, restrictive dermopathy, and NestorGuillermo progeria syndrome (Table 109.1 ). Patients often fall under none of these diagnoses and represent ultra-rare, unnamed progeroid laminopathies that carry either non–progerin-producing mutations in LMNA or the lamin-associated enzyme (ZMPSTE24) , or progeroid syndromes without lamin-associated mutations.

FIG. 109.3 Unrelated 7 yr old female and 10 yr old male with progeria. Appearance is remarkably similar between patients. (Photograph courtesy of The Progeria Research Foundation)

Table 109.1

Features of Hutchinson-Gilford Progeria Syndrome and Other Disorders With Overlapping Features

Causative gene(s)

Inheritance Onset Growth retardation Hair loss

Skin abnormalities Subcutaneous

HUTCHINSONGILFORD PROGERIA SYNDROME LMNA

WIEDEMANNWERNER COCKAYNE RAUTENSTRAUCH SYNDROME SYNDROME SYNDROME Unknown

WRN , LMNA

Autosomal Dominant Infancy Postnatal

Unknown, likely recessive Newborn Intrauterine

Recessive

+ Total

+ Scalp patchy

+ +

CSA (ERCC8) CSB (ERCC6) Recessive

ROTHMUNDRESTRICTIVE THOMPSON DERMOPATHY SYNDROME RECQL4

ZMPSTE24, LMNA

Recessive

Recessive

Newborn/infancy Infancy Postnatal Postnatal

Newborn Intrauterine

−

+ Diffuse

+ Diffuse

+

Young adult Onset after puberty + Scalp, sparse, graying +

+

+

+

+

+

+

−

−

fat loss Skin calcification Short stature Coxa valga Acroosteolysis Mandibular dysplasia Osteopenia Vasculopathy Heart failure Strokes Insulin Resistance Diabetes Hypogonadism Dental abnormality Voice abnormality Hearing loss Joint contractures Hyperkeratosis Cataracts Tumor predisposition Intellectual disability Neurologic disorder

+ Rarely

−

+

−

−

−

+ + + +

+ − + +

+ − + −

+ − − −

+ − − −

+ − − +

+ Mild + + + +

+ − − − −

+ + + − + Rarely

− + − − −

+ − − − −

+ − − − −

− + +

− − +

+ + +

− + +

− + +

− − +

+

−

+

−

−

−

+ +

− −

− −

+ −

− −

− +

− − −

− − −

+ + +

− + −

+ + +

− − −

−

+

−

+

−

−

−

+

+ Mild

+

−

−

Adapted from Hegele RA: Drawing the line in Progeria syndromes, Lancet 362;416–417, 2003.

Treatment and Prognosis Children with progeria develop a severe premature form of atherosclerosis. Prior to death, cardiac decline with left-sided hypertrophy, valvular insufficiency, and pulmonary edema develop; neurovascular decline with transient ischemic attacks (TIAs), strokes, and occasionally seizures can result in significant morbidity. Death occurs generally between ages 5 and 20 yr, with a median life span of 14.5 yr, resulting from heart failure, sometimes with superimposed respiratory infection (approximately 80%); from head injury or trauma, including subdural hematoma (approximately 15%); and rarely from stroke (1–3%) or complications from anesthesia during surgery (1–3%). Growth hormone , 0.05 mg/kg/day subcutaneously, has resulted in increased rate of weight gain and overall size, but still well below that seen in normal

children. Low-dose aspirin therapy is recommended at 2 mg/kg/day, as an extension of what is known about decreasing cardiovascular risk in the general at-risk adult population. It is not known whether growth hormone or low-dose aspirin has any effect on morbidity or mortality. Several clinical treatment trials have been based on medications that target the posttranslational pathway of progerin (see Fig. 109.2 ). Inhibiting posttranslational progerin farnesylation is aimed at preventing this diseasecausing protein from anchoring to the nuclear membrane, where it carries out much of its damage. A prospective single-arm clinical trial was conducted with the farnesyltransferase inhibitor lonafarnib (NCT00425607). Lonafarnib was well tolerated; the most common side effects were diarrhea, nausea, and loss of appetite, which generally improved with time. Subgroups of patients experienced increased rate of weight gain, decreased vascular stiffness measured by decreased PWVcf and carotid artery echodensity, improved left ventricular diastolic function, increased radial bone structural rigidity, improved sensorineural hearing, and early evidence of decreased headache, TIA, and stroke rates. Dermatologic, dental, joint contracture, insulin resistance, lipodystrophy, BMD, and joint contractures were unaffected by drug treatment. A lonafarnib extension study was initiated, which added 30 children to the study. Children treated with lonafarnib demonstrated an increase in estimated survival over untreated children with progeria. A clinical trial that added pravastatin (FDA approved to lower cholesterol) and zoledronate (FDA approved for osteoporosis) to the lonafarnib regimen was similarly aimed at inhibiting progerin farnesylation (NCT00916747), but results showed no detected improvements in clinical status over lonafarnib monotherapy. An ongoing clinical trial adding everolimus (FDA-approved mTOR inhibitor) to the lonafarnib regimen is aimed at accelerating autophagy of progerin, thus theoretically reducing its accumulation and cellular damage (NCT02579044). Results of this study are forthcoming.

Patient Resources The Progeria Research Foundation (www.progeriaresearch.org ) maintains an international progeria patient registry, provides a diagnostics program and complete patient care manual, and coordinates clinical treatment trials. It funds preclinical and clinical research to define the molecular basis of the disorder and

to discover treatments and a cure. The Foundation website is an excellent source of current information on progeria for families of children with the disorder, their physicians, and interested scientists. Additional resources include the National Human Genome Research Institute (www.genome.gov/11007255/ ), National Center for Biotechnology Information Genereviews (www.ncbi.nlm.nih.gov/books/NBK1121/ ), and National Center for Advancing Translational Sciences (www.rarediseases.info.nih.gov/diseases/7467/progeria ).

Bibliography Cleveland RH, Gordon LB, Kleinman ME, et al. A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome. Pediatr Radiol . 2012;42(9):1089–1098. Gordon LB, Brown WT, Collis FS. Hutchinson-Gilford progeria syndrome. GeneReviews at GeneTests. Medical Genetics Information Resource . 2017 http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/disease/progeria? db=genetests&search_param=contains . Gordon AS, Gordon LB. The Progeria Research Foundation: its remarkable journey from obscurity to treatment. Expert Opin Orphan Drugs . 2014;2(11):1–9. Gordon CM, Gordon LB, Snyder BD, et al. Hutchinson-Gilford progeria is a skeletal dysplasia. J Bone Miner Res . 2011;26(7):1670–1679. Gordon LB, Kleinman ME, Massaro J, et al. Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson-Gilford progeria syndrome. Circulation . 2016;134(2):114–125. Gordon LB, Kleinman ME, Miller DT, et al. Clinical trial of a farnesyltransferase inhibitor in children with HutchinsonGilford progeria syndrome. Proc Natl Acad Sci USA . 2012;109(41):16666–16671. Gordon LB, Massaro J, D'Agostino RB, et al. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford

progeria syndrome. Circulation . 2014;130(1):27–34. Gordon LB, McCarten KM, Giobbie-Hurder A, et al. Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics . 2007;120(4):824–833. Guardiani E, Zalewski C, Brewer C, et al. Otologic and audiologic manifestations of Hutchinson-Gilford progeria syndrome. Laryngoscope . 2011;121(10):2250–2255. Jung HJ, Coffinier C, Choe Y, et al. Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA. Proc Natl Acad Sci USA . 2012;109(7):E423–E431. Merideth MA, Gordon L, Clauss S, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med . 2008;358(6):592–604. Olive M, Harten I, Mitchell R, et al. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol . 2010;30(11):2301–2309. Rork JF, Huang JT, Gordon LB, et al. Initial cutaneous manifestations of Hutchinson-Gilford progeria syndrome. Pediatr Dermatol . 2014;31(2):196–202. Silvera VM, Gordon LB, Orbach DB, et al. Imaging characteristics of cerebrovascular arteriopathy and stroke in Hutchinson-Gilford progeria syndrome. AJNR Am J Neuroradiol . 2013;34(5):1091–1097. Sinensky M, Fantle K, Trujillo M, et al. The processing pathway of prelamin A. J Cell Sci . 1994;107(Pt 1):61–67. Ullrich NJ, Kieran MW, Miller DT, et al. Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology . 2013;81:427–430.

C H A P T E R 11 0

The Porphyrias Manisha Balwani, Robert J. Desnick, Karl E. Anderson

Porphyrias are metabolic diseases resulting from altered activities of specific enzymes of the heme biosynthetic pathway. These enzymes are most active in bone marrow and liver. Erythropoietic porphyrias , in which overproduction of heme pathway intermediates occurs primarily in bone marrow erythroid cells, usually present at birth or in early childhood with cutaneous photosensitivity, or in the case of congenital erythropoietic porphyria, even in utero as nonimmune hydrops. Erythropoietic protoporphyria is the most common porphyria in children and of most interest to pediatricians. Most porphyrias are hepatic, with overproduction and initial accumulation of porphyrin precursors or porphyrins in the liver. Activation of hepatic porphyrias is very rare during childhood, reflecting the distinct hepatic regulatory mechanisms for heme biosynthesis that are influenced by pubertal development. Homozygous forms of the hepatic porphyrias may manifest clinically before puberty. Children who are heterozygous for inherited hepatic porphyrias may present with nonspecific and unrelated symptoms, and parents often request advice about long-term prognosis and express concerns about drugs that may exacerbate these conditions. The DNA sequences and chromosomal locations are established for the genes of the enzymes in this pathway, and multiple disease-related mutations have been found for each porphyria. However, benign variants identified by gene sequencing can be misleading. The inherited porphyrias display autosomal dominant, autosomal recessive, or X-linked inheritance. Although initial diagnosis of porphyria by biochemical methods remains essential, it is especially important to confirm the diagnosis by demonstrating a specific pathogenic gene mutation(s).

The Heme Biosynthetic Pathway Heme is required for a variety of hemoproteins, such as hemoglobin, myoglobin, respiratory cytochromes, and cytochrome P450 enzymes (CYPs). It is believed that the 8 enzymes in the pathway for heme biosynthesis are active in all tissues. Hemoglobin synthesis in erythroid precursor cells accounts for approximately 85% of daily heme synthesis in humans. Hepatocytes account for most of the rest, primarily for synthesis of CYPs, which are especially abundant in the liver endoplasmic reticulum, and turn over more rapidly than many other hemoproteins, such as the mitochondrial respiratory cytochromes. Pathway intermediates are the porphyrin precursors δ-aminolevulinic acid (ALA , also known as 5-aminolevulinic acid) and porphobilinogen (PBG) , as well as porphyrins (mostly in their reduced forms, known as porphyrinogens ) (Fig. 110.1 ). These intermediates do not accumulate in significant amounts under normal conditions or have important physiologic functions.

FIG. 110.1 Enzymes and intermediates of the heme biosynthetic pathway. The pathway is regulated in the liver by the end product, heme, mainly by feedback repression

(dashed arrow) .

Altered activity of each enzyme in the pathway has been associated with a specific type of porphyria (Table 110.1 ). The first enzyme, ALA synthase (ALAS), occurs in 2 forms. An erythroid specific form, ALAS2, is deficient in X-linked sideroblastic anemia, as a result of mutations of the ALAS2 gene on chromosome Xp11.2. Gain-of-function mutations of ALAS2 caused by deletions in the last exon cause X-linked protoporphyria (XLP ), which is phenotypically identical to erythropoietic protoporphyria. Table 110.1

The Human Porphyrias: Mutations, Time of Presentation, and Tissue- and Symptom-Based Classifications Classification* DISEASE

ENZYME

INHERITANCE

PRESENTATION

X-Linked protoporphyria (XLP) δ-Aminolevulinic acid dehydratase porphyria (ADP) Acute intermittent porphyria (AIP) Homozygous AIP Congenital erythropoietic porphyria (CEP) Porphyria cutanea tarda (PCT) type 1

δ-Aminolevulinate synthase 2 (ALAS2) δ-Aminolevulinic acid dehydratase (ALAD) Porphobilinogen deaminase (PBGD)

X-linked

Childhood

Autosomal recessive

Mostly post puberty

X X* X

Autosomal dominant

Post puberty

X

Homozygous dominant Autosomal recessive

Childhood X X In utero or infancy X

Sporadic

Adults

X

X

Autosomal dominant Unknown Homozygous dominant

Adults Adults Childhood

X X X X*

X X X

Post puberty

X

X

X

Childhood Post puberty

X X X

X X

X X

Childhood Childhood

X X X

X

X X

PCT type 2 † PCT type 3 Hepatoerythropoietic porphyria (HEP) Hereditary coproporphyria (HCP) Homozygous HCP Variegate porphyria (VP) Homozygous VP Erythropoietic protoporphyria (EPP)

Uroporphyrinogen III synthase (UROS) Uroporphyrinogen decarboxylase (UROD)

Coproporphyrinogen Autosomal dominant oxidase (CPOX) Homozygous dominant Protoporphyrinogen Autosomal dominant oxidase (PPOX) Homozygous dominant Ferrochelatase Autosomal recessive (most (FECH) commonly heteroallelic with hypomorphic allele)

H E X

A/N C X

X X X

* Classification abbreviations: H, Hepatic; E, Erythropoietic; A/N, Acute/Neurologic; C, Cutaneous. † PCT is a result of inhibition of hepatic UROD. Autosomal dominant inheritance of a partial

deficiency of UROD is a predisposing factor in cases defined as familial (type 2) PCT. ADP and HEP are considered primarily hepatic porphyrias, but substantial increases in erythrocyte zinc protoporphyrin suggest an erythropoietic component.

Regulation of heme synthesis differs in the 2 major heme-forming tissues. Liver heme biosynthesis is primary controlled by the ubiquitous form of ALAS (ALAS1). Synthesis of ALAS1 in liver is regulated by a “free” heme pool (see Fig. 110.1 ), which can be augmented by newly synthesized heme or by existing heme released from hemoproteins and destined for breakdown to biliverdin by heme oxygenase. In the erythron, novel regulatory mechanisms allow for the production of the very large amounts of heme needed for hemoglobin synthesis. The response to stimuli for hemoglobin synthesis occurs during cell differentiation, leading to an increase in cell number. Also, unlike the liver, heme has a stimulatory role in hemoglobin formation, and the stimulation of heme synthesis in erythroid cells is accompanied by increases not only in ALAS2, but also by sequential induction of other heme biosynthetic enzymes. Separate erythroid-specific and nonerythroid or “housekeeping” transcripts are known for the first 4 enzymes in the pathway. The separate forms of ALAS are encoded by genes on different chromosomes, but for each of the other three, erythroid and nonerythroid transcripts are transcribed by alternative promoters in the same gene. Heme also regulates the rate of its synthesis in erythroid cells by controlling the transport of iron into reticulocytes. Intermediates of the heme biosynthetic pathway are efficiently converted to heme and, normally, only small amounts of the intermediates are excreted. Some may undergo chemical modifications before excretion. Whereas the porphyrin precursors ALA and PBG are colorless, nonfluorescent, and largely excreted unchanged in urine, PBG may degrade to colored products such as the brownish pigment called porphobilin or spontaneously polymerize to uroporphyrins. Porphyrins are red in color and display bright-red fluorescence when exposed to long-wavelength ultraviolet (UV) light. Porphyrinogens are the reduced form of porphyrins, and are colorless and nonfluorescent, but are readily autoxidized to the corresponding porphyrins when they accumulate or are outside the cell. Only the type III isomers of uroporphyrinogen and coproporphyrinogen are converted to heme (see Fig. 110.1 ). ALA and PBG are excreted in urine. Excretion of porphyrins and

porphyrinogens in urine or bile is determined by the number of carboxyl groups. Those with many carboxyl groups, such as uroporphyrin (octacarboxyl porphyrin) and heptacarboxyl porphyrin, are water soluble and readily excreted in urine. Those with fewer carboxyl groups, such as protoporphyrin (dicarboxyl porphyrin), are not water soluble and are excreted in bile and feces. Coproporphyrin (tetracarboxyl porphyrin) is excreted partly in urine and partly in bile. Because coproporphyrin I is more readily excreted in bile than coproporphyrin III, impaired hepatobiliary function may increase total urinary coproporphyrin excretion and the ratio of these isomers.

Classification and Diagnosis of Porphyrias Two useful classification schemes reflect either the underlying pathophysiology or the clinical features of porphyrias (see Table 110.1 ). In hepatic porphyrias and erythropoietic porphyrias the source of excess production of porphyrin precursors and porphyrins is the liver and bone marrow, respectively. Acute porphyrias cause neurologic symptoms that are associated with increases of one or both of the porphyrin precursors, ALA and PBG. In the cutaneous porphyrias, photosensitivity results from transport of porphyrins in blood from the liver or bone marrow to the skin. Dual porphyria refers to the very rare cases of porphyria with deficiencies of 2 different heme pathway enzymes. Porphyria cutanea tarda (PCT ), acute intermittent porphyria (AIP ), and erythropoietic protoporphyria (EPP ) are the 3 most common porphyrias, in that order, considering all age-groups, and are very different in clinical presentation, precipitating factors, methods of diagnosis, and effective therapy (Table 110.2 ). Two less common acute porphyrias, hereditary coproporphyria (HCP ) and variegate porphyria (VP ), can also cause blistering photosensitivity (see Table 110.1 ). Congenital erythropoietic porphyria (CEP ) causes more severe blistering lesions, often with secondary infection and mutilation. EPP and XLP have the same phenotype and are distinct from the other cutaneous porphyrias in causing nonblistering photosensitivity that occurs acutely after sun exposure. EPP is also the most common porphyria to become manifest before puberty. Table 110.2

Three Most Common Human Porphyrias and Major

Features

Acute intermittent porphyria Porphyria cutanea tarda

PRESENTING SYMPTOMS Neurologic, adult onset Skin blistering and fragility (chronic), adult onset

Erythropoietic Phototoxic pain and protoporphyria swelling (mostly acute), childhood onset

EXACERBATING FACTORS Drugs (mostly P450 inducers), progesterone, dietary restriction Iron, alcohol, smoking, estrogens, hepatitis C, HIV, halogenated hydrocarbons

MOST IMPORTANT SCREENING TESTS Urinary porphobilinogen

TREATMENT Hemin, glucose

Plasma (or urine) porphyrins

Phlebotomy, lowdose hydroxychloroquine

Total erythrocyte protoporphyrin with metal-free and zinc protoporphyrin

Sun protection

First-Line Laboratory Diagnostic Testing A few sensitive and specific first-line laboratory tests should be obtained whenever symptoms or signs suggest the diagnosis of porphyria. If a first-line or screening test is significantly abnormal, more comprehensive testing should follow to establish the type of porphyria. Overuse of lab tests for screening can lead to unnecessary expense and even delay in diagnosis. In patients who present with a past diagnosis of porphyria, lab reports that were the basis for the original diagnosis must be reviewed, and if these were inadequate, further testing considered. Acute porphyria should be suspected in patients with neurovisceral symptoms such as abdominal pain after puberty, when initial clinical evaluation does not suggest another cause. Urinary PBG and total porphyrins should be measured. Urinary PBG is virtually always increased during acute attacks of AIP, HCP, and VP and is not substantially increased in any other medical conditions. Therefore this measurement is both sensitive and specific. Results from spot (single void) urine specimens are highly informative because very substantial increases are expected during acute attacks of porphyria. A 24 hr collection can unnecessarily delay diagnosis. The same spot urine specimen should be saved for quantitative determination of PBG and total porphyrins (both expressed relative to creatinine) to confirm the qualitative PBG result. ALA is often measured as well, but is usually less elevated than PBG in AIP, HCP, and VP. In ALA dehydratase porphyria, urinary ALA and porphyrins, but not PBG, are greatly elevated. Urinary porphyrins may remain increased longer than porphyrin precursors in some cases of HCP and VP. Measurement of urinary porphyrins alone should be

avoided for screening, however, because they are often increased in many disorders other than porphyrias, such as liver diseases, and misdiagnoses of porphyria can result from minimal increases in urinary porphyrins that have no diagnostic significance.

Blistering Cutaneous Porphyrias Blistering skin lesions caused by porphyria are virtually always accompanied by increases in total plasma and urinary porphyrins. Porphyrins in plasma in VP are mostly covalently linked to plasma proteins and readily detected by a diagnostic peak in a fluorescence scanning method. The normal range for plasma porphyrins is somewhat increased in patients with end-stage renal disease.

Nonblistering Cutaneous Porphyria Measurement of total erythrocyte protoporphyrin and, if the total amount is elevated, fractionation of protoporphyrin into its metal-free and zinc-chelated forms, is essential for diagnosis of EPP and XLP. Unfortunately, this is not offered by some major commercial laboratories. Results of zinc protoporphyrin measurements are often recorded (even in the same report) as both protoporphyrin and free erythrocyte protoporphyrin , with each calculated differently, based on past practices for screening for lead poisoning (which only increases zinc protoporphyrin). Thus the obsolete term free protoporphyrin does not mean metal-free protoporphyrin, because it was defined as iron-free protoporphyrin, and dates from before it was known that (except in protoporphyrias) protoporphyrin in erythrocytes is mostly zinc chelated. This unnecessary confusion makes diagnosis and reliable exclusion of protoporphyrias difficult. Total plasma porphyrins are elevated in most but not all cases of protoporphyria, so a normal level should not be relied on to exclude protoporphyria when total erythrocyte protoporphyrin is elevated. Increases in erythrocyte total and zinc-chelated protoporphyrin occur in many other conditions, including iron deficiency, lead poisoning, hemolysis, anemia of chronic disease, and other erythrocyte disorders. Therefore the diagnosis of EPP must be confirmed by showing a predominant increase in metal-free protoporphyrin. In XLP, both free and zinc protoporphyrin are elevated.

Second-Line Testing More extensive testing is well justified when a first-line test is positive. For

example, a substantial increase in PBG may be caused by AIP, HCP, or VP, and these can be distinguished by measuring erythrocyte porphobilinogen deaminase, urinary porphyrins (using the same spot urine sample), fecal porphyrins, and plasma porphyrins. The various porphyrias that cause blistering skin lesions are differentiated by measuring porphyrins in urine, feces, and plasma. Confirmation at the gene level is important once the diagnosis is established by biochemical testing.

Testing for Subclinical Porphyria It is often difficult to diagnose or rule out porphyria in patients who had suggestive symptoms months or years in the past, and in relatives of patients with acute porphyrias, because porphyrin precursors and porphyrins may be normal. More extensive testing and consultation with a specialist laboratory and physician may be needed. Before evaluating relatives, the diagnosis of porphyria should be firmly established in an index case, and the lab results reviewed to guide the choice of tests for the family members. The index case or another family member with confirmed porphyria should be retested if necessary. Identification of a disease-causing mutation in an index case greatly facilitates detection of additional gene carriers, because biochemical tests in latent carriers may be normal.

δ-Aminolevulinic Acid Dehydratase Deficient Porphyria ALA dehydratase deficient porphyria (ADP ) is sometimes termed Doss porphyria after the investigator who described the first cases. The term plumboporphyria emphasizes the similarity of this condition to lead poisoning, but incorrectly implies that it is caused by lead exposure.

Etiology This porphyria results from a deficiency of ALA dehydratase (ALAD), which is inherited as an autosomal recessive trait. Only six cases have been confirmed by mutation analysis. The prevalence of heterozygous ALAD deficiency was estimated to be 50 yr old, should be screened at least yearly by ultrasound or an alternative imaging method. The risk of chronic hypertension and impaired renal function is increased in these patients, most often with evidence of interstitial nephritis. A nephrotoxic effect of ALA may contribute. This may progress to severe renal failure and require renal transplantation. Patients with recurrent attacks may develop chronic neuropathic pain , although this has not been well characterized. Referral to a neurologist is recommended for any patient with ongoing or residual neurologic symptoms. In addition, depression and anxiety are common in these patients.

Treatment Hemin Intravenous (IV) hemin is the treatment of choice for most acute attacks of porphyria. There is a favorable biochemical and clinical response to early treatment with hemin, but less rapid clinical improvement if treatment is delayed. It is no longer recommended that therapy with hemin for a severe attack be started only after an unsuccessful trial of IV glucose for several days. Mild attacks without severe manifestations, such as paresis, seizures, hyponatremia, or pain requiring opioids, may be treated with IV glucose. After IV administration, hemin binds to hemopexin and albumin in plasma and is taken up primarily in hepatocytes, where it augments the regulatory heme pool in hepatocytes, represses the synthesis of hepatic ALAS1, and dramatically reduces porphyrin precursor overproduction. Hemin* is available for IV administration in the United States as lyophilized hematin (Panhematin, Recordati). Degradation products begin to form as soon as the lyophilized product is reconstituted with sterile water, and these are responsible for phlebitis at the site of infusion and a transient anticoagulant effect. Loss of venous access due to phlebitis is common after repeated administration. Stabilization of lyophilized hematin by reconstitution with 30% human albumin can prevent these adverse effects; this is recommended especially if a peripheral vein is used for the infusion. Uncommon side effects of hemin include fever, aching, malaise, hemolysis, anaphylaxis, and circulatory collapse. Heme arginate, a more stable hemin preparation, is available in Europe and South Africa. Hemin treatment should be instituted only after a diagnosis of acute porphyria has been initially confirmed by a marked increase in urinary PBG. When prior documentation of the diagnosis is available for review, it is not essential to confirm an increase in PBG with every recurrent attack, if other causes of the symptoms are excluded clinically. The standard regimen of hemin for treatment of acute porphyric attacks is 3-4 mg/kg/day for 4 days. Lower doses have less effect on porphyrin precursor excretion and probably less clinical benefit.

General and Supportive Measures Drugs that may exacerbate porphyrias (see Table 110.3 ) should be discontinued whenever possible, and other precipitating factors identified. Hospitalization is warranted, except for mild attacks; for treatment of severe pain, nausea, and

vomiting; for administration of hemin and fluids; and for monitoring vital capacity, nutritional status, neurologic function, and electrolytes. Pain usually requires an opioid; there is low risk for addiction after recovery from the acute attack. Ondansetron or a phenothiazine such as chlorpromazine is needed for nausea, vomiting, anxiety, and restlessness. Low doses of short-acting benzodiazepines can be given for restlessness or insomnia. β-Adrenergic blocking agents may be useful during acute attacks to control tachycardia and hypertension but may be hazardous in patients with hypovolemia and incipient cardiac failure.

Carbohydrate Loading The effects of carbohydrates on repressing hepatic ALAS1 and reducing porphyrin precursor excretion are weak compared to those of hemin. Therefore, carbohydrate loading is seldom beneficial except in mild attacks. Glucose polymer solutions by mouth are sometimes tolerated. At least 300 g of IV glucose, usually given as a 10% solution, has been recommended for adults hospitalized with attacks of porphyria. Amounts up to 500 g daily may be more effective, but large volumes may favor development of hyponatremia.

Other Therapies Liver transplantation was effective in several patients with severe AIP. A group from the United Kingdom reported their experience with liver transplantation in 10 AIP patients with significantly impaired quality of life and recurrent attacks refractory to medical management. Patients had a complete biochemical and symptomatic resolution after transplantation; 2 patients succumbed to multiorgan failure. Liver transplantation was also successful in a U.S. patient with AIP and intractable symptoms who became unresponsive to hemin therapy; liver transplantation normalized porphyrin precursor excretion, and symptoms resolved. However, liver transplantation is a high-risk procedure and should be considered only as a last resort. Hepatocyte-targeted RNA interference (RNAi ) therapy is being developed to reverse directly the extremely elevated hepatic ALAS1 mRNA in this disease. Preliminary results from clinical trials are promising.

Seizures and Other Complications Seizures caused by hyponatremia or other electrolyte imbalances may not

require prolonged treatment with anticonvulsant drugs, most of which have at least some potential for exacerbating acute porphyrias. Bromides, gabapentin, and probably vigabatrin are safe. Clonazepam may be less harmful than phenytoin or barbiturates. Control of hypertension is important and may help prevent chronic renal impairment, which can progress and require renal transplantation.

Safe and Unsafe Drugs Patients often do well with avoidance of harmful drugs. Table 110.3 lists some drugs known or strongly suspected to be harmful or safe in the acute porphyrias. More extensive listings are available from the European Porphyria Network (www.porphyria-europe.com ) and American Porphyria Foundation (www.porphyriafoundation.com ), but some listings are controversial. Information regarding safety is lacking for many drugs, especially for those recently introduced. Exogenous progestins, usually in combination with estrogens, can induce attacks of porphyria. Estrogens are seldom reported to be harmful when given alone. Synthetic steroids with an ethynyl substituent can cause a mechanismbased destruction of hepatic CYPs and should probably be avoided in patients with acute porphyria. Danazol is especially contraindicated.

Other Situations Major surgery can be carried out safely in patients with acute porphyria, especially if barbiturates are avoided. Halothane has been recommended as an inhalation agent and propofol and midazolam as IV induction agents. Pregnancy is usually well tolerated, which is surprising, because levels of progesterone, a potent inducer of hepatic ALAS1, are considerably increased during pregnancy. Some women do experience continuing attacks during pregnancy. This has sometimes been attributed to reduced caloric intake or metoclopramide, a drug sometimes used to treat hyperemesis gravidarum and considered harmful in acute porphyrias. Diabetes mellitus and other endocrine conditions are not known to precipitate attacks of porphyria. In fact, the onset of diabetes mellitus and resulting high circulating glucose levels may decrease the frequency of attacks and lower porphyrin precursor levels in AIP.

Prognosis The outlook for patients with acute porphyrias has improved greatly in the past several decades. In Finland, for example, 74% of patients with AIP or VP reported that they led normal lives, and C splice variant is common in whites and Japanese but rare in Africans, which explains lower disease prevalence in populations of African origin.

Pathology and Pathogenesis FECH is deficient in all tissues in EPP, but bone marrow reticulocytes are thought to be the primary source of the excess protoporphyrin, some of which enters plasma and circulates to the skin. Circulating erythrocytes are no longer synthesizing heme and hemoglobin, but they contain excess free protoporphyrin, which also contributes. In XLP caused by terminal deletions in exon 11 of ALAS2 , all intermediates of the heme pathway are overproduced and ultimately accumulate in bone marrow erythroblasts as protoporphyrin. FECH is not deficient in XLP, so this enzyme chelates some of the excess protoporphyrin with zinc. An aberrantly spliced mitoferrin transcript, which limits iron transport into mitochondria, has also been described in XLP. The liver functions as an excretory organ rather than a major source for excess protoporphyrin. FECH deficiency in the skin and liver may be important, however, because tissue transplantation studies in mice suggest that skin photosensitivity and liver damage occur only when FECH is deficient in these tissues. Patients with EPP and XLP are maximally sensitive to light in the 400 nm range, which corresponds to the so-called Soret band, the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins. Having absorbed light, porphyrins enter an excited energy state and release energy as fluorescence, singlet oxygen, and other ROS. Resulting tissue damage is accompanied by lipid peroxidation, oxidation of amino acids, cross linking of proteins in cell membranes, and damage to capillary endothelial cells. Such damage may be mediated by photoactivation of the complement system and release of histamine, kinins, and chemotactic factors. Repeated acute damage leads to thickening of the vessel walls and perivascular deposits from

accumulation of serum components. Deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, acid glycosaminoglycans, and lipids occurs around blood vessels in the upper dermis. There is little evidence for impaired erythropoiesis or hemolysis in EPP. However, mild anemia with microcytosis, hypochromia, and reticulocytosis is common. Iron accumulation in erythroblasts and ring sideroblasts has been noted in bone marrow in some patients. Decreased transferrin saturation and low or low-normal serum ferritin suggest iron deficiency. Iron status should be carefully evaluated in EPP patients, keeping in mind that iron deficiency may lead to further increases in protoporphyrin and increase the risk for cholestasis. Poor response to oral iron supplements is described in EPP and is unexplained. Some patients report increased photosensitivity when given iron supplements, but whether this is from transient increases in porphyrins when iron deficiency is corrected and erythropoiesis increases is not known. Case reports suggest that iron supplementation decreases protoporphyrin and improves anemia, especially in patients with XLP. Liver damage develops in a small proportion of EPP and XLP patients and is attributed to excess protoporphyrin, which is insoluble in water and excreted only by hepatic uptake, and biliary excretion is cholestatic. Some may be reabsorbed by the intestine and undergo enterohepatic circulation. With cholestasis the excess protoporphyrin that accumulates in the liver can form crystalline structures in hepatocytes and impair mitochondrial function.

Clinical Manifestations Symptoms of cutaneous photosensitivity begin in childhood and consist of acute pain and itching often occurring within minutes of sunlight exposure and followed by redness and swelling with continued exposure (Fig. 110.7 ). Petechiae and purpuric lesions may be seen, but blisters are rare. Swelling may resemble angioneurotic edema and solar urticaria. Symptoms are usually worse in the spring and summer. Chronic changes may include lichenification, leathery pseudovesicles, labial grooving, and nail changes, but changes in pigmentation and pronounced scarring are unusual. Although physical findings in EPP and XLP may not be impressive, the symptoms significantly impair quality of life to a greater extent than in PCT or VP. An association between EPP caused by mutations affecting both FECH alleles and seasonal palmar keratoderma is unexplained. Neuropathy develops only in some patients with severe hepatic

decompensation. XLP males have a more severe phenotype with higher protoporphyrin levels than most EPP patients. XLP females have a variable clinical presentation—some with no symptoms or mild symptoms and others with severe symptoms similar to XLP males. This variability in females is likely the result of random X-chromosome inactivation.

FIG. 110.7 Erythropoietic protoporphyria (EPP). A, Linear erosions of the lateral nasal bridge and lower lip in a patient with EPP. B, Erosions with crusting on the left helix of a patient with EPP. (From Horner ME, Alikhan A, Tintle S, et al: Cutaneous porphyrias. Part 1. epidemiology, pathogenesis, presentation, diagnosis, and histopathology, Int J Dermatol 52:1464–1480, 2013, Figs 7 and 8, p 1473.)

Unless hepatic or other complications develop, protoporphyrin levels and symptoms of photosensitivity remain remarkably stable for many years in most patients. Factors that exacerbate hepatic porphyrias play little or no role in EPP or XLP. Erythrocyte protoporphyrin levels may decrease and sunlight tolerance may improve during pregnancy, which is unexplained.

Laboratory Findings Protoporphyrin is substantially increased in circulating erythrocytes in EPP and consists almost entirely of free protoporphyrin. In XLP, both zinc protoporphyrin and free protoporphyrin are increased, although the latter still predominates. Protoporphyrin is also increased in bone marrow, plasma, bile, and feces. Other porphyrins and porphyrin precursors are normal in uncomplicated EPP and XLP.

Diagnosis and Differential Diagnosis A diagnosis of EPP is confirmed biochemically by finding a substantially elevated concentration of total erythrocyte protoporphyrin, which is predominantly (at least 85%) metal free and not complexed with zinc. In XLP, both free and zinc-complexed protoporphyrins are elevated. Erythrocyte total protoporphyrin levels are on average higher in XLP and more variable between individuals with EPP, possible reflecting differences in severity of the many reported FECH mutations. Erythrocyte zinc protoporphyrin concentration is increased with little increase in metal-free protoporphyrin in homozygous porphyrias (except CEP), iron deficiency, lead poisoning, anemia of chronic disease, hemolytic conditions, and many other erythrocytic disorders. Measurement of FECH activity requires cells containing mitochondria and is not widely available. Plasma total porphyrin concentration is often less increased in EPP than in other cutaneous porphyrias and may be normal. Great care must be taken to avoid light exposure during sample processing, because plasma porphyrins in EPP are particularly subject to photodegradation. Urinary porphyrin precursors and porphyrins are not increased. DNA studies are strongly recommended for confirming FECH or ALAS2 mutations and for genetic counseling. Life-threatening protoporphyric hepatopathy is characterized by greater increases in erythrocyte and plasma protoporphyrin levels, increased photosensitivity and either chronically abnormal liver function tests or rapidly progressive hepatic failure. Presumably this is heralded by increases above the patient's baseline erythrocyte and plasma porphyrin levels, but this has not been documented, because most such patients have not had adequate baseline determinations of porphyrin values. Increases in urinary porphyrins, especially coproporphyrin, in this setting are attributable to liver dysfunction.

Complications There is an increased risk of biliary stones, which contain protoporphyrin and are sometimes symptomatic, requiring cholecystectomy. Protoporphyric hepatopathy occurs in C hypoexpression allele, but some may have 2 severe mutant FECH alleles or XLP caused by ALAS2 exon 11 deletions. The bone marrow is probably the major source of protoporphyrin, even in EPP patients with hepatic failure.

Treatment Exposure to sunlight should be avoided, which is aided by wearing closely woven clothing. A systematic review of treatment options, including betacarotene, oral cysteine, and vitamin C, showed no proven efficacy of these treatments. One report suggested that high doses of cimetidine were effective in reducing symptoms in 3 children with EPP, but no objective clinical evidence of efficacy was presented. Measures to darken the skin may also be helpful. This may be accomplished by narrow-band UV-B phototherapy. Double-blind, placebo-controlled studies in the United States and Europe of afamelanotide , a synthetic analog of melanocyte-stimulating hormone, showed an increase in pain-free sun exposure and improved quality of life in patients with protoporphyria. This drug is approved for adult use in Europe and is pending U.S. Food and Drug Administration (FDA) approval, and studies in children are anticipated. Drugs or hormone preparations that impair hepatic excretory function should be avoided, particularly in patients with liver dysfunction, and iron deficiency should be corrected if present, especially in XLP. Vitamin D supplementation and hepatitis A and B vaccination are recommended. Treatment of protoporphyric hepatopathy must be individualized, and results are unpredictable. Ursodeoxycholic acid may be of some value in early stages. Cholestyramine or activated charcoal may interrupt the enterohepatic circulation of protoporphyrin, promote its fecal excretion, and reduce liver protoporphyrin content. Spontaneous resolution may occur, especially if another reversible cause

of liver dysfunction, such as viral hepatitis or alcohol abuse, is contributing. In patients with severe hepatic decompensation, combined treatment with plasmapheresis, transfusion to correct anemia and suppress erythropoiesis, IV hemin to suppress erythroid and possibly hepatic protoporphyrin production, ursodeoxycholic acid, vitamin E, and cholestyramine may be beneficial and bridge patients to liver transplantation. Motor neuropathy resembling that seen in acute porphyrias sometimes develops in protoporphyria patients with liver disease before or after transfusion or liver transplantation and is sometimes reversible. Artificial lights, such as operating room lights during liver transplantation or other surgery, may cause severe photosensitivity, with extensive burns of the skin and peritoneum and damage to circulating erythrocytes. Although liver disease may recur in the transplanted liver as a result of continued bone marrow production of excess protoporphyrin, outcomes are comparable to transplantation for other types of liver disease. Bone marrow transplantation should also be considered after liver transplantation if a suitable donor is available.

Prognosis Typical EPP patients have lifelong photosensitivity but can otherwise expect normal longevity. Protoporphyric liver disease is often life-threatening; however, the incidence is low.

Prevention and Genetic Counseling Symptoms can be prevented by avoiding sunlight. Avoiding agents that may cause liver damage may help prevent liver complications. Opinions vary on the value of iron replacement, and this is currently under study. DNA studies to identify FECH mutations, the common IVS3–48T>C FECH hypoexpression allele, or ALAS2 exon 11 deletions are important for genetic counseling. When EPP is caused by a severe FECH mutation and the common IVS3–48T>C FECH allele, DNA studies in the spouse to determine the presence, or more likely the absence, of the hypoexpression allele can predict whether offspring are at risk for EPP. EPP may improve during pregnancy.

Dual Porphyria An unusual pattern of porphyrin precursors and porphyrins may suggest mutations of 2 heme pathway enzymes, as documented in 2 patients. One presented with acute porphyria and had heterozygous mutations of both CPOX and ALAD . The other had symptoms of AIP and PCT and was reported to have both HMBS and UROD mutations. In other reported cases, 1 or both enzyme deficiencies were based on enzyme measurements.

Porphyria Resulting From Tumors Very rarely, hepatocellular tumors contain and presumably produce excess porphyrins, but such cases have not been studied carefully. Hepatocellular carcinomas complicating PCT and acute hepatic porphyrias usually are not described as containing large amounts of porphyrins. Erythropoietic porphyrias can develop late in life from clonal expansion of erythroid cells containing a specific enzyme deficiency in patients who have developed myelodysplastic or myeloproliferative syndromes.

Bibliography Bonkovsky HL, Guo JT, Hou W, et al. Porphyrin and heme metabolism and the porphyrias. Compr Physiol . 2013;3(1):365–401. Phillips JD, Anderson KE. The porphyrias. Kaushansky K, Lichtman MA, Beutler E, et al. Williams hematology . ed 9. McGraw-Hill: New York; 2016:889–914.

Acute Porphyrias Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med . 2005;142(6):439–450. Besur S, Schmeltzer P, Bonkovsky HL. Acute porphyrias. J Emerg Med . 2015;49(3):305–312.

Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med . 2017;377(9):862–872. Horner ME, Alikhan A, Tintle S, et al. Cutaneous porphyrias. Part 1. Epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol . 2013;52:1464–1480. Singal AK, Parker C, Bowden C, et al. Liver transplantation in the management of porphyria. Hepatology . 2014;60(3):1082–1089. Stein P, Badminton M, Barth J, et al. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem . 2013;50(Pt 3):217–223.

Congenital Erythropoietic Porphyria Katugampola RP, Anstey AV, Finlay AY, et al. A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases. Br J Dermatol . 2012;167(4):888– 900.

Porphyria Cutanea Tarda Singal AK, Kormos-Hallberg C, Lee C, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol . 2012;10(12):1402–1409. Thawani RJ, Moghe A, Idhate T, et al. Porphyria cutanea tarda in a child with acute lymphoblastic leukemia. Q J Med . 2016;109(3):191–192.

Erythropoietic Protoporphyria and X-Linked Protoporphyria Balwani M, Doheny D, Bishop DF, et al. Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-

aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med . 2013;19:26–35. Gou E, Balwani M, Bissell DM, et al. Pitfalls in erythrocyte protoporphyrin measurement for diagnosis and monitoring of protoporphyrias. Clin Chem . 2015;61(12):1453–1456. Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med . 2015;373(1):48–59. Minder EI, Schneider-Yin X, Steurer J, et al. A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria. Cell Mol Biol (Noisy-LeGrand) . 2009;55:84–97. Whatley SD, Mason NG, Holme SA, et al. Molecular epidemiology of erythropoietic protoporphyria in the UK. Br J Dermatol . 2010;162(3):642–646. * Hemin is the generic name for all heme preparations used for intravenous

administration. Hemin is also a chemical term that refers to the oxidized (ferric) form of heme (iron protoporphyrin IX) and is usually isolated as hemin chloride. In alkaline solution, the chloride is replaced by the hydroxyl ion, forming hydroxyheme, or hematin.

C H A P T E R 111

Hypoglycemia Mark A. Sperling

Glucose has a central role in fuel economy and is a source of energy storage in the form of glycogen, fat, and protein (see Chapter 105 ). As an immediate source of energy, glucose provides 38 mol of adenosine triphosphate (ATP) per mole of glucose oxidized. Glucose is essential for energy metabolism in the brain, where it is usually the preferred substrate and where its utilization accounts for nearly all the brain's oxygen consumption. Cerebral transport of glucose is a GLUT-1, carrier-mediated, facilitated diffusion process that is dependent on blood glucose concentration and not regulated by insulin. Therefore, low concentrations of blood glucose result in cerebral glucopenia. Deficiency of brain glucose transporters can result in seizures because of low cerebral and cerebrospinal fluid (CSF) glucose concentrations (hypoglycorrhachia) despite normal blood glucose levels. To maintain the blood glucose concentration and prevent it from falling precipitously to levels that impair brain function, an elaborate regulatory system has evolved. The defense against hypoglycemia includes the autonomic nervous system and hormones that act in concert to enhance glucose production through enzymatic modulation of glycogenolysis and gluconeogenesis, while simultaneously limiting peripheral glucose utilization, which conserves glucose for cerebral metabolism. Hypoglycemia represents a defect in one or several of the complex interactions that normally integrate glucose homeostasis during feeding and fasting. This process is particularly important for neonates, in whom there is an abrupt transition from intrauterine life, characterized by dependence on transplacental glucose supply, to extrauterine life, characterized ultimately by the autonomous ability to maintain euglycemia. Because prematurity or placental insufficiency may limit tissue nutrient deposits, and genetic abnormalities in enzymes or hormones may become evident in the neonate, hypoglycemia is

common in the neonatal period.

Definition In neonates, there is not always an obvious correlation between blood glucose concentration and the classic clinical manifestations of hypoglycemia. The absence of symptoms does not indicate that glucose concentration is normal and has not fallen to less than some optimal level for maintaining brain metabolism. There is evidence that hypoxemia and ischemia may potentiate the role of hypoglycemia in causing permanent brain sequelae. Consequently, the lower limit of accepted normality of the blood glucose level in newborn infants with associated illness that already impairs cerebral metabolism has not been determined (see Chapter 127 ). Because of concern for possible neurologic, intellectual, or psychologic sequelae in later life, most authorities recommend that any value of blood glucose 0.4; plasma insulin-like growth factor binding protein-1 (IGFBP-1), β-hydroxybutyrate, and FFA levels are low with hyperinsulinism. Rare instances of activating mutations in the insulin receptor signaling pathway have been reported where the clinical and biochemical features are similar to states of excessive insulin secretion, yet insulin concentrations are low to the point of being undetectable. Therefore, the preferred term is hyperinsulinism , to describe a state of increased insulin action. Macrosomic infants may present with hypoglycemia from the 1st days of life. Infants with lesser degrees of hyperinsulinism may manifest hypoglycemia only after the 1st few wk to mo, when the frequency of feedings has been decreased to permit the infant to sleep through the night, and hyperinsulinism prevents the mobilization of endogenous glucose. Increasing appetite and demands for feeding, wilting spells, jitteriness, and frank seizures are the most common presenting features. Additional clues include the rapid development of fasting hypoglycemia within 4-8 hr of food deprivation, compared with other causes of hypoglycemia (Tables 111.3 and 111.4 ); the need for high rates of exogenous glucose infusion to prevent hypoglycemia, often at rates >10-15 mg/kg/min; the absence of ketonemia or acidosis; and elevated C-peptide or proinsulin levels at the time of hypoglycemia. The latter insulin-related products are absent in factitious hypoglycemia from exogenous administration of insulin as a form of child abuse (see Chapter 16.2 ). Hypoglycemia is invariably provoked by withholding feedings for several hours, permitting simultaneous measurement of glucose, insulin, ketones, and FFAs in the same sample at the time of clinically manifested hypoglycemia. This is termed the critical sample. The glycemic response to glucagon at the time of hypoglycemia reveals a brisk increment in glucose concentration of at least 40 mg/dL, which implies that glucose mobilization has been restrained by insulin but that glycogenolytic mechanisms are intact (Tables 111.5 to 111.7 ). Table 111.3

Hypoglycemia in Infants and Children: Clinical and Laboratory Features AGE AT DIAGNOSIS (mo) Hyperinsulinemia (N = 12) Mean 7.4 SEM 2.0 Nonhyperinsulinemia (N = 16) Mean 41.8 SEM 7.3 GROUP

GLUCOSE* (mg/dL)

INSULIN (µU/mL)

FASTING TIME TO HYPOGLYCEMIA (hr)

23.1 2.7

22.4 3.2

2.1 † 0.6

36.1 2.4

5.8 0.9

18.2 2.9

* In hypoglycemia caused by hyperinsulinism β-hydroxybutyrate and free fatty acids are low

compared with normal at same duration of fasting. † Milder forms of hyperinsulinism may require up to 18 hr of fasting to provoke hypoglycemia.

SEM, Standard error of mean. Adapted from Antunes JD, Geffner ME, Lippe BM, et al: Childhood hypoglycemia: differentiating hyperinsulinemic from nonhyperinsulinemic causes, J Pediatr 116:105–108, 1990.

Table 111.4

Correlation of Clinical Features With Molecular Defects in Persistent Hyperinsulinemic Hypoglycemia in Infancy

TYPE

MACROSOMIA HYPOGLYCEMIA/HYPERINSULINEMIA

FAMILY MOLECULAR HISTORY DEFECTS

Sporadic

Present at birth

Negative

Moderate/severe in 1st days to weeks of life

? SUR1 /KIR 6.2 mutations not always identified in diffuse hyperplasia

SUR /KIR 6.2

Autosomal recessive

Present at birth

Severe in 1st days to weeks of life

Positive

Autosomal dominant

Unusual

Moderate onset usually >6 mo of age

Positive

Glucokinase (activating) Some cases gene unknown

Autosomal dominant

Unusual

Moderate onset usually >6 mo of age

Positive

BeckwithWiedemann syndrome

Present at birth

Moderate, spontaneously resolves >6 mo of age

Negative

Glutamate dehydrogenase (activating) Duplicating/imprinting in chromosome 11p15.1

Moderate/onset >3 mo of age

Negative

Congenital Not usual disorders of glycosylation

Phosphomannose isomerase deficiency

Table 111.5

Analysis of Critical Blood Sample During Hypoglycemia and 30 Min After Glucagon* Substrates Glucose Free fatty acids Ketones Lactate Uric acid Ammonia

Hormones Insulin Cortisol

Growth hormone Thyroxine, thyroid-stimulating hormone Insulin-like growth factor binding protein-1 †

* Glucagon 0.5 mg with maximum of 1 mg IV or IM. † Measure once only before or after glucagon administration. Rise in glucose of

≥40 mg/dL after glucagon given at the time of hypoglycemia strongly suggests a hyperinsulinemic state with adequate hepatic glycogen stores and intact glycogenolytic enzymes. If ammonia is elevated to 100-200 µM, consider activating mutation of glutamate dehydrogenase.

Table 111.6

Criteria for Diagnosing Hyperinsulinism Based on “Critical” Samples (Drawn at a Time of Fasting Hypoglycemia: Plasma Glucose 2 µU/mL)* 2. Hypofatty acidemia (plasma free fatty acids 5 µU/mL, suspect endogenous hyperinsulinemia; if >100 µU/mL, suspect factitious hyperinsulinemia (exogenous insulin injection). Admit to hospital for supervised fast. 6. If cortisol is 60 breaths/min during periods of regular breathing that persists for >1 hr after birth is an indication to rule out pulmonary, cardiac, or metabolic disease (acidosis) etiologies. Preterm infants

may breathe with a Cheyne-Stokes rhythm, known as periodic respiration , or with complete irregularity. Irregular gasping, sometimes accompanied by spasmodic movements of the mouth and chin, strongly indicates serious impairment of the respiratory centers. The breathing of newborn infants at rest is almost entirely diaphragmatic, so during inspiration, the soft front of the thorax is usually drawn inward while the abdomen protrudes. If the baby is quiet, relaxed, and with good color, this “paradoxical movement” does not necessarily signify insufficient ventilation. On the other hand, labored respiration with retractions is important evidence of respiratory distress syndrome, pneumonia, anomalies, or mechanical disturbance of the lungs. A weak, persistent or intermittent groaning, whining cry, or grunting during expiration can signify potentially serious cardiopulmonary disease or sepsis and warrants immediate attention. When benign, the grunting resolves 30-60 min after birth. Flaring of the alae nasi and retraction of the intercostal muscles and sternum are common signs of pulmonary pathology. Normally, the breath sounds are bronchovesicular. Suspicion of pulmonary pathology because of diminished breath sounds, rhonchi, retractions, or cyanosis should always be verified with a chest radiograph.

Heart Normal variation in the size and shape of the chest makes it difficult to estimate the size of the heart. The location of the heart should be determined to detect dextrocardia . The pulse is usually 110-140 beats/min at rest but may vary normally from 90 beats/min in relaxed sleep to 180 beats/min during activity. The still higher rate of supraventricular tachycardia (>220 beats/min) may be determined better with a cardiac monitor or electrocardiogram (ECG) than by auscultation. Preterm infants usually have a higher resting heart rate, up to about 160 beats/min, but may have a sudden onset of sinus bradycardia secondary to apnea. On both admission to and discharge from the nursery, the infant's pulses should be palpated in the upper and lower extremities to detect coarctation of the aorta . Transitory murmurs usually represent a closing ductus arteriosus. Although congenital heart disease (CHD) may not initially produce a murmur, a substantial portion of infants in whom persistent murmurs are detected during routine neonatal examination have underlying malformation. Routine screening for critical CHD using pulse oximetry is performed between 24 and 48 hr of life, which overall yields a sensitivity approaching 80% and specificity >99%. Pulse

oximetry screening with SO 2 of ≥95% in the right hand or either foot and 15% cigarette use. Multiple drug use is also common. For mothers desiring to breastfeed with a history of current or past illegal drug abuse or legal drug use or abuse, healthcare providers must carefully and thoughtfully weigh the documented benefits of human milk and breastfeeding against the risks associated with the substance that the infant may be exposed to during lactation. Most illicit drugs are found in human milk with varying degrees of oral bioavailability, and breastfeeding is generally contraindicated (Table 113.6 ). However, mothers with substance use disorders should be encouraged to breastfeed under the following circumstances: established engagement in substance abuse treatment (e.g., methadone or buprenorphine maintenance therapy) that includes counseling and social support; abstinence from drug use for 90 days before delivery, with maternal urine toxicology testing at delivery negative other than prescribed substances, ability to maintain sobriety demonstrated in an outpatient setting, and engagement and compliance with care.

Table 113.6

Drugs of Abuse and Adverse Infant Effects CONTRAINDICATED Amphetamines Antineoplastic agents Bromocriptine Chloramphenicol Clozapine Cocaine Cyclophosphamide Doxorubicin Ecstasy (MDMA) Ergots Gold salts Heroin Immunosuppressants Methamphetamine Phencyclidine (PCP) Radiopharmaceuticals Thiouracil USE WITH CAUTION Alcohol Amiodarone Anthraquinones (laxatives) Aspirin (salicylates) Atropine β-Adrenergic blocking agents Benzodiazepines Birth control pills Bromides Cascara Codeine Dicumarol Dihydrotachysterol Domperidone Estrogens Hydrocodone Lithium Marijuana Metoclopramide Meperidine Oxycodone Phenobarbital* Primidone Reserpine Salicylazosulfapyridine (sulfasalazine) * Watch for sedation.

Contraindications to Breastfeeding

Medical contraindications to breastfeeding in the United States include infants with galactosemia, maple syrup urine disease, and phenylketonuria. Maternal conditions that contraindicate breastfeeding include infection with human T-cell lymphotropic virus types 1 and 2, active tuberculosis (until appropriately treated ≥2 wk and not considered contagious), herpesvirus infection on breast, use of or dependence on certain illicit drugs, and maternal treatment with some radioactive compounds (Table 113.7 ). Because clean water and affordable replacement feeding are available in the United States, it is recommended that HIV-infected mothers not breastfeed their infants regardless of maternal viral load and antiretroviral therapy. However, in resource-limited countries where diarrhea and pneumonia are significant causes of infant and child mortality, breastfeeding may not be contraindicated for HIV-positive mothers receiving antiretroviral therapy. Donor human milk, particularly that purchased online, may be contaminated with potential pathogens. Contamination is much less of a concern with pasteurized human milk obtained from a milk bank. Table 113.7

Summary of Infectious Agents Detected in Milk and Newborn Disease INFECTIOUS AGENT

BREAST MILK DETECTED REPORTED AS CAUSE IN BREAST OF NEWBORN MILK? DISEASE?

MATERNAL INFECTION CONTRAINDICATION TO BREASTFEEDING?

BACTERIA Mastitis/Staphylococcus aureus

Yes

No

No, unless breast abscess present

Mycobacterium tuberculosis : Active disease

Yes

No

No

No

Yes, because of aerosol spread, or tuberculosis mastitis No

Yes, stored

Yes, stored

—

Yes Yes Yes No

Yes Yes Yes No

No* No* No* No †

Yes

Yes

Yes, developed countries

Yes

Yes

No

Purified protein derivative skin test result positive, chest radiograph findings negative Escherichia coli , other gramnegative rods Group B streptococci Listeria monocytogenes Coxiella burnetii Syphilis VIRUSES HIV Cytomegalovirus: Term infant

Preterm infant Hepatitis B virus Hepatitis C virus Hepatitis E virus Human T-cell leukemia virus (HTLV)-1 HTLV-2 Herpes simplex virus Rubella Wild type Vaccine Varicella-zoster virus Epstein-Barr virus Human herpesvirus (HHV)-6 HHV-7 West Nile virus Zika virus PARASITES Toxoplasma gondii

Yes Yes, surface antigen Yes Yes Yes

Yes No

Evaluate on an individual basis No, developed countries ‡

No No Yes

No § No Yes, developed countries

Yes Yes

Uncertain Yes

Yes, developed countries No, unless breast vesicles present

Yes Yes Yes Yes No Yes Possible Yes

Yes, rare No No No No No Possible No

No No No, cover active lesions ¶ No No No Unknown No

Yes

Yes, 1 case

No

* Provided that the mother and child are taking appropriate antibiotics. †

Treat mother and child if active disease.

‡ Immunize and immune globulin at birth. § Provided that the mother is HIV seronegative. Mothers should be counseled that breast milk

transmission of hepatitis C virus has not been documented, but is theoretically possible. ¶ Provide appropriate antivaricella therapy or prophylaxis to newborn.

Adapted from Jones CA: Maternal transmission of infectious pathogens in breast milk, J Paediatr Child Health 37:576–582, 2001.

Bibliography American Academy of Pediatrics, Committee on Pediatric AIDS. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics . 2013;131:391–396. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics . 2012;129:e827–e841. Becker GE, Remmington S, Remmington T. Early additional food and fluids for healthy breastfed full-term infants.

Cochrane Database Syst Rev . 2011;(12) [CD006462]. Keim SA, Hogan JS, McNamara KA, et al. Microbial contamination of human milk purchased via the internet. Pediatrics . 2013;132:e1227–e1235. Kennell JH, Klaus MH. Bonding: recent observations that alter perinatal care. Pediatr Rev . 1998;19:4–12. Neu J, Sullivan S. Baby and breast: a dynamic interaction. Pediatr Res . 2012;71:135. Perrine CG, Galuska DA, Dohack JL, et al. Vital signs: improvements in maternity care policies and practices that support breastfeeding—United States, 2007–2013. MMWR Morb Mortal Wkly Rep . 2015;64:1112–1117. Reece-Stremtan S, Marinelli K. ABM clinical protocol #21: guidelines for breastfeeding and substance use or substance use disorder, revised 2015. Breastfeed Med . 2015;10(3):135– 141. Sachs HC, American Academy of Pediatrics Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics . 2013;132:e796–e809. World Health Organization, United Nations Children's Fund. Updates on HIV and infant feeding: the duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV . WHO: Geneva; 2016.

C H A P T E R 11 4

High-Risk Pregnancies Kristen R. Suhrie, Sammy M. Tabbah

The care of high-risk pregnancies should be coordinated with an experienced maternal-fetal medicine specialist. In general, high-risk pregnancies are those that increase the likelihood of maternal complications, miscarriage, fetal death, preterm delivery, intrauterine growth restriction (IUGR), poor cardiopulmonary or metabolic transitioning at birth, fetal or neonatal disease, congenital malformations, or intellectual impairment and other handicaps (Table 114.1 ).There is no accepted comprehensive definition of what constitutes a high-risk pregnancy , therefore, specific epidemiologic data regarding the incidence/prevalence cannot be reliably reported. Some factors, such as ingestion of a teratogenic drug in the first trimester, are causally related to the risk, while others, such as polyhydramnios, are associations that alert a physician to determine the etiology and avoid the inherent risks associated with excessive amniotic fluid. Although assessing antepartum risk is important in reducing perinatal mortality and morbidity, some pregnancies become high risk only during labor and delivery; therefore careful monitoring is critical throughout the intrapartum course. Table 114.1

Factors Associated With High-Risk Pregnancy ECONOMIC Poverty Unemployment Uninsured, underinsured Poor access to prenatal care CULTURAL/BEHAVIORAL Low educational status Poor healthcare attitudes

No care or inadequate prenatal care Cigarette, alcohol, or illicit drug use Age 40 yr Unmarried Short interpregnancy interval (40 wk) Prolonged labor Previous infant with cerebral palsy, intellectual impairment, birth trauma, or congenital anomalies Abnormal lie (breech) Multiple gestations Premature rupture of membranes Infection (systemic, amniotic, extra-amniotic, cervical) Preeclampsia or eclampsia Uterine bleeding (abruptio placentae, placenta previa) Parity (0 or >5 previous deliveries) Uterine or cervical anomalies Fetal disease Abnormal fetal growth Idiopathic premature labor Iatrogenic prematurity High or low levels of maternal serum α-fetoprotein MEDICAL Diabetes mellitus Hypertension Congenital heart disease Autoimmune disease Sickle cell anemia Intercurrent surgery or trauma Sexually transmitted infection Maternal hypercoagulable states Exposure to prescription medications TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) infection

Identifying high-risk pregnancies is important not only because it is the first

step toward prevention but also because critical steps may often be taken to reduce the risks to the fetus or neonate if the physician is alerted to the specific condition early in pregnancy.

Genetic Factors The occurrence of chromosomal abnormalities, congenital anomalies, inborn errors of metabolism, cognitive delay, or any familial disease in blood relatives increases the risk of the same condition in the infant. Because many parents recognize only obvious clinical manifestations of genetically determined diseases, specific inquiry should be made about any disease affecting one or more blood relatives. A high index of suspicion should be maintained to the possibility of autosomal recessive disorders in offspring of couples who are closely related (i.e., consanguinity).

Maternal Factors The lowest neonatal mortality rate occurs in infants of mothers who receive adequate prenatal care and who are 20-30 yr of age. Pregnancies in both teenagers and women older than 40, particularly primiparous women, are at increased risk for IUGR, fetal distress, preeclampsia, and stillbirth. Advanced maternal age increases the risk of both chromosomal and nonchromosomal fetal malformations (Fig. 114.1 ).

FIG. 114.1 Natural birth prevalence of Down syndrome according to maternal age. (From Wald NJ, Leck I: Antenatal and neonatal screening, ed 2, Oxford, 2000, Oxford University Press.)

Maternal illness (Table 114.2 ), multiple pregnancies (particularly those involving monochorionic twins), infections (Table 114.3 ), and certain drugs (see Chapter 115.4 ) increase the risk for the fetus. The use of assisted reproductive technology (e.g., ovulation induction, in vitro fertilization, intracytoplasmic sperm injection) increases the risk of prematurity, perinatal mortality, infant morbidity, low and very-low birthweight, imprinting disorders, and cerebral palsy. These risks are largely because of the increase in multiple gestations with such technology and the association with prematurity . The risks for birth defects are also increased with assisted reproductive technology, in part because of epigenetic effects on gene expression. Table 114.2

Maternal Conditions Affecting the Fetus or Neonate DISORDER Assisted reproductive technology Autoantibody against folate receptors Cervical neoplasia

EFFECT(S) Beckwith-Wiedemann, Silver-Russel, Angelman syndromes Neural tube defects

MECHANISM(S) Altered imprinting

Preterm premature rupture of membranes, preterm birth

Associated with loop electrosurgical excision procedure or cone therapy

Blockage of cellular uptake of folate

Cholestasis

Preterm delivery, intrauterine fetal demise Cyanotic heart disease IUGR Diabetes mellitus: Mild LGA, hypoglycemia Severe Drug addiction Endemic goiter Graves' disease

Growth restriction IUGR, neonatal withdrawal Hypothyroidism Transient neonatal thyrotoxicosis

Herpes gestationis (noninfectious) Hyperparathyroidism

Bullous rash, intrauterine fetal demise

Hypertension Idiopathic thrombocytopenic purpura Isoimmune neutropenia or thrombocytopenia Malignant melanoma Myasthenia gravis

IUGR, intrauterine fetal demise Thrombocytopenia

Myotonic dystrophy

Neonatal myotonic dystrophy, congenital contractures, respiratory insufficiency Cortical dysplasia

NMDAR antibody encephalitis Obesity Phenylketonuria Poor nutrition

Neonatal hypocalcemia

Neutropenia or thrombocytopenia

Placental or fetal tumor Transient neonatal myasthenia

LGA or IUGR, hypoglycemia Microcephaly, retardation IUGR, adult insulin resistance

Preeclampsia, eclampsia Renal transplantation Rhesus or other blood group sensitization Sickle cell anemia

IUGR, thrombocytopenia, neutropenia, fetal demise IUGR Fetal anemia, hypoalbuminemia, hydrops, neonatal jaundice Preterm birth, IUGR, stillbirth

Systemic lupus erythematosus

Congenital heart block, rash, anemia, thrombocytopenia, neutropenia

Unknown, possibly bile acid–induced fetal arrhythmia Low fetal oxygen delivery Fetal hyperglycemia: produces hyperinsulinemia; insulin promotes growth Vascular disease, placental insufficiency Direct drug effect plus poor nutrition Iodine deficiency Transplacental passage of IgG thyroidstimulating antibody Autoantibody similar to that in bullous pemphigoid Maternal calcium crosses to fetus and suppresses fetal parathyroid gland Placental insufficiency, fetal hypoxia Nonspecific maternal platelet antibodies cross placenta Specific antifetus neutrophil or platelet antibody crosses placenta after sensitization of mother Placental metastasis IgG antibody to acetylcholine receptor crosses placenta Genetic anticipation

Transplacental antibody Unknown, similarities to diabetes Elevated fetal phenylalanine values Reduced fetal nutrients, nutritional programming Uteroplacental insufficiency, fetal hypoxia, vasoconstriction Uteroplacental insufficiency IgG crosses placenta and is directed to fetal cells with antigen Placental insufficiency via maternal sickling, producing fetal hypoxia Antibody directed to fetal heart, red and white blood cells, and platelets

IgG, Immunoglobulin G; LGA, large for gestational age; NMDAR, antibody to N -methyl-D aspartate receptor; IUGR, intrauterine growth restriction.

Table 114.3

Maternal Infections Affecting the Fetus or Newborn INFECTION

MODE(S) OF

NEONATAL OUTCOME

TRANSMISSION BACTERIA Group B streptococcus Escherichia coli Listeria monocytogenes Mycoplasma hominis Chlamydia trachomatis Syphilis Neisseria gonorrhoeae Mycobacterium tuberculosis VIRUS Rubella Cytomegalovirus HIV Hepatitis B Hepatitis C Herpes simplex type 2 or 1 Varicella-zoster

Parvovirus Coxsackievirus B Rubeola West Nile Zika Chikungunya Dengue PARASITES Toxoplasmosis Malaria FUNGI Candida

Ascending cervical

Sepsis, pneumonia

Ascending cervical Transplacental

Sepsis, pneumonia Sepsis, pneumonia

Ascending cervical

Pneumonia

Vaginal passage

Conjunctivitis, pneumonia

Transplacental, vaginal passage Vaginal passage

Congenital syphilis

Transplacental

Prematurity, fetal demise, congenital tuberculosis

Transplacental Transplacental, breast milk (rare) Transplacental, vaginal passage, breast milk Vaginal passage, transplacental, breast milk Transplacental and vaginal passage Intrapartum exposure

Congenital rubella Congenital cytomegalovirus or asymptomatic

Transplacental: Early Late Transplacental Fecal-oral Transplacental Transplacental (rare) Possible perinatal Transplacental Transplacental (rare), perinatal Transplacental, perinatal

Ophthalmia (conjunctivitis), sepsis, meningitis

Congenital or acquired immunodeficiency syndrome Neonatal hepatitis, chronic hepatitis B surface antigen carrier state Rarely neonatal hepatitis, ~5% chronic carrier state possible Neonatal herpes simplex virus Neonatal encephalitis; disseminated viremia, or cutaneous infection Congenital anomalies Neonatal varicella Fetal anemia, hydrops Myocarditis, meningitis, hepatitis Abortion, fetal measles Uncertain, possible rash, encephalitis Congenital microcephaly, intracranial calcifications, brain abnormalities, retinal lesions Neonatal encephalitis Neonatal sepsis-like symptoms

Transplacental Transplacental

Congenital toxoplasmosis Abortion, prematurity, intrauterine growth restriction

Ascending, cervical

Sepsis, pneumonia, rash

Preterm birth is common in high-risk pregnancies (see Chapter 117 ). Factors associated with prematurity (see Table 114.1 ) include multiple gestations as well as biologic markers such as cervical shortening, genital

infection, presence of fetal fibronectin in cervicovaginal secretions, serum αfetoprotein (AFP), and premature rupture of membranes (PROM). PROM occurs in 3% of all pregnancies in the United States and is a leading identifiable cause of prematurity. The presence of polyhydramnios or oligohydramnios indicates high-risk pregnancies. Amniotic fluid volume is variable throughout pregnancy and progressively increases from 10 to 30 wk of gestation. On average, volume is typically 24 cm suggests polyhydramnios, whereas an index 30

min after birth. Cesarean-born infants are also at increased risk for persistent pulmonary hypertension of the newborn . An elective cesarean birth should be delayed until ≥39 wk of gestation, assuming there is no indication for delivery earlier. Obstetric anesthesia is a vital component of care on the labor and delivery unit. The most common form of anesthesia in this patient population is regional (i.e., epidural or spinal). From the fetal/neonatal standpoint, the most significant complication encountered with this procedure is acute maternal hypotension, which can significantly impair uteroplacental perfusion. Fetal heart rate (FHR) abnormalities are common in this circumstance and, rarely, require emergent cesarean delivery if not amenable to standard in utero resuscitative efforts. Opioid analgesia is sometimes used in women who are not candidates for regional anesthesia. This form of pain relief is best avoided as delivery approaches, to minimize risk of neonatal depression. To this end, when opioid use is necessary, it is best to prescribe regimens that have a very short half-life. It is essential that the pediatric team is present at the birth in women receiving opioid analgesia. Furthermore, the pediatricians must be alerted to the specific type of opioid used, because all these drugs cross the placenta and have varying neonatal pharmacokinetics. Some of the common regimens used and their respective neonatal half-life are listed in the referenced American College of Obstetricians and Gynecologists (ACOG) practice bulletin on obstetric anesthesia.

Bibliography Abele H, Starz S, Hoopmann M, et al. Idiopathic polyhydramnios and postnatal abnormalities. Fetal Diagn Ther . 2012;32:251. American College of Obstetricians and Gynecologists. Obstetric analgesia and anesthesia, ACOG Practice Bulletin No 36. Obstet Gynecol . 2002;100:177–191. American College of Obstetricians and Gynecologists. Operative vaginal delivery, ACOG Practice Bulletin No 154. Obstet Gynecol . 2015;126:e56–e65. American College of Obstetricians and Gynecologists.

Management of preterm labor, ACOG Practice Bulletin No 171. Obstet Gynecol . 2016;128:e155–e164. American College of Obstetricians and Gynecologists. Premature rupture of membranes, ACOG Practice Bulletin No 172. Obstet Gynecol . 2016;128:e165–e177. Charlier C, Beaudoin MC, Couderc T, et al. Arbovirused and pregnancy: maternal, fetal, and neonatal effects. Lancet . 2017;1:134–146. Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med . 2012;366(19):1803–1812. De Fatima Vasco Aragao M, et al. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ . 2016;353:i1901. De Luca R, et al. Incidence of early neonatal mortality and morbidity after late-preterm and term cesarean delivery. Pediatrics . 2009;123(6):e1064–e1071. Delaney C, Cornfield DN. Risk factors for persistent pulmonary hypertension of the newborn. Pulm Circ . 2012;2(1):15–20. Dorleijn DM, Cohen-Overbeek TE, Groenendaal F, et al. Idiopathic polyhydramnios and postnatal findings. J Matern Fetal Neonatal Med . 2009;22:315. Ecker JL, Frigoletto FD Jr. Cesarean delivery and the riskbenefit calculus. N Engl J Med . 2007;356:885–888. Glavind J, et al. Neonatal morbidity after spontaneous labor onset prior to intended cesarean delivery at term: a cohort study. Acta Obstet Gynecol Scand . 2017;96(4):479–486. Jagota P, Vincent A, Bhidayasiri R. Transplacental transfer of NMDA receptor antibodies in an infant with cortical dysplasia. Neurology . 2014;82:1662–1663. Laghmani K, Beck BB, Yang SS, et al. Polyhydramnios, transient antenatal Bartter's syndrome, and MAGED 2

mutations. N Engl J Med . 2016;374(19):1853–1862. Mussa A, Molinatto C, Cerrato F, et al. Assisted reproductive techniques and risk of Beckwith-Wiedemann syndrome. Pediatrics . 2016;140(1). Sousa AQ, et al. Postmortem findings for 7 neonates with congenital Zika virus infection. Emerg Infect Dis . 2017;23(7). Steer PJ, Modi N. Elective caesarean sections—risks to the infant. Lancet . 2009;374:675–676. Touboul C, Boileau P, Picone O, et al. Outcome of children born out of pregnancies complicated by unexplained polyhydramnios. BJOG . 2007;114:489. Touboul C, Picone O, Levaillant JM, et al. Clinical application of fetal urine production rate in unexplained polyhydramnios. Ultrasound Obstet Gynecol . 2009;34:521.

C H A P T E R 11 5

The Fetus Kristen R. Suhrie, Sammy M. Tabbah

The major emphasis in fetal medicine involves (1) assessment of fetal growth and maturity, (2) evaluation of fetal well-being or distress, (3) assessment of the effects of maternal disease on the fetus, (4) evaluation of the effects of drugs administered to the mother on the fetus, and (5) identification and when possible treatment of fetal disease or anomalies. One of the most important tools used to access fetal well-being is ultrasonography (ultrasound, US); it is both safe and reasonably accurate. Indications for antenatal US include estimation of gestational age (unknown dates, discrepancy between uterine size and dates, or suspected growth restriction), assessment of amniotic fluid volume, estimation of fetal weight and growth, determination of the location of the placenta and the number and position of fetuses, and identification of congenital anomalies. Fetal MRI is a more advanced imaging method that is thought to be safe to the fetus and neonate and is used for more advanced diagnostic and therapeutic planning (Fig. 115.1 ).

FIG. 115.1 MRI of fetal pathology. A, Fetus with sacral myelomeningocele at 30 wk gestation. B, Ventriculomegaly in the same fetus as in A. C, MRI can also be used for postmortem examination, here in a 33 wk old fetus, demonstrating ventriculomegaly with heterotopic foci in the ventricular walls. D, Chiari II malformation of the brainstem. (Courtesy of Filip Claus, Aalst, Belgium. )

115.1

Fetal Growth and Maturity Kristen R. Suhrie, Sammy M. Tabbah

Fetal growth can be assessed by US as early as 6-8 wk of gestation by measurement of the crown-rump length. Accurate determination of gestational age can be achieved through the 1st half of pregnancy; however, first-trimester assessment by crown-rump length measurement is the most effective method of pregnancy dating. In the second trimester and beyond, a combination of biometric measures (i.e., biparietal diameter, head and abdominal circumference, femoral diaphysis length) is used for gestational age and growth assessment (Fig. 115.2 ). If a single US examination is performed, the most information can be obtained with a scan at 18-20 wk, when both gestational age and fetal anatomy

can be evaluated. Serial scans assessing fetal growth are performed when risk factors for fetal growth restriction (FGR) are present. Two patterns of FGR have been identified: symmetric FGR, typically present early in pregnancy, and asymmetric FGR, typically occurring later in gestation. The most widely accepted definition of FGR in the United States is an estimated fetal weight (EFW) of less than the 10th percentile (Fig. 115.3 ). Some aspects of human fetal growth and development are summarized in Chapter 20 .

FIG. 115.2 Fetal measurements: 3rd, 10th, 50th, 90th, and 97th smoothed centile curves. A, Fetal head circumference; B, fetal biparietal diameter; C, fetal occipitofrontal diameter; D, fetal abdominal circumference; and E, fetal femur length measured by ultrasound (US) according to gestational age. (From Papageorghiou AT, Ohyma EO, Altman DG, et al: International standards for fetal growth based on serial US measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project, Lancet 384:869–878, 2014, Fig 3.)

FIG. 115.3 A, Example of a “low-profile” growth restriction pattern in an uneventful pregnancy and labor. The baby cried at 1 min, and hypoglycemia did not develop. Birthweight was below the 5th percentile for gestational age. B, Example of a “late-flattening” growth restriction pattern. The mother had a typical history of preeclampsia, and the infant had intrapartum fetal distress, a low Apgar score, and postnatal hypoglycemia. Birthweight was below the 5th percentile for gestational age. (From Campbell S: Fetal growth, Clin Obstet Gynecol 1:41–65, 1974.)

Fetal maturity and dating are usually assessed by last menstrual period (LMP), assisted reproductive technology (ART)–derived gestational age, or US assessments. Dating by LMP assumes an accurate recall of the 1st day of LMP, a menstrual cycle that lasted 28 days, and ovulation occurring on the 14th day of the cycle, which would place the estimated delivery date (EDD) 280 days after LMP. Inaccuracies with any of these parameters can lead to an incorrectly assigned gestational age if the LMP is used for dating. Dating by ART is the most accurate method for assigning gestational age with EDD occurring 266 days after conception (when egg is fertilized by sperm). When US is used for dating, the most accurate assessment of gestational age is by first-trimester (≤ wk) US measurement of crown-rump length, which is accurate to within 5-7 days. In contrast, US dating in the second trimester is accurate to 10-14 days, and third trimester is only accurate to 21-30 days. Dating of a pregnancy is critical to determine when delivery should occur, if growth is appropriate during the pregnancy, and when testing and interventions should be offered. The earliest assessment of pregnancy dating should be used throughout the pregnancy unless methodologies used later in pregnancy are significantly different.

Bibliography American College of Obstetricians and Gynecologists. Fetal growth restriction, ACOG practice bulletin no 134. Obstet Gynecol . 2013;121:1122–1133. American College of Obstetricians and Gynecologists. Method for estimating due date, ACOG committee opinion no 611. Obstet Gynecol . 2014;124:863–866. American College of Obstetricians and Gynecologists. Ultrasound in pregnancy, ACOG practice bulletin no 175. Obstet Gynecol . 2016;128:e241–e256. Griffiths PD, Bradburn M, Campbell MJ, et al. Use of MRI in the diagnosis of fetal brain abnormalities in utero (MERIDIAN): a multi-centre, prospective cohort study. Lancet . 2017;389:538–546. Grimes DA. When to deliver a stunted fetus. Lancet . 2004;364:483–484. Lee ACC, Katz J, Blencowe H, et al. National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010. Lancet . 2013;1:e26–e36. Nielsen BW, Scott RC. Brain abnormalities in fetuses: in-utero MRI versus ultrasound. Lancet . 2017;389:483–484. Ott WJ. Intrauterine growth restriction and doppler ultrasonography. J Ultrasound Med . 2000;19:661–665. Papageorghiou AT, Ohyma EO, Altman DG, et al. International standards for fetal growth based on serial ultrasound measurements: the fetal growth longitudinal study of the INTERGROWTH-21st project. Lancet . 2014;384:869–878. Ray JG, Vermeulen MJ, Bharatha A, et al. Association between MRI exposure during pregnancy and fetal childhood outcomes. JAMA . 2016;316(9):952–961. Romero R, Deter R. Should serial fetal biometry be used in all

pregnancies? Lancet . 2015;386:2038–2040. Simchen MJ, Toi A, Bona M, et al. Fetal hepatic calcifications: prenatal diagnosis and outcome. Am J Obstet Gynecol . 2002;187(6):1617–1622. Stock SJ, Bricker L, Norman JE. Immediate versus deferred delivery of the preterm baby with suspected fetal compromise for improving outcomes. Cochrane Database Syst Rev . 2012; (7) [CD008968].

115.2

Fetal Distress Kristen R. Suhrie, Sammy M. Tabbah

Fetal compromise may occur during the antepartum or intrapartum period. It may be asymptomatic in the antenatal period but is often suspected by maternal perception of decreased fetal movement. Antepartum fetal surveillance is warranted for women at increased risk for fetal death, including those with a history of stillbirth, intrauterine growth restriction (IUGR), oligohydramnios or polyhydramnios, multiple gestation, rhesus sensitization, hypertensive disorders, diabetes mellitus or other chronic maternal disease, decreased fetal movement, preterm labor, preterm rupture of membranes (PROM), and postterm pregnancy. The predominant cause of antepartum fetal distress is uteroplacental insufficiency, which may manifest clinically as IUGR, fetal hypoxia, increased vascular resistance in fetal blood vessels (Figs. 115.4 and 115.5 ), and, when severe, mixed respiratory and metabolic (lactic) acidosis. The goal of antepartum fetal surveillance is to identify the fetus at risk of stillbirth such that appropriate interventions (i.e., delivery vs optimization of underlying maternal medical condition) can be implemented to allow for a healthy live-born infant. Table 115.1 lists methods for assessing fetal well-being.

FIG. 115.4 Normal doppler velocity in sequential studies of fetal umbilical artery flow velocity waveforms from one normal pregnancy. Note the systolic peak flow with lower but constant heart flow during diastole. The systolic/diastolic ratio can be determined and, in normal pregnancies, is 37.7°C (99.9°F; or feels hot) or 105 CFU/mL and • Bacteria identified in blood (culture-based or nonculture-based microbiologic method) that matches at least one of the bacteria present at more than 105 CFU/mL in urine. Catheter–Associated Urinary Tract Infection: • Urinary tract infection (as defined above, either SUTI or ABUTI) and • Indwelling urinary catheter for >2 days and • Urinary catheter in place on day of or day before urinary tract infection diagnosis. * Centers for Disease Control and Prevention/National Healthcare Safety Network.

CFU, Colony-forming units. Adapted from Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care–associated infection and criteria for specific types of infections in the acute care setting, Am J Infect Control 36:309–332, 2008.

Incidence The most common HAIs in the neonatal intensive care unit (NICU) are bloodstream infections, predominantly central line–associated bloodstream infections. Ventilator-associated pneumonia (VAP) is the next most common, followed by surgical site infection and catheter-associated urinary tract infection. Approximately 11% of NICU patients develop nosocomial infection during their hospitalization; up to 25% of VLBW infants will have blood culture– proven sepsis during their hospitalization. Infection rates are highest among the most premature infants. Ventilator-associated pneumonia accounts for approximately 25% of HAIs.

Epidemiology HAIs in the NICU are predominantly caused by gram-positive organisms. The

largest fraction of bloodstream infections (BSIs) in the NICU are caused by coagulase-negative staphylococci (Table 130.2 ). Other agents that often cause HAIs in the newborn include Staphylococcus aureus, enterococci, gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa ), and Candida. Viruses contributing to HAIs in the neonate include rotavirus, enteroviruses, hepatitis A virus (HAV), adenoviruses, influenza, respiratory syncytial virus (RSV), rhinovirus, parainfluenza, and herpes simplex virus (HSV). Table 130.2

Distribution of Organisms Responsible for Late-Onset Sepsis ORGANISM Incidence of late-onset sepsis GRAM POSITIVE Staphylococcus, coagulase-negative Staphylococcus aureus Enterococcus /group D streptococcus Group B streptococcus Other GRAM NEGATIVE Enterobacter Escherichia coli Klebsiella Pseudomonas Other Fungi Candida albicans Candida parapsilosis Other

VLBW INFANTS: NICHD NRN (%) 1991–1993 1998–2000 2002–2008 25 21 25 55 9 5 2 2

48 8 3 2 9

53 11 4 2 7

4 4 4 2 4

3 5 4 3 1

3 5 4 2 2

5

6

5

2

2

1

VLBW, Very-low-birthweight (≤1,500 g); NICHD NRN, National Institutes of Child Health and Human Development Neonatal Research Network. Data from (1) 1991–1993: Stoll BJ, Gordon T, Korones SB, et al: Late-onset sepsis in very low birth weight neonates: a report from the NICHD NRN, J Pediatr 129:63–71, 1996; (2) 1998–2000: Stoll BJ, Hansen N, Fanaroff AA, et al: Late-onset sepsis in very low birth weight neonates: the experience of the NICHD NRN, Pediatrics 110:285–291, 2002; (3) 2002–2008: Boghossian NS, Page GP, Bell EF, et al: Late-onset sepsis in very low birth weight infants from singleton and multiple gestation births, J Pediatr 162:1120–1120, 2015. Adapted from Ramasethu J. Prevention and treatment of neonatal nosocomial infections, Matern Health Neonatol Perinatol 3(5), 2017.

Bacteria responsible for most cases of nosocomial pneumonia typically

include staphylococcal species, gram-negative enteric aerobes, and occasionally, P. aeruginosa. Fungi are responsible for an increasing number of systemic infections, usually acquired during prolonged hospitalization of preterm neonates. Respiratory viruses cause isolated cases and outbreaks of nosocomial pneumonia. These viruses, usually endemic during the winter months and acquired from infected hospital staff or visitors to the nursery, include RSV, parainfluenza virus, influenza viruses, and adenovirus.

Pathogenesis Colonization of the skin, oropharynx, or gastrointestinal (GI) tract is an important precursor to infection in hospitalized infants. Premature infants may first be exposed to pathogenic organisms from a parent or more frequently from the hospital environment. Hospitalized infants are more likely to be colonized with Staphylococcus aureus , pathogenic gram-negative bacteria, and Candida than are infants in the community setting. Antibiotic exposure, indwelling devices, and frequent contact with contaminated medical equipment or healthcare providers all likely contribute to high rates of pathogen colonization. Following colonization, organisms may gain access to the bloodstream directly through damaged skin or central venous catheters. Recent evidence suggests the intestine is an important reservoir for invasive organisms, which may transit directly from the gut to the bloodstream. Oropharyngeal colonization with subsequent aspiration into the lower respiratory tract is thought to be the major route of infection in infants with ventilator-associated pneumonia. Gestational age and birthweight are the most important risk factors for HAI. Prolonged use of central venous or umbilical catheters, exposure to broadspectrum antibiotics, parenteral nutrition, and high nurse-to-patient ratios are other documented risk factors. These factors may alter the patient's endogenous microbial community, placing the infant at risk for colonization with pathogenic organisms.

Types of Infection Central Line–Associated Bloodstream Infection

Central venous catheters have become an essential component of the care of critically ill newborns. Presence of a percutaneous or umbilical catheter introduces risk for infection and thrombosis. Central line–associated bloodstream infection (CLABSI ) is the most common HAI in NICUs, imposing significant burden on the affected infant and on healthcare systems. Each episode has an attributable mortality of 4–20%. Infants with CLABSI subsequently have increased requirement for NICU stay, mechanical ventilation, and increased rates of bronchopulmonary dysplasia and necrotizing enterocolitis. The median estimated additional cost per CLABSI episode is $42,609, and hospitalization is prolonged for a median of 24 days. Coagulase-negative staphylococci (CoNS) are the most common cause of CLABSI, accounting for approximately half of cases. CoNS are much more likely to cause clinically evident sepsis in VLBW infants than in term infants of comparable postnatal age, despite the organism's low pathogenic potential. Isolation of the organism from blood culture may represent contamination from the infant's or healthcare worker's skin, and blood cultures should be obtained from both peripheral and central venous sites. If both yield CoNS, the likelihood of true infection is high, whereas a single positive is considered questionable. In practice, often a single culture is obtained, and antibiotics are initiated before availability of a 2nd culture. In this circumstance, clinical judgment is often used to assess the need for targeted therapy. S. aureus , Enterococcus spp., and gramnegative rods account for most of the remaining CLABSIs during the 1st mo of hospitalization. Thereafter, Candida spp. become more prevalent, caused at least in part by their enrichment after broad-spectrum antibiotic exposure. CLABSIs are generally thought to result from contamination of the central venous catheter, predominantly at the connecting hub or the skin entry site. An association has been shown between density of hub colonization and risk for CLABSI. Prevention of CLABSI is aimed at reducing contamination of these sites. BSI may also result from direct transit from the GI tract or other cutaneous or mucosal surfaces, analogous to recently defined mucosal barrier injury– associated BSIs. The contribution of mucosal sites to direct invasive infection remains to be clarified but has implications for infection prevention.

Healthcare-Associated Pneumonia Ventilator-associated pneumonia (VAP) is overall the 2nd most common HAI in neonatal units, although reported VAP rates vary widely (0.2-1.6 per 1,000

ventilator days). There is also variability in diagnosis of VAP, which consists of clinical, radiographic, and laboratory criteria, some of which are subjective or may be seen in noninfectious circumstances. The National Healthcare Safety Network and Centers for Disease Control and Prevention (CDC) definition of VAP requires at least 48 hr of mechanical ventilation accompanied by new and persistent radiographic infiltrates after the initiation of mechanical ventilation. In addition to these criteria, infants 15 Male

+1 15 yr old or a single follow-up dose at 6-12 mo if ≤15 yr old

As Indicated All persons offered PEP should be prescribed a 28-day course of a two- or three-drug antiretroviral regimen. Human Immunodeficiency Virus (HIV) † Preferred regimen: Tenofovir 300 mg and fixed-dose combination emtricitabine, 200 mg (Truvada) once daily plus Raltegravir 400 mg twice daily or Dolutegravir 50 mg daily ‡ Alternative regimens available (The National Clinicians Consultation Center is a resource for providers prescribing PEP, reachable at 1-888448-4911.) Hepatitis B virus (HBV) Specific indications for vaccine, immunoglobulin and/or booster dependent upon assailant's status

* Provided for patients with negative urine pregnancy screen. In addition,

antiemetic (Compazine, Zofran) can be prescribed for patients receiving emergency contraception. † HIV PEP is provided for patients with penetration and when the assailant is

known to be HIV-positive or at high risk because of a history of incarceration, intravenous drug use, or multiple sexual partners. If provided, laboratory studies must be drawn before administration of medication (HIV, CBC, LFTs, BUN/Cr, amylase, lipase), and follow-up must be arranged. ‡ Dolutegravir has been associated with neural tube defects if the exposure

occurs within the first trimester of pregnancy. Therefore it should be avoided in pregnant patients or those at risk for becoming pregnant. U.S. Department of Health and Human Services, U.S. Food & Drug Administration. Julica, Tivicay, Triumeq (dolutegravir): FDA to evaluate potential risk of neural tube birth defects. May 18, 2018. https://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproduct . Data from Centers for Disease Control and Prevention: Sexually transmitted diseases: treatment guidelines 2015, MMWR Recomm Rep 64(RR-3):1–140, 2015, and Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV—United States, 2016.

FIG. 145.1 Algorithm for evaluation and treatment of possible human immunodeficiency virus (HIV) infection. nPEP, Nonoccupational postexposure prophylaxis. (From Seńa AC, Hsu KK, Kellogg N, et al: Sexual assault and sexually transmitted infections in adults, adolescents, and children, Clin Infect Dis 61(Suppl 8):S859, 2015.)

At the time of presentation, the clinician should address the need for followup care, including psychological counseling. Adolescent victims are at increased risk of posttraumatic stress disorder, depression, self-abusive behaviors, suicidal ideation, delinquency, substance abuse, eating disorders, and sexual revictimization. It is important for the adolescent victim and parents to understand the value of timely counseling services to decrease these potential long-term sequelae. Counseling services should be arranged during the initial evaluation, with follow-up arranged with the primary care physician to improve compliance. Counseling services for family members of the victim may improve their ability to provide appropriate support to the adolescent victim. Caution parents not to use the assault as a validation of their parental guidance, as it will only serve to place blame inappropriately on the adolescent victim.

Prevention Primary prevention may be accomplished through education of preadolescents and adolescents on the issues of rape, healthy relationships, internet dangers, and drug- and alcohol-facilitated rape. Prevention messages should be targeted to both males and females at high schools and colleges. Particular emphasis on prevention efforts during college orientation is highly recommended. High-risk situations that may increase the likelihood of a sexual assault (use of drugs or alcohol) should be discouraged. Secondary prevention includes informing adolescents of the benefits of timely medical evaluations when rape has occurred. Individual clinicians should ask adolescents about past experiences of forced and unwanted sexual behaviors and offer help in dealing with those experiences. The importance of prevention cannot be overstated because adolescents are disproportionately affected by rape, and they are particularly vulnerable to long-term consequences.

Bibliography Bass JK, Annan J, Murray SM, et al. Controlled trial of psychotherapy for Congolese survivors of sexual violence. N Engl J Med . 2013;368:2182–2190. Blythe MJ, Fortenberry JD, Temkit M, et al. Incidence and correlates of unwanted sex in relationships of middle and late adolescent women. Arch Pediatr Adolesc Med . 2006;160:591–595. Bicanic IA, Hehenkamp LM, van de Putte EM, et al. Predictors of delayed disclosure of rape in female adolescents and young adults. Eur J Psychotraumatol . 2015;6:25883. Bullock CM, Beckson M. Male victims of sexual assault: phenomenology, psychology, physiology. J Am Acad Psychiatry Law . 2011;39(2):197–205. Catalano S, Smith E, Snyder H, et al. Female victims of violence . 2009 [Washington, DC; US Department of Justice, Office of Justice Programs, Bureau of Justice Statistics]. Centers for Disease Control and Prevention. Sexually

transmitted diseases: treatment guidelines 2015. MMWR Recomm Rep . 2015;64(RR–3):1–140. Center for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV —United States . 2016. Center for Disease Control and Prevention. Neisseria gonorrhoeae antimicrobial susceptibility surveillance. MMWR . 2016;65(7):1–19. Cooper SW, Estes RJ, Giardino AP, et al. Medical, legal and social science aspects of child sexual exploitation . GW Medical Publishing: St Louis; 2005. Dick RN, McCauley HL, Jones KA, et al. Cyber dating abuse among teens using school-based health centers. Pediatrics . 2014;134(6):e1560–e1567. Finkelhor D, Turner H, Shattuck A, Hamby SL. Prevalence of childhood exposure to violence, crime, and abuse: results from the National Survey of Children's Exposure to Violence. JAMA Pediatr . 2015;169(8):746–754. Foshee VA, Bauman KE, Greene WF, et al. The safe dates program: 1-year follow-up results. Am J Public Health . 2000;90:1619–1622. Goldberg AP, Moore JL, Houck C. Domestic minor sex trafficking patients: a retrospective analysis of medical presentation. J Pediatr Adolesc Gynecol . 2016;30(1):109– 115. Irwin CE Jr, Rickert VI. Coercive sexual experiences during adolescence and young adulthood: a public health problem. J Adolesc Health . 2005;36:359–361. Jackson AM, Deye K. Aspects of abuse: consequences of childhood victimization. Curr Probl Pediatr Adolesc Health Care . 2015;45:86–93. Jimenez M, Jackson AM, Deye K. Aspects of abuse:

commercial sexual exploitation of children. Curr Probl Pediatr Adolesc Health Care . 2015;45:80–85. Jenny C, Lowen DE, Pierce MC, et al. Child abuse and neglect: diagnosis, treatment, and evidence . Elsevier Saunders: St Louis; 2011. Kaufman M. Committee on Adolescence: care of the adolescent sexual assault victim. Pediatrics . 2008;122:462–470. MacDowall W, Gibson LJ, Tanton C, et al. Lifetime prevalence, associated factors, and circumstances of non-volitional sex in women and men in Britain: findings from the Third National Survey of Sexual Attitudes and Lifestyles (NATSAL-3). Lancet . 2013;382:1845–1854. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR . 2016;65:1405–1408. Miller E, McCauley HL. Adolescent relationship abuse and reproductive and sexual coercion among teens. Curr Opin Obstet Gynecol . 2013;25(5):364–369. Nofzigen S, Stein RE. To tell or not to tell: lifestyle impacts on whether adolescents tell about violent victimization. Violence Vict . 2006;21:371–382. Planty M, Langston L, Krebs C, et al. Female victims of sexual violence, 1994–2010 . 2013 [Washington, DC; US Department of Justice. Office of Justice Programs, Bureau of Justice Statistics]. Rand MR. Criminal victimization survey, 2008 . 2009 [Bureau of Justice Statistics Bulletin, Washington, DC; US Department of Justice]. Rothman EF, Exner D, Baughman A. The prevalence of sexual assault against people who identify as gay, lesbian or bisexual in the United States: a systematic review. Trauma Violence Abuse . 2011;12(2):55–66.

Saar MS, Epstein R, Rosenthal L, Vafa Y. The sexual abuse to prison pipeline: the girls' story . http://rights4girls.org/wpcontent/uploads/r4g/2015/02/2015_COP_sexualabuse_layout_web-1.pdf ; 2015. Seńa AC, Hsu KK, Kellpgg N, et al. Sexual assault and sexually transmitted infections in adults, adolescents, and children. Clin Infect Dis . 2015;61(Suppl 8):S856–S864. Sinozich S, Langton L, Bureau of Justice Statistics. Rape and sexual assault victimization among college-age females, 1995–2013 . [Bureau of Justice Statistics] https://www.bjs.gov/content/pub/pdf/rsavcaf9513.pdf ; 2014. Taylor CA, Sorenson SB. Injunctive social norms of adults regarding teen dating violence. J Adolesc Health . 2004;34:468–479. Trotman GE, Young-Anderson C, Deye KP. Acute sexual assault in the pediatric and adolescent population. J Pediatri Adolesc Gynecol . 2016;29:518–526. US Department of Justice. An updated definition of rape . [January 6] https://www.justice.gov/opa/blog/updateddefinition-rape ; 2012. US Department of Justice, Office on Violence Against Women. A national protocol for sexual assault medical forensic examinations: adults/adolescents . [ed 2] https://www.ncjrs.gov/pdffiles1/ovw/241903.pdf ; 2013. US Department of Justice, Office on Violence Against Women. A national protocol for sexual abuse medical forensic examinations: Pediatric . https://www.justice.gov/ovw/file/846856/download ; 2016.

CHAPTER 146

Sexually Transmitted Infections Gale R. Burstein

Age-specific rates of many sexually transmitted infections (STIs ) are highest among sexually experienced adolescents and young adults, after controlling for sexual activity. Although some STI pathogens present as STI syndromes with a specific constellation of symptoms, most are asymptomatic and only detected by a laboratory test. The approach to prevention and control of these infections lies in education, screening, and early diagnosis and treatment.

Etiology Any adolescent who has had oral, vaginal, or anal sexual intercourse is at risk for acquiring an STI. Not all adolescents are at equal risk; physical, behavioral, and social factors contribute to the adolescent's higher risk (Table 146.1 ). Adolescents who initiate sex at a younger age, youth residing in detention facilities, youth attending sexually transmitted disease (STD) clinics, young men having sex with men, and youth who are injection drug users are at higher risk for STIs. Risky behaviors, such as sex with multiple concurrent partners or multiple sequential partners of limited duration, failure to use barrier protection consistently and correctly, and increased biologic susceptibility to infection, also contribute to risk. Although all 50 states and the District of Columbia explicitly allow minors to consent for their own sexual health services, many adolescents encounter multiple obstacles to accessing this care. Adolescents who are victims of sexual assault may not consider themselves “sexually active,” given the context of the encounter, and need reassurance, protection, and appropriate intervention when these circumstances are uncovered (see Chapter 145 ).

Table 146.1

Circumstances Contributing to Adolescents' Susceptibility to Sexually Transmitted Infections Physical Younger age at puberty Cervical ectopy Smaller introitus leading to traumatic sex Asymptomatic nature of sexually transmitted infection Uncircumcised penis

Behavior Limited by Cognitive Stage of Development Early adolescence: have not developed ability to think abstractly Middle adolescence: develop belief of uniqueness and invulnerability

Social Factors Poverty Limited access to “adolescent-friendly” healthcare services Adolescent health-seeking behaviors (forgoing care because of confidentiality concerns or denial of health problem) Sexual abuse, trafficking, and violence Homelessness Drug use Young adolescent females with older male partners Young men having sex with men From Shafii T, Burstein G: An overview of sexually transmitted infections among adolescents, Adolesc Med Clin 15:207, 2004.

Epidemiology

STI prevalence varies by age, gender, and race/ethnicity. In the United States, although adolescents and young adults ages 15-24 yr represent 25% of the sexually experienced population, this age-group accounts for almost 50% of all incident STIs each year. Adolescents and young adults 90% of all primary and secondary syphilis cases. Of those male cases, men who have sex with men (MSM) account for 82% of male cases when the gender of the sex partner is known. Males age 20-24 yr have the 2nd highest rate of primary and secondary syphilis among males of any age-group (36/100,000); whereas rates among males 15-19 yr old (8/100,000) are much lower. Female primary and secondary syphilis rates are much lower than male rates (5/100,000 among 20-24 yr olds; 3/100,000 among 15-19 yr olds) (see Chapter 245 ). Pelvic inflammatory disease (PID) rates are highest among females age 15-24 compared with older women. Adolescents also carry a large burden of viral STIs. U.S. youth are at persistent risk for HIV infection (see Chapter 302 ). In 2015, youth age 13-24 yr accounted for 22% (8,807) of all new HIV diagnoses in the United States, with most (81%) occurring among gay and bisexual males. Of those new infections, 55% (4,881) were among blacks, 22% (1,957) among Hispanic/Latinos, and 17% (1,506) among whites. Only 10% of high school students have been tested

for HIV. Among male students who had sexual contact with other males, only 21% have ever been tested for HIV. Human papillomavirus (HPV) is the most frequently acquired STI in the United States. According to NHANES, prevalence of HPV vaccine types 6, 11, 16, and 18 (4vHPV ) declined between the prevacccine (2003–2006) and vaccine (2009–2012) eras: from 11.5% to 4.3% among females age 14-19 yr and from 18.5% to 12.1% among females age 20-24 (see Chapter 293 ). Herpes simplex virus type 2 (HSV-2) is the most prevalent viral STI (see Chapter 279 ). NHANES data show that among 14-19 yr olds, HSV-2 seroprevalence has remained low (4.5) is common with bacterial vaginosis or trichomoniasis. Because pH testing is not highly specific, discharge should be further examined. For microscopic exam, a slide can be made with the discharge diluted in 1-2 drops of 0.9% normal saline solution and another slide with discharge diluted in 10% potassium hydroxide (KOH) solution. Examining the saline specimen slide under a microscope may reveal motile or dead T. vaginalis or clue cells (epithelial cells with borders obscured by small bacteria), which are characteristic of bacterial vaginosis . WBCs without evidence of trichomonads or yeast are usually suggestive of cervicitis. The yeast or pseudohyphae of Candida species are more easily identified in the KOH specimen (Fig. 146.8 ). The sensitivity of microscopy is approximately 50% and requires immediate evaluation of the slide for optimal results. Therefore, lack of findings does not eliminate the possibility of infection. More sensitive point-of-care vaginitis tests include the OSOM Trichomonas Rapid Test (Sekisui Diagnostics, Lexington, MA), an immunochromatographic capillary flow dipstick technology with reported 83% sensitivity. The OSOM BVBLUE Test (Sekisui) detects elevated vaginal fluid sialidase activity, an enzyme produced by bacterial pathogens associated with bacterial vaginosis, including Gardnerella , Bacteroides , Prevotella, and Mobiluncus , and has a reported 90% sensitivity. Both tests are CLIA waived, with results available in 10 min.

FIG. 146.8 Common normal and abnormal microscopic findings during examination of vaginal fluid. KOH, Potassium hydroxide solution; PMN, polymorphonuclear leukocyte; RBCs, red blood cells. (From Adolescent medicine: state of the art reviews, vol 14, no 2, Philadelphia, 2003, Hanley & Belfus, pp 350–351.)

Clinical laboratory–based vaginitis tests are also available. The Affirm VPIII (Becton Dickenson, San Jose, CA) is a moderate-complexity nucleic acid probe test that evaluates for T. vaginalis , G. vaginalis , and C. albicans and has a sensitivity of 63% and specificity >99.9%, with results available in 45 min. Some gonorrhea and chlamydia NAATs also offer an assay for T. vaginalis testing of female specimens tested for N. gonorrhoeae and C. trachomatis , considered the gold standard for Trichomonas testing. Objective signs of vulvar inflammation in the absence of vaginal pathogens, along with a minimal amount of discharge, suggest the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva (Table 146.4 ). Table 146.4

Pathologic Vaginal Discharge INFECTIVE DISCHARGE

OTHER REASONS FOR DISCHARGE

COMMON CAUSES Organisms Candida albicans Trichomonas vaginalis Chlamydia trachomatis Neisseria gonorrhoeae Mycoplasma genitalium Conditions Bacterial vaginosis Acute pelvic inflammatory disease Postoperative pelvic infection Postabortal sepsis Puerperal sepsis LESS COMMON CAUSES Ureaplasma urealyticum Syphilis Escherichia coli

COMMON CAUSES Retained tampon or condom Chemical irritation Allergic responses Ectropion Endocervical polyp Intrauterine device Atrophic changes LESS COMMON CAUSES Physical trauma Vault granulation tissue Vesicovaginal fistula Rectovaginal fistula Neoplasia Cervicitis

From Mitchell H: Vaginal discharge—causes, diagnosis, and treatment, BMJ 328:1306–1308, 2004.

The definitive diagnosis of PID is difficult based on clinical findings alone. Clinical diagnosis is imprecise, and no single historical, physical, or laboratory finding is both sensitive and specific for the diagnosis of acute PID. Clinical criteria have a positive predictive value of only 65–90% compared with laparoscopy. Although healthcare providers should maintain a low threshold for the diagnosis of PID, additional criteria to enhance specificity of diagnosis, such as transvaginal ultrasonography, can be considered (Table 146.5 ).

Table 146.5

Evaluation for Pelvic Inflammatory Disease (PID) 2015 CDC Diagnostic Criteria Minimal Criteria • Cervical motion tenderness or • Uterine tenderness or • Adnexal tenderness Additional Criteria to Enhance Specificity of the Minimal Criteria

• Oral temperature >38.3°C (101°F) • Abnormal cervical or vaginal mucopurulent discharge* • Presence of abundant numbers of WBCs on saline microscopy of vaginal secretions* • Elevated ESR or C-reactive protein • Laboratory documentation of cervical Neisseria gonorrhoeae or Chlamydia trachomatis infection Most Specific Criteria to Enhance the Specificity of the Minimal Criteria • Transvaginal sonography or MRI techniques showing thickened, fluid-filled tubes, with or without free pelvic fluid or tuboovarian complex, or Doppler studies suggesting pelvic infection (e.g., tubal hyperemia) • Endometrial biopsy with histopathologic evidence of endometritis • Laparoscopic abnormalities consistent with PID Differential Diagnosis (Partial List) • Gastrointestinal: appendicitis, constipation, diverticulitis, gastroenteritis, inflammatory bowel disease, irritable bowel syndrome • Gynecologic: ovarian cyst (intact, ruptured, or torsed), endometriosis, dysmenorrhea, ectopic pregnancy, mittelschmerz, ruptured follicle, septic or threatened abortion, tuboovarian abscess • Urinary tract: cystitis, pyelonephritis, urethritis, nephrolithiasis ESR, Erythrocyte sedimentation rate; WBCs, white blood cells.

* If the cervical discharge appears normal and no WBCs are observed on the wet

prep of vaginal fluid, the diagnosis of PID is unlikely, and alternative causes of pain should be investigated. Adapted from Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/std/tg2015/screening-recommendations.htm .

Cell culture and polymerase chain reaction (PCR) are the preferred HSV tests . Viral culture sensitivity is low, and intermittent viral shedding causes falsenegative results. NAATs, including PCR assays for HSV DNA, are more sensitive and increasingly available for diagnosing genital HSV. The Tzanck test is insensitive and nonspecific and should not be considered reliable. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoproteins G2 (HSV-2) and G1 (HSV-1). Both laboratory-based point-of-care tests are available. Because almost all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. The presence of HSV-1 antibody alone is more difficult to interpret because of the frequency of oral HSV infection acquired during childhood. Type-specific HSV serologic assays might be useful in the following scenarios: (1) recurrent genital symptoms or atypical symptoms with negative HSV cultures; (2) a clinical diagnosis of genital herpes without laboratory confirmation; and (3) a patient with a partner with genital herpes, especially if considering suppressive antiviral therapy to prevent transmission. For syphilis testing , nontreponemal tests, such as the rapid plasma reagin (RPR) or Venereal Disease Research Laboratories (VDRL), and treponemal testing, such as fluorescent treponemal antibody absorbed tests, the T. pallidum passive particle agglutination (TP-PA) assay, and various enzyme and chemiluminescence immunoassays (EIA/CIA), are recommended. However, many clinical laboratories have adopted a reverse sequence of screening in which a treponemal EIA/CIA is performed first, followed by testing of reactive sera with a nontreponemal test (e.g., RPR). A positive treponemal EIA or CIA test can identify both previously treated and untreated or incompletely treated syphilis . False-positive results can occur, particularly among populations with low syphilis prevalence. Persons with a positive treponemal screening test should have a standard nontreponemal test with titer (RPR or VDRL) to guide patient management decisions. If EIA/CIA and RPR/VDRL results are discordant, the laboratory should perform a different treponemal test to confirm the results of the initial test. Patients with discordant serologic results by EIA/CIA and RPR/VDRL testing whose sera are reactive by TP-PA testing are considered to have past or present syphilis; if sera is TP-PA nonreactive, syphilis is unlikely (Fig. 146.9 ).

FIG. 146.9 Centers for Disease Control and Prevention (CDC) recommended algorithm for reverse-sequence syphilis screening: treponemal test screening followed by nontreponemal test confirmation. (From Association of Public Health Laboratories: Suggested reporting language for syphilis serology testing, 2015.)

Rapid HIV testing with results available in 10-20 min can be useful when the likelihood of adolescents returning for their results is low. Point-of-care CLIAwaived tests for whole blood fingerstick and oral fluid specimen testing are available. Clinical studies have demonstrated that the rapid HIV test performance is comparable to those of EIAs. Because some reactive test results may be false positive, every reactive rapid test must be confirmed.

Treatment See Part XVI for chapters on the treatment of specific microorganisms and Tables 146.6 to 146.8 . Treatment regimens using nonprescription products for candidal vaginitis and pediculosis reduce financial and access barriers to rapid treatment for adolescents, but potential risks for inappropriate self-treatment and

complications from untreated more serious infections must be considered before using this approach. Minimizing noncompliance with treatment, notifying and treating the sexual partners, addressing prevention and contraceptive issues, offering available vaccines to prevent STIs, and making every effort to preserve fertility are additional physician responsibilities. Table 146.6 Management Guidelines for Uncomplicated Bacterial STIs in Adolescents and Adults ALTERNATIVE REGIMENS AND SPECIAL CONSIDERATIONS Chlamydia For pregnancy: trachomatis Azithromycin 1 g orally once Alternative regimens: Erythromycin base 500 mg orally 4 times daily for 7 days or Erythromycin ethylsuccinate 800 mg orally 4 times daily for 7 days or Levofloxacin 500 mg orally once daily for 7 days or Ofloxacin 300 mg orally twice daily for 7 days Neisseria Ceftriaxone 250 mg Single-dose injectable cephalosporin regimens (other than gonorrhoeae (cervix, IM in a single dose ceftriaxone 250 mg IM) that are safe and effective against urethra, and rectum) plus uncomplicated urogenital and anorectal gonococcal Azithromycin 1 g infections include ceftizoxime 500 mg IM, cefoxitin 2 g IM orally once with probenecid 1 g orally, and cefotaxime 500 mg IM plus Azithromycin 1 g orally once Alternative if unable to offer IM: Cefixime 400 mg orally in a single dose plus Azithromycin 1 g orally in a single dose If patient is allergic to azithromycin: Doxycycline 100 mg orally twice daily for 7 days may be substituted for azithromycin as the 2nd antimicrobial. Severe cephalosporin allergy: Gemifloxacin 320 mg orally plus azithromycin 2 g orally in a single dose or Gentamicin 240 mg IM plus oral azithromycin 2 g orally in a single dose N. gonorrhoeae Ceftriaxone 250 mg No recommended alternative therapy (pharynx) IM in a single dose Possibly gemifloxacin plus azithromycin as above for plus cervix, urethra, rectum Azithromycin 1 g Patients treated with an alternative regimen should return orally once 14 days after treatment for a test of cure using either culture or NAAT. Treponema pallidum Benzathine penicillin G Penicillin allergy: Doxycycline 100 mg orally twice daily (primary and 2.4 million units IM in a for 14 days, or tetracycline 500 mg orally 4 times daily for PATHOGEN

RECOMMENDED REGIMENS Azithromycin 1 g orally once or Doxycycline 100 mg orally twice daily for 7 days

secondary syphilis or single dose early latent syphilis, i.e., infection 60 days, even if the partner is asymptomatic. Abstinence is recommended for at least 7 days after both patient and partner are treated. A test for pregnancy should be performed for all females with suspected PID because the test outcome will affect management. Repeat testing 3 mo after treatment is also recommended for Trichomonas infection.

Diagnosis and therapy are often carried out within the context of a confidential relationship between the physician and the patient. Therefore, the need to report certain STIs to health department authorities should be clarified at the outset. Health departments are Health Insurance Portability and Affordability Act (HIPAA) exempt and will not violate confidentiality. The health department's role is to ensure that treatment and case finding have been accomplished and that sexual partners have been notified of their STI exposure. Expedited partner therapy (EPT) , the clinical practice of treating sex partners of patients diagnosed with chlamydia or gonorrhea, by providing prescriptions or medications to the patient to take to the partner without the healthcare provider first examining the partner, is a strategy to reduce further transmission of infection. In randomized trials, EPT has reduced the rates of persistent or recurrent gonorrhea and chlamydia infection. Serious adverse reactions are rare with recommended chlamydia and gonorrhea treatment regimens, such as doxycycline, azithromycin, and cefixime. Transient gastrointestinal side effects are more common but rarely result in severe morbidity. Most states expressly permit EPT or may allow its practice. Resources for information regarding EPT and state laws are available at the Centers for Disease Control and Prevention website (http://www.cdc.gov/std/ept/ ).

Prevention Healthcare providers should integrate sexuality education into clinical practice with children from early childhood through adolescence. Providers should counsel adolescents regarding sexual behaviors associated with risk of STI acquisition and should educate using evidence-based prevention strategies, which include a discussion of abstinence and other risk reduction strategies, such as consistent and correct condom use. The U.S. Preventive Services Task Force recommends high-intensity behavioral counseling to prevent STIs for all sexually active adolescents. The HPV vaccine (Gardasil 9) is recommended for 11 and 12 yr old males and females as routine immunization. Catch-up vaccination is recommended for females age 13-26 and for males age 13-21 who have not yet received or completed the vaccine series; males age 22 through 26 may be vaccinated.

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CHAPTER 147

Chronic Overlapping Pain Conditions Thomas C. Chelimsky, Gisela G. Chelimsky

This chapter was made possible with the support of an Advancing Healthier Wisconsin 5520298 grant. In chronic overlapping pain conditions (COPCs ), several painful symptoms affecting different body systems coexist without clear underlying pathophysiology. Other terms for COPCs include medically unexplained symptoms , functional somatic syndromes (FSS), and central sensitivity syndromes . These disorders are probably highly prevalent; for example, 2 COPCs, irritable bowel syndrome (IBS) and migraine, each affect 10–20% of the population. Pediatric COPC studies usually focus on populations with 1 painful condition (headaches) and their psychiatric comorbidities, rather than somatic comorbidities. The overlap of these disorders with psychiatric conditions has led both the public and the medical specialists to dichotomize these disorders artificially into “physical,” by implication, “real” disorders; and “psychological,” by implication, “not real” disorders. This classification ignores the unity of brain and body and hinders progress in understanding these disorders. COPC connotes a nonassumptive neutral position, appropriately attributing no assumed pathophysiology to the disorder, in contrast to other terms, such as “medically unexplained syndrome,” subtly suggesting a psychological process, more strongly implied in the term “functional.”

Prevalence The prevalence of COPCs is unknown, ranging from 20% to >50% depending on which symptom is being assessed and how much overlap exists across disorders. A large study from 28 countries (about 400,000 participants) found a prevalence of headache of 54%, stomachache 50%, and backache 37%,

occurring at least once a month for at least 6 mo. Females had a higher prevalence of having all 3 complaints when compared to males; the prevalence increased with age. These three pain syndromes, headache, stomach-ache and backache, frequently coexist. IBS and chronic abdominal pain affect 6–20% of children and adolescents. Idiopathic musculoskeletal pain affects about 16% of schoolchildren age 5-16 yr and is often associated with sleep disturbances, headache, abdominal pain, daytime tiredness, and feeling sad (see Chapter 193 ). Migraines present >6 mo occur in about 8% of the population (children and adolescents 40 beats/min in the 1st 10 min of upright tilt test associated with orthostatic symptoms. POTS is also associated with multiple comorbidities, including sleep disruption, chronic pain, Raynaud-like symptoms, GI abnormalities, and less frequently headaches, syncope, and urinary complaints. Patients with both POTS and hEDS usually have more migraines and syncope than those with POTS alone. The prevalence of comorbid disorders in children with COPC is identical whether they have POTS or hEDS.

Psychiatric Comorbidities Many of these disorders have significant psychiatric comorbidities. Juvenile fibromyalgia is associated with anxiety disorders and major mood disorders. Children with medically unexplained symptoms generally have more anxiety and depression than children with other chronic disorders. Other associations include disruptive behaviors, symptom internalization, fearfulness, greater dependency, hyperactivity, and concern about sickness.

Predisposing Factors Female gender and older age (adolescence) increase the risk of COPCs. Certain

conditions (e.g., headache) are more common in males or have similar prevalence across genders during childhood, but the prevalence in females increases after puberty. Trauma or posttraumatic stress disorder increases psychological comorbidities in juvenile fibromyalgia. Some studies suggest that anxiety predisposes to chronic pain. A population-based study following children from 18 mo to 14 yr of age suggested that maternal psychological distress in early childhood and depressive and pain complaints in preadolescence increase the risk of recurrent abdominal pain at age 14. Postinfectious IBS is an identifiable risk factor for new-onset anxiety, depression, and sleep disruption in adults. Children with recurrent abdominal pain often have parents with abdominal pain. It is unclear if this association is caused by a common environmental/genetic factor or a learned behavior of the child imitating the parent.

Natural History The natural history of COPC is not well known. Chronic disabling fatigue in the general adolescent population persists 2-3 yr in about 25% of patients, but only 8% of youth affected at age 13 still had the complaints at ages 16 and 18. A meta-analysis suggests that the prognosis of CFS in children is usually good, with a small minority having persistent disabling symptoms. The patient's belief in an underlying physical disorder and the presence of psychiatric comorbidities predicts a poorer outcome. In a study of children with FGID, the outcome depended on specific variables. Those who perceived their abdominal pain as more threatening, with high levels of pain catastrophization and little capacity to cope with pain because of reduced activity levels, had a poorer outcome. This “high pain dysfunctional profile” subgroup was predominantly female (70%) with a mean age of 12.2 yr. Two thirds of this subgroup still complained of FGID at follow-up, vs about one third of those in the other groups. These groups included a “high pain adaptive profile” group with similar pain levels but better adaptive skills and less catastrophization, predominantly slightly younger (11.8 yr) females, and a “low pain adaptive profile” group, slightly younger (11.1 yr), with equal males and females but less abdominal pain, better coping mechanisms, and less impairment of daily activities. In the high pain dysfunctional profile group, 41% had both FGID and nonabdominal chronic pain at follow-up, vs 11% in the high pain adaptive and 17% in the low pain adaptive group. Another study following

children age 4-16.6 yr with IBS demonstrated resolution of symptoms in 58%, usually without medication. The differences between these studies may result from the age of the groups, with better outcome in the younger patients, as well as the number of comorbidities and psychological profile.

Proposed Pathophysiology There may be dysfunction in the hypothalamic-hypophyseal-adrenal axis, circadian patterns, autonomic responses, some aspects of CNS processing, the inflammatory immune response, and the musculoskeletal system. Vagal tone measured by heart rate variability is decreased in some children with FGID symptoms and in children with COPCs. Alterations in the autonomic nervous system may affect the immune system, as well as circadian patterns. The stress response may increase muscle tone, which in turn leads to body aches and tension headaches. In fibromyalgia the cortisol response is altered, with lower cortisol levels on awakening and throughout the day. Orthostatic intolerance from autonomic abnormalities may also contribute to poor concentration from brain hypoperfusion and blood pooling in the lower extremities. The pathophysiology has been better studied in myalgic encephalomyelitis (ME)/CFS (Chapter 147.1 ). ME/CFS has been associated with joint hypermobility, orthostatic intolerance, decreased range of motion, and reduced activity. These patients demonstrate excessive glial activation resulting in neuroexcitation, neuroinflammation, and possibly neurodegeneration. These features may contribute to the cognitive issues and fatigue present in this disorder. Neuroinflammation and other changes in processing may lead to abnormal descending inhibitory pain pathways, resulting in distal pain and “central sensitization.” The malfunction of descending antinociceptive pathways allows pain to spread in the body, associated with increased activity of the nociceptive facilitator pathways. These facilitator pathways are further activated by psychological factors, such as catastrophization, depression, lack of acceptance, and hypervigilance. Other signals such as pressure, sound, heat, and cold are also aberrantly processed, with activation of areas of the brain that are typically activated only by acute pain stimuli, such as the insula, prefrontal cortex, and anterior cingulate cortex, as well as some regions usually not involved in pain processing.

Treatment As general rules, chronic pain should never be treated with opioids , and cognitive-behavioral therapy (CBT) and a gradually progressive exercise program constitute the cornerstones of treatment. The complex comorbid nature of COPCs typically requires a multidisciplinary approach. Since neither CBT nor exercise will have any effect in the absence of full patient engagement and understanding, the team must include the family and the patient, a pain psychologist with experience in CBT, a physical therapist, and the primary care physician. Depending on comorbid conditions, rheumatology, neurology, or gastroenterology may have important roles for symptom management and possible alternative diagnosis. Depending on the initial symptomatology, the differential diagnosis should include inflammatory bowel disease, celiac disease, juvenile idiopathic arthritis, systemic lupus erythematosus, dermatomyositis, autoinflammatory disorders, Fabry disease, porphyrias, hereditary sensoryautonomic neuropathies, and Ehlers-Danlos syndrome. When a thorough evaluation for a structural cause of symptoms is unrevealing, an important next step is patient and family education . This should include the common presentation, the expectation that “markers” for these types of disorders would typically be absent, and the presence of solid management tools with high probability of improvement. Families and patients need to receive encouragement to stop seeking a “magic diagnosis and cure” and to begin the path to full recovery. Without this step, critical patient engagement in the treatment will not occur. In our practice, we sometimes call functional disorders a problem of “software,” in contrast to structural issues that would involve “hardware.” We explain that successful management must change the software, not just mask symptoms. Approaches that accomplish such a goal include CBT, and a rehabilitative program that may require physical therapy, vigorous exercise program with interval training, meditation, and/or yoga. Patients are often deconditioned and may need to start with a very low level of physical activity. In addition, their exercise tolerance may be significantly hampered by an orthostatic intolerance syndrome (e.g., POTS). For these reasons, we frequently recommend starting with a water aerobics program, which provides several benefits: (1) very low gravitational force, so the patient can be set up for success, working only on conditioning and not simultaneously fighting an orthostatic challenge; (2) builds both limb and core strength; and (3) gentle on joints for those with arthralgias or a hypermobility syndrome. When

water is unavailable, we recommend starting with a recumbent exercise program such as a recumbent stationary bike. In both circumstances, we then slowly introduce upright aerobic activities on land over 2-3 mo. Strength exercises are also useful. A Cochrane Review in adults with painful disorders showed exercise to have minimal side effects, to improve functionality, reduce pain, and improve quality of life. Patients with fibromyalgia who undergo a 3 mo multidisciplinary program with twice-weekly physical therapy and CBT benefited in function and physical activity level, and most importantly continued to exercise regularly at 1 yr follow-up. Pharmacologic interventions have less impact than nonmedical treatments. When children are missing school or are homebound, it is important to work closely with the school to encourage reentry to school. This may require modifying the school schedule initially, starting with fewer hours at school, and providing extra time for homework on days that the children are not feeling well. Although medications such as tricyclic antidepressants are often added to the treatment, the improvement with these medications for chronic pain is minimal, and the side effects need to be considered. Nonetheless, amitriptyline is often used because it helps in treating headaches and abdominal pain and improves sleep quality, a critical element to manage any chronic pain condition.

147.1

Chronic Fatigue Syndrome Mark R. Magnusson

Keywords myalgic encephalomyelitis ME/CFS systemic exertion intolerance disease SEID

postexertion malaise infectious mononucleosis neutrally mediated hypotension postural orthostatic tachycardia syndrome fibromyalgia cognitive impairment cognitive-behavioral therapy orthostatic intolerance Chronic fatigue syndrome (CFS ), also known as myalgic encephalomyelitis (ME) , is a complex, diverse, and debilitating illness characterized by chronic or intermittent fatigue accompanied by select symptoms and occurring in children, adolescents, and adults. The combination of fatigue and other symptoms interferes significantly with daily activities and has no identified medical explanation (Fig. 147.1 ). The fatigue does not require exertion by the patient, nor does rest relieve it. Some consider postexertion malaise, or worsening of the fatigue with additional symptoms after mental or physical exertion and lasting >24 hr, to be characteristic of CFS. A definitive causal agent or process has not been identified, although the differential diagnosis includes infectious, inflammatory, metabolic, genetic, and autoimmune diseases. Our understanding of this condition is largely from studies of adults and adolescents, with limited descriptions of chronic fatiguing illnesses in younger children.

FIG. 147.1 Functional status* of 471 patients enrolled in CDC Multisite Clinical Assessment† of ME/CFS§ —United States, September 2015. *Measured by box plots of scores in the 8 subscales of Short-Form Health Survey (SF-36) scores (25th and 75th percentile at bottom and top of box). SF-36 scores range from 0-100, with higher scores indicating better functioning. † https://www.cdc.gov/cfs/programs/clinicalassessment/index.html . § ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) patients show significant impairment, particularly in vitality and physical functioning subscale scores, but with preservation of mental health and emotional role functioning. (From Unger ER, Lin JMS, Brimmer DJ, et al: CDC Grand Rounds: Chronic fatigue syndrome— advancing research and clinical education, MMWR 65(50-51):1434–1438, 2016.)

The illness was formally defined in 1988 as chronic fatigue syndrome because persistent unexplained fatigue was considered the principal and invariable physical symptom. A variety of other names have been used to describe the illness, including chronic mononucleosis, chronic Epstein-Barr virus (EBV) infection, postinfection syndrome, and immune dysfunction syndrome. Several case definitions have been developed and are in use in both clinical care and

research (Table 147.1 ). Table 147.1

Overview of Current Case Definitions for Systemic Exertion Intolerance Disease (SEID) and Past Definitions of Chronic Fatigue Syndrome or Myalgic Encephalomyelitis SYMPTOM Fatigue and impairment of daily function Sudden onset Muscle weakness Muscle pain Postexertional symptoms Sleep disturbance Memory or cognitive disturbances Autonomic symptoms Sore throat Lymph node involvement Cardiovascular symptoms Headaches Arthralgias

SEID ≥ 6 mo Yes

CFS ≥ 6 mo Yes

ME ≥ 6 mo Yes

Yes Yes Yes

Yes Yes

Yes Yes Yes Yes

Yes Yes Yes Yes Yes

Yes

CFS, Chronic fatigue syndrome; ME, myalgic encephalomyelitis. Data from Institute of Medicine: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Redefining an Illness. Washington, DC, National Academies Press 2015; Jason L, Evans M, Porter N, et al: The development of a revised Canadian myalgic encephalomyelitis chronic fatigue syndrome case definition. Am J Biochem Biotechnol 6:120 135, 2010; Reeves WC, Wagner D, Nisenbaum R, et al: Chronic fatigue syndrome—a clinically empirical approach to its definition and study. BMC Med 3:19, 2005.

The Institute of Medicine (IOM) 2015 recommendations apply to all ages and include a special focus on pediatrics. The IOM suggested new diagnostic criteria and a new name, systemic exertion intolerance disease (SEID) , to emphasize the postexertion malaise criterion and better understand the illness (Table 147.2 ). The most recent expert consensus report (June 2017) from the International Writing Group for Pediatric ME/CFS provides a primer for diagnosis and management.

Table 147.2

Criteria for Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Patient has each of the following 3 symptoms at least half the time, to at least a moderately severe degree: • A substantial reduction or impairment in the ability to engage in preillness levels of occupational, educational, social, or personal activities that persists for >6 mo and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest. • Postexertional malaise* • Unrefreshing sleep* Plus at least 1 of the 2 following manifestations (chronic, severe): • Cognitive impairment* • Orthostatic intolerance

* Frequency and severity of symptoms should be assessed. The diagnosis of

ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity. From Institute of Medicine: Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness, Washington, DC, 2015, National Academies Press.

Epidemiology Based on worldwide studies, 0.2–2.3% of adolescents or children have CFS. Most epidemiology studies use the 1994 definition. CFS is more prevalent in adolescents than in younger children. The variation in CFS prevalence estimates may result from variations in case definition, study methodology and application, study population composition (specialty vs general practice or general population), and data collection (parent, self-reporting vs clinician evaluation). Gender distribution in children differs from that in adults, with a more equal distribution in children 100 distinct substances, including cytokines, growth factors, and sterol hormones, placing it in a class with the hepatocyte. Because of the profound effect of some of these secretory products on other cells and the large number and widespread distribution of macrophages, this network of cells can be viewed as an important endocrine organ. IL-1 illustrates this point. Microbes and microbial products, burns, ischemia–reperfusion, and other causes of inflammation or tissue damage stimulate the release of IL-1, mainly by monocytes, macrophages, and epithelial cells. In turn, IL-1 elicits fever, sleep, and release of IL-6, which induces production of acute-phase proteins. The complex relationship between mononuclear phagocytes and cancer is becoming more clear. Macrophages have been demonstrated to kill tumor cells by ingestion and by means of secreted products, including lysosomal enzymes, nitric oxide, oxygen metabolites, and TNF-α. In contrast, M2-type tumorassociated macrophages (TAMs) can stimulate growth of tumors through secretion of growth and angiogenic factors such as vascular endothelial growth factor (VEGF), promote metastasis, and inhibit T-cell antitumor immune responses. TAMs are currently targets of clinical trials studying attempts to reprogram them to antitumor macrophages or otherwise blunt their tumorsupportive capacity.

As traumatic damage and infection subside, the macrophage population shifts toward playing an essential role in tissue repair and healing through removal of apoptotic cells and secretion of IL-10, transforming growth factor-β, lipoxins, and the “specialized proresolving mediators,” omega-3 fatty acid–derived resolvins, protectins, and maresins.

Dendritic Cells Dendritic cells are a type of mononuclear phagocyte found in blood, lymphoid organs, and all tissues. DCs are specialized to capture, process, and present antigens to T cells to generate adaptive immunity or tolerance to self-antigens. Human monocytes can be induced to differentiate into DCs in some circumstances, particularly inflammation. DCs express retractable dendritic (branched) extensions and potent endocytic capacity but are a heterogeneous population from the standpoint of location, surface markers, level of antigenpresenting activity, and function. Single-cell RNA sequencing has defined 6 human DC subtypes; but 2 major functional types of DCs can be identified: conventional DCs, which include Langerhans cells in the epithelial surfaces of skin and mucosa, dermal or interstitial DCs in subepithelial skin, and interstitial DCs in solid organs; and plasmacytoid DCs, sentinels for viral infection and principal source of antiviral IFN-α and IFN-β. DCs migrating from the bloodstream enter skin, epithelial surfaces, and lymphoid organs where, as immature cells, they internalize self and foreign antigens. Microbial products, cytokines, or molecules exposed in damaged tissue (“danger signals” or “alarmins”) induce DC maturation, with upregulation of cytokine receptors and MHC class II and co-stimulatory molecules that expedite cell-cell binding. Stimulated DCs in the periphery migrate to lymphoid organs, where they continue to mature. They function there as the most potent cells that present antigens to T lymphocytes and induce their proliferation, activities that are central to the antigen-specific adaptive immune response. Macrophage IL-10 acts to suppress DC maturation during resolution of inflammation. DCs from cancer patients have been used in an attempt to control their cancer. The patient's DCs are amplified and matured from blood monocytes or marrow progenitor cells by cytokines, exposed to antigens from the patient's tumor, then injected into the patient as a “vaccine” against the cancer.

Abnormalities of Monocyte-Macrophage or Dendritic Cell Function Mononuclear phagocytes and neutrophils from patients with chronic granulomatous disease (CGD) exhibit a profound defect of phagocytic killing (see Chapter 156 ). The inability of affected macrophages to kill ingested organisms leads to abscess formation and characteristic granulomas at sites of macrophage accumulation beneath the skin and in the liver, lungs, spleen, and lymph nodes. IFN-γ is used to prevent infection in CGD patients and to treat the decreased bone resorption of congenital osteopetrosis , which is caused by decreased function of osteoclasts. Genetic deficiency of the CD11/CD18 complex of membrane adherence glycoproteins (leukocyte adhesion defect 1), which includes a receptor for opsonic complement component 3, results in impaired phagocytosis by monocytes (see Chapter 156 ). The monocyte-macrophage system is prominently involved in lipid storage diseases called sphingolipidoses (see Chapter 104 ). In these conditions, macrophages express a systemic enzymatic defect that permits accumulation of cell debris that they normally clear. Resistance to infection can be impaired, at least partly because of impairment in macrophage function. In Gaucher disease , the prototype for these disorders, the enzyme glucocerebrosidase functions abnormally, allowing accumulation of glucocerebroside from cell membranes in Gaucher cells throughout the body. In all locations the Gaucher cell is an altered macrophage. These patients can be treated with infusions of the normal enzyme modified to expose mannose residues, which bind to mannose receptors on macrophages. The cytokine IL-12 is a powerful inducer of IFN-γ production by T cells and NK cells. Individuals with inherited deficiency in macrophage receptors for IFNγ or lymphocyte receptors for IL-12, or in IL-12 itself, undergo a severe, selective susceptibility to infection by nontuberculous mycobacteria such as Mycobacterium avium complex or bacille Calmette-Guérin (see Chapter 152 ). About half these patients have had disseminated Salmonella infection. These abnormalities are grouped as defects in the IFN- γ–IL-12 axis . Monocyte-macrophage function has been shown to be partially abnormal in various clinical conditions. Cultured mononuclear phagocytes of newborns are more readily infected than adult cells by HIV-1 and measles virus. Macrophages from newborns release less granulocyte colony-stimulating factor (G-CSF) and

IL-6 in culture, and this deficiency is accentuated in cells from preterm infants. This finding supports the observations that G-CSF levels are significantly decreased in blood from newborns, and that the marrow granulocyte storage pool is diminished in infants, particularly preterm infants. Mononuclear cells from newborns produce less IFN-γ and IL-12 than do adult cells, and macrophages cultured from cord blood are not activated normally by IFN-γ. This combination of deficiencies would be expected to blunt the newborn's response to infection by viruses, fungi, and intracellular bacteria. More than 100 different subtypes of the histiocytoses have been organized into 5 major groups based on clinical, pathologic, genetic, and other features. These rare disorders are characterized by accumulation of macrophages or DCs in tissues or organs. “Histiocyte” is a histologic term and not cell specific, but it has been retained because of its long usage to identify the classic members of this family. Familial and secondary hemophagocytic lymphohistiocytosis is characterized by uncontrolled activation of T cells and macrophages, with resultant fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, marked elevation of serum proinflammatory cytokines, and macrophage hemophagocytosis (see Chapter 534 ). The familial form usually presents in the 1st yr of life. Up to 5% of children with systemic-onset juvenile rheumatoid arthritis develop an acute severe complication termed macrophage activation syndrome , with persistent fever (rather than typical febrile spikes), hepatosplenomegaly, pancytopenia, macrophage hemophagocytosis, and coagulopathy, which can progress to disseminated intravascular coagulation and death if not recognized (see Chapter 180 ). Two genetic autoinflammatory diseases result from dysregulation of the mononuclear phagocyte–produced proinflammatory cytokine IL-1. In neonatalonset multisystem inflammatory disorder , monocytes overproduce IL-1. In deficiency of the IL-1 receptor antagonist , normal activity levels of IL-1 go unopposed. In both conditions, patients present in the 1st few days or weeks of life with pustular or urticarial rash, bony overgrowth, sterile osteomyelitis, elevated erythrocyte sedimentation rate, and other evidence of systemic inflammation. The recombinant IL-1 receptor antagonist anakinra is effective treatment for both these disorders (Chapter 188 ).

Bibliography Emile J-F, Oussama A, Fraitag S, et al. Revised classification of

histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood . 2016;127:2672–2681. Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol . 2017;17:349–362. Serhan CN. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. EMBO J . 2017;31:1273–1288. Tam VC, Aderem A. Macrophage activation as an effector mechanism for cell-mediated immunity. J Immunol . 2014;193:3183–3184 [Introducing reproduced pillar articles: Mackaness GB: J Exp Med 116:381–406, 1962 and J Exp Med 120:105–120, 1964]. Underwood E. Wired: Beth Stevens and her network of collaborators are showing how immune cells sculpt connections in the brain. Science . 2016;353:762–785. Villani A-C, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science . 2017;356:283. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature . 2013;496:445–455. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol . 2017;10:58–69.

CHAPTER 155

Eosinophils Benjamin L. Wright, Brian P. Vickery

Eosinophils are distinguished from other leukocytes by their morphology, constituent products, and association with specific diseases. Eosinophils are nondividing, fully differentiated cells with a diameter of approximately 8 µm and a bilobed nucleus. They differentiate from stem cell precursors in the bone marrow under the control of T-cell–derived interleukin-3 (IL-3), granulocytemacrophage colony-stimulating factor (GM-CSF), and especially IL-5. Their characteristic membrane-bound specific granules stain bright pink with eosin and consist of a crystalline core made up of major basic protein (MBP) surrounded by a matrix containing the eosinophil cationic protein (ECP), eosinophil peroxidase (EPX), and eosinophil-derived neurotoxin (EDN). These basic proteins are cytotoxic for the larval stages of helminthic parasites and are also thought to contribute to much of the inflammation associated with chronic allergic diseases such as asthma (see Chapter 169 ). Eosinophil MBP, ECP, and EPX are also present in large quantities in the airways of patients who have died of asthma and are thought to inflict epithelial cell damage leading to airway hyperresponsiveness, although recent studies indicate the role of these granule proteins may be more nuanced and not purely destructive. Eosinophil granule contents also contribute to eosinophilic endomyocardial disease associated with the hypereosinophilic syndrome. MBP has the potential to activate other proinflammatory cells, including mast cells, basophils, neutrophils, and platelets. Eosinophils have the capacity to generate large amounts of the lipid mediators platelet-activating factor and leukotriene C4 , both of which can cause vasoconstriction, smooth muscle contraction, and mucus hypersecretion (Fig. 155.1 ). Eosinophils are a source of a number of proinflammatory cytokines, including IL-1, IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. They have also been shown to influence T-cell recruitment and

immune polarization in inflammatory settings. Thus, eosinophils have considerable potential to initiate and sustain the inflammatory response of the innate and acquired immune systems.

FIG. 155.1 Schematic diagram of an eosinophil and its diverse properties. Eosinophils are bilobed granulocytes that respond to diverse stimuli, including allergens, helminths, viral infections, allografts, and nonspecific tissue injury. Eosinophils express the receptor for IL-5, a critical eosinophil growth and differentiation factor, as well as the receptor for eotaxin and related chemokines (CCR3). The secondary granules contain four primary cationic proteins designated eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil cationic protein (ECP) and eosinophilderived neurotoxin (EDN). All 4 proteins are cytotoxic molecules; also, ECP and EDN are ribonucleases. In addition to releasing their preformed cationic proteins, eosinophils can release a variety of cytokines, chemokines and neuromediators and generate large amounts of LTC4. Lastly, eosinophils can be induced to express MHC class II and co-stimulatory molecules and may be involved in propagating immune responses by presenting antigen to T cells. (From Leung YM, Szefler SJ, Bomilla FA, Akdis CA, Sampson HA: Pediatric allergy principles and practice, ed 3, Philadelphia, 2016, Elsevier, p 42.)

Eosinophil migration from the vasculature into the extracellular tissue is mediated by the binding of leukocyte adhesion receptors to their ligands or counterstructures on the postcapillary endothelium. Similar to neutrophils (see Fig. 153.2 ), transmigration begins as the eosinophil selectin receptor binds to the endothelial carbohydrate ligand in loose association, which promotes eosinophils rolling along the endothelial surface until they encounter a priming stimulus such as a chemotactic mediator. Eosinophils then establish a high-

affinity bond between integrin receptors and their corresponding immunoglobulin-like ligand. Unlike neutrophils, which become flattened before transmigrating between the tight junctions of the endothelial cells, eosinophils can use unique integrins, known as very late antigens (VLA-4), to bind to vascular cell adhesion molecule (VCAM)-1, which enhances eosinophil adhesion and transmigration through endothelium. Eosinophils are recruited to tissues in inflammatory states by a group of chemokines known as eotaxins (eotaxin 1, 2, and 3). These unique pathways account for selective accumulation of eosinophils in allergic and inflammatory disorders. Eosinophils normally dwell primarily in tissues, especially tissues with an epithelial interface with the environment, including the respiratory, gastrointestinal (GI), and lower genitourinary tracts. The life span of eosinophils may extend for weeks within tissues. IL-5 selectively enhances eosinophil production, adhesion to endothelial cells, and function. Considerable evidence shows that IL-5 has a pivotal role in promoting eosinophilpoeisis. It is the predominant cytokine in allergen-induced pulmonary late-phase reaction, and antibodies against IL-5 (mepolizumab, reslizumab, benralizumab), decrease sputum eosinophils and reduce exacerbations in a subset of patients with asthma. Eosinophils also bear unique receptors for several chemokines, including RANTES (regulated on activation, normal T-cell expressed and secreted), eotaxin, and monocyte chemotactic proteins 3 and 4. These chemokines appear to be key mediators in the induction of tissue eosinophilia.

Diseases Associated With Eosinophilia The absolute eosinophil count (AEC ) is used to quantify peripheral blood eosinophilia. Calculated as the white blood cell (WBC) count/µL × percent of eosinophils, it is usually 5,000 cells/µL) eosinophilia in peripheral blood (Table 155.1 ). These disorders may range from mild and transient to chronic and life threatening. Importantly, blood eosinophil numbers do not always reflect the extent of eosinophil involvement in tissues and degranulation products may

more accurately reflect disease activity. Because prolonged eosinophilia is associated with end-organ damage, especially involving the heart, patients with persistently elevated AECs should undergo a thorough evaluation to search for an underlying cause.

Table 155.1

Causes of Eosinophilia Allergic Disorders Allergic rhinitis Asthma Acute and chronic urticaria Eczema Angioedema Hypersensitivity drug reactions (drug rash with eosinophilia and systemic symptoms [DRESS]) Eosinophilic gastrointestinal disorders Interstitial nephritis

Infectious Diseases Tissue-Invasive Helminth Infections Trichinosis Toxocariasis Strongyloidosis Ascariasis Filariasis Schistosomiasis Echinococcosis Amebiasis Malaria Scabies Toxoplasmosis Other Infections

Pneumocystis jirovecii Scarlet fever Allergic bronchopulmonary aspergillosis (ABPA) Coccidioidomycosis Human immunodeficiency virus (HIV)

Malignant Disorders Hodgkin disease and T-cell lymphoma Acute myelogenous leukemia Myeloproliferative disorders Eosinophilic leukemia Brain tumors

Gastrointestinal Disorders Inflammatory bowel disease Peritoneal dialysis Chronic active hepatitis Eosinophilic gastrointestinal disorders: Eosinophilic esophagitis Eosinophilic gastroenteritis Eosinophilic colitis

Rheumatologic Disease Rheumatoid arthritis Eosinophilic fasciitis Scleroderma Dermatomyositis Systemic lupus erythematosus IgG4-related disease Eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis)

Immunodeficiency/Immune Dysregulation Disease

Hyperimmunoglobulin E syndromes Wiskott-Aldrich syndrome Graft-versus-host disease Omenn syndrome Severe congenital neutropenia Autoimmune lymphoproliferative syndromes (ALPS) Immune dysregulation, polyendocrinopathy, X-linked (IPEX) Transplant rejection (solid organ)

Miscellaneous Thrombocytopenia with absent radii Hypersensitivity pneumonitis Adrenal insufficiency Postirradiation of abdomen Histiocytosis with cutaneous involvement Hypereosinophilic syndromes Cytokine infusion Pemphigoid

Allergic Diseases Allergy is the most common cause of eosinophilia in children in the United States. Patients with allergic asthma typically have eosinophils in the blood, sputum, and/or lung tissue. Hypersensitivity drug reactions can elicit eosinophilia, and when associated with organ dysfunction (e.g., DRESS [drug rash with eosinophilia and systemic symptoms]), these reactions can be serious (see Chapter 177 ). If a drug is suspected of triggering eosinophilia, biochemical evidence of organ dysfunction should be sought, and if found, the drug should be discontinued. Various skin diseases have also been associated with eosinophilia, including atopic dermatitis/eczema, pemphigus, urticaria, and toxic epidermal necrolysis. Eosinophilic gastrointestinal diseases are important emerging allergic causes of eosinophilia in tissue and, in some cases, peripheral blood (see Chapter 363 ). In these conditions, eosinophils are recruited to esophagus, stomach, and/or intestine, where they cause tissue inflammation and clinical symptoms such as dysphagia, food aversion, abdominal pain, vomiting, and diarrhea. Treatment

options include allergen elimination diets and swallowed or inhaled corticosteroids.

Infectious Diseases Eosinophilia is often associated with invasive infection with multicellular helminthic parasites, which are the most common cause in developing countries. Table 155.1 includes examples of specific organisms. The level of eosinophilia tends to parallel the magnitude and extent of tissue invasion, especially by larvae such as visceral larva migrans (see Chapter 324 ). Eosinophilia often does not occur in established parasitic infections that are well contained within tissues or are solely intraluminal in the gastrointestinal tract, such as Giardia lamblia and Enterobius vermicularis infection. In evaluating patients with unexplained eosinophilia, the dietary history and geographic or travel history may indicate potential exposures to helminthic parasites. It is frequently necessary to examine the stool for ova and larvae at least 3 times. Additionally, the diagnostic parasite stages of many of the helminthic parasites that cause eosinophilia never appear in feces. Thus, normal results of stool examinations do not absolutely preclude a helminthic cause of eosinophilia; diagnostic blood tests or tissue biopsy may be needed. Toxocara causes visceral larva migrans usually in toddlers with pica (see Chapter 324 ). Most young children are asymptomatic, but some develop fever, pneumonitis, hepatomegaly, and hypergammaglobulinemia accompanied by severe eosinophilia. Isohemagglutinins are frequently elevated, and serology can establish the diagnosis. Two fungal diseases may be associated with eosinophilia: aspergillosis in the form of allergic bronchopulmonary aspergillosis (see Chapter 264.1 ) and coccidioidomycosis (see Chapter 267 ) following primary infection, especially in conjunction with erythema nodosum. HIV infection can also be associated with peripheral eosinophilia.

Hypereosinophilic Syndrome The idiopathic hypereosinophilic syndrome is a heterogeneous group of disorders characterized by sustained overproduction of eosinophils. The 3 diagnostic criteria for this disorder are (1) AEC >1,500 cells/µL persisting for 6 mo or longer or at least on 2 occasions or with evidence of tissue eosinophilia;

(2) absence of another diagnosis to explain the eosinophilia; and (3) signs and symptoms of organ involvement. The clinical signs and symptoms of hypereosinophilic syndrome can be heterogeneous because of the diversity of potential organ (pulmonary, cutaneous, neurologic, serosal, GI) involvement. Eosinophilic endomyocardial disease, one of the most serious and lifethreatening complications, can cause heart failure from endomyocardial thrombosis and fibrosis. Eosinophilic leukemia, a clonal myeloproliferative variant, may be distinguished from idiopathic hypereosinophilic syndrome by demonstrating a clonal interstitial deletion on chromosome 4q12 that fuses the platelet-derived growth factor receptor-α (PDGFRA ) and FIP1-like-1 (FIP1L1 ) genes; this disorder is treated with imatinib mesylate, a tyrosine kinase inhibitor, which helps target the fusion oncoprotein (Fig. 155.2 ).

FIG. 155.2 Revised classification of hypereosinophilic syndromes. Changes from the previous classification are indicated in red. Dashed arrows identify hypereosinophilic syndrome (HES) forms for which at least some patients have T-cell–driven disease. Classification of myeloproliferative forms has been simplified, and patients with HES and eosinophil hematopoietin–producing T cells in the absence of a T-cell clone are included in the lymphocytic forms of HES. CEL, Chronic eosinophilic leukemia; CSS, Churg-Strauss syndrome; IBD, inflammatory bowel disease. (From Simon HU, Rothenberg ME, Bocher BS, et al: Refining the definition of hypereosinophilic syndrome, J Allergy Clin Immunol 126:47, 2010.)

Therapy is aimed at suppressing eosinophilia and is initiated with corticosteroids. Imatinib mesylate may be effective in FIP1L1-PDGFRA– negative patients. Hydroxyurea or interferon-alfa may be beneficial in patients

unresponsive to corticosteroids. Specific anti–IL-5 monoclonal antibodies (mepolizumab) target this cytokine, which has a central role in eosinophil differentiation, mobilization, and activity. With therapy, the eosinophil count declines and corticosteroid doses may be reduced. For patients with prominent organ involvement who fail to respond to therapy, the mortality is about 75% after 3 yr.

Miscellaneous Diseases Eosinophilia is observed in many patients with primary immunodeficiency syndromes, especially hyper-IgE syndrome, Wiskott-Aldrich syndrome, and Omenn syndrome (see Chapters 148 and 152 ). Eosinophilia is also frequently present in the syndrome of thrombocytopenia with absent radii and in familial reticuloendotheliosis with eosinophilia. Eosinophilia can be found in patients with Hodgkin disease, as well as in acute lymphoid and myeloid leukemia. Other considerations include GI disorders such as ulcerative colitis, Crohn disease during symptomatic phases, chronic hepatitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis), and adrenal insufficiency.

Bibliography Bochner BS, Book W, Busse WW, et al. Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD). J Allergy Clin Immunol . 2012;130(3):587–596. Curtis C, Ogbogu PU. Evaluation and differential diagnosis of persistent marked eosinophilia. Immunol Allergy Clin North Am . 2015;35(3):387–402. Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med . 2015;373(17):1640–1648. Gotlib J. World Health Organization–defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management. Am J Hematol . 2015;90(11):1077–1089. Klion AD. How I treat hypereosinophilic syndromes. Blood . 2015;126(9):1069–1077.

Legraand F, Klion AD. Biologic therapies targeting eosinophils: current status and future prospects. J Allergy Clin Immunol Pract . 2015;3(2):167–174. Rosenberg HF, Dyer KD, Foster PS. Eosinophils: changing perspectives in health and disease. Nat Rev Immunol . 2013;13(1):9–22. Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol . 2010;126(1):39– 44. Simon HU, Rothenberg ME, Bocher BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol . 2010;126:45–49. Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol . 2012;130(3):607–612.

CHAPTER 156

Disorders of Phagocyte Function Thomas D. Coates

Neutrophils are the first line of defense against microbial invasion. They arrive at the site of inflammation during the critical 2-4 hr after microbial invasion to contain the infection and prevent hematogenous dissemination. This wellorchestrated process is one of the most interesting stories in modern cell biology. In fact, much of our knowledge about neutrophil function derives from studies done in patients with genetic errors in neutrophil function. These critical functions and their associated disorders are depicted in Fig. 153.2 . Children with phagocytic dysfunction present at a young age with recurrent infections that often involve unusual organisms and are poorly responsive to treatment. Primary defects of phagocytic function comprise 54.4°C [130°F]). The only effective measure for avoiding animal allergens in the home is the removal of the pet. Avoidance of pollen and outdoor molds can be accomplished by staying in a controlled environment. Air conditioning allows for keeping windows and doors closed, reducing the pollen exposure. High-efficiency particulate air (HEPA) filters lower the counts of airborne mold spores. Oral antihistamines help reduce sneezing, rhinorrhea, and ocular symptoms. Administered as needed, antihistamines provide acceptable treatment for mildintermittent disease. Antihistamines have been classified as first generation (relatively sedating) or second generation (relatively nonsedating). Antihistamines usually are administered by mouth but are also available for topical ophthalmic and intranasal use. Both first- and second-generation antihistamines are available as nonprescription drugs. Second-generation antihistamines are preferred because they cause less sedation . Preparations containing pseudoephedrine , typically in combination with other agents, are used for relief of nasal and sinus congestion and pressure and other symptoms such as rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, and cough. Pseudoephedrine is available without prescription (generally in fixed combination with other agents such as first-generation antihistamines: brompheniramine, chlorpheniramine, triprolidine; second-generation antihistamines: desloratadine, fexofenadine, loratadine; antipyretics: acetaminophen, ibuprofen; antitussives: guaifenesin, dextromethorphan; anticholinergic: methscopolamine). Pseudoephedrine is an oral vasoconstrictor distrusted for causing irritability and insomnia and for its association with infant mortality. Because younger children (2-3 yr) are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations have voluntarily revised their product labeling to warn against the use of preparations containing pseudoephedrine for children 14 yr: 10 mg daily

* Contains phenylalanine.

Dosing recommendations taken in part from Engorn B, Flerlage J, for the Johns Hopkins Hospital: The Harriet Lane Handbook , ed 20, Philadelphia, 2015, Elsevier/Saunders.

Table 168.3

Oral Allergic Rhinitis Treatments (Nonprescription, Examples) GENERIC/BRAND STRENGTH FORMULATIONS FIRST-GENERATION H1 ANTAGONISTS Chlorpheniramine maleate Chlor-Trimeton 4 mg Tablets OTC (over the counter) Chlor-Trimeton 2 mg/5 mL Syrup Syrup OTC SECOND-GENERATION H1 ANTAGONISTS Cetirizine Children's 1 mg/mL Syrup Zyrtec Allergy Syrup OTC Children's 5 mg, 10 mg Chewable tablets Zyrtec Chewable OTC Zyrtec tablets 5 mg, 10 mg Tablets

DOSING

2-5 yr: 1 mg every 4-6 hr (max 6 mg/day) 6-11 yr: 2 mg every 4-6 hr (max 12 mg/day) >12 yr: 4 mg every 4-6 hr (max 24 mg/day)

6-12 mo: 2.5 mg once daily

12-23 mo: initial: 2.5 mg once daily; dosage may be increased to 2.5 mg twice daily

2-5 yr: 2.5 mg/day; may be increased to max of 5

OTC Zyrtec Liquid Gels OTC Levocetirizine Xyzal Desloratadine Clarinex Desloratadine Clarinex Fexofenadine HCl OTC Children's Claritin OTC Children's Allegra OTC ODT* Children's Allegra Oral Suspension OTC Allegra OTC Loratadine Alavert OTC ODT*

10 mg

Liquid-filled gels

Tablet Oral solution

mg/day given either as a single dose or divided into 2 doses ≥6 yr: 5-10 mg/day as a single dose or divided into 2 doses

5 mg 0.5 mg/mL 0.5 mg/mL

Oral solution

5 mg

Tablet

30 mg, 60 mg, 180 mg

Tablet

6-11 yr: 30 mg twice daily 12-adult: 60 mg twice daily; 180 mg once daily

5 mg/5 mL

Syrup

2-5 yr: 5 mg once daily 6-adult: 10 mg once daily

30 mg

Orally disintegrating tablets

6-11 yr: 30 mg twice daily

30 mg/5 mL

Suspension

>2-11 yr: 30 mg every 12 hr

Tabs 30, 60, 180 mg

Tablet

>12 yr-adult: 60 mg every 12 hr; 180 mg once daily

10 mg 10 mg 10 mg 5 mg 1 mg/mL

Orally disintegrating tablets Tablets Liquid-filled caps Chewable tablets Syrup

2-5 yr: 1.25 mg once daily in the evening 6-11 yr: 2.5 mg orally once daily in the evening ≥12 yr: 5 mg orally once daily in the evening 6-11 mo: 2 mL once daily 12 mo-5 yr: 2.5 mL once daily 6-11 yr: 5 mL once daily 12-adult: 5 mg once daily

2-5 yr: 5 mg once daily >6 yr: 10 mg once daily or 5 mg twice daily

* Contains phenylalanine.

Dosing recommendations taken in part from Engorn B, Flerlage J, for the Johns Hopkins Hospital: The Harriet Lane Handbook , ed 20. Philadelphia, 2015 Elsevier/Saunders.

Table 168.4

Combined Antihistamine + Sympathomimetic (Examples) GENERIC Chlorpheniramine maleate Phenylephrine

STRENGTH 4 mg 10 mg

FORMULATIONS DOSING Tablets >12 yr: 1 tablet every 4 hr, not to exceed 6 tablets per day

HCl Sudafed Sinus & Allergy Cetirizine + pseudoephedrine Zyrtec-D 12 hour

5 mg cetirizine + 120 mg pseudoephedrine

Extended-release tablet

>12 yr: 1 tablet every 12 hr

Dosing recommendations taken in part from Engorn B, MD, Flerlage J for the Johns Hopkins Hospital: The Harriet Lane Handbook , ed 20. Philadelphia, 2015 Elsevier/Saunders.

The anticholinergic nasal spray ipratropium bromide is effective for the treatment of serous rhinorrhea (Table 168.5 ). Intranasal decongestants (oxymetazoline and phenylephrine) should be used for 12 yr: 1-2 sprays bid Cromolyn sodium: I: AR. M: Inhibition of mast cell degranulation NasalCrom >2 yr: 1 spray tid-qid; max 6 times daily Oxymetazoline: I: Symptomatic relief of nasal Afrin mucosal congestion Nostrilla M: Adrenergic agonist, vasoconstricting agent 0.05% solution: instill 2-3 sprays into each nostril bid; therapy should not exceed 3 days.

Phenylephrine:

Neo-Synephrine

I: Symptomatic relief of nasal mucosal congestion M: Adrenergic, vasoconstricting agent 2-6 yr: 1 drop every 2-4 hr of 0.125% solution as needed. Note: Therapy should not exceed 3 continuous days. 6-12 yr: 1-2 sprays or 1-2 drops every 4 hr of 0.25% solution as needed. Note: Therapy should not exceed 3 continuous days. >12 yr: 1-2 sprays or 1-2 drops every 4 hr of 0.25% to 0.5% solution as needed; 1% solution may be used in adults with extreme nasal congestion. Note: Therapy should not exceed 3 continuous days.

bitter taste

Not effective immediately; requires frequent administration

Excessive dosage may cause profound central nervous system (CNS) depression. Use in excess of 3 days may result in severe rebound nasal congestion. Do not repeat more than once a month. Use with caution in patients with hyperthyroidism, heart disease, hypertension, or diabetes. Adverse effects: Hypertension, palpitations, reflex bradycardia, nervousness, dizziness, insomnia, headache, CNS depression, convulsions, hallucinations, nausea, vomiting, mydriasis, elevated intraocular pressure, blurred vision Use in excess of 3 days may result in severe rebound nasal congestion. Do not repeat more than once a month. 0.16% and 0.125% solutions are not commercially available. Adverse effects: Reflex bradycardia, excitability, headache, anxiety, dizziness

bid, 2 times daily; tid, 3 times daily; qid, 4 times daily.

Table 168.6

Intranasal Inhaled Corticosteroids DRUG Beclomethasone: OTC (over the

INDICATIONS (I), MECHANISM(s) OF ACTION (M), AND DOSING I: AR M: Antiinflammatory,

COMMENTS, CAUTIONS, ADVERSE EVENTS, AND MONITORING Shake container before use; blow nose; occlude 1 nostril, administer dose to the other nostril.

counter) Beconase AQ (42 µg/spray) Qnasl (80 µg/spray) OTC

Flunisolide OTC

Triamcinolone Nasacort AQ (55 µg/spray) OTC Fluticasone propionate (available as generic preparation): OTC

immune modulator 6-12 yr: 1 spray in each nostril bid; may increase if needed to 2 sprays in each nostril bid >12 yr: 1 or 2 sprays in each nostril bid 6-14 yr: 1 spray each nostril tid or 2 sprays in each nostril bid; not to exceed 4 sprays/day in each nostril ≥15 yr: 2 sprays each nostril bid (morning and evening); may increase to 2 sprays tid; maximum dose: 8 sprays/day in each nostril (400 µg/day)

Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth.

I: AR M: Antiinflammatory, immune modulator 2-6 yr: 1 spray in each nostril qd 6-12 yr: 1-2 sprays in each nostril qd ≥12 yr: 2 sprays in each nostril qd I: AR M: Antiinflammatory, immune modulator

Shake container before use; blow nose; occlude 1 nostril, administer dose to the other nostril. Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth.

Flonase (50 µg/spray) ≥4 yr: 1-2 sprays in each OTC nostril qd Fluticasone furoate: 2-12 yr: Veramyst (27.5 Initial dose: 1 spray µg/spray) (27.5 µg/spray) per nostril qd (55 µg/day) Patients who do not show adequate response may use 2 sprays per nostril qd (110 µg/day) Once symptoms are controlled, dosage may be reduced to 55 µg qd Total daily dosage should not exceed 2 sprays in each nostril

Shake container before use; blow nose; occlude 1 nostril, administer dose to the other nostril. Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth.

Shake container before use; blow nose; occlude 1 nostril, administer dose to the other nostril. Ritonavir significantly increases fluticasone serum concentrations and may result in systemic corticosteroid effects. Use fluticasone with caution in patients receiving ketoconazole or other potent cytochrome P450 3A4 isoenzyme inhibitor. Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth.

Mometasone:

Nasonex (50 µg/spray)

(110 µg)/day ≥12 yr and adolescents: Initial dose: 2 sprays (27.5 µg/spray) per nostril qd (110 µg/day) Once symptoms are controlled, dosage may be reduced to 1 spray per nostril qd (55 µg/day). Total daily dosage should not exceed 2 sprays in each nostril (110 µg)/day. I: AR M: Antiinflammatory, immune modulator 2-12 yr: 1 spray in each nostril qd >12 yr: 2 sprays in each nostril qd

Mometasone and its major metabolites are undetectable in plasma after nasal administration of recommended doses. Preventive treatment of seasonal AR should begin 2-4 wk prior to pollen season. Shake container before use; blow nose; occlude 1 nostril, administer dose to the other nostril. Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth.

I: AR Shake container before use; blow nose; occlude 1 M: Antiinflammatory, nostril, administer dose to the other nostril. immune modulator Adverse effects: Burning and irritation of nasal mucosa, epistaxis Rhinocort Aqua (32 6-12 yr: 2 sprays in each Monitor growth. µg/spray) nostril qd OTC >12 yr: up to 4 sprays in each nostril qd (max dose) Ciclesonide: I: AR Prior to initial use, gently shake, then prime the M: Antiinflammatory, pump by actuating 8 times. immune modulator If the product is not used for 4 consecutive days, gently shake and reprime with 1 spray or until a Omnaris 2-12 yr: 1-2 sprays in fine mist appears. Zetonna (50 each nostril qd µg/spray) >12 yr: 2 sprays in each nostril qd Azelastine/fluticasone >12 yr: 1 spray in each Shake bottle gently before using. Blow nose to clear (137 µg azelastine/50 nostril bid nostrils. Keep head tilted downward when spraying. µg fluticasone) Insert applicator tip to inch into nostril, keeping Dymista bottle upright, and close off the other nostril. Breathe in through nose. While inhaling, press pump to release spray. Budesonide: OTC

qd, Once daily; bid, 2 times daily; tid, 3 times daily.

Allergen-specific immunotherapy is a well-defined treatment for IgE-mediated allergic disease. It may be administered by subcutaneous or sublingual routes. Sublingual immunotherapy (SLIT) has been used successfully in Europe and South America and is now approved by the U.S. Food and Drug Administration.

Allergy immunotherapy (AIT) is an effective treatment for AR and allergic conjunctivitis. In addition to reducing symptoms, it may change the course of allergic disease and induce allergen-specific immune tolerance. Immunotherapy should be considered for children in whom IgE-mediated allergic symptoms cannot be adequately controlled by avoidance and medication, especially in the presence of comorbid conditions. Immunotherapy for AR prevents the onset of asthma. Moreover, progress in molecular characterization of allergens raises the possibility of defined vaccines for allergen immunotherapy. Omalizumab (antiIgE antibody) is effective for difficult-to-control asthma and is likely to have a beneficial effect on coexisting AR. Typically, treatment of AR with oral antihistamines and nasal corticosteroids provides sufficient relief for most patients with coexisting allergic conjunctivitis . If it fails, additional therapies directed primarily at allergic conjunctivitis may be added (see Chapter 172 ). Intranasal corticosteroids are of some value for the treatment of ocular symptoms, but ophthalmic corticosteroids remain the most potent pharmacologic agents for ocular allergy, although they carry the risk of adverse effects such as delayed wound healing, secondary infection, elevated intraocular pressure, and formation of cataracts. Ophthalmic corticosteroids are only suited for the treatment of allergic conjunctivitis that does not respond to the medications previously discussed. Sound practice calls for the assistance of an ophthalmologist.

Prognosis Therapy with nonsedating antihistamines and topical corticosteroids, when taken appropriately, improves health-related quality-of-life measures in patients with allergic rhinitis. The reported rates of remission among children are 10–23%. Pharmacotherapy that will target cells and cytokines involved in inflammation and treat allergy as a systemic process is on the horizon, and more selective targeting of drugs based on the development of specific biomarkers and genetic profiling may soon be realized.

Bibliography Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev . 2011;242:31–50.

Burks AW, Calderon MA, Casale T, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol . 2013;131:1288–1296. Calderon MA, Gerth van Wijk R, Eichler I, et al. Perspectives on allergen-specific immunotherapy in childhood: an EAACI position statement. Pediatr Allergy Immunol . 2012;23:300– 306. Codispoti CD, Bernstein DI, Levin L, et al. Early-life mold and tree sensitivity is associated with allergic eosinophilic rhinitis at 4 yr of age. Ann Allergy Asthma Immunol . 2015;114:193– 198 e4. Cox LS. Sublingual immunotherapy for allergic rhinitis—is 2year treatment sufficient for long-term benefit? JAMA . 2017;317(6):591–593. Garcia-Aymerich J, Benet M, Saeys Y, et al. Phenotyping asthma, rhinitis and eczema in MeDALL population-based birth cohorts: an allergic comorbidity cluster. Allergy . 2015;70:973–984. Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet . 2011;378:2112–2120. Howarth PH, Mygind N, Silkoff PE, et al. Preface to outcome measures in allergic rhinitis. J Allergy Clin Immunol . 2005;115:S387–S389. Kim JM, Lin SY, Suarez-Cuervo C, et al. Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review. Pediatrics . 2013;131(6):1155–1167. La Rosa M, Lionetti E, Reibaldi M, et al. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr . 2013;39:18. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic

rhinoconjunctivitis and asthma: a systematic review. JAMA . 2013;309:1278–1288. 2017. The Medical Letter: Allergic rhinitis. Med Lett Drugs Ther . 2017;59:71–80. Nwaru BI, Takkinen HM, Niemela O, et al. Timing of infant feeding in relation to childhood asthma and allergic diseases. J Allergy Clin Immunol . 2013;131:78–86. Patil VK, Kurukulaaratchy RJ, Venter C, et al. Changing prevalence of wheeze, rhinitis and allergic sensitisation in late childhood: findings from 2 Isle of Wight birth cohorts 12 yr apart. Clin Exp Allergy . 2015;45:1430–1438. Roberts G, Xatzipsalti M, Borrego LM, et al. Paediatric rhinitis: position paper of the European Academy of Allergy and Clinical Immunology. Allergy . 2013;68:1102–1116. Scadding GK, Durham SR, Mirakian R, et al. BASCI guidelines for the management of allergic and non-allergic rhinitis. Clin Exp Allergy . 2008;38:19–42. Scadding GK. Optimal management of allergic rhinitis. Arch Dis Child . 2015;100:576–582. Schmitt J, Schwarz K, Stadler E, et al. Allergy immunotherapy for allergic rhinitis effectively prevents asthma: results from a large retrospective cohort study. J Allergy Clin Immunol . 2015;136:1511–1516. Valenta R, Campana R, Focke-Tejkl M, et al. Vaccine development for allergen-specific immunotherapy based on recombinant allergens and synthetic allergen peptides: lessons from the past and novel mechanisms of action for the future. J Allergy Clin Immunol . 2016;137:351–357. Westman M, Lupinek C, Bousquet J, et al. Early childhood IgE reactivity to pathogenesis-related class 10 proteins predicts allergic rhinitis in adolescence. J Allergy Clin Immunol . 2015;135:1199–1206 e1–e11. Wheatly LM, Togias A. Allergic rhinitis. N Engl J Med .

2015;372(15):456–462.

CHAPTER 169

Childhood Asthma Andrew H. Liu, Joseph D. Spahn, Scott H. Sicherer

Asthma is a chronic inflammatory condition of the lung airways resulting in episodic airflow obstruction. This chronic inflammation heightens the twitchiness of the airways—airways hyperresponsiveness (AHR)— to common provocative exposures. Asthma management is aimed at reducing airways inflammation by minimizing proinflammatory environmental exposures, using daily controller antiinflammatory medications, and controlling comorbid conditions that can worsen asthma. Less inflammation typically leads to better asthma control, with fewer exacerbations and decreased need for quick-reliever asthma medications. Nevertheless, exacerbations can still occur. Early intervention with systemic corticosteroids greatly reduces the severity of such episodes. Advances in asthma management and especially pharmacotherapy enable all but the uncommon child with difficult asthma to live normally.

Etiology Although the cause of childhood asthma has not been determined, a combination of environmental exposures and inherent biologic and genetic susceptibilities has been implicated (Fig. 169.1 ). In the susceptible host, immune responses to common airways exposures (e.g., respiratory viruses, allergens, tobacco smoke, air pollutants) can stimulate prolonged, pathogenic inflammation and aberrant repair of injured airways tissues (Fig. 169.2 ). Lung dysfunction (AHR, reduced airflow) and airway remodeling develop. These pathogenic processes in the growing lung during early life adversely affect airways growth and differentiation, leading to altered airways at mature ages. Once asthma has developed, ongoing inflammatory exposures appear to worsen it, driving disease persistence and increasing the risk of severe exacerbations.

FIG. 169.1 Etiology and pathogenesis of asthma. A combination of environmental and genetic factors in early life shape how the immune system develops and responds to ubiquitous environmental exposures. Respiratory microbes, inhaled allergens, and pollutants that can inflame the lower airways target the disease process to the lungs. Aberrant immune and repair responses to airways injury underlie persistent disease. AHR, Airways hyperresponsiveness; ETS, environmental tobacco smoke.

FIG. 169.2 Asthmatic inflammation (effector phase). Epithelial cell activation with production of proinflammatory cytokines and chemokines induces inflammation and contributes to a T-helper cell type 2 (Th2) response with tumor necrosis factor (TNF)-α, interleukin (IL)-13, thymic stromal lymphopoietin (TSLP), IL-25, IL-31, and IL-33. Migration of inflammatory cells to asthmatic tissues is regulated by chemokines. Th2 and eosinophil migration are induced by eotaxin, monocyte-derived chemokine (MDC), and activation-regulated chemokine (TARC). Epithelial apoptosis and shedding is observed, mainly mediated by interferon (IFN)-γ and TNF-α. The adaptive Th2 response includes the production of IL-4, IL-5, IL-9, and IL-13. Innate lymphoid cells, particularly ILC2, also secrete IL-5 and IL-13. Tissue eosinophilia is regulated by IL-5, IL-25, and IL33. Local and systemic IgE production is observed in bronchial mucosa. Cross-linking of IgE receptor FcεRI on the surface of mast cells and basophils and their degranulation take place on allergen challenge. (From Leung DYM, Szefler SJ, Bonilla FA, et al, editors: Pediatric allergy principles and practice, ed 3, Philadelphia, 2016, Elsevier, p 260).

Genetics To date, more than 100 genetic loci have been linked to asthma, although

relatively few have consistently been linked to asthma in different study cohorts. Consistent loci include genetic variants that underlie susceptibility to common exposures such as respiratory viruses and air pollutants.

Environment Recurrent wheezing episodes in early childhood are associated with common respiratory viruses, especially rhinoviruses, respiratory syncytial virus (RSV), influenza virus, adenovirus, parainfluenza virus, and human metapneumovirus. This association implies that host features affecting immunologic host defense, inflammation, and the extent of airways injury from ubiquitous viral pathogens underlie susceptibility to recurrent wheezing in early childhood. Other airways exposures can also exacerbate ongoing airways inflammation, increase disease severity, and drive asthma persistence. Home allergen exposures in sensitized individuals can initiate airways inflammation and hypersensitivity to other irritant exposures and are causally linked to disease severity, exacerbations, and persistence. Consequently, eliminating the offending allergen(s) can lead to resolution of asthma symptoms and can sometimes cure asthma. Environmental tobacco smoke and common air pollutants can aggravate airways inflammation and increase asthma severity. Cold, dry air, hyperventilation from physical play or exercise, and strong odors can trigger bronchoconstriction. Although many exposures that trigger and aggravate asthma are well recognized, the causal environmental features underlying the development of host susceptibilities to the various common airway exposures are not as well defined. Living in rural or farming communities may be a protective environmental factor.

Epidemiology Asthma is a common chronic disease, causing considerable morbidity. In 2011, >10 million children (14% of U.S. children) had ever been diagnosed with asthma, with 70% of this group reporting current asthma. Male gender and living in poverty are demographic risk factors for having childhood asthma in the United States. About 15% of boys vs 13% of girls have had asthma; and 18% of all children living in poor families (income 30 breaths/min Usually

Pulse rate (beats/min)

120

SUBSET: RESPIRATORY ARREST IMMINENT Extreme dyspnea Anxiety Upright, leaning forward Unable to talk Drowsy or confused

Paradoxical thoracoabdominal movement Absence of wheeze

Bradycardia

‡

Pulsus paradoxus

Absent 25 mm Hg (adult) 20-40 mm Hg (child)

Approx. 40–69% or response lasts 80% of predicted (and FEV1 /FVC ratio >80% for children 5-11 yr); no interference with normal activity; and 130°F); (3) removing wall-to-wall carpeting and upholstered furniture; and (4) reducing and maintaining indoor humidity 2 days/wk for symptom relief (not prevention of exercise-induced bronchospasm) generally indicates inadequate control and the need to step up treatment. For ages 0-4 yr: With viral respiratory infection: SABA q4-6h up to 24 hr (longer with physician consult). Consider short course of systemic corticosteroids if exacerbation is severe or patient has history of previous severe exacerbations. * Notes: † Alphabetical order is used when more than 1 treatment option is listed within either preferred or

alternative therapy. • The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. • If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up. • If clear benefit is not observed within 4-6 wk and patient/family medication technique and adherence are satisfactory, consider adjusting therapy or alternative diagnosis. • Studies on children age 0-4 yr are limited. • Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur.

• Theophylline is a less desirable alternative because of the need to monitor serum concentration levels. The 2016 GINA guidelines do not recommend the use of theophylline as a controller medication and in IV forms to treat status asthmaticus due to its severe adverse effects profile. • Zileuton is less desirable alternative because of limited studies as adjunctive therapy and the need to monitor liver function. ICS, Inhaled corticosteroid; LABA, inhaled long-acting β2 -agonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; prn, as needed; SABA, inhaled short-acting β2 -agonist. Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3): Guidelines for the diagnosis and management of asthma—summary report 2007, J Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

The preferred treatment for all patients with persistent asthma is ICS therapy, as monotherapy or in combination with adjunctive therapy. The type(s) and amount(s) of daily controller medications to be used are determined by the asthma severity and control rating. Low-dose ICS therapy is the treatment of choice for all children at Treatment Step 2 (mild persistent asthma). Alternative medications include a leukotrienemodifying agent (montelukast), nonsteroidal antiinflammatory drugs (cromolyn, nedocromil), and theophylline. There are 4 co-equal choices for the treatment of school-aged children at Treatment Step 3 (moderate persistent asthma): mediumdose ICS, combination low-dose ICS and inhaled long-acting β2 -agonist (LABA) , a leukotriene receptor antagonist (LTRA) , or theophylline. In a study of children with uncontrolled asthma receiving low-dose ICS, the addition of LABA provided greater improvement than either adding an LTRA or increasing ICS dosage. However, some children had a good response to mediumdose ICS or the addition of an LTRA, justifying them as step-up controller therapy options. The preferred therapy for children at Treatment Step 4 (also moderate persistent asthma) is medium-dose ICS/LABA combination. Alternatives include medium-dose ICS with either theophylline or an LTRA. For young children (≤4 yr) at Treatment Step 3, medium-dose ICS is recommended, while medium-dose ICS plus either an LABA or an LTRA are recommended for preschool-age children at Treatment Step 4. Children with severe persistent asthma (Treatment Steps 5 and 6) should receive combination high-dose ICS plus LABA. Long-term administration of oral corticosteroids as controller therapy is effective but is rarely required. In addition, omalizumab can be used in children ≥6 yr old with severe allergic asthma, while mepolizumab is approved for children ≥12 yr with severe asthma eosinophilic asthma. A rescue course of systemic corticosteroids may be necessary at any step for very poorly controlled asthma. For children age ≥5 yr

with allergic asthma requiring Treatment Steps 2-4 care, allergen immunotherapy can also be considered.

“Step-Up, Step-Down” Approach The NIH guidelines emphasize initiating higher-level controller therapy at the outset to establish prompt control, with measures to “step-down” therapy once good asthma control is achieved. Initially, airflow limitation and the pathology of asthma may limit the delivery and efficacy of ICS such that stepping up to higher doses and/or combination therapy may be needed to gain asthma control. Furthermore, ICS requires weeks to months of daily administration for optimal efficacy to occur. Combination pharmacotherapy can achieve relatively immediate improvement while also providing daily ICS to improve long-term control and reduce exacerbation risk. Asthma therapy can be stepped down after good asthma control has been achieved and maintained for at least 3 mo. By determining the lowest number or dose of daily controller medications that can maintain good control, the potential for medication adverse effects is reduced. Regular follow-up is still emphasized because the variability of asthma's course is well recognized. When asthma is not well controlled, therapy should be escalated by increasing controller treatment step by 1 level and closely monitoring for clinical improvement. For a child with very poorly controlled asthma, the recommendations are to consider a short course of prednisone, or to increase therapy by 2 steps, with reevaluation in 2 wk. If step-up therapy is being considered, it is important to check inhaler technique and adherence, implement environmental control measures, and identify and treat comorbid conditions.

Referral to Asthma Specialist Referral to an asthma specialist for consultation or co-management is recommended if there are difficulties in achieving or maintaining good asthma control. For children 320 µg

200 µg

200-400 µg

>400 µg

0.5 mg

1.0 mg

2.0 mg

80 µg

80-160 µg

160 µg

(Approved for children ≥12 yr) Flunisolide (Aerospan) MDI: 80 µg/puff (Approved for children ≥6 yr) Fluticasone propionate (Flovent, Flovent Diskus) MDI: 44, 110, 220 µg DPI: 50, 100, 250 µg (44 and 50 µg approved for children ≥4 yr) Fluticasone furoate (Arnuity Ellipta) DPI: 100, 200 µg (Approved for children ≥12 yr) Mometasone Furoate (Asmanex, Asmanex Twisthaler) MDI: 100, 200 µg DPI: 110, 220 µg (Approved for children ≥4 yr)

80 µg

88-176 µg 100-200 µg

100 µg

110 µg 100 µg

80-160 µg

176-440 µg 200-500 µg

100-200 µg

110 µg 100 µg

160 µg

>440 µg >500 µg

200 µg

110 µg 100 µg

DPI, Dry powder inhaler; MDI, metered-dose inhaler. Adapted from National Asthma Education and Prevention Program Expert Panel Report 3 (EPR3): Guidelines for the diagnosis and management of asthma—summary report 2007, J Allergy Clin Immunol 120(Suppl):S94–S138, 2007.

Inhaled Corticosteroids ICS therapy improves lung function; reduces asthma symptoms, AHR, and use of “rescue” medications; improves quality of life; and most importantly reduces the need for prednisone, urgent care visits, and hospitalizations by approximately 50%. Epidemiologic studies have also shown that ICS therapy substantially lowers the risk of death attributable to asthma if used regularly. Because ICS therapy can achieve all the goals of asthma management, it is viewed as first-line treatment for persistent asthma. Seven ICSs are FDA approved for use in children. The NIH and GINA guidelines provide equivalence classifications (see Table 169.13 ), although direct comparisons of efficacy and safety outcomes are lacking. ICSs are available in metered-dose inhalers (MDIs) using hydrofluoroalkane (HFA) as their propellant, in dry powder inhalers (DPIs), or in suspension for nebulization. Fluticasone propionate, fluticasone furoate, mometasone furoate, ciclesonide, and to a lesser extent budesonide are considered “second-generation” ICSs, in that they have greater antiinflammatory potency and less systemic bioavailability (and thus potential for systemic adverse effects) because of their extensive firstpass hepatic metabolism. The selection of the initial ICS dose is based on the determination of disease severity. Even though ICSs can be very effective, there has been some reluctance to

treat children with ICSs due to parental and occasionally physician concerns regarding their potential for adverse effects with chronic use. The adverse effects that occur with long-term systemic corticosteroid therapy have not been seen or have only rarely been reported in children receiving ICSs in recommended doses. The risk of adverse effects from ICS therapy is related to the dose and frequency of administration (Table 169.14 ). High doses (≥1,000 µg/day in children) and frequent administration (4 times/day) are more likely to have both local and systemic adverse effects. Children who receive maintenance therapy with higher ICS doses are also likely to require frequent systemic corticosteroid courses for asthma exacerbations, further increasing their risk of corticosteroid adverse effects. Table 169.14 Risk Assessment for Corticosteroid Adverse Effects Low risk

Medium risk

High risk

CONDITIONS (≤1 risk factor* ) Low- to medium-dose ICS (see Table 169.13 )

(If >1 risk factor,* consider evaluating as high risk) High-dose ICS (see Table 169.13 ) At least 4 courses of OCS/yr Chronic systemic corticosteroids (>7.5 mg daily or equivalent for >1 mo) ≥7 OCS burst treatments/year Very-high-dose ICS (e.g., fluticasone propionate ≥800 µg/day)

RECOMMENDATIONS Monitor blood pressure and weight with each physician visit. Measure height annually (stadiometry); monitor periodically for declining growth rate and pubertal developmental delay. Encourage regular physical exercise. Ensure adequate dietary calcium and vitamin D with additional supplements for daily calcium if needed. Avoid smoking and alcohol. Ensure TSH status if patient has history of thyroid abnormality. As above, plus : Yearly ophthalmologic evaluations to monitor for cataracts or glaucoma Baseline bone densitometry (DEXA scan) Consider patient at increased risk for adrenal insufficiency, especially with physiologic stressors (e.g., surgery, accident, significant illness). As above, plus : DEXA scan: if DEXA z score ≤1.0, recommend close monitoring (every 12 mo) Consider referral to a bone or endocrine specialist. Bone age assessment Complete blood count Serum calcium, phosphorus, and alkaline phosphatase determinations Urine calcium and creatinine measurements Measurements of testosterone in males, estradiol in amenorrheic premenopausal women, vitamin D (25-OH and 1,25-OH vitamin D), parathyroid hormone, and osteocalcin Urine telopeptides for those receiving long-term systemic or frequent OCS treatment Assume adrenal insufficiency for physiologic stressors (e.g., surgery, accident, significant illness).

* Risk factors for osteoporosis: presence of other chronic illness(es), medications (corticosteroids,

anticonvulsants, heparin, diuretics), low body weight, family history of osteoporosis, significant fracture history disproportionate to trauma, recurrent falls, impaired vision, low dietary calcium and vitamin D intake, and lifestyle factors (decreased physical activity, smoking, alcohol intake). DEXA, Dual-energy x-ray absorptiometry; ICS, inhaled corticosteroid; OCS, oral corticosteroid; TSH, thyroid-stimulating hormone.

The most commonly encountered ICS adverse effects are local: oral candidiasis (thrush) and dysphonia (hoarse voice). Thrush results from propellant-induced mucosal irritation and local immunosuppression, and dysphonia is the result of vocal cord myopathy. These effects are dose dependent and are most common in individuals receiving high-dose ICS or oral corticosteroid therapy. The incidence of these local effects can be greatly minimized by using a spacer with an MDI with the ICS, because spacers reduce oropharyngeal deposition of the drug and propellant. Mouth rinsing using a “swish and spit” technique after ICS use is also recommended. The potential for growth suppression and osteoporosis with long-term ICS use had been an unanswered concern. However, a long-term, prospective NIHsponsored study (CAMP) followed the growth and bone mineral density (BMD) of >1,000 children (age 6-12 yr at entry) with mild to moderate asthma until they reached adulthood and found slight growth suppression and osteopenia in some children who received long-term ICS therapy. A small (1.1 cm), limited (1 year) growth suppressive effect was noted in children receiving budesonide, 200 µg twice daily, after 5 yr of therapy. Height was then followed until all children had reached adulthood (mean age 25 yr). Those who received ICS therapy remained approximately 1 cm shorter than those who received placebo. Thus, children treated with long-term ICS therapy are likely to be about 1 cm shorter than expected as an adult, which is of little clinical significance. BMD was no different in those receiving budesonide vs placebo during the duration of the study, while a follow-up study after a mean of 7 years found a slight dosedependent effect of ICS therapy on bone mineral accretion only among males. A much greater effect on BMD was observed with increasing numbers of oral corticosteroid bursts for acute asthma, as well as an increase in risk for osteopenia, which was again limited to males. These findings were with use of low-dose budesonide; higher ICS doses, especially of agents with increased potency, have a greater potential for adverse effects. Thus, corticosteroid adverse effects screening and osteoporosis prevention measures are recommended for patients receiving higher ICS doses, since these patients are also likely to require systemic courses for exacerbations (see Table 169.14 ).

Systemic Corticosteroids The development of second-generation ICSs, especially when used in combination with a LABA in a single device, have allowed the vast majority of children with asthma to achieve and maintain good control without need for maintenance oral corticosteroid (OCS) therapy. Thus, OCSs are used primarily to treat asthma exacerbations and, rarely, in children with very severe disease. In these patients, every attempt should be made to exclude comorbid conditions and to keep the OCS dose at ≤20 mg every other day. Doses exceeding this amount are associated with numerous adverse effects (see Chapter 593 ). To determine the need for continued OCS therapy, tapering of the OCS dose over several weeks should be attempted, with close monitoring of the patient's symptoms and lung function. Prednisone, prednisolone, and methylprednisolone are rapidly and completely absorbed, with peak plasma concentrations occurring within 1-2 hr. Prednisone is an inactive prodrug that requires biotransformation via first-pass hepatic metabolism to prednisolone, its active form. Corticosteroids are metabolized in the liver into inactive compounds, with the rate of metabolism influenced by drug interactions and disease states. Anticonvulsants (phenytoin, phenobarbital, carbamazepine) increase the metabolism of prednisolone, methylprednisolone, and dexamethasone, with methylprednisolone most significantly affected. Rifampin also enhances the clearance of corticosteroids and can result in diminished therapeutic effect. Other medications (ketoconazole, oral contraceptives) can significantly delay corticosteroid metabolism. Some macrolide antibiotics, such as erythromycin and clarithromycin, delay the clearance of only methylprednisolone. Long-term OCS therapy can result in a number of adverse effects over time (see Chapter 595 ). Some occur immediately (metabolic effects), whereas others can develop insidiously over several months to years (growth suppression, osteoporosis, cataracts). Most adverse effects occur in a cumulative dose- and duration-dependent manner. Children who require routine or frequent short courses of OCSs, especially with concurrent high-dose ICSs, should receive corticosteroid adverse effects screening (see Table 169.14 ) and osteoporosis preventive measures (see Chapter 726 ).

Long-Acting Inhaled β-Agonists Although considered daily controller medications, LABAs (salmeterol,

formoterol) are not intended for use as monotherapy for persistent asthma because they can increase the risk for serious asthma exacerbations (ICU admission, endotracheal intubation) and asthma-related deaths when used without an ICS. The likely mechanism involves the ability of LABAs to “mask” worsening asthma inflammation and asthma severity, leading to a delay in seeking urgent care and increased risk of a life-threatening exacerbation. Although both salmeterol and formoterol have a prolonged duration of effect (≥12 hr), salmeterol has a prolonged onset of effect (60 min), while formoterol's onset of effect is rapid (5-10 min) after administration. Given their long duration of action, LABAs are well suited for patients with nocturnal asthma and for individuals who require frequent use of SABA inhalations during the day to prevent exercise-induced bronchospasm (EIB), but only in combination with ICSs. Of note, the FDA requires all LABA-containing medications to be labeled with a warning of an increase in severe asthma episodes associated with these agents. In addition, the FDA recommends that once a patient is well controlled on combination ICS/LABA therapy, the LABA component should be discontinued while continuing treatment with the ICS.

Combination ICS/LABA Therapy Combination ICS/LABA therapy is recommended for patients who are suboptimally controlled with ICS therapy alone and those with moderate or severe persistent asthma. In those inadequately controlled with ICS alone, combination ICS/LABA therapy is superior to add-on therapy with either an LTRA or theophylline or doubling the ICS dose. Benefits include improvement in baseline lung function, less need for rescue SABA therapy, improved quality of life, and fewer asthma exacerbations. A large study by the NIH-sponsored CARE Network found that in children inadequately controlled with low-dose ICS therapy, combination low-dose fluticasone/salmeterol (100 µg/21 µg) twice daily was almost twice as effective as other step-up regimens, including fluticasone (250 µg) twice daily or low-dose fluticasone (100 µg twice daily) plus montelukast once daily, with the greatest improvement in reducing exacerbations requiring prednisone and study withdrawals due to poorly controlled asthma. In addition, combination fluticasone/salmeterol was as effective as medium-dose fluticasone and was superior to combination fluticasone/montelukast therapy in black children, arguing against the notion that black children are more prone to serious asthma exacerbations than white children when treated with combination ICS/LABA therapy.

Despite their efficacy and widespread use, the long-term safety of LABAs, even when used in combination with ICS in a single inhaler, has been questioned. To address this concern of rare, severe asthma-related events with LABA/ICS use, large randomized controlled trials (RCTs) compared the safety of combination ICS/LABA vs ICS monotherapy. Two studies of >23,000 adults and adolescents ≥12 yr old with various levels of asthma severity were randomized to receive ICS (low or medium dose) monotherapy vs equivalent ICS/LABA (fluticasone vs fluticasone/salmeterol; budesonide vs budesonide/formoterol) over 26 weeks to determine if small but significant differences might occur in asthma hospitalization, intubation, or death attributable to ICS/LABA. No intubations or asthma deaths occurred during the study, and no differences in asthma hospitalizations between treatment groups were observed. The similar pediatric study enrolled >6,000 children age 4-11 yr with various levels of asthma severity to receive either fluticasone (low or medium dose) or equivalent fluticasone/salmeterol dose over 26 weeks, with similar findings of no significant differences in severe asthma-related events between treatment groups. These results strongly suggest that the use of combination ICS/LABA products in children and adults with moderate to severe persistent asthma is both effective and safe.

Leukotriene-Modifying Agents Leukotrienes are potent proinflammatory mediators that can induce bronchospasm, mucus secretion, and airways edema. Two classes of leukotriene modifiers have been developed: inhibitors of leukotriene synthesis and leukotriene receptor antagonists (LTRAs). Zileuton, the only synthesis inhibitor, is not approved for use in children 2 canisters of short-acting β-agonists per month Poor response to systemic corticosteroid therapy Male gender Low birthweight Nonwhite (especially black) ethnicity Sensitivity to Alternaria

Environmental Allergen exposure Environmental tobacco smoke exposure Air pollution exposure Urban environment

Economic and Psychosocial Poverty Crowding Mother 6 yr: 1-2 gtt qid

CAUTIONS AND ADVERSE EVENTS Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10 min after administration before inserting soft contact lenses. Soft contact lenses should not be worn if the eye is red. Wait at least 10 min after administration before inserting soft contact lenses. Not for use in patients wearing soft contact lenses during treatment.

Avoid prolonged use (>3-4 days) to avoid rebound symptoms. Not for use with contact lenses.

hydrochloride 0.025% Naphcon-A, OpconA Cromolyn sodium 4% Crolom, Opticrom Lodoxamide tromethamine 0.1% Alomide Nedocromil sodium 2% Alocril Pemirolast potassium 0.1% Alamast Epinastine hydrochloride 0.05% Elestat Ketotifen fumarate 0.025% Zaditor Olopatadine hydrochloride 0.1%, 0.2%, 0.7% Patanol Pataday Pazeo Alcaftadine, 0.25% Lastacaft Bepotastine besilate 1.5% Bepreve Ketorolac tromethamine 0.5% Acular

Fluorometholone 0.1%, 0.25% suspension (0.1%, 0.25%) and ointment

Mast cell stabilizer Children >4 yr: 1-2 gtt q4-6h

Can be used to treat giant papillary conjunctivitis and vernal keratitis. Not for use with contact lenses.

Mast cell stabilizer Children ≥2 yr: 1-2 gtt qid up to 3 mo

Can be used to treat vernal keratoconjunctivitis. Not for use in patients wearing soft contact lenses during treatment.

Mast cell stabilizer Children ≥3 yr: 1-2 gtt bid Mast cell stabilizer Children >3 yr: 1-2 gtt qid

Avoid wearing contact lenses while exhibiting the signs and symptoms of allergic conjunctivitis. Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10 min after administration before inserting soft contact lenses. Contact lenses should be removed before use. Wait at least 15 min after administration before inserting soft contact lenses. Not for the treatment of contact lens irritation. Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10 min after administration before inserting soft contact lenses. Not for treatment of contact lens–related irritation; the preservative may be absorbed by soft contact lenses. Wait at least 10 min after administration before inserting soft contact lenses.

Antihistamine/mast cell stabilizer Children ≥3 yr: 1 gtt bid Antihistamine/mast cell stabilizer Children ≥3 yr: 1 gtt bid q812h Antihistamine/mast cell stabilizer Children ≥3 yr: 1 gtt bid (8 hr apart) Children≥2 yr: 1 gtt qd

Antihistamine/mast cell stabilizer Children > 2 yr: 1 gtt bid q812h Antihistamine/mast cell stabilizer Children >2 yr: 1 gtt bid q812h NSAID Children ≥3 yr: 1 gtt qid

Fluorinated corticosteroid Children ≥2 yr, 1 gtt into conjunctival sac of affected eye(s) bid-qid. During initial 24-48 hr, dosage may be

Contact lenses should be removed before application; may be inserted after 10 min. Not for the treatment of contact lens irritation. Contact lenses should be removed before application, may be inserted after 10 min. Not for the treatment of contact lens irritation. Avoid with aspirin or NSAID sensitivity. Use ocular product with caution in patients with complicated ocular surgeries, corneal denervation or epithelial defects, ocular surface diseases (e.g., dry eye syndrome), repeated ocular surgeries within a short period, diabetes mellitus, or rheumatoid arthritis; these patients may be at risk for corneal adverse events that may be sight threatening. Do not use while wearing contact lenses. If improvement does not occur after 2 days, patient should be reevaluated. Patient should remove soft contact lenses before administering (contains benzalkonium chloride) and delay reinsertion of lenses for ≥15 min after administration. Close monitoring for

(0.1%) FML, FML Forte, Flarex

increased to 1 gtt q4h. Ointment (~1.3 cm in length) into conjunctival sac of affected eye(s) 1-3 times daily. May be applied q4h during initial 24-48 hr of therapy.

development of glaucoma and cataracts.

NSAID, Nonsteroidal antiinflammatory drug; bid, 2 times daily; gtt, drops; qid, 4 times daily; q4-6h; every 4-6 hr; qd, every day.

Tertiary treatment of ocular allergy includes topical (or rarely oral) corticosteroids and should be conducted in conjunction with an ophthalmologist. Local administration of topical corticosteroids may be associated with increased intraocular pressure, viral infections, and cataract formation. Other immunomodulatory medications, such as topical tacrolimus or topical cyclosporine, are used as steroid-sparing agents by ophthalmologists. Allergen immunotherapy can be very effective in seasonal and perennial allergic conjunctivitis, especially when associated with rhinitis, and can decrease the need for oral or topical medications to control allergy symptoms. Because vernal and atopic keratoconjunctivitis can be associated with visual morbidity, if these diagnoses are suspected, the patient should be referred to an ophthalmologist. Symptoms that should prompt referral to an ophthalmologist include unilateral red eye with pain, photophobia, change in vision, refractory dry eyes, or corneal abnormality.

Bibliography Bielory BP, Shah SP, O'Brien TP, et al. Emerging therapeutics for ocular surface disease. Curr Opin Allergy Clin Immunol . 2016;16(5):477–486. Castillo M, Scott NW, Mustafa MZ, et al. Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis. Cochrane Database Syst Rev . 2015;(6) [CD009566]. Chen JJ, Applebaum DS, Sun GS, et al. Atopic keratoconjunctivitis: a review. J Am Acad Dermatol . 2014;70(3):569–575. Esposito S, Fior G, Mori A, et al. An update on the therapeutic

approach to vernal keratoconjunctivitis. Paediatr Drugs . 2016;18(5):347–355. Gomes PJ. Trends in prevalence and treatment of ocular allergy. Curr Opin Allergy Clin Immunol . 2014;14(5):451–456. Jutel M, Agache I, Bonini S, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol . 2015;136(3):556–568. Shaker M, Salcone E. An update on ocular allergy. Curr Opin Allergy Clin Immunol . 2016;16(5):505–510.

CHAPTER 173

Urticaria (Hives) and Angioedema Amy P. Stallings, Stephen C. Dreskin, Michael M. Frank, Scott H. Sicherer

Urticaria and angioedema affect 20% of individuals at some point in their life. Episodes of hives that last for 6 wk are designated chronic. The distinction is important, because the causes and mechanisms of urticaria formation and the therapeutic approaches are different in each instance.

Etiology and Pathogenesis Acute urticaria and angioedema are often caused by an allergic IgE–mediated reaction (Table 173.1 ). This form of urticaria is a self-limited process that occurs when an allergen activates mast cells in the skin. Common causes of acute generalized urticaria include foods, drugs (particularly antibiotics), and stinging-insect venoms. If an allergen (latex, animal dander) penetrates the skin locally, hives often can develop at the site of exposure. Acute urticaria can also result from non–IgE-mediated stimulation of mast cells, caused by radiocontrast agents, viral agents (including hepatitis B and Epstein-Barr virus), opiates, and nonsteroidal antiinflammatory drugs (NSAIDs). The diagnosis of chronic urticaria is established when lesions occur on most days of the week for >6 wk and are not physical urticaria or recurrent acute urticaria with repeated exposures to a specific agent (Tables 173.2 and 173.3 ). In about half the cases, chronic urticaria is accompanied by angioedema. Rarely, angioedema occurs without urticaria. Angioedema without urticaria is often a result of allergy, but recurrent angioedema suggests other diagnoses. Table 173.1 Etiology of Acute Urticaria

Etiology of Acute Urticaria Foods Medications Insect stings Infections

Egg, milk, wheat, peanuts, tree nuts, soy, shellfish, fish, (direct mast cell degranulation) Suspect all medications, even nonprescription or homeopathic Hymenoptera (honeybee, yellow jacket, hornets, wasp, fire ants), biting insects (papular urticaria) Bacterial (streptococcal pharyngitis, Mycoplasma , sinusitis); viral (hepatitis, mononucleosis [Epstein-Barr virus], coxsackieviruses A and B); Parasitic (Ascaris, Ancylostoma, Echinococcus, Fasciola, Filaria, Schistosoma, Strongyloides, Toxocara, Trichinella); Fungal (dermatophytes, Candida ) Latex, pollen, animal saliva, nettle plants, caterpillars

Contact allergy Transfusion Blood, blood products, or IV immune globulin administration reactions

From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW, Williams PV, editors: Allergy in primary care , Philadelphia, 2000, Saunders, p 232.

Table 173.2

Etiology of Chronic Urticaria Idiopathic/autoimmune

Approximately 30% of chronic urticaria cases are physical urticaria, and 60–70% are idiopathic. Of the idiopathic cases approximately 35–40% have anti-IgE or antiFcεRI (high-affinity IgE receptor α chain) autoantibodies (autoimmune chronic urticaria) Physical Dermatographism Cholinergic urticaria Cold urticaria (see Table 173.5 ) Delayed pressure urticaria Solar urticaria Vibratory urticaria Aquagenic urticaria Autoimmune diseases Systemic lupus erythematosus Juvenile idiopathic arthritis Thyroid disease (Graves, Hashimoto) Celiac disease Inflammatory bowel disease Leukocytoclastic vasculitis Autoinflammatory/periodic See Tables 173.3 and 173.5 . fever syndromes Neoplastic Lymphoma Mastocytosis Leukemia Angioedema Hereditary angioedema (autosomal dominant inherited deficiency of C1-esterase inhibitor) Acquired angioedema Angiotensin-converting enzyme inhibitors

From Lasley MV, Kennedy MS, Altman LC: Urticaria and angioedema. In Altman LC, Becker JW, Williams PV, editors: Allergy in primary care , Philadelphia, 2000, Saunders, p 234.

Table 173.3

Febrile Autoinflammatory Diseases Causing Urticaria in Children DISEASE FCAS

MuckleWells syndrome

TIMING GENE ATTACK INHERITANCE OF (PROTEIN) LENGTH ONSET NLRP3 AD Brief; Neonatal (cryopyrin) minutes to or 3 days infantile NLRP3 AD 1-3 days Neonatal, (cryopyrin) infantile, childhood (can be later)

Chronic NLRP3 infantile (cryopyrin) neurologic cutaneous articular syndrome; neonatalonset multisystem inflammatory disease

AD

Continuous Neonatal flares or infantile

CUTANEOUS FEATURES Cold-induced urticaria Widespread urticaria

Widespread urticaria

HIDS

MVK AR (mevalonate kinase)

3-7 days

Infancy (7 days

Childhood

Systemic-

Polygenic

Varies

Daily

Peak

Intermittent migratory erythematous macules and edematous plaques overlying areas of myalgia, often on limbs Periorbital edema Nonfixed

EXTRACUTANEOUS CLINICAL FEATURES Arthralgia Conjunctivitis Headache Arthralgia/arthritis Sensorineural hearing loss Conjunctivitis/episcleritis Headache Amyloidosis Deforming osteoarthropathy, epiphyseal overgrowth Sensorineural hearing loss Dysmorphic facies Chronic aseptic meningitis, headaches, papilledema, seizures Conjunctivitis/uveitis, optic atrophy Growth retardation Developmental delay Amyloidosis Arthralgia/arthritis Cervical lymphadenopathy Severe abdominal pain Diarrhea/vomiting Headache Elevated IgD and IgA antibody levels Elevated urine mevalonic acid during attacks Migratory myalgia Conjunctivitis Serositis Amyloidosis

Polyarthritis

onset juvenile idiopathic arthritis (SoJIA)

PLAID

(quotidian) onset at 16 yr

PLCG2

AD

N/A

Infancy

erythematous rash; may be urticarial With or without dermatographism With or without periorbital edema Urticaria induced by evaporative cooling Ulcers in coldexposed areas

Myalgia Hepatosplenomegaly Lymphadenopathy Serositis

Allergies Autoimmune disease Recurrent sinopulmonary infections Elevated IgE antibody levels Decreased IgA and IgM antibody levels Often elevated antinuclear antibody titers

AD, Autosomal dominant; AR, autosomal recessive; HIDS, hyperimmunoglobulinemia D syndrome; FCAS, familial cold-induced autoinflammatory syndrome; N/A, not available; PLAID, PLCγ2-associated antibody deficiency and immune dysregulation. From Youseff MJ, Chiu YE: Eczema and urticaria as manifestations of undiagnosed and rare diseases, Pediatr Clin North Am 64:39–56, 2017 (Table 2, pp 49–50).

A typical hive is an erythematous, pruritic, raised wheal that blanches with pressure, is transient, and resolves without residual lesions, unless the area was intensely scratched. In contrast, urticaria associated with serum sickness reactions, systemic lupus erythematosus (SLE), or other vasculitides in which a skin biopsy reveals a small-vessel vasculitis, often have distinguishing clinical features. Lesions that burn more than itch, last >24 hr, do not blanch, blister, heal with scarring, or that are associated with bleeding into the skin (purpura) suggest urticarial vasculitis. Atypical aspects of the gross appearance of the hives or associated symptoms should heighten concern that the urticaria or angioedema may be the manifestation of a systemic disease process (Table 173.4 ). Table 173.4 Distinguishing Features Between Urticaria and Systemic Urticarial Syndromes COMMON URTICARIA URTICARIAL SYNDROMES (≥1 of following) Only typical wheals: Atypical “wheals”: Erythematous edematous lesions Infiltrated plaques Transient (24-36 hr) Asymmetric distribution Symmetric distribution Resolution without signs Resolution with signs (hypo/hyperpigmentation, bruising, or No associated different elementary scarring) lesions (papules, vesicles, purpura, Associated different elementary lesions (papules, vesicles, purpura, crustae) scaling, crustae)

Pruritic (rarely stinging/burning) Possibly associated with angioedema No associated systemic symptoms

Not pruritic; rather painful or burning Usually no associated angioedema Often associated with systemic symptoms (fever, malaise, arthralgia, abdominal pain, weight loss, acral circulatory abnormalities, neurologic signs

From Peroni A, Colato C, Zanoni G, Girolomoni G: Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria, J Am Acad Dermatol 62(4):559, 2009.

Physical Urticaria Physically induced urticaria and angioedema share the common property of being induced by an environmental stimulus, such as a change in temperature or direct stimulation of the skin with pressure, stroking, vibration, or light (see Table 173.2 ).

Cold-Dependent Disorders Cold urticaria is characterized by the development of localized pruritus, erythema, and urticaria/angioedema after exposure to a cold stimulus. Total body exposure, as seen with swimming in cold water, can cause massive release of vasoactive mediators, resulting in hypotension, loss of consciousness, and even death if not promptly treated. The diagnosis is confirmed by challenge testing for an isomorphic cold reaction by holding an ice cube in place on the patient's skin for 5 min. In patients with cold urticaria, an urticarial lesion develops about 10 min after removal of the ice cube and on rewarming of the chilled skin. Cold urticaria can be associated with the presence of cryoproteins such as cold agglutinins, cryoglobulins, cryofibrinogen, and the Donath-Landsteiner antibody seen in secondary syphilis (paroxysmal cold hemoglobinuria). In patients with cryoglobulins the isolated proteins appear to transfer cold sensitivity and activate the complement cascade on in vitro incubation with normal plasma. The term idiopathic cold urticaria generally applies to patients without abnormal circulating plasma proteins such as cryoglobulins. Cold urticaria has also been reported after viral infections. Cold urticaria must be distinguished from the familial cold autoinflammatory syndrome (see later, Diagnosis) (Table 173.5 ; see also Table 173.3 and Chapter 188 ). Table 173.5

Hereditary Diseases With Cold-Induced Urticaria

EPISODIC SYMPTOMS Urticarial rash, arthralgia, myalgia, chills, fever, swelling of extremities MWS Urticarial rash, arthralgia, chills, fever CINCA Fever

CAPS FCAS

NAPS12 (FCAS2) PLAID (FCAS3)

SUSTAINED/PROGRESSIVE SYMPTOMS Renal amyloidosis Sensorineural deafness, renal amyloidosis Rash, arthritis, chronic meningitis, visual defect, deafness, growth retardation, renal amyloidosis Sensorineural deafness

Fever, arthralgia, myalgia, urticaria, abdominal pain, aphthous ulcers, lymphadenopathy Urticaria induced by evaporative cooling, Serum low IgM and IgA levels; high IgE levels; sinopulmonary infections decreased B and NK cells; granulomata; antinuclear antibodies

CAPS, Cryopyrin-associated periodic syndromes; FCAS, familial cold-induced autoinflammatory syndrome; MWS, Muckle-Wells syndrome; CINCA, chronic infantile neurologic cutaneous articular syndrome; NAPS, NLRP-12–associated periodic syndrome; PLAID, PLCG2-associated antibody deficiency and immune dysregulation. From Kanazawa N: Hereditary disorders presenting with urticaria, Immunol Allergy Clin NORTH Am 34:169–179, 2014 (Table 4, p 176).

Cholinergic Urticaria Cholinergic urticaria is characterized by the onset of small, punctate pruritic wheals surrounded by a prominent erythematous flare and associated with exercise, hot showers, and sweating. Once the patient cools down, the rash usually subsides in 30-60 min. Occasionally, symptoms of more generalized cholinergic stimulation, such as lacrimation, wheezing, salivation, and syncope, are observed. These symptoms are mediated by cholinergic nerve fibers that innervate the musculature via parasympathetic neurons and innervate the sweat glands by cholinergic fibers that travel with the sympathetic nerves. Elevated plasma histamine values parallel the onset of urticaria triggered by changes in body temperature.

Dermatographism The ability to write on skin, dermatographism (also called dermographism or urticaria factitia ) may occur as an isolated disorder or may accompany chronic urticaria or other physical urticaria. It can be diagnosed by observing the skin after stroking it with a tongue depressor. In patients with dermatographism, a linear response occurs secondary to reflex vasoconstriction, followed by pruritus, erythema, and a linear flare caused by secondary dilation of the vessel and extravasation of plasma.

Pressure-Induced Urticaria and Angioedema Pressure-induced urticaria differs from most types of urticaria or angioedema in that symptoms typically occur 4-6 hr after pressure has been applied. The disorder is clinically heterogeneous. Some patients may complain of swelling, with or without pruritus, secondary to pressure, with normal-appearing skin (no urticaria), so the term angioedema is more appropriate. Other lesions are predominantly urticarial and may or may not be associated with significant swelling. When urticaria is present, an infiltrative skin lesion is seen, characterized by a perivascular mononuclear cell infiltrate and dermal edema similar to that seen in chronic idiopathic urticaria. Symptoms occur at sites of tight clothing; foot swelling is common after walking; and buttock swelling may be prominent after sitting for a few hours. This condition can coexist with chronic idiopathic urticaria or can occur separately. The diagnosis is confirmed by challenge testing in which pressure is applied perpendicular to the skin. This is often done with a sling attached to a 10 lb weight that is placed over the patient's arm for 20 min.

Solar Urticaria Solar urticaria is a rare disorder in which urticaria develops within minutes of direct sun exposure. Typically, pruritus occurs first, in approximately 30 sec, followed by edema confined to the light-exposed area and surrounded by a prominent erythematous zone. The lesions usually disappear within 1-3 hr after cessation of sun exposure. When large areas of the body are exposed, systemic symptoms may occur, including hypotension and wheezing. Solar urticaria has been classified into 6 types, depending on the wavelength of light that induces skin lesions and the ability or inability to transfer the disorder passively with serum IgE. The rare inborn error of metabolism erythropoietic protoporphyria can be confused with solar urticaria because of the development of itching and burning of exposed skin immediately after sun exposure. In erythropoietic protoporphyria, fluorescence of ultraviolet-irradiated red blood cells can be demonstrated, and protoporphyrins are found in the urine.

Aquagenic Urticaria Patients with aquagenic urticaria demonstrate small wheals after contact with water, regardless of its temperature, and are thereby distinguishable from

patients with cold urticaria or cholinergic urticaria. Direct application of a compress of water to the skin is used to test for the presence of aquagenic urticaria. Rarely, chlorine or other trace contaminants may be responsible for the reaction.

Chronic Idiopathic Urticaria and Angioedema A common disorder of unknown origin, chronic idiopathic urticaria and angioedema is often associated with normal routine laboratory values and no evidence of systemic disease. Chronic urticaria does not appear to result from an allergic reaction. It differs from allergen-induced skin reactions and from physically induced urticaria in that histologic studies reveal cellular infiltrate predominantly around small venules. Skin examination reveals infiltrative hives with palpably elevated borders, sometimes varying greatly in size and shape but generally being rounded. Biopsy of a typical lesion reveals nonnecrotizing, perivascular, mononuclear cellular infiltration. Varying histopathologic processes can occur in the skin and manifest as urticaria. Patients with hypocomplementemia and cutaneous vasculitis can have urticaria and/or angioedema. Biopsy of these lesions in patients with urticaria, arthralgias, myalgias, and an elevated erythrocyte sedimentation rate (ESR) as manifestations of necrotizing venulitis can reveal fibrinoid necrosis with a predominantly neutrophilic infiltrate. However, the urticarial lesions may be clinically indistinguishable from those seen in the more typical, nonvasculitic cases. Chronic urticaria is increasingly associated with the presence of antithyroid antibodies. Affected patients generally have antibodies to thyroglobulin or a microsomally derived antigen (peroxidase), even if they are euthyroid. The incidence of elevated thyroid antibodies in patients with chronic urticaria is approximately 12%, compared with 3–6% in the general population. Although some patients show clinical reduction of the urticaria with thyroid replacement therapy, others do not. The role of thyroid autoantibodies in chronic urticaria is uncertain; their presence may reflect a tendency of the patient to develop autoantibodies, but they may not play a direct role in chronic urticaria. Of patients with chronic urticaria, 35–40% have a positive autologous serum skin test result: If serum from these patients is intradermally injected into their skin, a

significant wheal and flare reaction develops. Such patients frequently have a complement-activating IgG antibody directed against the α subunit of the IgE receptor that can cross-link the IgE receptor (α subunit) and degranulate mast cells and basophils. An additional 5–10% of patients with chronic urticaria have anti-IgE antibodies rather than an anti–IgE receptor antibody.

Diagnosis The diagnosis of both acute and chronic urticaria is primarily clinical and requires that the physician be aware of the various forms of urticaria. Urticaria is transient, pruritic, erythematous, raised wheals that may become tense and painful. The lesions may coalesce and form polymorphous, serpiginous, or annular lesions (Figs. 173.1 and 173.2 ). Individual lesions usually last 20 min to 3 hr and rarely more than 24 hr. The lesions often disappear, only to reappear at another site. Angioedema involves the deeper subcutaneous tissues in locations such as the eyelids, lips, tongue, genitals, dorsum of the hands or feet, or wall of the gastrointestinal (GI) tract.

FIG. 173.1 Polycyclic lesions of urticaria associated with prostaglandin E2 infusion. (From Eichenfield LF, Friedan IJ, Esterly NB: Textbook of neonatal dermatology , Philadelphia, 2001, WB Saunders, p. 300.)

FIG. 173.2 Annular urticaria of unknown etiology. (From Eichenfield LF, Friedan IJ, Esterly NB: Textbook of neonatal dermatology , Philadelphia, 2001, WB Saunders, p. 301.)

Drugs and foods are the most common causes of acute urticaria. In children, viral infections also frequently trigger hives. Allergy skin testing for foods can be helpful in sorting out causes of acute urticaria, especially when supported by historical evidence. The role of an offending food can then be proved by elimination and careful challenge in a controlled setting, when needed. In the absence of information implicating an ingestant cause, skin testing for foods and implementation of elimination diets are generally not useful for either acute or chronic urticaria. Patients with delayed urticaria 3-6 hr after a meal consisting of mammalian meat should be evaluated for IgE to galactose-α-1,3-galactose (“alpha-gal”), a carbohydrate allergen. Alpha-gal has been identified as a trigger in this circumstance, with sensitization apparently linked to tick bites in specific geographic regions, such as the mid-Atlantic area of the United States. Skin testing for aeroallergens is not indicated unless there is a concern about contact urticaria (animal dander or grass pollen). Dermatographism is common in patients with urticaria and can complicate allergy skin testing by causing falsepositive reactions, but this distinction is usually discernible. Autoimmune diseases are rare causes of chronic urticarial or angioedema. In vitro testing for serum-derived activity that activates basophils involves detection of the expression of the surface marker CD63 or CD203c by donor basophils after incubation with patient serum. The clinical applicability and significance of these tests remains debated. The differential diagnosis of chronic urticaria includes cutaneous or systemic mastocytosis, complementmediated mast cell degranulation as may occur with circulating immune

complexes, malignancies, mixed connective tissue diseases, and cutaneous blistering disorders (e.g., bullous pemphigoid; see Table 173.2 ). In general, laboratory testing should be limited to a complete blood cell count with differential, ESR determination, urinalysis, thyroid autoantibody testing, and liver function tests. Further studies are warranted if the patient has fever, arthralgias, or elevated ESR (Table 173.6 ; see also Table 173.4 ). Testing for antibodies directed at the high-affinity IgE receptor may be warranted in patients with intractable urticaria. Hereditary angioedema is potentially life threatening, usually associated with deficient C1 inhibitor activity, and the most important familial form of angioedema (see Chapter 160.3 ), but it is not associated with typical urticaria. In patients with eosinophilia, stools should be obtained for ova and parasite testing, because infection with helminthic parasites has been associated with urticaria. A syndrome of episodic angioedema/urticaria and fever with associated eosinophilia has been described in both adults and children. In contrast to other hypereosinophilic syndromes, this entity has a benign course. Table 173.6 Diagnostic Testing for Urticaria and Angioedema DIAGNOSIS Food and drug reactions Autoimmune urticaria Thyroiditis Infections Collagen vascular diseases and cutaneous vasculitis Malignancy with angioedema Cold urticaria Solar urticaria Dermatographism Pressure urticaria Vibratory urticaria Aquagenic urticaria Urticaria pigmentosa Hereditary angioedema Familial cold urticaria C3b inactivator deficiency Chronic idiopathic urticaria

DIAGNOSTIC TESTING Elimination of offending agent, skin testing, and challenge with suspected foods Autologous serum skin test; antithyroid antibodies; antibodies against the highaffinity IgE receptor Thyroid-stimulating hormone; antithyroid antibodies Appropriate cultures or serology Skin biopsy, CH50 , C1q, C4, C3, factor B, immunofluorescence of tissues, antinuclear antibodies, cryoglobulins CH50 , C1q, C4, C1-INH determinations Ice cube test usually positive but may be negative in some familial autoinflammatory disorders Exposure to defined wavelengths of light, red blood cell protoporphyrin, fecal protoporphyrin, and coproporphyrin Stroking with narrow object (e.g., tongue blade, fingernail) Application of pressure for defined time and intensity Vibration for 4 min Challenge with tap water at various temperatures Skin biopsy, test for dermatographism C4, C2, CH50 , C1-INH testing by protein and function Challenge by cold exposure, measurement of temperature, white blood cell count, erythrocyte sedimentation rate, skin biopsy C3, factor B, C3b inactivator determinations Skin biopsy, immunofluorescence (negative result), autologous skin test

Skin biopsy for diagnosis of possible urticarial vasculitis is recommended

for urticarial lesions that persist at the same location for >24 hr, those with pigmented or purpuric components, and those that burn more than itch. Collagen vascular diseases such as SLE may manifest urticarial vasculitis as a presenting feature. The skin biopsy in urticarial vasculitis typically shows endothelial cell swelling of postcapillary venules with necrosis of the vessel wall, perivenular neutrophil infiltrate, diapedesis of red blood cells, and fibrin deposition associated with deposition of immune complexes. Mastocytosis is characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, and skin. Clinical effects of mast cell activation are common, including pruritus, flushing, urtication, abdominal pain, nausea, and vomiting. The diagnosis is confirmed by a bone marrow biopsy showing increased numbers of spindle-shaped mast cells that express CD2 and CD25. Urticaria pigmentosa is the most common skin manifestation of mastocytosis and may occur as an isolated skin finding. It appears as small, yellow-tan to reddish brown macules or raised papules that urticate on scratching (Darier sign ). This sign can be masked by antihistamines. The diagnosis is confirmed by a skin biopsy that shows increased numbers of dermal mast cells. Physical urticaria should be considered in any patient with chronic urticaria and a suggestive history (see Table 173.2 ). Papular urticaria often occurs in small children, generally on the extremities. It manifests as grouped or linear, highly pruritic wheals or papules mainly on exposed skin at the sites of insect bites. Exercise-induced anaphylaxis manifests as varying combinations of pruritus, urticaria, angioedema, wheezing, laryngeal obstruction, or hypotension after exercise (see Chapter 174 ). Cholinergic urticaria is differentiated by positive results of heat challenge tests and the rare occurrence of anaphylactic shock. The combination of ingestion of various food allergens and postprandial exercise has been associated with urticaria/angioedema and anaphylaxis. In patients with this combination disorder, food or exercise alone does not produce the reaction. Muckle-Wells syndrome and familial cold autoinflammatory syndrome are rare, dominantly inherited conditions associated with recurrent urticaria-like lesions. Muckle-Wells syndrome is characterized by arthritis and joint pain that usually appears in adolescence. It is associated with progressive nerve deafness, recurrent fever, elevated ESR (see Tables 173.3 and 173.5 ), hypergammaglobulinemia, renal amyloidosis, and a poor prognosis. Familial cold autoinflammatory syndrome is characterized by a cold-induced rash that has urticarial features but is rarely pruritic. Cold exposure leads to additional

symptoms such as conjunctivitis, sweating, headache, and nausea. Patient longevity is usually normal.

Treatment Acute urticaria is a self-limited illness requiring little treatment other than antihistamines and avoidance of any identified trigger. Hydroxyzine and diphenhydramine are sedating but are effective and frequently used for treatment of urticaria. Loratadine, fexofenadine, and cetirizine are also effective and are preferable because of reduced frequency of drowsiness and longer duration of action (Table 173.7 ). Epinephrine 1 : 1,000, 0.01 mL/kg (maximum 0.3 mL) intramuscularly, usually provides rapid relief of acute, severe urticaria/angioedema but is seldom required. A short course of oral corticosteroids should be given only for severe episodes of urticaria and angioedema that are unresponsive to antihistamines. Table 173.7

Treatment of Urticaria and Angioedema CLASS/DRUG DOSE ANTIHISTAMINES, TYPE H1 (SECOND GENERATION) Fexofenadine 6-11 yr: 30 mg >12 yr: 60 mg Adult: 180 mg Loratadine 2-5 yr: 5 mg >6 yr: 10 mg Desloratadine 6-11 mo: 1 mg 12 mo-5 yr: 1.25 mg 6-11 yr: 2.5 mg >12 yr: 5 mg Cetirizine 6-23 mo: 2.5 mg 2-6 yr: 2.5-5 mg >6 yr: 5-10 mg Levocetirizine 6 mo-5 yr: 1.25 mg 6-11 yr: 2.5 mg >12 yr: 5 mg ANTIHISTAMINES, TYPE H2 Cimetidine Infants: 10-20 mg/kg/day Children: 20-40 mg/kg/day Ranitidine 1 mo-16 yr: 5-10 mg/kg/day Famotidine 3-12 mo: 1 mg/kg/day 1-16 yr: 1-2 mg/kg/day LEUKOTRIENE PATHWAY MODIFIERS

FREQUENCY Twice daily Once daily Once daily Once daily

Once daily

Once daily Once daily Once daily Divided q6-12h Divided q12h Divided q12h

Montelukast

Zafirlukast IMMUNOMODULATORY DRUGS Omalizumab (anti IgE) Cyclosporine Sulfasalazine Intravenous immune globulin (IVIG)

12 mo-5 yr: 4 mg 6-14 yr: 5 mg >14 yr: 10 mg 5-11 yr: 10 mg

Once daily

>11 yr: 150 mg or 300 mg 3-4 mg/kg/day >6 yr: 30 mg/kg/day 400 mg/kg/day

Every 28 days Divided q12h* Divided q6h † 5 consecutive days

Twice daily

* Monitor blood pressure and serum creatinine, potassium, and magnesium levels monthly. † Monitor complete blood count and liver function tests at baseline, every 2 wk for 3 mo, and then

every 1-3 mo.

The best treatment of physical urticaria is avoidance of the stimulus. Antihistamines are also helpful. Cyproheptadine in divided doses is the drug of choice for cold-induced urticaria. Treatment of dermatographism consists of local skin care and antihistamines; for severe symptoms, high doses may be needed. The initial objective of therapy is to decrease pruritus so that the stimulation for scratching is diminished. A combination of antihistamines, sunscreens, and avoidance of sunlight is helpful for most patients. Chronic urticaria only rarely responds favorably to dietary manipulation. The mainstay of therapy is the use of nonsedating or low-sedating H1 antihistamines. In those patients not showing response to standard doses, pushing the H1 blockade with higher than the usual recommended doses of these agents is a common next approach. The 3-drug combination of H1 and H2 antihistamine with a leukotriene receptor antagonist (montelukast) is helpful for many patients. If hives persist after maximal H1 - and/or H2 -receptor blockade has been achieved, a brief course of oral corticosteroids may be considered, but long-term steroid use is best avoided. The monoclonal antibody omalizumab (anti-IgE) is FDA approved for the treatment of chronic urticaria in children 12 years and older. Other agents that have been used for chronic urticaria but are not approved by the U.S. Food and Drug Administration (FDA) for this condition include cyclosporine, hydroxychloroquine, sulfasalazine, colchicine, dapsone, mycophenolate, intravenous immune globulin (IVIG), and plasmapheresis.

Hereditary Angioedema Hereditary angioedema (HAE , types 1 and 2) is an inherited autosomal dominant disease caused by low functional levels of the plasma protein C1

inhibitor (C1-INH) (see Chapter 160.3 ). Patients typically report episodic attacks of angioedema or deep localized swelling, most often on a hand or foot, that begin during childhood and become much more severe during adolescence. Cutaneous nonpitting and nonpruritic edema not associated with urticaria is the most common symptom. The swelling usually becomes more severe over about 1.5 days and then resolves over about the same period. However, the duration of attacks can be quite variable. In some patients, attacks are preceded by the development of a rash, erythema marginatum , that is erythematous, not raised, and not pruritic. A 2nd major symptom complex noted by patients is attacks of severe abdominal pain caused by edema of the mucosa of any portion of the GI tract. The intensity of the pain can approximate that of an acute abdomen, often resulting in unnecessary surgery. Either constipation or diarrhea during these attacks can be noted. The GI edema generally follows the same time course to resolution as the cutaneous attacks and often does not occur at the same time as the peripheral edema. Patients usually have a prodrome, a tightness or tingling in the area that will swell, usually lasting several hours, followed by the development of angioedema. Laryngeal edema , the most feared complication of HAE, can cause complete respiratory obstruction. Although life-threatening attacks are infrequent, more than half of patients with HAE experience laryngeal involvement at some time during their lives. Dental work with the injection of procaine hydrochloride (Novocain) into the gums is a common precipitant, but laryngeal edema can be spontaneous. The clinical condition may deteriorate rapidly, progressing through mild discomfort to complete airway obstruction over hours. Soft tissue edema can be readily seen when the disease involves the throat and uvula. If this edema progresses to difficulty swallowing secretions or a change in the tone of the voice, the patient may require emergency intubation or even tracheostomy to ensure an adequate airway. Other presentations are less common. These patients typically do not respond well to treatment with epinephrine, antihistamines, or glucocorticoids. In most cases the cause of the attack is unknown, but in some patients, trauma or emotional stress clearly precipitates attacks. Drugs such as angiotensinconverting enzyme (ACE) inhibitors that inhibit the degradation of bradykinin make the disease strikingly worse, and estrogens also make attacks more severe. In some females, menstruation also regularly induces attacks. The frequency of attacks varies greatly among affected individuals and at different times in the same individual. Some individuals experience weekly episodes, whereas others

may go years between attacks. Episodes can start at any age. C1-INH is a member of the serpin family of proteases, similar to αantitrypsin, antithrombin III, and angiotensinogen. These proteins stoichiometrically inactivate their target proteases by forming stable, 1 : 1 complexes with the protein to be inhibited. Synthesized primarily by hepatocytes, C1-INH is also synthesized by monocytes. The regulation of the protein production is not completely understood, but it is believed that androgens may stimulate C1-INH synthesis, because patients with the disorder respond clinically to androgen therapy with elevated serum C1-INH levels. C1-INH deficiency is an autosomal dominant disease, with as many as 25% of patients giving no family history. Because all C1-INH–deficient patients are heterozygous for this gene defect, it is believed that half the normal level of C1INH is not sufficient to prevent attacks. Fig. 173.3 shows the diagnostic approach.

FIG. 173.3 A, Diagnosis of C1-INH deficiency in families with known C1INH-HAE. B, Diagnosis of C1-INH-HAE in pediatric patients with

angioedema of unknown etiology. (From Farkas H, Martinez-Saguer I, Bork K, et al: International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Eur J Allergy Clin Immunol 72:300-313, 2017, Fig.1, p. 304.)

Although named for its action on the 1st component of complement (C1 esterase), C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor (factor XII), activated factor XI, plasma thromboplastin antecedent, and kallikrein. Within the complement system, C1-INH blocks the activation of C1 and the rest of the classical complement pathway by binding to C1r and C1s. Without adequate C1-INH, unchecked activation of C1 causes cleavage of C4 and C2, the proteins following in the complement cascade. Levels of C3 are normal. C1-INH also inhibits serine proteases associated with activation of the lectin activation pathway. The major factor responsible for the edema formation is bradykinin, an important nonapeptide mediator that can induce leakage of postcapillary venules. Bradykinin is derived from cleavage of the circulating protein high-molecular-weight kininogen by the plasma enzyme kallikrein. Two major genetic types of C1-INH deficiency are described that result in essentially the same phenotypic expression. The C1-INH gene is located on chromosome 11 in the p11-q13 region. The inheritance is autosomal dominant with incomplete penetrance. Persons inheriting the abnormal gene can have a clinical spectrum ranging from asymptomatic to severely affected. Type 1 HAE is the most common form, accounting for approximately 85% of cases. Synthesis of C1-INH is blocked at the site of the faulty allele, or the protein is not secreted normally because of faulty protein processing, but secretion occurs at the normal allele. The result is secretion of the normal protein, yielding quantitative serum concentrations of C1-INH approximately 20–40% of normal. Type 2 HAE accounts for approximately 15% of cases. Mutations of 1 of the amino acids near the active site of the inhibitor lead to synthesis of nonfunctional C1-INH protein and again less than half of the normal functioning protein. Patients with type 2 HAE have either normal or increased concentrations of the protein but low values in assays of C1-INH function. A clinical syndrome resembling HAE termed HAE with normal C1-INH has been described that affects mostly women, with a tendency to cause fewer abdominal attacks and more upper airway attacks. In this condition, no abnormalities of complement or of C1-INH have been described. Approximately 20% of affected patients have been found to have a gain-of-function abnormality

of clotting factor XII, but the fundamental cause is of this syndrome still unknown. The FDA has approved purified C1-INH for prophylaxis to prevent attacks. Androgens like the gonadotropin inhibitor danazol were previously used to prevent attacks. Weak androgens have many side effects that preclude their use in some patients. Their use in children is problematic because of the possibility of premature closure of the epiphyses, and these agents are not used in pregnant women. The fibrinolysis inhibitor ε-aminocaproic acid (EACA ) is also effective in preventing attacks and has been used in children, but its use is attended by the development of severe fatigue and muscle weakness over time. A cyclized analog of EACA, tranexamic acid , has been used extensively in Europe; because of limited availability, it has been used less extensively in the United States. Tranexamic acid is believed to be more effective than EACA and has lower toxicity, but there have been few direct studies. Its mechanism of action is not clearly defined, and not all patients respond to this agent. In 2008 the FDA approved, for adolescents and older patients, the use of purified C1-INH (Cinryze), prepared from human plasma and given intravenously, for prophylaxis of this disease. The half-life of this plasma protein is relatively short, about 40 hr, and the approved regimen is 1,000 units twice a week. In 2009 a similar purified C1-inhibitor product, Berinert, administered as 20 U/kg intravenously, was approved for the treatment of acute attacks. A recombinant C1-INH product has been FDA approved for treatment of acute attacks (and in Europe). In 2009 the FDA approved a kallikrein inhibitor, ecallantide , given subcutaneously, for acute treatment in patients age 16 yr and older. This 60–amino acid peptide causes anaphylaxis rarely and is approved only for administration by medical personnel. In 2010 a bradykinin type 2 receptor antagonist, icatibant , was approved for acute treatment in patients age 18 yr and older and in summer 2016 was approved for the treatment of all children. All treatments are most effective when given early in an attack and begin to have noticeable effect about 1-4 hr after treatment.

Bibliography Barniol C, Dehours E, Mallet J, et al. Levocetirizine and prednisone are not superior to levocetirizine alone for the treatment of acute urticaria: a randomized double-blind

clinical trial. Ann Emerg Med . 2018;71(1):125–131. Boyden SE, Desai A, Cruse G, et al. Vibratory urticaria associated with a missense variant in ADGRE2 . N Engl J Med . 2016;374(7):656–663. Farkas H, Martinez-Saguer I, Bork K, et al. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Allergy . 2017;72:300–313. Frank MM. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am . 2006;26:653–668. Frank MM, Zuraw B, Banerji A, et al. Management of children with hereditary angioedema due to C1 inhibitor deficiency. Pediatrics . 2016;138(5):e20160575. Hawkey S, Ghaffar SA. Glove-related hand urticaria: an increasing occupational problem amongst health care workers. Br J Dermatol . 2016;174(5):1137–1140. Kanazawa N. Hereditary disorders presenting with urticaria. Immunol Allergy Clin North Am . 2014;34:169–179. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy . 2009;39:777–787. Kennedy JL, Stallings AP, Platts-Mills TA, et al. Galactosealpha-1,3-galactose and delayed anaphylaxis, angioedema, and urticaria in children. Pediatrics . 2013;131(5):e1545– e1552. Longhurst H, Cicardi M, Craig T, et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med . 2017;376(12):1131–1140. Maurer M, Rosen K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticarial. N Engl J Med . 2013;368(10):924–934. 2017. The Medical Letter: allergic rhinitis. Med Lett Drugs Ther . 2017;59(1520):71–80.

2013. The Medical Letter: omalizumab (Xolair) for chronic urticarial. Med Lett Drugs Ther . 2013;55(1417):43–44. Ombrello MJ, Remmers EF, Sun G, et al. Cold urticarial, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med . 2012;366(4):330–338. Peroni A, Colato C, Zanoni G, Girolomoni G. Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria. J Am Acad Dermatol . 2009;62(4):557–570. Powell RJ, Du Toit GL, Siddique N, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clin Exp Allergy . 2007;37:631–650. Riedl MA. Update on the acute treatment of hereditary angioedema. Allergy Asthma Proc . 2011;32:11–16. Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebocontrolled, dose-ranging study of single-dose omalizumab in patients with H1 -antihistimine-refractory chronic idiopathic urticarial. J Allergy Clin Immunol . 2011;128(3):567–573. Youseff MJ, Chiu YE. Eczema and urticaria as manifestations of undiagnosed and rare diseases. Pediatr Clin North Am . 2017;64:39–56. Zitelli KB, Cordoro KM. Evidence-based evaluation and management of chronic urticaria in children. Pediatr Dermatol . 2011;28:629–639. Zuberbier T. A summary of the new international EAACI/GA(2)LEN/EDF/WAO guidelines in urticaria. World Allergy Organ J . 2012;5:S1–S5. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med . 2008;359:1027–1036.

CHAPTER 174

Anaphylaxis Hugh A. Sampson, Julie Wang, Scott H. Sicherer

Anaphylaxis is defined as a serious allergic reaction that is rapid in onset and may cause death. Anaphylaxis in children, particularly infants, is underdiagnosed. Anaphylaxis occurs when there is a sudden release of potent, biologically active mediators from mast cells and basophils, leading to cutaneous (urticaria, angioedema, flushing), respiratory (bronchospasm, laryngeal edema), cardiovascular (hypotension, dysrhythmias, myocardial ischemia), and gastrointestinal (nausea, colicky abdominal pain, vomiting, diarrhea) symptoms (Table 174.1 and Fig. 174.1 ). Table 174.1

Symptoms and Signs of Anaphylaxis in Infants ANAPHYLAXIS SYMPTOMS ANAPHYLAXIS SIGNS THAT MAY BE DIFFICULT THAT INFANTS TO INTERPRET/UNHELPFUL IN INFANTS, AND CANNOT WHY DESCRIBE GENERAL Feeling of Nonspecific behavioral changes such as persistent crying, warmth, fussing, irritability, fright, suddenly becoming quiet weakness, anxiety, apprehension, impending doom SKIN/MUCOUS MEMBRANES Itching of lips, Flushing (may also occur with fever, hyperthermia, or tongue, palate, crying spells) uvula, ears, throat, nose, eyes, etc.; mouth-tingling or metallic taste RESPIRATORY SYSTEM

ANAPHYLAXIS SIGNS IN INFANTS

Rapid onset of hives (potentially difficult to discern in infants with acute atopic dermatitis; scratching and excoriations will be absent in young infants); angioedema (face, tongue, oropharynx)

Nasal congestion, Hoarseness, dysphonia (common after a crying spell); throat tightness; drooling or increased secretions (common in infants) chest tightness; shortness of breath GASTROINTESTINAL SYSTEM Dysphagia, Spitting up/regurgitation (common after feeds), loose nausea, stools (normal in infants, especially if breastfed); colicky abdominal abdominal pain pain/cramping CARDIOVASCULAR SYSTEM Feeling faint, Hypotension (need appropriate-size blood pressure cuff; presyncope, low systolic blood pressure for children is defined as 140 vision, difficulty beats/min from 3 mo to 2 yr, inclusive; loss of bowel and in hearing bladder control (ubiquitous in infants) CENTRAL NERVOUS SYSTEM Headache Drowsiness, somnolence (common in infants after feeds)

Rapid onset of coughing, choking, stridor, wheezing, dyspnea, apnea, cyanosis

Sudden, profuse vomiting

Weak pulse, arrhythmia, diaphoresis/sweating, collapse/unconsciousness

Rapid onset of unresponsiveness, lethargy, or hypotonia; seizures

Adapted from Simons FER: Anaphylaxis in infants: can recognition and management be improved? J Allergy Clin Immunol 120:537–540, 2007.

FIG. 174.1 Summary of the pathogenesis of anaphylaxis. See text for details about mechanisms, triggers, key cells, and mediators. Two or more target organ systems are typically involved in anaphylaxis. CNS, Central nervous system; CVS, cardiovascular system; GI, gastrointestinal; PAF, platelet-activating factor. (From Leung DYM, Szefler SJ, Bonilla FA Akdis CA, Sampson HA, editors: Pediatric allergy principles and practice, ed 3, Philadelphia, 2016, Elsevier, p 525.)

Etiology The most common causes of anaphylaxis in children are different for hospital and community settings. Anaphylaxis occurring in the hospital results primarily from allergic reactions to medications and latex. Food allergy is the most common cause of anaphylaxis occurring outside the hospital, accounting for about half the anaphylactic reactions reported in pediatric surveys from the United States, Italy, and South Australia (Table 174.2 ). Peanut allergy is an important cause of food-induced anaphylaxis, accounting for the majority of fatal and near-fatal reactions. In the hospital, latex is a particular problem for children undergoing multiple operations, such as patients with spina bifida and urologic disorders, and has prompted many hospitals to switch to latex-free

products. Patients with latex allergy may also experience food-allergic reactions from homologous proteins in foods such as bananas, kiwi, avocado, chestnut, and passion fruit. Anaphylaxis to galactose-α-1,3-galactose has been reported 36 hr after eating red meat.

Table 174.2

Anaphylaxis Triggers in the Community* Allergen Triggers (IgE-Dependent Immunologic Mechanism)* Foods (e.g., peanut, tree nuts, shellfish, fish, milk, egg, wheat, soy, sesame, meat [galactose-α-1,3-galactose]) Food additives (e.g., spices, colorants, vegetable gums, contaminants) Stinging insects: Hymenoptera species (e.g., bees, yellow jackets, wasps, hornets, fire ants) Medications (e.g., β-lactam antibiotics, ibuprofen) Biologic agents (e.g., monoclonal antibodies [infliximab, omalizumab] and allergens [challenge tests, specific immunotherapy]) Natural rubber latex Vaccines Inhalants (rare) (e.g., horse or hamster dander, grass pollen) Previously unrecognized allergens (foods, venoms, biting insect saliva, medications, biologic agents)

Other Immune Mechanisms (IgE Independent) IgG mediated (infliximab, high-molecular-weight dextrans) Immune aggregates (IVIG) Drugs (aspirin, NSAID, opiates, contrast material, ethylene oxide/dialysis tubing) Complement activation Physical factors (e.g., exercise, † cold, heat, sunlight/ultraviolet radiation) Ethanol Idiopathic* IVIG, Intravenous immune globulin; NSAID, nonsteroidal antiinflammatory drug.

* In the pediatric population, some anaphylaxis triggers, such as hormones

(progesterone), seminal fluid, and occupational allergens, are uncommon, as is idiopathic anaphylaxis. † Exercise with or without a co-trigger, such as a food or medication, cold air, or

cold water. Adapted from Leung DYM, Sampson HA, Geha RS, et al: Pediatric allergy principles and practice , Philadelphia, 2010, Elsevier, p 652.

Epidemiology The overall annual incidence of anaphylaxis in the United States is estimated at 42 cases per 100,000 person-years, totaling >150,000 cases/yr. Food allergens are the most common trigger in children, with an incidence rate of approximately 20 per 100,000 person-years. An Australian parental survey found that 0.59% of children 3-17 yr of age had experienced at least 1 anaphylactic event. Having asthma and the severity of asthma are important anaphylaxis risk factors (Table 174.3 ). In addition, patients with systemic mastocytosis or monoclonal mast cell–activating syndrome are at increased risk for anaphylaxis, as are patients with an elevated baseline serum tryptase level.

Table 174.3

Patient Risk Factors for Anaphylaxis Age-Related Factors Infants: anaphylaxis can be difficult to recognize, especially if the first episode; patients cannot describe symptoms. Adolescents and young adults: increased risk-taking behaviors, such as failure to avoid known triggers and to carry an epinephrine autoinjector consistently Pregnancy: risk of iatrogenic anaphylaxis, as from β lactam antibiotics to prevent neonatal group B streptococcal infection, agents used perioperatively during caesarean sections, and natural rubber latex Older people: increased risk of death because of concomitant disease and drugs

Concomitant Diseases Asthma and other chronic respiratory diseases Cardiovascular diseases Systemic mastocytosis or monoclonal mast cell–activating syndrome Allergic rhinitis and eczema* Depression, cognitive dysfunction, substance misuse

Drugs β-Adrenergic blockers † Angiotensin-converting enzyme (ACE) inhibitors † Sedatives, antidepressants, narcotics, recreational drugs, and alcohol may decrease the patient's ability to recognize triggers and symptoms.

Factors That May Increase Risk for Anaphylaxis or Make It More Difficult to Treat Age Asthma Atopy Drugs Alcohol Other cofactors such as exercise, infection, menses

* Atopic diseases are a risk factor for anaphylaxis triggered by food, latex, and

exercise, but not for anaphylaxis triggered by most drugs or by insect stings. † Patients taking β-blockers or ACE inhibitors seem to be at increased risk for

severe anaphylaxis. In addition, those taking β-blockers may not respond optimally to epinephrine treatment and may need glucagon, a polypeptide with non–catecholamine-dependent inotropic and chronotropic cardiac effects, atropine for persistent bradycardia, or ipratropium for persistent bronchospasm.

Adapted from Lieberman P, Nicklas RA, Randolph C, et al: Anaphylaxis—a practice parameter update 2015, Ann Allergy Asthma Immunol 115(5):341–384, 2015, Table I-9.

Pathogenesis Principal pathologic features in fatal anaphylaxis include acute bronchial obstruction with pulmonary hyperinflation, pulmonary edema, intraalveolar hemorrhaging, visceral congestion, laryngeal edema, and urticaria and angioedema. Acute hypotension is attributed to vasomotor dilation and cardiac dysrhythmias. Most cases of anaphylaxis are believed to be the result of activation of mast cells and basophils via cell-bound allergen-specific IgE molecules (see Fig. 174.1 ). Patients initially must be exposed to the responsible allergen to generate allergen-specific antibodies. In many cases the child and the parent are unaware of the initial exposure, which may be from passage of food proteins in maternal breast milk or exposure to inflamed skin (e.g., eczematous lesions). When the child is reexposed to the sensitizing allergen, mast cells and basophils, and possibly other cells such as macrophages, release a variety of mediators (histamine, tryptase) and cytokines that can produce allergic symptoms in any or all target organs. Clinical anaphylaxis may also be caused by mechanisms other than IgE-mediated reactions, including direct release of mediators from mast cells by medications and physical factors (morphine, exercise, cold), disturbances of leukotriene metabolism (aspirin and nonsteroidal antiinflammatory drugs), immune aggregates and complement activation (blood products), probable complement activation (radiocontrast dyes, dialysis membranes), and IgG-mediated reactions (high-molecular-weight dextran, chimeric or humanized monoclonal antibodies) (see Table 174.2 ). Idiopathic anaphylaxis is a diagnosis of exclusion when no inciting agent is identified and other disorders have been excluded (see Chapter 678.1 ). Symptoms are similar to IgE mediated causes of anaphylaxis; episodes often recur.

Clinical Manifestations The onset of symptoms may vary depending on the cause of the reaction.

Reactions from ingested allergens (foods, medications) are delayed in onset (minutes to 2 hr) compared with those from injected allergens (insect sting, medications) and tend to have more gastrointestinal (GI) symptoms. Initial symptoms may include any of the following constellation of symptoms: pruritus about the mouth and face; flushing, urticaria and angioedema, oral or cutaneous pruritus; a sensation of warmth, weakness, and apprehension (sense of doom); tightness in the throat, dry staccato cough and hoarseness, periocular pruritus, nasal congestion, sneezing, dyspnea, deep cough and wheezing; nausea, abdominal cramping, and vomiting, especially with ingested allergens; uterine contractions (manifesting as lower back pain); and faintness and loss of consciousness in severe cases. Some degree of obstructive laryngeal edema is typically encountered with severe reactions. Cutaneous symptoms may be absent in up to 10% of cases, and the acute onset of severe bronchospasm in a previously well person with asthma should suggest the diagnosis of anaphylaxis. Sudden collapse in the absence of cutaneous symptoms should also raise suspicion of vasovagal collapse, myocardial infarction, aspiration, pulmonary embolism, or seizure disorder. Laryngeal edema, especially with abdominal pain, may also be a result of hereditary angioedema (see Chapter 173 ). Symptoms in infants may not be easy to identify (see Table 174.1 ).

Laboratory Findings Laboratory studies may indicate the presence of IgE antibodies to a suspected causative agent, but this result is not definitive. Plasma histamine is elevated for a brief period but is unstable and difficult to measure in a clinical setting. Plasma tryptase is more stable and remains elevated for several hours but often is not elevated, especially in food-induced anaphylactic reactions.

Diagnosis A National Institutes of Health (NIH)–sponsored expert panel has recommended an approach to the diagnosis of anaphylaxis (Table 174.4 ). The differential diagnosis includes other forms of shock (hemorrhagic, cardiogenic, septic); vasopressor reactions, including flushing syndromes (e.g., carcinoid syndrome); ingestion of monosodium glutamate; scombroidosis; and hereditary angioedema. In addition, panic attack, vocal cord dysfunction, pheochromocytoma, and red

man syndrome (caused by vancomycin) should be considered.

Table 174.4

Diagnosis of Anaphylaxis Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin and/or mucosal tissue (e.g., generalized hives, pruritus or flushing, swollen lips/tongue/uvula) AND at least 1 of the following : a. Respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced peak PEF, hypoxemia) b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): a. Involvement of the skin/mucosal tissue (e.g., generalized hives, itch/flush, swollen lips/tongue/uvula) b. Respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor, reduced PEF, hypoxemia) c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 3. Reduced BP following exposure to known allergen for that patient (minutes to several hours): a. Infants and children: low systolic BP (age specific) or >30% drop in systolic BP b. Adults: systolic BP 30% drop from patient's baseline BP, Blood pressure; PEF, peak expiratory flow.

Adapted from Sampson HA, Muñoz-Furlong A, Campbell RL, et al: Second Symposium on the Definition and Management of Anaphylaxis: summary report, Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium, J Allergy Clin Immunol 117:391–397, 2006.

Treatment Anaphylaxis is a medical emergency requiring aggressive management with intramuscular (IM, first line) or intravenous (IV) epinephrine, IM or IV H1 and H2 antihistamine antagonists, oxygen, IV fluids, inhaled β-agonists, and corticosteroids (Table 174.5 and Fig. 174.2 ). The initial assessment should ensure an adequate airway with effective respiration, circulation, and perfusion. Epinephrine is the most important medication, and there should be no delay in its administration. Epinephrine should be given by the IM route to the lateral thigh (1 : 1000 dilution, 0.01 mg/kg; maximum 0.5 mg). For children ≥12 yr, many recommend the 0.5 mg IM dose. The IM dose can be repeated at intervals of 5-15 min if symptoms persist or worsen. If there is no response to multiple doses of epinephrine, IV epinephrine using the 1 : 10,000 dilution may be needed. If IV access is not readily available, epinephrine can be administered via the endotracheal or intraosseous routes. Table 174.5

Management of a Patient With Anaphylaxis MECHANISM(S) DOSAGE(S) COMMENTS; ADVERSE REACTIONS OF EFFECT PATIENT EMERGENCY MANAGEMENT (dependent on severity of symptoms) Epinephrine α1 -, β1 -, β2 0.01 mg/kg, up to Tachycardia, hypertension, nervousness, (adrenaline) 0.5 mg IM in headache, nausea, irritability, tremor Adrenergic effects lateral thigh Adrenaclick, Auvi-Q, EpiPen Jr/EpiPen: 0.15 mg IM for 825 kg 0.3 mg IM for 25 kg or more Epinephrine autoinjector: 0.1 mg for 7.5-15 TREATMENT

Cetirizine (liquid)

Antihistamine (competitive of H1 receptor)

Alternative: Diphenhydramine

kg 0.15 mg for 15 to 25 kg 0.3 mg for 25 kg or more Cetirizine liquid: 5 Hypotension, tachycardia, somnolence mg/5 mL 0.25 mg/kg, up to 10 mg PO 1.25 mg/kg up to 50 Hypotension, tachycardia, somnolence, mg PO or IM paradoxical excitement

Antihistamine (competitive of H1 receptor) Transport to an emergency facility EMERGENCY PERSONNEL MANAGEMENT (dependent on severity of symptoms) Epinephrine α1 -, β1 -, β2 0.01 mg/kg, up to Tachycardia, hypertension, nervousness, (adrenaline) 0.5 mg IM in headache, nausea, irritability, tremor Adrenergic effects lateral thigh Epinephrine autoinjector: 0.1 mg for 7.5-15 kg 0.15 mg for 15 to 25 kg 0.3 mg for 25 kg or more 0.01 mL/kg/dose of 1 : 1,000 (vial) solution, up to 0.5 mL IM May repeat every 10-15 min For severe hypotension: 0.01 mL/kg/dose of 1 : 10,000 slow IV push Supplemental oxygen and airway management Volume Expanders Crystalloids 30 mL/kg in 1st hr Rate titrated against BP response (normal saline or If tolerated, place patient supine with legs Ringer lactate) raised. Colloids 10 mL/kg rapidly Rate titrated against BP response (hydroxyethyl followed by slow If tolerated, place patient supine with legs starch) infusion raised. Antihistamines Cetirizine (liquid) Antihistamine Cetirizine liquid: 5 Hypotension, tachycardia, somnolence (competitive of H1 mg/5 mL 0.25 mg/kg, up to receptor) 10 mg PO Alternative: Antihistamine 1.25 mg/kg, up to 50 Hypotension, tachycardia, somnolence, Diphenhydramine (competitive of H1 mg PO, IM, or IV paradoxical excitement receptor) Ranitidine

Antihistamine (competitive of H2

1 mg/kg, up to 50 mg IV

Headache, mental confusion

receptor)

Alternative: Cimetidine

Antihistamine (competitive of H2 receptor)

Corticosteroids Methylprednisolone Antiinflammatory

Prednisone

Antiinflammatory

Nebulized albuterol β-Agonist

Should be administered slowly 4 mg/kg, up to 200 Headache, mental confusion mg IV Should be administered slowly Solu-Medrol (IV): 1-2 mg/kg, up to 125 mg IV Depo-Medrol (IM): 1 mg/kg, up to 80 mg IM 1 mg/kg up, to 75 mg PO 0.83 mg/mL (3 mL) via mask with O2

Hypertension, edema, nervousness, agitation

Hypertension, edema, nervousness, agitation Palpitations, nervousness, CNS stimulation, tachycardia; use to supplement epinephrine when bronchospasm appears unresponsive; may repeat

POSTEMERGENCY MANAGEMENT Antihistamine Cetirizine (5-10 mg qd) or loratadine (5-10 mg qd) for 3 days Corticosteroids Optional: Oral prednisone (1 mg/kg up to 75 mg) daily for 3 days Preventive Treatment Prescription for epinephrine autoinjector and antihistamine Provide written plan outlining patient emergency management (may download form from http://www.aap.org or http://www.foodallergy.org ) Follow-up evaluation to determine/confirm etiology Immunotherapy for insect sting allergy Patient Education Instruction on avoidance of causative agent Information on recognizing early signs of anaphylaxis Stress early treatment of allergic symptoms to avoid systemic anaphylaxis Encourage wearing medical identification jewelry

BP, Blood pressure; CNS, central nervous system; IM, Intramuscularly; IV, intravenously; PO, orally; qd, every day.

FIG. 174.2 Algorithm for treatment of anaphylactic event in outpatient setting. ACLS, Advance cardiac life support; CPR, cardiopulmonary resuscitation; ICU, intensive care unit; IV, intravenous. (From Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update, J Allergy Clin Immunol 126:477–480 e471–442, 2010.)

For refractory hypotension, other vasopressors may be used as alternative agents to epinephrine. Anaphylaxis refractory to repeated doses of epinephrine in a patient receiving β-adrenergic blockers has anecdotally been treated with glucagon. The patient should be placed in a supine position when there is concern for hemodynamic compromise. Fluids are also important in patients with shock. Other drugs (antihistamines, glucocorticosteroids) have a secondary

role in the management of anaphylaxis. Patients may experience biphasic anaphylaxis , which occurs when anaphylactic symptoms recur after apparent resolution. The mechanism of this phenomenon is unknown, but it appears to be more common when therapy is initiated late and symptoms at presentation are more severe. It does not appear to be affected by the administration of corticosteroids during the initial therapy. More than 90% of biphasic responses occur within 4 hr, so patients should be observed for at least 4 hr before being discharged from the emergency department. Referrals should be made to appropriate specialists for further evaluation and follow-up.

Prevention For patients experiencing anaphylactic reactions, the triggering agent should be avoided, and education regarding early recognition of anaphylactic symptoms and administration of emergency medications should be provided. Patients with food allergies must be educated in allergen avoidance, including active reading of food ingredient labels and knowledge of potential contamination and high-risk situations. Any child with food allergy and a history of asthma, peanut, tree nut, fish, or shellfish allergy or a previous systemic reaction should be given an epinephrine autoinjector. The expert panel also indicates that epinephrine autoinjectors should be considered for any patient with IgE-mediated food allergy. In addition, liquid cetirizine (or alternatively, diphenhydramine) and a written emergency plan should also be provided in case of accidental ingestion or allergic reaction. A form can be downloaded from the American Academy of Pediatrics (www.aap.org ) or Food Allergy Research & Education (www.foodallergy.org ). In cases of food-associated exercise-induced anaphylaxis, children must not exercise within 2-3 hr of ingesting the triggering food and, as in children with exercise-induced anaphylaxis, should exercise with a friend, learn to recognize the early signs of anaphylaxis (sensation of warmth, facial pruritus), stop exercising, and seek help immediately if symptoms develop. Children experiencing a systemic anaphylactic reaction, including respiratory symptoms, to an insect sting should be evaluated and treated with immunotherapy, which is >90% protective. Reactions to medications can be reduced and minimized by using oral medications instead of injected forms and avoiding cross-reacting medications. Low-osmolarity radiocontrast dyes and pretreatment can be used in

patients with suspected reactions to previous radiocontrast dye. Nonlatex gloves and materials should be used in children undergoing multiple operations. Any child at risk for anaphylaxis should receive emergency medications (including epinephrine autoinjector), education on identification of signs and symptoms of anaphylaxis and proper administration of medications (Table 174.6 ), and a written emergency plan in case of accidental exposure. They should be encouraged to wear medical identification jewelry.

Table 174.6

Considerations With Epinephrine Injection for Anaphylaxis Why Healthcare Professionals Fail to Inject Epinephrine Promptly • Lack of recognition of anaphylaxis symptoms; failure to diagnose anaphylaxis • Episode appears mild, or there is a history of previous mild episode(s)* • Inappropriate concern about transient mild pharmacologic effects of epinephrine (e.g., tremor) • Lack of awareness that serious adverse effects are almost always attributable to epinephrine overdose or IV administration, especially IV bolus, rapid IV infusion, or IV infusion of a 1 : 1,000 epinephrine solution instead of an appropriately diluted solution (1 : 10,000 or 1 : 100,000 concentration) Why Patients and Caregivers Fail to Inject Epinephrine Promptly • Lack of recognition of anaphylaxis symptoms; failure to diagnose anaphylaxis • Episode appears mild, or there is a history of previous mild episode(s)* • H1 antihistamine or asthma puffer is used initially instead, relieving early warning signs such as itch or cough, respectively. • Prescription for epinephrine autoinjectors (EAIs) is not provided by physician. • Prescription for EAIs is provided but not filled at pharmacy (e.g., not affordable).

• Patients do not carry EAIs consistently (due to size and bulk, or “don't think they’ll need it”). • Patients and caregivers are afraid to use EAIs (concern about making an error when giving the injection or about a bad outcome). • Patients and caregivers are concerned about injury from EAIs. • Competence in using EAIs is associated with regular allergy clinic visits; it decreases as time elapses from first EAI instruction; regular retraining is needed. • Difficulty in understanding how to use EAIs (15% of mothers with no EAI experience could not fire an EAI immediately after a one-on-one demonstration) • Errors in EAI use can occur despite education, possibly related to the design of some EAIs. Why Patients Occasionally Fail to Respond to Epinephrine Injection • Delayed recognition of anaphylaxis symptoms; delayed diagnosis • Error in diagnosis: problem being treated (e.g., foreign body inhalation) is not anaphylaxis. • Rapid progression of anaphylaxis † Epinephrine † : • Injected too late; dose too low on mg/kg basis; dose too low because epinephrine solution has degraded (e.g., past the expiration date, stored in a hot place) • Injection route or site not optimal; dose took too long to be absorbed. • Patient suddenly sits up or walks or runs, leading to the empty ventricle syndrome. • Concurrent use of certain medications (e.g., β-adrenergic blockers)

* Subsequent anaphylaxis episodes can be more severe, less severe, or similar in

severity.

† Median times to respiratory or cardiac arrest are 5 min in iatrogenic

anaphylaxis, 15 min in stinging-insect venom anaphylaxis, and 30 min in food anaphylaxis; however, regardless of the trigger, respiratory or cardiac arrest can occur within 1 min in anaphylaxis. Adapted from Leung DYM, Szefler SJ, Bonilla FA Akdis CA, Sampson HA, editors: Pediatric allergy principles and practice, Philadelphia, 2016, Elsevier, p 531.

Bibliography Akin C. Mast cell activation syndromes presenting as anaphylaxis. Immunol Allergy Clin North Am . 2015;35(2):277–285. Alqurashi W, Stiell I, Chan K, et al. Epidemiology and clinical predictors of biphasic reactions in children with anaphylaxis. Ann Allergy Asthma Immunol . 2015;115(3):217–223.e2. Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol . 2010;126:S1–S58. Brown JC, Tuuri RE, Akhter S, et al. Lacerations and embedded needles caused by epinephrine autoinjector use in children. Ann Emerg Med . 2017;67(3):307–315. Dahdah L, Ceccarelli S, Amendola S, et al. IgE immunoadsorption knocks down the risk of food-related anaphylaxis. Pediatrics . 2015;136(6):e1617–e1620. Dhami S, Panesar SS, Roberts G, et al. Management of anaphylaxis: a systematic review. Allergy . 2014;69(2):168– 175. Farbman KS, Michelson KA. Anaphylaxis in children. Curr Opin Pediatr . 2016;28:294–297. Fellinger C, Hemmer W, Wohrl S, et al. Clinical characteristics and risk profile of patients with elevated baseline serum

tryptase. Allergol Immunopathol (Madr) . 2014;42(6):544– 552. Fenny N, Grammer LC. Idiopathic anaphylaxis. Immunol Allergy Clin North Am . 2015;35:349–362. Gonzalez-Quintela A, Vizcaino L, Gude F, et al. Factors influencing serum total tryptase concentrations in a general adult population. Clin Chem Lad Med . 2010;48(5):701–706. Kennedy JL, Stallings AP, Platts-Mills TAE, et al. Galactoseα-1,3-galactose and delayed anaphylaxis, angioedema, and urticaria in children. Pediatrics . 2013;131(5):e1545–e1552. Koplin JJ, Martin PE, Allen KJ. An update on epidemiology of anaphylaxis in children and adults. Curr Opin Allergy Clin Immunol . 2011;11(5):492–496. Lee S, Hess EP, Lohse C, et al. Trends, characteristics, and incidence of anaphylaxis in 2001–2010: a population-based study. J Allergy Clin Immunol . 2017;139(1):182–188. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis—a practice parameter update 2015. Ann Allergy Asthma Immunol . 2015;115(5):341–384. Loprinzi Brauer CE, Motosue MS, Li JT, et al. Prospective validation of the NIAID/FAAN criteria for emergency department diagnosis of anaphylaxis. J Allergy Clin Immunol Pract . 2016;4(6):1220–1226. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy . 2014;69(8):1026–1045. O'Keefe A, Clarke A, St Pierre Y, et al. The risk of recurrent anaphylaxis. J Pediatr . 2017;180:217–221. Russell S, Monroe K, Losek JD. Anaphylaxis management in the pediatric emergency department. Pediatr Emerg Care . 2010;26(2):71–76. Sicherer SH, Simons FE. Epinephrine for first-aid management of anaphylaxis. Pediatrics . 2017;139(3):e20164006.

Simons FE, Ardusso LR, Bilò MB, et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J . 2014;7(1):9. Simons FE, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J . 2015;8(1):32. Wang J, Sicherer SH. Guidance on completing a written allergy and anaphylaxis emergency plan. Pediatrics . 2017;139(3):e20164005.

CHAPTER 175

Serum Sickness Anna Nowak-Węgrzyn, Scott H. Sicherer

Serum sickness is a systemic, immune complex–mediated hypersensitivity vasculitis classically attributed to the therapeutic administration of foreign serum proteins or other medications (Table 175.1 ).

Table 175.1

Proteins and Medications That Cause Serum Sickness* Proteins From Other Species Antibotulinum globulin Antithymocyte globulin Antitetanus toxoid Antivenin (Crotalidae) polyvalent (horse serum based) Crotalidae polyvalent immune Fab (ovine serum based) Antirabies globulin Infliximab Rituximab Etanercept Anti-HIV antibodies ([PE]HRG214) Hymenoptera stings Streptokinase H1N1 influenza vaccine

Drugs Antibiotics

Cefaclor Penicillins Trimethoprim sulfate Minocycline Meropenem Neurologic Bupropion Carbamazepine Phenytoin Sulfonamides Barbiturates HIV, Human immunodeficiency virus.

* Based on review of most current literature. Other medications that are not

listed might also cause serum sickness. From Aceves SS: Serum sickness. In Burg FD, Ingelfinger JR, Polin RA, Gershon AA, editors: Current pediatric therapy , ed 18, Philadelphia, 2006, Elsevier, p 1138.

Etiology Immune complexes involving heterologous (animal) serum proteins and complement activation are important pathogenic mechanisms in serum sickness. Antibody therapies derived from the horse, sheep, or rabbit are available for treatment of envenomation by the black widow spider and a variety of snakes, for treatment of botulism, and for immunosuppression (antithymocyte globulin , ATG). The availability of alternative medical therapies, modified or bioengineered antibodies, and biologics of human origin have supplanted the use of nonhuman antisera, reducing the risk of serum sickness. However, rabbitgenerated ATGs, which target human T cells, continue to be widely used as immunosuppressive agents during treatment of kidney allograft recipients; serum

sickness is associated with a late graft loss in kidney transplant recipients. A serum sickness–like reaction may be attributed to drug allergy, triggered by antibiotics (particularly cefaclor). In contrast to a true serum sickness, serum sickness–like reactions do not exhibit the immune complexes, hypocomplementemia, vasculitis, and renal lesions that are seen in serum sickness reactions.

Pathogenesis Serum sickness is a classic example of a type III hypersensitivity reaction caused by antigen-antibody complexes. In the rabbit model using bovine serum albumin as the antigen, symptoms develop with the appearance of antibody against the injected antigen. As free antigen concentration falls and antibody production increases over days, antigen-antibody complexes of various sizes develop in a manner analogous to a precipitin curve. Whereas small complexes usually circulate harmlessly and large complexes are cleared by the reticuloendothelial system, intermediate-sized complexes that develop at the point of slight antigen excess may deposit in blood vessel walls and tissues. There the immune microprecipitates induce vascular (leukocytoclastic vasculitis with immune complex deposition) and tissue damage through activation of complement and granulocytes. Complement activation (C3a, C5a) promotes chemotaxis and adherence of neutrophils to the site of immune complex deposition. The processes of immune complex deposition and of neutrophil accumulation may be facilitated by increased vascular permeability, because of the release of vasoactive amines from tissue mast cells. Mast cells may be activated by binding of antigen to IgE or through contact with anaphylatoxins (C3a). Tissue injury results from the liberation of proteolytic enzymes and oxygen radicals from the neutrophils.

Clinical Manifestations The symptoms of serum sickness generally begin 7-12 days after injection of the foreign material, but may appear as late as 3 wk afterward. The onset of symptoms may be accelerated if there has been earlier exposure or previous allergic reaction to the same antigen. A few days before the onset of generalized symptoms, the site of injection may become edematous and erythematous.

Symptoms usually include fever, malaise, and rashes. Urticaria and morbilliform rashes are the predominant types of skin eruptions (Fig. 175.1 ). In a prospective study of serum sickness induced by administration of equine ATG, an initial rash was noted in most patients. It began as a thin, serpiginous band of erythema along the sides of the hands, fingers, feet, and toes at the junction of the palmar or plantar skin with the skin of the dorsolateral surface. In most patients the band of erythema was replaced by petechiae or purpura, presumably because of low platelet counts or local damage to small blood vessels. Additional symptoms include edema, myalgia, lymphadenopathy, symmetric arthralgia or arthritis involving multiple joints, and gastrointestinal complaints, including pain, nausea, diarrhea, and melena. Symptoms typically resolve within 2 wk of removal of the offending agent, although in unusual cases, symptoms can persist for as long as 2-3 mo.

FIG. 175.1 Serum sickness–like reaction (SSLR). Note the swollen hand and large urticarial wheals in this girl with SSLR and arthralgias. (From Paller AS, Mancini AJ, editors: Hurwitz clinical pediatric dermatology , ed 5, Philadelphia, 2016, Elsevier, p 476.)

Carditis, glomerulonephritis, Guillain-Barré syndrome, and peripheral neuritis are rare complications. Serum sickness–like reactions from drugs are characterized by fever, pruritus, urticaria, and arthralgias that usually begin 1-3 wk after drug exposure. The urticarial skin eruption becomes increasingly erythematous as the reaction progresses and can evolve into dusky centers with round plaques.

Differential Diagnosis The differential diagnosis of serum sickness and serum sickness–like reactions includes viral illnesses with exanthems, hypersensitivity vasculitis, Kawasaki disease, acute rheumatic fever, acute meningococcal or gonococcal infection, endocarditis, systemic-onset juvenile idiopathic arthritis (Still disease), Lyme disease, hepatitis, and other types of drug reactions (see Chapter 177 ).

Diagnosis In most patients the diagnosis of serum sickness is made clinically based on the characteristic pattern of acute or subacute onset of a rash, fever, and severe arthralgia and myalgia disproportionate to the degree of swelling, occurring after exposure to a potential culprit. Patients who appear moderately or severely ill, or who are not taking a medication that can be readily identified as the culprit, should be evaluated with the following laboratory tests:

◆ Complete blood count and differential; thrombocytopenia is often present. ◆ Erythrocyte sedimentation rate (ESR) and Creactive protein; ESR is usually elevated. ◆ Urinalysis; mild proteinuria, hemoglobinuria, and microscopic hematuria may be seen. ◆ Serum chemistries, including blood urea nitrogen, creatinine, and liver function tests. ◆ Complement studies, including CH50 , C3, and C4; serum complement levels (C3 and C4) are generally decreased and reach a nadir at about day 10. C3a anaphylatoxin may be increased. ◆ Testing for specific infectious diseases, if indicated by the history or physical examination.

◆ Appropriate viral or bacterial cultures if an infection is suspected. Skin biopsies are not usually necessary for confirming the diagnosis, because the findings are variable and not specific for serum sickness. Direct immunofluorescence studies of skin lesions often reveal immune deposits of IgM, IgA, IgE, or C3.

Treatment There are no evidence-based guidelines or controlled trials on which to base therapy recommendations. Treatment is primarily supportive, consisting of discontinuation of the offending agent, antihistamines for pruritus, and nonsteroidal antiinflammatory drugs and analgesics for low-grade fever and mild arthralgia. When the symptoms are especially severe, for example, fever >38.5°C (101.3°F), severe arthralgia or myalgia, or renal dysfunction, systemic corticosteroids can be used. Prednisone (1-2 mg/kg/day; maximum 60 mg/day) for 1-2 wk is usually sufficient. Once the offending agent is discontinued and depending on its half-life, symptoms resolve spontaneously in 1-4 wk. Symptoms lasting longer suggest another diagnosis.

Prevention The primary mode of prevention of serum sickness is to seek alternative therapies. In some cases, non–animal-derived formulations may be available (human-derived botulinum immune globulin). Other alternatives are partially digested antibodies of animal origin and engineered (humanized) antibodies. The potential of these therapies to elicit serum sickness–like disease appears low. When only animal-derived antitoxin/antivenom is available, skin tests should be performed before administration of serum, but this procedure indicates the risk only of anaphylaxis, not of serum sickness. For patients who have evidence of anaphylactic sensitivity to horse serum, a risk/benefit assessment must be made to determine the need to proceed with treatment. If needed, the serum can usually be successfully administered by a process of rapid desensitization using protocols of gradual administration outlined by the manufacturers. Serum

sickness is not prevented by desensitization or by pretreatment with corticosteroids.

Bibliography American Academy of Pediatrics, Pickering LK. Red book: 2012 report of the committee on infectious diseases . ed 29. American Academy of Pediatrics: Elk Grove Village, IL; 2012:63–66. Bonds RS, Kelly BC. Severe serum sickness after H1N1 influenza vaccination. Am J Med Sci . 2013;345:412–413. Chiong FJ, Loewenthal M, Boyle M, Attia J. Serum sickness– like reaction after influenza vaccination. BMJ Case Rep . 2015;16. Couvrat-Desvergnes G, Salama A, Le Berre L, et al. Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival. J Clin Invest . 2015;125:4655– 4665. Hansel TT, Kropshofer H, Singer T, et al. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov . 2010;9:325. Kojis FG. Serum sickness and anaphylaxis: analysis of cases of 6,211 patients treated with horse serum for various infections. Am J Dis Child . 1942;64:93–143. Lawley TJ, Bielory L, Gascon P, et al. A prospective clinical and immunological analysis of patients with serum sickness. N Engl J Med . 1984;311:1407–1413. Le Guenno G, Ruivard M, Charra L, et al. Rituximab-induced serum sickness in refractory immune thrombocytopenic purpura. Intern Med J . 2011;41(2):202–205. Schaeffer TH, Khatri V, Reifler LM, et al. Incidence of immediate hypersensitivity reactions and serum sickness following administration of Crotalidae polyvalent immune

Fab antivenom: a meta-analysis. Acad Emerg Med . 2012;19(2):121–131.

CHAPTER 176

Food Allergy and Adverse Reactions to Foods Anna Nowak-Węgrzyn, Hugh A. Sampson, Scott H. Sicherer

Adverse reactions to foods consist of any untoward reaction following the ingestion of a food or food additive and are classically divided into food intolerances (e.g., lactose intolerance ), which are adverse physiologic responses, and food allergies, which are adverse immunologic responses and can be IgE mediated or non–IgE mediated (Tables 176.1 and 176.2 ). As with other atopic disorders, food allergies appear to have increased over the past 3 decades, primarily in countries with a Western lifestyle. Worldwide, estimates of food allergy prevalence range from 1–10%; food allergies affect an estimated 3.5% of the U.S. population. Up to 6% of children experience food allergic reactions in the 1st 3 yr of life, including approximately 2.5% with cow's milk allergy, 2% with egg allergy, and 2–3% with peanut allergy. Peanut allergy prevalence tripled over the past decade. Most children “outgrow” milk and egg allergies, with approximately 50% doing so by school-age. In contrast, 80–90% of children with peanut, tree nut, or seafood allergy retain their allergy for life.

Table 176.1

Adverse Food Reactions Food Intolerance (non–immune system mediated, nontoxic, noninfectious) Host Factors Enzyme deficiencies—lactase (primary or secondary), sucrase/isomaltase, hereditary fructose intolerance, galactosemia Gastrointestinal disorders—inflammatory bowel disease, irritable bowel

syndrome, pseudoobstruction, colic Idiosyncratic reactions—caffeine in soft drinks (“hyperactivity”) Psychologic—food phobias, obsessive/compulsive disorder Migraines (rare) Food Factors (Toxic or Infectious or Pharmacologic) Infectious organisms—Escherichia coli, Staphylococcus aureus, Clostridium perfringens, Shigella, botulism, Salmonella, Yersinia, Campylobacter Toxins—histamine (scombroid poisoning), saxitoxin (shellfish) Pharmacologic agents—caffeine, theobromine (chocolate, tea), tryptamine (tomatoes), tyramine (cheese), benzoic acid in citrus fruits (perioral flare) Contaminants—heavy metals, pesticides, antibiotics

Food Allergy IgE Mediated Cutaneous—urticaria, angioedema, morbilliform rashes, flushing, contact urticarial Gastrointestinal—oral allergy syndrome, gastrointestinal anaphylaxis Respiratory—acute rhinoconjunctivitis, bronchospasm Generalized—anaphylactic shock, exercise-induced anaphylaxis Mixed IgE Mediated and Non–IgE Mediated Cutaneous—atopic dermatitis, contact dermatitis Gastrointestinal—allergic eosinophilic esophagitis and gastroenteritis Respiratory—asthma Non–IgE Mediated Cutaneous—contact dermatitis, dermatitis herpetiformis (celiac disease) Gastrointestinal—food protein–induced enterocolitis, proctocolitis, and enteropathy syndromes, celiac disease

Respiratory—food-induced pulmonary hemosiderosis (Heiner syndrome) Unclassified IgE, Immunoglobulin E.

Table 176.2

Differential Diagnosis of Adverse Food Reactions Gastrointestinal Disorders (with vomiting and/or diarrhea) Structural abnormalities (pyloric stenosis, Hirschsprung disease, reflux) Enzyme deficiencies (primary or secondary) : Disaccharidase deficiency—lactase, fructase, sucrase-isomaltase Galactosemia Malignancy with obstruction Other: pancreatic insufficiency (cystic fibrosis), peptic disease

Contaminants and Additives Flavorings and preservatives—rarely cause symptoms: Sodium metabisulfite, monosodium glutamate, nitrites Dyes and colorings—very rarely cause symptoms (urticaria, eczema): Tartrazine Toxins: Bacterial, fungal (aflatoxin), fish related (scombroid, ciguatera) Infectious organisms: Bacteria (Salmonella, Escherichia coli, Shigella) Virus (rotavirus, enterovirus) Parasites (Giardia, Akis simplex [in fish]) Accidental contaminants: Heavy metals, pesticides Pharmacologic agents: Caffeine, glycosidal alkaloid solanine (potato spuds), histamine (fish), serotonin (banana, tomato), tryptamine (tomato), tyramine (cheese)

Psychologic Reactions Food phobias

Genetics Genetic factors play an important role in the development of food allergy. Family and twin studies show that family history confers a 2-10–fold increased risk, depending on the study setting, population, specific food, and diagnostic test. Candidate gene studies suggest that genetic variants in the HLA-DQ locus (HLA-DQB1*02 and DQB1*06:03P), filaggrin, interleukin-10, STAT6, and FOXP3 genes are associated with food allergy, although the results are inconsistent across different populations. In a genome-wide association study, differential methylation at the HLA-DR and -DQ regions was associated with food allergy. Epigenetic studies implicate DNA methylation effects on interleukins 4, 5, and 10 and interferon (IFN)-γ genes and in the mitogenactivated protein kinase (MAPK) pathway.

Pathogenesis Food intolerances are the result of a variety of mechanisms, whereas food allergy is predominantly caused by IgE-mediated and cell-mediated immune mechanisms. In susceptible individuals exposed to certain allergens, foodspecific IgE antibodies are formed that bind to Fcε receptors on mast cells, basophils, macrophages, and dendritic cells. When food allergens penetrate mucosal barriers and reach cell-bound IgE antibodies, mediators are released that induce vasodilation, smooth muscle contraction, and mucus secretion, which result in symptoms of immediate hypersensitivity (allergy). Activated mast cells and macrophages may release several cytokines that attract and activate other cells, such as eosinophils and lymphocytes, leading to prolonged inflammation. Symptoms elicited during acute IgE-mediated reactions can affect the skin (urticaria, angioedema, flushing), gastrointestinal (GI) tract (oral pruritus, angioedema, nausea, abdominal pain, vomiting, diarrhea), respiratory tract (nasal congestion, rhinorrhea, nasal pruritus, sneezing, laryngeal edema, dyspnea, wheezing), and cardiovascular system (dysrhythmias, hypotension, loss of consciousness). In non-IgE food allergies, lymphocytes, primarily food allergen–

specific T cells, secrete excessive amounts of various cytokines that lead to a “delayed,” more chronic inflammatory process affecting the skin (pruritus, erythematous rash), GI tract (failure to thrive, early satiety, abdominal pain, vomiting, diarrhea), and respiratory tract (food-induced pulmonary hemosiderosis). Mixed IgE and cellular responses to food allergens can also lead to chronic disorders, such as atopic dermatitis, asthma, eosinophilic esophagitis, and gastroenteritis. Children who develop IgE-mediated food allergies may be sensitized by food allergens penetrating the GI barrier, referred to as class 1 food allergens , or by food allergens that are partially homologous to plant pollens penetrating the respiratory tract, referred to as class 2 food allergens . Any food may serve as a class 1 food allergen, but egg, milk, peanuts, tree nuts, fish, soy, and wheat account for 90% of food allergies during childhood. Many of the major allergenic proteins of these foods have been characterized. There is variable but significant cross-reactivity with other proteins within an individual food group. Exposure and sensitization to these proteins often occur very early in life. Virtually all milk allergies develop by 12 mo of age and all egg allergies by 18 mo, and the median age of 1st peanut allergic reactions is 14 mo. Class 2 food allergens are typically vegetable, fruit, or nut proteins that are partially homologous with pollen proteins (Table 176.3 ). With the development of seasonal allergic rhinitis from birch, grass, or ragweed pollens, subsequent ingestion of certain uncooked fruits or vegetables provokes the oral allergy syndrome . Intermittent ingestion of allergenic foods may lead to acute symptoms such as urticaria or anaphylaxis, whereas prolonged exposure may lead to chronic disorders such as atopic dermatitis and asthma. Cell-mediated sensitivity typically develops to class 1 allergens. Table 176.3

Natural History of Food Allergy and Cross-Reactivity Between Common Food Allergies

Hen's egg white

USUAL AGE AT ONSET OF ALLERGY 0-1 yr

Cow's milk

0-1 yr

Peanuts

1-2 yr

FOOD

CROSS REACTIVITY Other avian eggs Goat's milk, sheep's milk, buffalo milk Other legumes, peas, lentils; coreactivity with tree nuts

USUAL AGE AT RESOLUTION 7 yr (75% of cases resolve)* 5 yr (76% of cases resolve)* Persistent (20% of cases resolve)

Tree nuts Fish Shellfish

1-2 yr; in adults, onset occurs after cross reactivity to birch pollen Late childhood and adulthood

Other tree nuts; co-reactivity with peanuts Other fish (low cross-reactivity with tuna and swordfish) Other shellfish

Persistent (9% of cases resolve) Persistent †

5 yr (80% of cases resolve) 2 yr (67% of cases resolve) Unknown Unknown

Wheat*

Adulthood (in 60% of patients with this allergy) 6-24 mo

Soybeans*

6-24 mo

Other grains containing gluten (rye, barley) Other legumes

Kiwi Apples, carrots, and peaches §

Any age Late childhood and adulthood

Banana, avocado, latex Birch pollen, other fruits, nuts

Persistent

*

Recent studies suggest that resolution may occur at a later age, especially in children with multiple food allergies and lifetime peak food-specific IgE >50 kUA /L. † Fish allergy that is acquired in childhood can resolve. § Allergy to fresh apples, carrots, and peaches (oral allergy syndrome ) is typically caused by

heat-labile proteins. Fresh fruit causes oral pruritus, but cooked fruit is tolerated. There is generally no risk of anaphylaxis, although in rare cases, allergies to cross-reactive lipid transfer protein can cause anaphylaxis after ingestion of fruits (e.g., peach) and vegetables. Adapted from Lack G: Food allergy, N Engl J Med 359:1252–1260, 2008.

Clinical Manifestations From a clinical and diagnostic standpoint, it is most useful to subdivide food hypersensitivity disorders according to the predominant target organ (Table 176.4 ) and immune mechanism (see Table 176.1 ). Table 176.4 Symptoms of Food-Induced Allergic Reactions TARGET ORGAN Cutaneous

Ocular

Upper

IMMEDIATE SYMPTOMS Erythema Pruritus Urticaria Morbilliform eruption Angioedema Pruritus Conjunctival erythema Tearing Periorbital edema Nasal congestion

DELAYED SYMPTOMS Erythema Flushing Pruritus Morbilliform eruption Angioedema Eczematous rash Pruritus Conjunctival erythema Tearing Periorbital edema

respiratory

Lower respiratory

Gastrointestinal (oral)

Gastrointestinal (lower)

Cardiovascular

Miscellaneous

Pruritus Rhinorrhea Sneezing Laryngeal edema Hoarseness Dry staccato cough Cough Chest tightness Dyspnea Wheezing Intercostal retractions Accessory muscle use Angioedema of the lips, tongue, or palate Oral pruritus Tongue swelling Nausea Colicky abdominal pain Reflux Vomiting Diarrhea

Cough, dyspnea, wheezing

Nausea Abdominal pain Reflux Vomiting Diarrhea Hematochezia Irritability and food refusal with weight loss (young children)

Tachycardia (occasionally bradycardia in anaphylaxis) Hypotension Dizziness Fainting Loss of consciousness Uterine contractions Sense of “impending doom”

From Boyce JA, Assa'ad A, Burks AW, et al: Guideline for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel, J Allergy Clin Immunol 126(6):S1–S58, 2010 (Table IV, p S19).

Gastrointestinal Manifestations GI food allergies are often the 1st form of allergy to affect infants and young children and typically manifest as irritability, vomiting or “spitting-up,” diarrhea, and poor weight gain. Cell-mediated hypersensitivities without IgE involvement predominate, making standard allergy tests such as skin-prick tests and in vitro tests for food-specific IgE antibodies of little diagnostic value. Food protein–induced enterocolitis syndrome (FPIES) typically manifests in the 1st several mo of life as irritability, intermittent vomiting, and protracted diarrhea and may result in dehydration (Table 176.5 ). Vomiting generally occurs 1-4 hr after feeding, and continued exposure may result in abdominal distention, bloody diarrhea, anemia, and failure to thrive. Symptoms are most often

provoked by cow's milk or soy protein–based formulas. A similar enterocolitis syndrome occurs in older infants and children from rice, oat, wheat, egg, peanut, nut, chicken, turkey, or fish. Hypotension occurs in approximately 15% of patients after allergen ingestion and may initially be thought to be caused by sepsis. FPIES usually resolves by age 3-5 yr. Table 176.5

Food Protein–Induced Gastrointestinal Syndromes FPIES Age at onset

Food proteins implicated Most common Less common

Multiple food hypersensitivities Feeding at the time of onset Atopic background Family history of atopy Personal history of atopy Symptoms Emesis Diarrhea Bloody stools Edema Shock Failure to thrive Laboratory findings Anemia Hypoalbuminemia Methemoglobinemia

PROCTOCOLITIS ENTEROPATHY

1 day–1 year 1 day–6 months

Dependent of age of exposure to antigen, cow's milk and soy up to 2 yr

Cow's milk, soy Rice, chicken, turkey, fish, pea >50% both cow's milk and soy Formula

Cow's milk, soy

Cow's milk, soy

Egg, corn, chocolate

Wheat, egg

EOSINOPHILIC GASTROENTEROPATHIES* Infant to adolescent

Cow's milk, soy, egg white, wheat, peanut Meats, corn, rice, fruits, vegetables, fish

40% both cow's milk Rare and soy

Common

>50% exclusive breastfeeding

Formula

Formula

40–70%

25%

Unknown

30%

22%

22%

~50% (often history of eosinophilic esophagitis) ~50%

Prominent Severe Severe Acute, severe 15% Moderate

No No Moderate No No No

Intermittent Moderate Rare Moderate No Moderate

Intermittent Moderate Moderate Moderate No Moderate

Moderate Acute May be present

Mild Rare No

Moderate Moderate No

Mild-moderate Mild-severe No

Negative

Negative

Positive in ~50%

Allergy evaluation Food skin-prick test Negative †

Serum food allergen IgE Total IgE Peripheral blood eosinophilia Biopsy findings Colitis Lymph nodular hyperplasia Eosinophils

Negative †

Negative

Negative

Positive in ~50%

Normal No

Negative Occasional

Normal No

Normal to elevated Present in 3 related foods is very low (60 kg: 1,000 mg 40 mg/kg/day PO in 3 divided doses Max: 2400 mg/day 15 mg/kg/day PO in 2 divided doses Max 1,000 mg/day 10-25 kg: 50 mg PO bid >25 kg: 100 mg PO bid 0.125 mg/kg PO qd Max 7.5 mg 10-20 mg/m2 /wk (0.35-0.65 mg/kg/wk) PO 20-30 mg/m2 /wk (0.65-1 mg/kg/wk) SC; higher doses better absorbed by SC injection

Leflunomide

PO once daily: 10 to 40 kg: 20 mg

Hydroxychloroquine

5 mg/kg PO qd; do not exceed 5 mg/kg/daily Max 400 mg daily

Sulfasalazine a

30-50 mg/kg/day in 2 divided doses Adult max 3 g/day

headache, renal disease

JIA Uveitis

JIA

SLE JDMS Antiphospholipid antibody syndrome

Spondyloarthropathy, JIA

GI intolerance (nausea, vomiting), hepatitis, myelosuppression, mucositis, teratogenesis, lymphoma, interstitial pneumonitis Hepatitis, hepatic necrosis, cytopenias, mucositis, teratogenesis, peripheral neuropathy Retinal toxicity, GI intolerance, rash, skin discoloration, anemia, cytopenias, myopathy, CNS stimulation, death (overdose) GI intolerance, rash, hypersensitivity reactions, StevensJohnson syndrome, cytopenias, hepatitis, headache

Tumor necrosis factor (TNF)-α antagonists

Adalimumab a

Etanercept a

SC once every other wk: 10 to 3 mo, and increased inflammatory markers, such as platelet count and ESR, for >6 mo. IL-1 and IL-6 inhibitors have changed the management and improved the outcomes for

children with severe and prolonged systemic disease. Orthopedic complications include leg length discrepancy and flexion contractures, particularly of the knees, hips, and wrists. Discrepancies in leg length can be managed with a shoe lift on the shorter side to prevent secondary scoliosis. Joint contractures require aggressive medical control of arthritis, often in conjunction with intraarticular corticosteroid injections, appropriate splinting, and stretching of the affected tendons. Popliteal cysts may require no treatment if they are small or respond to intraarticular corticosteroids in the anterior knee. Psychosocial adaptation may be affected by JIA. Studies indicate that, compared with controls, a significant number of children with JIA have problems with lifetime adjustment and employment. Disability not directly associated with arthritis may continue into young adulthood in as many as 20% of patients, together with continuing chronic pain syndromes at a similar frequency. Psychological complications, including problems with school attendance and socialization, may respond to counseling by mental health professionals.

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in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis . 2013;72:517–524. Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet . 2017;389:2338–2346. Cassidy J, Kivlin J, Lindsley C, et al. Ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics . 2006;117:1843–1845. Cavello S, Brousseau L, Toupin-April K, et al. Ottawa Panel evidence-based clinical practice guidelines for structured physical activity in the management of juvenile idiopathic arthritis. Arch Phys Med Rehabil . 2017;98(5):1018–1041. Clark SLN, Sen ES, Ramanan AV. Juvenile idiopathic arthritis– associated uveitis. Pediatr Rheumatol . 2016;14:27. DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res . 2012;64:1001–1010. Dougados M, Baeten D. Arthritis. 2. Spondyloarthritis. Lancet . 2011;377:2127–2134. Foell D, Wulffraat N, Wedderburn LR, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission. JAMA . 2010;303:1266–1273. Fox DA. Kinase inhibition: a new approach to the treatment of rheumatoid arthritis. N Engl J Med . 2012;367:565–566. Gowdie PJ, Tse SM. Juvenile idiopathic arthritis. Pediatr Clin North Am . 2012;59:301–372. Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: a comprehensive review. J Autoimmun . 2015;64:113–124. Grom AA. Primary hemophagocytic lymphohistiocytosis and macrophage activation syndrome: the importance of timely clinical differentiation. J Pediatr . 2017;189:19–21. Guzman J, Henrey A, Loughlin T, et al. Predicting which

children with juvenile idiopathic arthritis will have a severe disease course: results from the ReACCH-Out cohort. J Rheumatol . 2017;44(2):230–240. Kaufman KM, Linghu B, Szustakowski JD, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphophistiocytosis. Arthritis Rheumatol . 2014;66(12):3486–3495. LeBovidge JS, Lavigne JV, Donenberg GR, et al. Psychological adjustment of children and adolescents with chronic arthritis: a meta-analytic review. J Pediatr Psychol . 2003;28:29–39. Lovell DJ, Ruperto N, Mouy R, et al. Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years. Arthritis Rheumatol . 2015;67:1759–2770. McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet . 2017;389:2328–2336. The Medical Letter. Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs Ther . 2013;55(1407):1–4. Minoia F, Bovis F, Davi S, et al. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome. J Pediatr . 2017;189:72–78. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis: second revision, Edmonton. J Rheumatol . 2001;31:390–392 [2004]. Prince FHM, Otten MH, van Suijlekom-Smit WA. Diagnosis and management of juvenile idiopathic arthritis. BMJ . 2011;342:95–102. Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus

methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med . 2017;376(17):1637–1646. Ravelli A, Grom A, Behrens E, et al. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun . 2012;13:289–298. Ravelli A, Minoia F, Davì S, et al. Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol . 2016;68:566–576. Ringold S, Weiss PF, Colbert RA, et al. Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for new-onset polyarticular juvenile idiopathic arthritis. Arthritis Care Res . 2014;66:1063–1072. Scott DL, Stevenson MD. Treating active rheumatoid arthritis with Janus kinase inhibitors. Lancet . 2017;390:431–432. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet . 2010;376:1094–1106. Shenoi S, Wallace CA. Diagnosis and treatment of systemic juvenile idiopathic arthritis. J Pediatr . 2016;177:19–26. Sikora KA, Grom AA. Update on the pathogenesis and treatment of systemic idiopathic arthritis. Curr Opin Pediatr . 2011;23:640–646. Toussi SS, Pan N, Walters HM, Walsh TJ. Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-α inhibitors: systematic review of the literature. Clin Infect Dis . 2013;57:1318–1330. Ungar WJ, Costa V, Burnett HF, et al. The use of biologic response modifiers in polyarticular-course juvenile idiopathic arthritis: a systematic review. Semin Arthritis Rheum .

2013;42:597–618. Wittkowski H, Frosch M, Wulffraat N, et al. S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin. Arthritis Rheum . 2008;58:3924–3931.

CHAPTER 181

Ankylosing Spondylitis and Other Spondyloarthritides Pamela F. Weiss, Robert A. Colbert

The diseases collectively referred to as spondyloarthritides include ankylosing spondylitis (AS) , arthritis associated with inflammatory bowel disease (IBD) or psoriasis, and reactive arthritis following gastrointestinal (GI) or genitourinary (GU) infections (Table 181.1 and Table 181.2 ). Spondyloarthritis is more common in adults, but all forms can present during childhood with varying symptoms and signs. Many children with spondyloarthritis are classified in the juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) or psoriatic arthritis. Children and adolescents with spondyloarthritis who may not meet JIA criteria include arthritis associated with IBD, juvenile ankylosing spondylitis (JAS), and reactive arthritis. Table 181.1

Overlapping Characteristics of the Spondyloarthritides* JUVENILE CHARACTERISTIC ANKYLOSING SPONDYLITIS Enthesitis +++ Axial arthritis +++ Peripheral arthritis +++ HLA-B27 positive +++ Antinuclear antibody − positive Rheumatoid factor − positive SYSTEMIC DISEASE: Eyes + Skin − Mucous membranes −

JUVENILE PSORIATIC ARTHRITIS + ++ +++ + ++

INFLAMMATORY BOWEL DISEASE

REACTIVE ARTHRITIS

+ ++ +++ ++ −

++ + +++ +++ −

−

−

−

+ +++ −

+ + +

+ + +

Gastrointestinal tract

−

−

++++

+++

* Frequency of characteristics: −, absent; +, 100 additional genetic loci accounting for only one third. Genes that influence interleukin (IL)-23 responses (e.g., CARD9 , IL23R, JAK2, TYK2 , STAT3 ) and the function of HLA-B27 (ERAP1) are particularly important. Unusual properties of HLA-B27, such as its tendency to misfold and form abnormal cell surface structures, may have a role. Infection with certain GI or GU pathogens can trigger reactive arthritis (see Table 181.2 and Chapter 182 ). Altered gut microbiota and an abnormal immune response to normal microbiota may also play a role in pathogenesis. Inflamed joints and entheses in spondyloarthritis contain T and B cells, macrophages, osteoclasts, proliferating fibroblasts, and osteoblasts, with activation of the IL23/IL-17 pathway. Bone loss and osteoproliferation in and around vertebral bodies and facet joints in long-standing AS contribute to significant morbidity.

Clinical Manifestations and Diagnosis Clinical manifestations that help distinguish spondyloarthritis from other forms of juvenile arthritis include arthritis of the axial skeleton (sacroiliac joints) and

hips, enthesitis (inflammation at the site of tendon, ligament, or joint capsule attachment to bone), symptomatic eye inflammation (acute anterior uveitis), and GI inflammation (even in the absence of IBD) (Tables 181.1 and 181.3 ). Table 181.3

Assessment in Spondyloarthritis International Society (ASAS) Classification Criteria for Spondyloarthritis (SpA) AXIAL SpA In patients with ≥3 mo back pain and age at onset 80% of children with JDM. Serologic testing results are divided into 2 groups: myositis-associated antibodies (MAAs) and myositis-specific antibodies (MSAs) . MAAs are associated with JDM, but are not specific and can be seen in both overlap conditions and other rheumatic diseases. MSAs are specific for myositis. Presence of MAAs such as SSA, SSB, Sm, ribonucleoprotein (RNP), and double-stranded (ds) DNA may increase the likelihood of overlap disease or connective tissue myositis. Antibodies to Pm/Scl identify a small, distinct subgroup of myopathies with a protracted disease course, often complicated by pulmonary interstitial fibrosis and cardiac involvement. Similar to what is seen in adults, the presence of MSAs in JDM such as anti–Jo-1, anti–Mi-2, anti-p155/140, anti-NXP2, and other myositisspecific autoantibodies help define distinct clinical subsets and may predict the development of complications, although differences remain in certain aspects such as malignancy between adults and children. Anti-p155/140 antibodies also

known as TIF-1-γ are reported in 23–30% of children with JDM and are associated with photosensitive rashes, ulceration, and lipodystrophy. Unlike in adults, this antibody is not associated with malignancy in children with JDM. Anti-MJ antibodies, also known as NXP2, are reported in 12–23% of children with JDM and are associated with cramps, muscle atrophy, contractures, and dysphonia. Anti-MDA5 antibodies have been recently reported in 7–33% of children with JDM, and are concerning for development of interstitial lung disease. Radiographic studies aid both diagnosis and medical management. MRI using T2-weighted images and fat suppression (Fig. 184.3B ) identifies active sites of disease, reducing sampling error and increasing the sensitivity of muscle biopsy and EMG, results of which are nondiagnostic in 20% of cases if the procedures are not directed by MRI. Extensive rash and abnormal MRI findings may be found despite normal serum levels of muscle-derived enzymes. Muscle biopsy often demonstrates evidence of disease activity and chronicity that is not suspected from the levels of the serum enzymes alone. A contrast swallow study may document palatal dysfunction and risk of aspiration. Pulmonary function testing detects a restrictive defect consistent with respiratory weakness and reduced diffusion capacity of carbon monoxide from alveolar fibrosis associated with other connective tissue diseases. Serial measurement of vital capacity or negative inspiratory force can document changes in respiratory weakness, especially in an inpatient setting. Calcinosis is seen easily on radiographs, along the fascial planes and within muscles (Figs. 184.3D, E and 184.4 ).

FIG. 184.4 Calcifications in dermatomyositis. A, Skin effects of calcification. B, Radiographic evidence of calcification.

Treatment The aid of an experienced pediatric rheumatologist is invaluable in outlining an appropriate course of treatment for a child with JDM. Before the advent of corticosteroids, one third of patients spontaneously improved, a third had a chronic, lingering course, and a third died from the disease. Corticosteroids have altered the course of disease, lowering morbidity and mortality. Methotrexate decreases the length of treatment with corticosteroids, thereby reducing morbidity from steroid toxicity. Intravenous (IV) gamma globulin is frequently used as an adjunct for treatment of severe disease and can be given at 2 g/kg (maximum 70 g) every 2 wk for 3 doses, then every 4 wk as needed. Consensus treatment plans for guiding treatment of North American children with JDM are available from the Childhood Arthritis and Rheumatology Research Alliance online through PubMed. Corticosteroids are still the mainstay of treatment. In a clinically stable child without debilitating weakness, oral prednisone at 2 mg/kg/day (maximum 60 mg daily) is usually started. Children with GI involvement have decreased absorption of oral corticosteroids and require IV administration. In more severe cases with respiratory or oropharyngeal weakness, high-dose pulse methylprednisolone is used (30 mg/kg/day for 3 days, maximum dose 1 g/day) with ongoing weekly or monthly IV dosing along with daily oral corticosteroids as needed. Corticosteroid dosage is slowly tapered over 12 mo, after indicators of inflammation (muscle enzymes) normalize and strength improves. Weekly oral, IV, or subcutaneous methotrexate (the lesser of 1 mg/kg or 15 mg/m2 , maximum 40 mg) is often used as a steroid-sparing agent in JDM. The concomitant use of methotrexate halves the cumulative dosage of steroids needed for disease control. Risks of methotrexate include immunosuppression, blood count dyscrasias, chemical hepatitis, pulmonary toxicity, nausea/vomiting, and teratogenicity. Folic acid is typically given with methotrexate starting at a dose of 1 mg daily to reduce toxicity and side effects of folate inhibition (oral ulcers, nausea, anemia). Children who are taking immunosuppressive medications such as methotrexate should avoid live-virus vaccination, although inactivated influenza vaccination is recommended yearly. An international trial found the combination of methotrexate plus corticosteroids to perform better than corticosteroids alone and with fewer side effects than corticosteroids plus

cyclosporine A. Hydroxychloroquine has little toxicity risk and is used as a secondary diseasemodifying agent to reduce rash and maintain remission. Typically, it is administered at doses of 4-6 mg/kg/day orally in either tablet or liquid form. Ophthalmologic follow-up 1-2 times per year to monitor for rare retinal toxicity is recommended. Other side effects include hemolysis in patients with glucose-6phosphate deficiency, GI intolerance, and skin/hair discoloration. The use of rituximab in a trial of steroid-dependent patients with resistant inflammatory myopathies, including JDM, did not meet the primary study endpoint showing a difference in time to improvement between individuals given rituximab at baseline or at 8 wk, but overall, 83% of all patients met the definition of improvement in the trial. Reports of the use of other biologic agents are based on case reports with mixed results. Other medications for severe unresponsive disease include intravenous immune globulin, mycophenolate mofetil, cyclosporine, and cyclophosphamide. Children with pharyngeal weakness may need nasogastric or gastrostomy feedings to avoid aspiration, whereas those with GI vasculitis require full bowel rest. Rarely, children with severe respiratory weakness require ventilator therapy and even tracheostomy until the respiratory weakness improves. Physical therapy and occupational therapy are integral parts of the treatment program, initially for passive stretching early in the disease course and then for direct reconditioning of muscles to regain strength and range of motion. Therapy may improve strength muscle measures and cardiovascular fitness. Bed rest is not indicated, because weight bearing improves bone density and prevents contractures. Social work and psychology services may facilitate adjustment to the frustration of physical impairment in a previously active child and aid with sleep disturbances associated with rheumatic disease. All children with JDM should avoid sun exposure and apply high-SPF (sun protection factor) sunscreen daily, even in winter and on cloudy days. Vitamin D and calcium supplements are indicated for all children undergoing long-term corticosteroid therapy to reduce drug-induced osteopenia and osteoporosis.

Complications Most complications from JDM are related to prolonged and severe weakness from muscle atrophy to cutaneous calcifications and scarring or atrophy to lipodystrophy. Secondary complications from medical treatments are also

common. Children with acute and severe weakness are at risk for aspiration pneumonia and respiratory failure and occasionally require nasogastric feeding and mechanical ventilation until weakness improves. Rarely, vasculitis of the GI tract develops in children with severe JDM. Crampy abdominal pain and occult GI bleeding may indicate bowel wall vasculitis and lead to ischemia, GI bleeding, and perforation if not treated with complete bowel rest and aggressive treatment for the underlying inflammation. Surgery should be avoided if possible, because the GI vasculitis is diffuse and not easily amenable to surgical intervention. Contrast-enhanced CT may show dilation or thickening of the bowel wall, intraluminal air, or evidence of bowel necrosis. Involvement of the cardiac muscle with pericarditis, myocarditis, and conduction defects with arrhythmias has been reported, as well as reduced diastolic and systolic function related to ongoing disease activity. Lipodystrophy and calcinosis are thought to be associated with long-standing or undertreated disease (Fig. 184.3, D-F ). Dystrophic deposition of calcium phosphate, hydroxyapatite, or fluoroapatite crystals occurs in subcutaneous plaques or nodules, resulting in painful ulceration of the skin with extrusion of crystals or calcific liquid. Calcification is found in up to 40% of large cohorts of children with JDM. Pathologic calcifications may be related to severity of disease and prolonged delay to treatment and potentially to genetic polymorphisms of TNF-α-308. Calcium deposits tend to form in subcutaneous tissue and along muscle. Some ulcerate through the skin and drain a soft calcific liquid, and others manifest as hard nodules along extensor surfaces or embedded along muscle. Draining lesions serve as a nidus for cellulitis or osteomyelitis. Nodules cause skin inflammation that may mimic cellulitis. Spontaneous regression of calcium deposits may occur, but there is no evidence-based recommendation for treatment of calcinosis. Some experts recommend aggressive treatment of underlying myositis. Others have recommended bisphosphonates, TNF inhibitors, and sodium thiosulfate, but no evidence-based trials have been conducted for this condition. Lipodystrophy manifests in 10–40% of patients with JDM and can be difficult to recognize. Lipodystrophy results in progressive loss of subcutaneous and visceral fat, typically over the face and upper body, and may be associated with a metabolic syndrome similar to polycystic ovarian syndrome with insulin resistance, hirsutism, acanthosis, hypertriglyceridemia, and abnormal glucose tolerance. Lipodystrophy may be generalized or localized. Children receiving prolonged corticosteroid therapy are prone to

complications such as cessation of linear growth, weight gain, hirsutism, adrenal suppression, immunosuppression, striae, cushingoid fat deposition, mood changes, osteoporosis, cataracts, avascular necrosis, and steroid myopathy. Families should be counseled on the effects of corticosteroids and advised to use medical alert identification and to consult a nutritionist regarding a low-salt, low-fat diet with adequate vitamin D and calcium supplementation. An association with malignancy at disease onset is observed in adults with dermatomyositis but very rarely in children.

Prognosis The mortality rate in JDM has decreased since the advent of corticosteroids, from 33% to currently approximately 1%; little is known about the long-term consequences of persistent vascular inflammation. The period of active symptoms has decreased from about 3.5 yr to 95%), but systemic sclerosis is associated with mortality and severe multiorgan morbidity.

Etiology and Pathogenesis The etiology of scleroderma is unknown, but the mechanism of disease appears to be a combination of a vasculopathy, autoimmunity, immune activation, and fibrosis. Triggers, including trauma, infection, and, possibly, subclinical graftversus-host reaction from persistent maternal cells (microchimerism ), injure vascular endothelial cells, resulting in increased expression of adhesion molecules. These molecules entrap platelets and inflammatory cells, resulting in vascular changes with manifestations such as Raynaud phenomenon and pulmonary hypertension. Inflammatory cells infiltrate the area of initial vascular damage, causing further vascular damage and resulting in thickened artery walls and reduction in capillary numbers. Macrophages and other inflammatory cells then migrate into affected tissues and secrete cytokines that induce fibroblasts to reproduce and synthesize excessive amounts of collagen, resulting in fibrosis and subsequent lipoatrophy, dermal fibrosis, with loss of sweat glands and hair follicles. In late stages the entire dermis may be replaced by compact collagen

fibers. Autoimmunity is believed to be a key process in the pathogenesis of both localized and systemic scleroderma, given the high percentage of affected children with autoantibodies. Children with localized disease often have a positive antinuclear antibody (ANA) test result (42%), and 47% of this subgroup have antihistone antibodies. Children with JSSc have higher rates of ANA positivity (80.7%) and may have anti–Scl-70 antibody (34%, antitopoisomerase I). The relationship between specific autoantibodies and the various forms of scleroderma is not well understood, and all antibody test results may be negative, especially in JLS.

Classification Localized scleroderma is distinct from systemic scleroderma and rarely progresses to systemic disease. The category of JLS includes several subtypes differentiated by both the distribution of the lesions and the depth of involvement (Tables 185.1 and 185.2 ). Up to 15% of children have a combination of 2 or more subtypes.

Table 185.1

Classification of Pediatric Scleroderma (Morphea) Localized Scleroderma Plaque Morphea Confined to dermis, occasionally superficial panniculus Well-circumscribed circular area of induration, often a central waxy, ivorycolored area surrounded by a violaceous halo; unilateral Generalized Morphea Involves dermis primarily, occasionally panniculus Defined as confluence of individual morphea plaques or lesions in ≥3 anatomic sites; more likely to be bilateral

Bullous Morphea Bullous lesions that can occur with any of the subtypes of morphea Linear Scleroderma Linear lesions can extend through the dermis, subcutaneous tissue, and muscle to underlying bone; more likely unilateral Limbs/trunk: One or more linear streaks of the extremities or trunk Flexion contracture occurs when lesion extends over a joint; limb length discrepancies En coup de sabre: Involves the scalp and/or face; lesions can extend into the central nervous system, resulting in neurologic sequelae, most commonly seizures and headaches Parry-Romberg syndrome: Hemifacial atrophy without a clearly definable en coup de sabre lesion; can also have neurologic involvement Deep Morphea Involves deeper layers, including panniculus, fascia, and muscle; more likely to be bilateral Subcutaneous morphea: Primarily involves the panniculus or subcutaneous tissue Plaques are hyperpigmented and symmetric Eosinophilic fasciitis: Fasciitis with marked blood eosinophilia Fascia is the primary site of involvement; typically involves extremities Classic description is “peau d'orange” or orange peel texture, but early disease manifests as edema (see Fig. 185.2 ) Morphea profunda: Deep lesion extending to fascia and sometimes muscle, but may be limited to a single plaque, often on trunk

Disabling pansclerotic morphea of childhood: Generalized full-thickness involvement of skin on the trunk, face and extremities, sparing fingertips and toes

Systemic Sclerosis Diffuse Most common type in childhood Symmetric thickening and hardening of the skin (sclerosis) with fibrous and degenerative changes of viscera Limited Rare in childhood Previously known as CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome

Table 185.2

Provisional Criteria for Classification of Juvenile Systemic Sclerosis (JSSc) Major Criterion (Required)* Proximal skin sclerosis/induration of the skin proximal to metacarpophalangeal or metatarsophalangeal joints

Minor Criteria (at Least 2 Required) Cutaneous: Sclerodactyly Peripheral vascular: Raynaud phenomenon, nail fold capillary abnormalities (telangiectasias), digital tip ulcers Gastrointestinal: Dysphagia, gastroesophageal reflux Cardiac: Arrhythmias, heart failure Renal: Renal crisis, new-onset arterial hypertension Respiratory: Pulmonary fibrosis (high-resolution CT/radiography),

decreased diffusing capacity for carbon monoxide, pulmonary arterial hypertension Neurologic: Neuropathy, carpal tunnel syndrome Musculoskeletal: Tendon friction rubs, arthritis, myositis Serologic: Antinuclear antibodies—SSc-selective autoantibodies (anticentromere, antitopoisomerase I [Scl-70], antifibrillarin, antiPM/Scl, antifibrillin, or anti-RNA polymerase I or III

* Diagnosis requires at least 1 major and at least 2 minor criteria.

From Zulian F, Woo P, Athreya BH, et al: The Pediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for juvenile systemic sclerosis, Arthritis Rheum 57:203–212, 2007.

Epidemiology Juvenile scleroderma is rare, with an estimated prevalence of 1 in 100,000 children. LS is much more common than SSc in children, by a 10 : 1 ratio, with linear scleroderma being the most common subtype. LS is predominantly a pediatric condition, with 65% of patients diagnosed before age 18 yr. After age 8 yr the female/male ratio for both LS and SSc is approximately 3 : 1, whereas in patients younger than 8 yr, there is no sex predilection.

Clinical Manifestations Localized Scleroderma The onset of scleroderma is generally insidious, and manifestations vary according to disease subtype. The initial skin manifestations of localized disease usually include erythema or a bluish hue seen around an area of waxy induration; subtle erythema may be the only presenting sign (Fig. 185.1 ). Edema and erythema are followed by indurated, hypopigmented or hyperpigmented atrophic lesions (Fig. 185.2 ). LS varies in size from a few centimeters to the entire length of the extremity, with varying depth. Patients

may present with arthralgias, synovitis, or flexion contractures (Fig. 185.3 ). Children also experience limb length discrepancies as a result of growth impairment caused by involvement of muscle and bone. Children with en coup de sabre may have symptoms unique to central nervous system (CNS) involvement, such as seizures, hemifacial atrophy, ipsilateral uveitis, and learning/behavioral changes (Fig. 185.4 ). Up to 25% of children with LS have extracutaneous manifestations, most frequently arthritis (47%) and neurologic symptoms (17%) associated with en coup de sabre.

FIG. 185.1 Boy with generalized morphea. Note the active circular lesion (arrowheads) with a surrounding rim of erythema. The largest lesion has areas of postinflammatory hyperpigmentation and depression with an area of erythema on the right. The small lesion (arrow) demonstrates depression caused by lipoatrophy.

FIG. 185.2 Inactive linear scleroderma demonstrating hyperpigmented lesion with areas of normal skin (skip lesions).

FIG. 185.3 Child with untreated linear scleroderma resulting in knee contracture, immobility of ankle, chronic skin breakdown of scar on the lateral knee, and areas of hypopigmentation and hyperpigmentation. The affected leg is 1 cm shorter.

FIG. 185.4 Child with en coup de sabre lesion on scalp extending down to forehead. Before treatment, the skin on the scalp was bound down with chronic skin breakdown. Note the area of hypopigmentation extending down the forehead (arrows).

Systemic Scleroderma SSc also has an insidious onset with a prolonged course characterized by periods of remission and exacerbation, ending in either remission or, more often, chronic disability and death.

The skin manifestations of SSc include an early phase of edema that spreads proximally from the dorsum of the hands and fingers and includes the face. An eventual decrease in edema is followed by induration and fibrosis of skin, ultimately resulting in loss of subcutaneous fat, sweat glands, and hair follicles. Later, atrophic skin becomes shiny and waxy in appearance. As lesions spread proximally, flexion contractures develop at the elbows, hips, and knees associated with secondary muscle weakness and atrophy. In the face, this process results in a small oral stoma with decreased mouth aperture. Skin ulceration over pressure points, such as the elbows, may be associated with subcutaneous calcifications. Severe Raynaud phenomenon causes ulceration of the fingertips with subsequent loss of tissue pulp and tapered fingers (sclerodactyly ) (Fig. 185.5 ). Resorption of the distal tufts of the distal phalanges may occur (acroosteolysis ). Hyperpigmented postinflammatory changes surrounded by atrophic depigmentation gives a salt-and-pepper appearance to skin. Over years, remodeling of lesions sometimes results in focal improvement in skin thickening.

FIG. 185.5 Sclerodactyly and finger ulcerations in a patient with systemic sclerosis who is poorly compliant with treatment.

Pulmonary disease is the most common visceral manifestation of SSc and includes both arterial and interstitial involvement (alveolitis). Symptoms range from asymptomatic disease to exercise intolerance, dyspnea at rest, and rightsided heart failure. Pulmonary arterial hypertension is a poor prognostic sign, developing because of lung disease or independently as part of the vasculopathy. Clinical manifestations of pulmonary arterial hypertension in children appear

late in the course, are subtle, and include cough and dyspnea on exertion. Pulmonary evaluation should include pulmonary function tests (PFTs) such as diffusion capacity of carbon monoxide (DLCO ), bronchoalveolar lavage (BAL), and high-resolution chest computed tomography (HRCT). PFTs reveal decreased vital capacity and decreased DLCO , whereas neutrophilia or eosinophilia on BAL suggest active alveolitis. Chest CT is much more sensitive than chest radiographs, which are often normal, showing typical basilar ground-glass abnormalities, reticular linear opacities, nodules, honeycombing, and mediastinal adenopathy. Gastrointestinal tract disease is seen in 25% of children with SSc. Common manifestations include esophageal and intestinal dysmotility resulting in dysphagia, reflux, dyspepsia, gastroparesis, bacterial overgrowth, dilated bowel loops and pseudoobstruction, and dental caries, as well as malabsorption and failure to thrive. Renal arterial disease can cause chronic or severe episodic hypertension; unlike adult disease, renal crisis is rare. Cardiac fibrosis is associated with arrhythmias, ventricular hypertrophy, and decreased cardiac function. Mortality from JSSc is usually a result of cardiopulmonary disease. A scoring system helps identify the severity of the multiorgan involvement (Table 185.3 ). Table 185.3

Medsger Systemic Sclerosis Severity Scale* ORGAN SYSTEM General

0 (NORMAL) Wt loss 6 wk Mostly unpredictable Truly periodic USEFUL LABORATORY TESTS Acute-phase reactants must be normal between attacks Urine mevalonic acid in attack IgD > 100 mg/dL Proteinuria (amyloidosis) RESPONSE TO THERAPY Corticosteroid dramatic Corticosteroid partial Colchicine Cimetidine Etanercept Anti–IL-1 dramatic Anti–IL-1 mostly Anti–IL-1 partial

HIDS, FCAS, NLRP12 PFAPA PAPA TRAPS, DITRA All others FMF FMF, DITRA (Arab Tunisian) HIDS, MWS, NLRP12 FCAS TRAPS DIRA All others HIDS FCAS, NLRP12 FMF, TRAPS, MWS, PAPA, DITRA PAPA, MWS, TRAPS, HIDS FMF, TRAPS DITRA All, especially DITRA FCAS, FMF FMF, MWS, DITRA (fever) HIDS, PFAPA TRAPS, PAPA NOMID, DIRA PFAPA, HIDS TRAPS All others PFAPA, cyclic neutropenia PFAPA HIDS HIDS FMF, TRAPS, MWS, NOMID PFAPA TRAPS, FCAS, MWS, NOMID, PAPA* FMF, PFAPA (30% effective) PFAPA (30% effective) TRAPS, FMF arthritis DIRA (anakinra), FCAS, MWS, NOMID, PFAPA TRAPS, FMF HIDS, PAPA

* For intraarticular corticosteroids.

DIRA, Deficiency of IL-1 receptor antagonist; DITRA, deficiency of IL-36 receptor antagonist (generalized pustular psoriasis); FCAS, familial cold autoinflammatory syndrome; FMF, familial

Mediterranean fever; HIDS, hyper-IgD syndrome; IL, interleukin; MWS, Muckle-Wells syndrome; NLRP, nucleotide oligomerization domain–like receptor family, pyrin domain; NOMID, neonatalonset multisystem inflammatory disorder; PAPA, pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, adenitis; TRAPS, tumor necrosis factor receptor–associated periodic syndrome. From Hashkes PJ, Toker O: Autoinflammatory syndromes, Pediatr Clin North Am 59:447–470, 2012 (Table 2).

Autoinflammatory Diseases With Periodic or Prominent Fevers The first descriptions of autoinflammatory disorders focused on genetic diseases that presented with prominent fevers, the periodic fever syndromes. As new autoinflammatory diseases were discovered, it was clear that a variety of inflammatory disorders can occur in the absence of fever.

Familial Mediterranean Fever FMF is a recessively inherited autoinflammatory disease usually characterized by recurrent, short-lived (1-3 days), self-limited episodes of fever, serositis, mono- or pauciarticular arthritis, or an erysipeloid rash, sometimes complicated by AA amyloidosis. Most patients with FMF present with symptoms in childhood, with 90% presenting before age 20. Clinical features of FMF may include fever, serositis presenting as pleuritic chest pain or severe abdominal pain, arthritis, and rash. The pleural pain is typically unilateral, whereas the abdominal pain (sterile peritonitis) can be generalized or localized to 1 quadrant, similar to other forms of peritonitis. FMF-associated arthritis occurs primarily in the large joints, may be accompanied by large, neutrophil-rich effusions, and is usually nonerosive and nondestructive. The hallmark cutaneous finding is an erysipeloid erythematous rash that overlies the ankle or dorsum of the foot (Fig. 188.2 ). Other clinical findings include scrotal pain caused by inflammation of the tunica vaginalis testis, febrile myalgia, exercise-induced myalgia (particularly common in children), and an association with various forms of vasculitis, including Henoch-Schönlein purpura, in as many as 5% of pediatric patients. FMF episodes may be triggered by stress, menses, or infections. Between flares, patients are generally symptom free but may have persistent elevation of their inflammatory markers. The attack frequency can vary from

weekly to 1-2 flares per year. Table 188.6 lists diagnostic criteria for FMF.

FIG. 188.2 Characteristic erysipeloid erythema associated with familial Mediterranean fever. This rash appears during a flare and overlies the ankle or dorsum of the foot.

Table 188.6

Diagnostic Criteria for Familial Mediterranean Fever (FMF)* Major Criteria 1. Typical attacks † with peritonitis (generalized) 2. Typical attacks with pleuritis (unilateral) or pericarditis 3. Typical attacks with monoarthritis (hip, knee, ankle) 4. Typical attacks with fever alone 5. Incomplete abdominal attack

Minor Criteria 1. Incomplete attacks ‡ involving chest pain 2. Incomplete attacks involving monoarthritis 3. Exertional leg pain 4. Favorable response to colchicine

* Requirements for diagnosis of FMF are ≥1 major criteria or ≥2 minor criteria. † Typical attacks are defined as recurrent (≥3 of the same type), febrile (≥38°C),

and short (lasting between 12 hr and 3 days). ‡ Incomplete attacks are defined as painful and recurrent attacks not fulfilling the

criteria for a typical attack. From Livneh A, Langevitz P, Zemer D, et al: Criteria for the diagnosis of familial Mediterranean fever, Arthritis Rheum 40:1879–1885, 1997. FMF is caused by autosomal recessive mutations in MEFV , a gene encoding a 781 amino acid protein denoted pyrin (Greek for “fever”). Pyrin is expressed in granulocytes, monocytes, and dendritic cells (DCs) and in peritoneal, synovial, and dermal fibroblasts. The N-terminal approximately 90 amino acids of pyrin are the prototype for a motif (the PYRIN domain) that mediates protein-protein interactions and is found in >20 different human proteins that regulate inflammation and apoptosis. Many of the FMF-associated mutations in pyrin are found at the C-terminal B30.2 domain of pyrin, encoded by exon 10 of MEFV. More than 50 such FMF mutations are listed in an online database (http://fmf.igh.cnrs.fr/ISSAID/infevers/ ), almost all of which are missense substitutions. Homozygosity for the M694V mutation may be associated with an earlier age of onset, arthritis, and an increased risk of amyloidosis. The substitution of glutamine for glutamic acid at residue 148 (E148Q) is considered either a mild mutation or a functional polymorphism in the pyrin protein. The carrier frequency of FMF mutations among several Mediterranean populations is very high, suggesting the possibility of a heterozygote advantage. FMF occurs primarily among ethnic groups of Mediterranean ancestry, most frequently Jews, Turks, Armenians, Arabs, and Italians. Because of a higher frequency of the M694V mutation, FMF is more severe and more readily recognized in the Sephardic (North African) than the Ashkenazi (East European) Jewish population. With the advent of genetic testing, mutation-positive FMF has been documented worldwide, although at lower frequency than in the Mediterranean basin and Middle East. Through PYRIN-domain interactions, pyrin can activate caspase-1 , the enzyme that converts the 31 kDa pro–IL-1β molecule into the biologically active 17 kDa IL-1β, which is a major mediator of fever and inflammation. FMF mutations lead to a gain-of-function activation of caspase-1 and IL-1β–

dependent inflammation, with a gene-dosage effect. These results may explain why as many as 30% of heterozygous carriers of FMF mutations have biochemical evidence of inflammation. Prophylactic daily oral colchicine decreases the frequency, duration, and intensity of FMF flares. This regimen also prevents the development of systemic AA amyloidosis. Colchicine is generally well tolerated and safe in children, with the most common side effects being diarrhea and other gastrointestinal (GI) complaints. Some patients develop lactose intolerance while taking colchicine. GI side effects can be minimized by initiating therapy at a low dose (for young children, 0.3 mg/day) and slowly titrating upward. A dose-related transaminitis may also be observed; bone marrow suppression is rarely seen at the dosages prescribed for FMF. Pediatric patients may require doses of colchicine similar to those needed in adults (1-2 mg/day), reflecting that children metabolize the drug more rapidly than adults. It is not always possible to find a tolerated dose of colchicine at which all symptoms are suppressed, but approximately 90% of patients have a marked improvement in disease-related symptoms. A small percentage of FMF patients are either unresponsive to or intolerant of therapeutic doses of colchicine. Based on the role of pyrin in IL-1β activation, a trial demonstrated the safety and effectiveness of rilonacept, an IL-1 inhibitor, in FMF; there are case reports of the effectiveness of anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist. Amyloidosis is the most serious complication of FMF, and in its absence FMF patients may live a normal life span. Amyloidosis may develop when serum AA, an acute-phase reactant found at extremely high levels in the blood during FMF attacks, is cleaved to produce a 76–amino acid fragment that misfolds and deposits ectopically, usually in the kidneys, GI tract, spleen, lungs, testes, thyroid, and adrenals. Rarely, cardiac amyloidosis may develop; macroglossia and amyloid neuropathy are generally not seen with the amyloidosis of FMF. The most common presenting sign of AA amyloidosis is proteinuria. The diagnosis is then usually confirmed by rectal or renal biopsy. In a small number of case reports, mostly from the Middle East, amyloidosis may actually precede overt FMF attacks, presumably because of subclinical inflammation. Risk factors for the development of amyloidosis in FMF include homozygosity for the M694V MEFV mutation, polymorphisms of the serum AA gene (encoding AA), noncompliance with colchicine treatment, male gender, and a positive family history of AA amyloid. For unclear reasons, country of origin is also a major risk factor for amyloidosis in FMF, with patients raised in the Middle East having a

much higher risk than genotypically identical patients raised in the West. Aggressive lifelong suppression of the acute-phase reactants should be the goal in patients with FMF amyloidosis, and documented cases show this may result in resorption of amyloid deposits. The natural history of untreated amyloidosis in FMF is the inexorable progression to renal failure, often within 3-5 yr.

Hyperimmunoglobulinemia D With Periodic Fever Syndrome HIDS, also known as mevalonate kinase deficiency , was initially described in a cohort of Dutch patients and occurs primarily in patients of Northern European descent. HIDS is recessively inherited and caused by mutations of MVK , a gene that encodes mevalonate kinase (MK). The clinical features of HIDS generally appear within the 1st 6 mo of life. Febrile attacks last 3-7 days, with abdominal pain often accompanied by diarrhea, nausea, and vomiting. Other clinical manifestations include cervical lymphadenopathy, diffuse macular rash, aphthous ulcers, headaches, and occasional splenomegaly (Figs. 188.3 to 188.5 ). Arthritis or arthralgia can be present in an oligoarticular or polyarticular pattern. Inflammatory disease–like illness and Kawasaki disease–like presentation have also been reported. Attacks are often precipitated by intercurrent illness, immunizations, and surgery. Families frequently recount flares around the time of birthdays, holidays, and family vacations. The symptoms of HIDS may persist for years but tend to become less prominent in adulthood. Patients with HIDS usually have a normal life span. Unlike FMF and TRAPS, the incidence of AA amyloidosis is quite low. Complete MK deficiency results in mevalonic aciduria that presents with severe mental retardation, ataxia, myopathy, cataracts, and failure to thrive (see Chapter 103 ).

FIG. 188.3 Polymorphic rash on the hands, arms, and legs of a patient with hyper-IgD syndrome (HIDS). (From Takada K, Aksentijevich I, Mahadevan V, et al. Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome, Arthritis Rheum 48:2646, 2003.)

FIG. 188.4 Petechiae on the leg of a hyper-IgD syndrome patient during a febrile attack. (From Simon A, van der Meer JWM, Drenth JPH: Familial autoinflammatory syndromes. In Firestein GS, Budd RC, Gabriel SE, et al, editors: Kelley's textbook of rheumatology, ed 9, Philadelphia, 2012, Saunders, Fig 97-7.)

FIG. 188.5 Aphthous ulceration detected on the tongue of a patient with hyper-IgD syndrome. (Courtesy Dr. K. Antila, North Carelian Central Hospital, Joensuu, Finland; from Simon A, van der Meer JWM, Drenth JPH: Familial autoinflammatory syndromes. In Firestein GS, Budd RC, Gabriel SE, et al, editors: Kelley's textbook of rheumatology, ed 9, Philadelphia, 2012, Saunders, Fig 97-8.)

MK is expressed in multiple tissues and catalyzes the conversion of mevalonic acid to 5-phosphomevalonic acid in the biosynthesis of cholesterol and nonsterol isoprenoids. Patients with HIDS-associated mutations have greatly reduced, but not absent, MK enzymatic activity. HIDS patients usually have low-normal serum cholesterol levels, but the deficiency of isoprenoids may cause increased IL-1β production by aberrant activation of the small guanosine triphosphatase Rac1. Temperature elevation may further exacerbate this process by more complete inhibition of MK activity, leading to a possible positive feedback loop. The diagnosis of HIDS may be confirmed either by 2 mutations in MVK (approximately 10% of patients with seemingly typical disease have only a single identifiable mutation) or by elevated levels of mevalonate in the urine during acute attacks. HIDS-associated mutations are distributed throughout the MK protein, but the 2 most common mutations are the substitution of isoleucine for valine at residue 377 (V377I), a variant that is quite common in the Dutch population, and the substitution of threonine for isoleucine at residue 268 (I268T). The eponymous elevation in serum IgD levels is not universally present, especially in young children; IgA levels can also be elevated. Conversely, serum IgD levels may be increased in other autoinflammatory disorders as well as in some chronic infections. During attacks, leukocytosis and increased serum levels of acute-phase reactants and proinflammatory cytokines are frequently present. Table 188.7 lists diagnostic criteria for HIDS.

Table 188.7

Diagnostic Indicators of Hyper-IgD Syndrome At Time of Attacks 1. Elevated erythrocyte sedimentation rate and leukocytosis 2. Abrupt onset of fever (≥38.5°C) 3. Recurrent attacks 4. Lymphadenopathy (especially cervical) 5. Abdominal distress (e.g., vomiting, diarrhea, pain) 6. Skin manifestations (e.g., erythematous macules and papules) 7. Arthralgias and arthritis 8. Splenomegaly

Constantly Present 1. Elevated IgD (above upper limit of normal) measured on 2 occasions at least 1 mo apart* 2. Elevated IgA (≥2.6 g/L)

Specific Features 1. Mutations in mevalonate kinase gene 2. Decreased mevalonate kinase enzyme activity

* Extremely high serum concentrations of IgD are characteristic but not

obligatory. From Firestein GS, Budd RC, Gabriel SE, et al, editors: Kelly & Firestein's textbook of rheumatology, ed 10, Philadelphia, 2016, Elsevier (Table 97-4, p 1674). Standards for the treatment of HIDS are evolving. Very few patients respond to colchicine, and milder disease courses may respond to nonsteroidal

antiinflammatory drugs (NSAIDs). Corticosteroids are of limited utility. Small trials of both etanercept and either intermittent or daily anakinra in HIDS are promising.

Tumor Necrosis Factor Receptor–Associated Periodic Syndrome TRAPS is characterized by recurrent fevers and localized inflammation and is inherited in an autosomal dominant manner. TRAPS has a number of distinguishing clinical and immunologic features. TRAPS was first recognized in patients of Irish descent and denoted familial Hibernian fever to draw a contrast with FMF, but the current nomenclature was proposed when mutations in TNFRSF1A were discovered not only in the original Irish family, but in families from a number of other ethnic backgrounds. TNFRSF1A encodes the 55 kDa receptor (denoted p55, TNFR1, or CD120a) for TNF-α that is widely expressed on a number of cell types. A 2nd 75 kDa receptor is largely restricted to leukocytes. Patients with TRAPS typically present within the 1st decade of life with flares that occur with variable frequency but of often substantially longer duration than FMF or HIDS flares. The febrile episodes of TRAPS last at least 3 days and can persist for weeks. There may be pleural and peritoneal involvement. At times, patients present with signs of an acute abdomen; on exploration such patients have sterile peritonitis , sometimes with adhesions from previous episodes. Patients may also have nausea and frequently report constipation at the onset of flares that progresses to diarrhea by the conclusion. Ocular signs include periorbital edema and conjunctivitis. TRAPS patients may also experience severe myalgia and on imaging, the muscle groups may have focal areas of edema. Many rashes can be seen in TRAPS patients, but the most common is an erythematous macular rash that on biopsy contains superficial and deep perivascular infiltrates of mononuclear cells. Patients often report that the rash migrates distally on a limb during its course with an underlying myalgia and can resemble cellulitis. Other rashes include erythematous annular patches as well as a serpiginous rash (Fig. 188.6 ). Approximately 10–15% of patients with TRAPS may develop AA amyloidosis; the presence of cysteine mutations and a positive family history are risk factors for this complication. If amyloidosis does not develop, TRAPS patients have a normal life expectancy. Table 188.8 lists diagnostic criteria.

FIG. 188.6 Cutaneous manifestations of tumor necrosis factor receptor–associated periodic syndrome. A, Right flank of a patient with the T50M mutation. B, Serpiginous rash involving the face, neck, torso, and upper extremities of a child with the C30S mutation. C, Erythematous, macular patches with crusting on the flexor surface of the right arm of a patient with the T50M mutation. (From Hull KM, Drewe, Aksentijevich I, et al: The TNF receptor-associated periodic syndrome [TRAPS]: emerging concepts of an autoinflammatory syndrome, Medicine (Baltimore) 81:349–368, 2002.)

Table 188.8

Diagnostic Indicators of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) 1. Recurrent episodes of inflammatory symptoms spanning >6 mo duration (several symptoms generally occur simultaneously) a. Fever b. Abdominal pain c. Myalgia (migratory) d. Rash (erythematous macular rash occurs with myalgia) e. Conjunctivitis or periorbital edema f. Chest pain g. Arthralgia or monoarticular synovitis 2. Episodes last >5 days on average (although variable) 3. Responsive to glucocorticosteroids but not colchicine 4. Affects family members in autosomal dominant pattern (although may not

always be present) 5. Any ethnicity may be affected From Hull KM, Drewe E, Aksentijevich I, et al: The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder, Medicine (Baltimore) 81:349–368, 2002. Almost all the TRAPS-associated mutations are in the extracellular domain of the TNFR1 protein, with about one-third involving the substitution of another amino acid for a highly conserved cysteine residue, thus disrupting disulfide bonds and leading to protein misfolding. A number of other missense mutations not involving cysteine residues have been shown to have a similar effect on TNFR1 protein folding. Misfolded TNFR1 aggregates intracellularly and leads to constitutive signaling through mitogen-activated protein kinases or nuclear factor (NF)-κB, resulting in the release of proinflammatory cytokines such as IL6, IL-1β and TNF-α. The substitution of glutamine for arginine at residue 92 (R92Q) and the substitution of leucine for proline at residue 46 (P46L) are seen in >1% of the white and black population, respectively. These variants do not lead to the same biochemical or signaling abnormalities seen with more-severe TRAPS mutations, and as with E148Q in FMF, debate surrounds whether they are mild mutations or functional polymorphisms. Colchicine is generally not effective in TRAPS. For relatively mild disease, NSAIDs may suffice. For more severe disease with infrequent attacks, corticosteroids at the time of an attack may be effective, but it is not unusual for steroid requirements to increase over time. Etanercept is often effective in reducing the severity and frequency of flares, but longitudinal follow-up of TRAPS patients treated with etanercept indicates waning efficacy with time. Of note, treatment of TRAPS with anti-TNF-α monoclonal antibodies has sometimes led to a paradoxical worsening of disease. Clinical responses to anakinra, canakinumab, a monoclonal anti–IL-1β antibody, and tocilizumab, a monoclonal anti-IL6 antibody, has been favorable in TRAPS patients.

Cryopyrin-Associated Periodic Fever Syndromes CAPS represent a spectrum of clinical disorders, including familial cold

autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID). Although 3 separate clinical diagnoses have been defined, it should be emphasized that the cryopyrinopathies are really a continuum of disease severity. This spectrum of illness is caused by mutations in NLRP3 (formerly known as CIAS1 ), which encodes a protein called cryopyrin ; >100 disease-associated NLRP3 mutations have been enumerated on the Infevers online database. Advances in nextgeneration sequencing have also permitted the identification of symptomatic individuals with somatic NLRP3 mosaicism. NLRP3 is a PYRIN domain-containing protein that is strongly expressed in myeloid cells and to a lesser degree in other tissues. It is a part of a macromolecular complex termed the NLRP3 inflammasome that activates pro– IL-1β to its mature form in response to a variety of endogenous dangerassociated molecular patterns and pathogen-associated molecular patterns. Patients with cryopyrinopathies have gain-of-function mutations in NLRP3 that result in constitutive or easily-triggered activation of the NLRP3 inflammasome. The cryopyrinopathies are characterized by recurrent fevers and an urticarialike rash that develops early in infancy (Fig. 188.7 ). Histopathologic examination reveals a perivascular neutrophilic infiltrate without the mast cells or mast cell degranulation seen with true urticaria. In patients with FCAS, febrile attacks generally begin 1-3 hr after generalized cold exposure. FCAS patients also experience polyarthralgia of the hands, knees, and ankles, and conjunctivitis may also develop during attacks. FCAS episodes are self-limited and generally resolve within 24 hr. AA amyloidosis rarely occurs in FCAS. Table 188.9 lists diagnostic criteria for FCAS.

FIG. 188.7 Urticarial-like rash. Inflammatory clinical manifestations and organ damage in the IL-1–mediated diseases; in neonatal-onset multisystem inflammatory disease (NOMID), which is the severe form of cryopyrin-associated periodic syndromes (CAPS); and deficiency of IL-1 receptor antagonist (DIRA). This rash is not truly urticarial and occurs due to neutrophil infiltrates into the skin. (From Jesus AA, Goldbach-Mansky R: IL-1 blockade in autoinflammatory syndromes. Annu Rev Med 65:223–244, 2014, Fig. 2.)

Table 188.9

Diagnostic Criteria for Familial Cold Autoinflammatory Syndrome (FCAS) 1. Recurrent intermittent episodes of fever and rash that primarily follow generalized cold exposures 2. Autosomal dominant pattern of disease inheritance 3. Age of onset 8 mm ID). Some experts believe that a z -score–based system for classification of aneurysm size may be more discriminating, because

it adjusts the coronary dimension for BSA. The AHA z -score classification system is as follows: 1. No involvement: always 16 yr Medication at disease onset Palpable purpura

DEFINITION Development of symptoms after 16 yr of age Medication that may have been a precipitating factor was taken at the onset of symptoms Slightly elevated purpuric rash over 1 or more areas; does not blanch with pressure and is not related to thrombocytopenia Maculopapular rash Flat and raised lesions of various sizes over 1 or more areas of the skin Biopsy, including arteriole Histologic changes showing granulocytes in a perivascular or extravascular location and venule * For purposes of classification, a patient is said to have hypersensitivity vasculitis if at least 3 of

these criteria are present. The presence of ≥3 criteria has a diagnostic sensitivity of 71.0% and specificity of 83.9%. The age criterion is not applicable for children. Adapted from Calabrese LH, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis, Arthritis Rheum 33:1108–1113, 1990 (Table 2, p 1110); and Textbook of pediatric rheumatology, ed 7, Philadelphia, 2016, Elsevier (Table 38.2, p 511).

Primary angiitis of the central nervous system represents vasculitis confined to the CNS and requires exclusion of other systemic vasculitides. Large vessel disease (angiography positive) may be progressive or nonprogressive and may manifest with focal deficits similar to an occlusive stroke, with hemiparesis, focal gross or fine motor deficits, language disorders, or cranial nerve deficits. Diffuse cognitive, memory, and concentration deficits as well as behavioral disorders are seen in 30–40% of patients. Small vessel disease (angiography negative, biopsy positive) more often results in language problems and diffuse deficits, such as cognitive, memory, behavior, and concentration problems, as well as focal seizures. In both types of cerebral angiitis, patients may have an elevated ESR or CRP and abnormal CSF findings

(increased protein, pleocytosis), although these are not consistent findings in all patients. Diagnosis remains a challenge, and brain biopsy is often indicated to confirm the diagnosis and exclude vasculitis mimics such as infections that could worsen with immunosuppressive therapy (Table 192.10 ).

Table 192.10

Differential Diagnosis of Small Vessel Primary Central Nervous System (CNS) Vasculitis in Children CNS Vasculitis Complicating Other Diseases Infections • Bacterial: Mycobacterium tuberculosis, Mycoplasma pneumoniae, Streptococcus pneumoniae • Viral: Epstein-Barr virus, cytomegalovirus, enterovirus, varicella-zoster virus, hepatitis C virus, parvovirus B19, West Nile virus • Fungal: Candida albicans, Actinomyces, Aspergillus • Spirochetal: Borrelia burgdorferi, Treponema pallidum Rheumatic and Inflammatory Diseases • Systemic vasculitis such as granulomatosis with polyangiitis, microscopic polyangiitis, Henoch-Schönlein purpura, Kawasaki disease, polyarteritis nodosa, Behçet disease • Systemic lupus erythematosus, juvenile dermatomyositis, morphea • Inflammatory bowel disease • Autoinflammatory syndromes • Hemophagocytic lymphohistiocytosis • Neurosarcoidosis • Adenosine deaminase-2 deficiency Other

• Drug-induced vasculitis • Malignancy-associated vasculitis

Nonvasculitis Inflammatory Brain Diseases Demyelinating Diseases • Multiple sclerosis, acute demyelinating encephalomyelitis (ADEM), optic neuritis, transverse myelitis Antibody-Mediated Inflammatory Brain Disease • Anti–NMDA receptor encephalitis, neuromyelitis optica (NMO), antibodyassociated limbic encephalitis (antibodies against LGI, AMP, AMP-binding protein), Hashimoto encephalopathy, celiac disease, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) T-Cell–Associated Inflammatory Brain Disease • Rasmussen encephalitis Other • Febrile infection-related epilepsy syndrome (FIRES)

Noninflammatory Vasculopathies • Hemoglobinopathies (sickle cell disease), thromboembolic disease • Radiation vasculopathy, graft-versus-host disease • Metabolic and genetic diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), moyamoya disease,

Fabray disease • Malignancy (lymphoma) Modified from Gowdie P, Twilt M, Benseler SM: Primary and secondary central nervous system vasculitis. J Child Neurol 27:1448–1459, 2012. Nonprogressive angiography-positive CNS vasculitis, also known as transient CNS angiopathy, represents a more benign variant and can be seen after varicella infection. Cogan syndrome is rare in children; its potential clinical manifestations include constitutional symptoms; inflammatory eye disease such as uveitis, episcleritis, or interstitial keratitis; vestibuloauditory dysfunction (vertigo, hearing loss, tinnitus); arthritis; and large vessel vasculitis or aortitis. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL ) is caused by mutations in the NOTCH3 gene and manifests with stroke, mood changes, cognitive decline, and migraines; it is a vasculitis mimic and demonstrates osmophilic granules in cerebral arteries. CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is another mimic of angiitis caused by mutations in the HTRA1 gene. It manifests with early-onset hair loss, spasticity, stroke, memory loss, and personality changes. Identification of these vasculitis syndromes requires a comprehensive history and physical examination. Table 192.11 outlines other diagnostic considerations. Although tailored to disease severity, treatment generally includes prednisone (up to 2 mg/kg/day). Potent immunosuppressive medications, such as cyclophosphamide, are often indicated, particularly in primary angiitis of the CNS to prevent rapid neurologic decline. For hypersensitivity vasculitis, withdrawal of the triggering medication or toxin is indicated if possible. Table 192.11 Diagnostic Considerations for Other Vasculitis Syndromes VASCULITIS SYNDROME Hypersensitivity vasculitis Hypocomplementemic urticarial vasculitis

Cryoglobulinemic vasculitis

APPROACH TO DIAGNOSIS Skin biopsy demonstrating leukocytoclastic vasculitis Biopsy of affected tissue demonstrating small vessel vasculitis Low levels of circulating C1q Biopsy of affected tissue demonstrating small vessel vasculitis Measurement of serum cryoglobulins

Primary angiitis of CNS Nonprogressive angiography-positive CNS vasculitis Cogan syndrome

Exclusion of hepatitides B and C infections Conventional, CT, or MRA evidence of CNS vasculitis Consideration of dura or brain biopsy Conventional, CT, or MRA evidence of CNS vasculitis Ophthalmology and audiology evaluations Conventional, CT, or MRA evidence of CNS or aortic vasculitis

CNS, Central nervous system; CT, computed tomography; MRA, magnetic resonance angiography.

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CHAPTER 193

Musculoskeletal Pain Syndromes Kelly K. Anthony, Laura E. Schanberg

Musculoskeletal pain is a frequent complaint of children presenting to general pediatricians and is the most common presenting problem of children referred to pediatric rheumatology clinics. Prevalence estimates of persistent musculoskeletal pain in community samples range from 10–30%. Although diseases such as juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) may manifest as persistent musculoskeletal pain, the majority of musculoskeletal pain complaints in children are benign in nature and attributable to trauma, overuse, and normal skeletal growth variations. In a subset of children, chronic pain complaints develop in the absence of physical or laboratory abnormalities. Children with idiopathic musculoskeletal pain syndromes also typically develop marked subjective distress and functional impairment. Therefore the treatment of children with musculoskeletal pain syndromes optimally includes both pharmacologic and nonpharmacologic interventions.

Clinical Manifestations Chronic musculoskeletal pain syndromes involve pain complaints at least 3 mo in duration in the absence of objective abnormalities on physical examination or laboratory screening. Additionally, children and adolescents with musculoskeletal pain syndromes often complain of persistent pain despite previous treatment with nonsteroidal antiinflammatory drugs (NSAIDs) and analgesic agents. The location varies, with pain complaints either localized to a single extremity or more diffuse and involving multiple extremities. The pain may start in a single area of the body before intensifying and radiating to other areas over time. The prevalence of musculoskeletal pain syndromes increases

with age and is higher in females, thus rendering adolescent girls at highest risk. The somatic complaints of children and adolescents with musculoskeletal pain syndromes are typically accompanied by psychological distress, sleep difficulties, and functional impairment across home, school, and peer domains. Psychological distress may include symptoms of anxiety and depression, such as frequent crying spells, fatigue, sleep disturbance, feelings of worthlessness, poor concentration, and frequent worry. Indeed, a substantial number of children with musculoskeletal pain syndromes display the full range of psychological symptoms, warranting an additional diagnosis of a comorbid mood or anxiety disorder (e.g., major depressive episode, generalized anxiety disorder). Sleep disturbance in children with musculoskeletal pain syndromes may include difficulty falling asleep, multiple night awakenings, disrupted sleep–wake cycles with increased daytime sleeping, nonrestorative sleep, and fatigue. For children and adolescents with musculoskeletal pain syndromes, the constellation of pain, psychological distress, and sleep disturbance often leads to a high degree of functional impairment. Poor school attendance is common, and children may struggle to complete other daily activities relating to self-care and participation in household chores. Decreased physical fitness can also occur, as well as changes in gait and posture, as children avoid contact with or use of the body area affected by pain. Peer relationships may also be disrupted by decreased opportunities for social interaction because of pain. As such, children and adolescents with musculoskeletal pain syndromes often report loneliness and social isolation characterized by few friends and lack of participation in extracurricular activities.

Diagnosis and Differential Diagnosis The diagnosis of a musculoskeletal pain syndrome is typically one of exclusion when careful, repeated physical examinations and laboratory testing do not reveal an etiology. At initial presentation, children with pain complaints require a thorough clinical history and a complete physical examination to look for an obvious etiology (sprains, strains, or fractures), characteristics of the pain (localized or diffuse), and evidence of systemic involvement. A comprehensive history can be particularly useful in providing clues to the possibility of underlying illness or systemic disease. The presence of current or recent fever can be indicative of an inflammatory or neoplastic process if the pain is also accompanied by worsening symptoms over time or weight loss.

Subsequent, repeated physical examinations of children with musculoskeletal pain complaints may reveal eventual development and manifestations of rheumatic or other diseases. The need for additional testing should be individualized, depending on the specific symptoms and physical findings. Laboratory screening and radiography should be pursued if there is suspicion of certain underlying disease processes. Possible indicators of a serious, vs a benign, cause of musculoskeletal pain include pain present at rest, pain that may be relieved by activity, objective joint swelling on physical examination, stiffness or limited range of motion in joints, bony tenderness, muscle weakness, poor growth and/or weight loss, and constitutional symptoms (e.g., fever, malaise) (Table 193.1 ). In the case of laboratory screenings, a complete blood count (CBC) and erythrocyte sedimentation rate (ESR) are likely to be abnormal in children whose pain is secondary to a bone or joint infection, SLE, or a malignancy. Bone tumors, fractures, and other focal pathology resulting from infection, malignancy, or trauma can often be identified through imaging studies, including plain radiographs, MRI, and less often technetium-99m bone scans. Table 193.1 Potential Indicators of Benign vs Serious Causes of Musculoskeletal Pain CLINICAL FINDING Effects of rest vs activity on pain Time of day pain occurs Objective joint swelling Joint characteristics Bony tenderness Muscle strength Gait Growth Constitutional symptoms (e.g., fever, malaise) Lab findings Imaging findings

BENIGN CAUSE Relieved by rest and worsened by activity End of the day and nights No Hypermobile/normal No Normal Normal Normal growth pattern or weight gain Fatigue without other constitutional symptoms Normal CBC, ESR, CRP Normal

SERIOUS CAUSE Present at rest and may be relieved by activity Morning* Yes Stiffness, limited range of motion Yes Muscle weakness Limp or refusal to walk Poor growth and/or weight loss Yes Abnormal CBC, raised ESR and CRP Effusion, osteopenia, radiolucent metaphyseal lines, joint space loss, bony destruction

* Cancer pain is often severe and worst at night.

CBC, Complete blood count; CRP, C-reactive protein level; ESR, erythrocyte sedimentation rate. Adapted from Malleson PN, Beauchamp RD: Diagnosing musculoskeletal pain in children, CMAJ 165:183–188, 2001.

The presence of persistent pain, accompanied by psychological distress, sleep

disturbance, and/or functional impairment, in the absence of objective laboratory or physical examination abnormalities, suggests the diagnosis of an idiopathic musculoskeletal pain syndrome. All pediatric musculoskeletal pain syndromes share this general constellation of symptoms at presentation. Several more specific pain syndromes routinely seen by pediatric practitioners can be differentiated by anatomic region and associated symptoms. Table 193.2 outlines pediatric musculoskeletal pain syndromes, including growing pains (see Chapter 193.1 ), fibromyalgia (Chapter 193.3 ), complex regional pain syndrome (Chapter 193.4 ), localized pain syndromes, low back pain, and chronic sportsrelated pain syndromes (e.g., Osgood-Schlatter disease). Table 193.2

Common Musculoskeletal Pain Syndromes in Children by Anatomic Region ANATOMIC REGION Shoulder Elbow

Arm Pelvis and hip Knee

Leg

Foot

Spine

Generalized

PAIN SYNDROMES Impingement syndrome “Little League elbow” Avulsion fractures Osteochondritis dissecans Localized hypermobility syndrome Complex regional pain syndrome Avulsion injuries Legg-Calvé-Perthes syndrome Osteochondritis dissecans Osgood-Schlatter disease Sinding-Larsen syndrome Growing pains Complex regional pain syndrome Localized hypermobility syndrome Plantar fasciitis Tarsal coalition Stress fractures Musculoskeletal strain Spondylolisthesis Spondylolysis Hypermobility syndrome Juvenile fibromyalgia Generalized pain syndrome

Tennis elbow Panner disease

Slipped capital femoral epiphysis Congenital hip dysplasia Patellofemoral syndrome Malalignment syndromes Shin splints Stress fractures Compartment syndromes Achilles tendonitis Juvenile bunion Scoliosis Scheuermann disease (kyphosis) Low back pain

Adapted from Anthony KK, Schanberg LE: Assessment and management of pain syndromes and arthritis pain in children and adolescents, Rheum Dis Clin North Am 33:625–660, 2007 (Box 1).

Treatment

The primary goal of treatment for pediatric musculoskeletal pain syndromes is to improve function rather than relieve pain, and these 2 desirable outcomes may not occur simultaneously. Indeed, it is common for children with musculoskeletal pain syndromes to continue complaining of pain even as they resume normal function (e.g., increased school attendance and participation in extracurricular activities). For all children and adolescents with pediatric musculoskeletal pain syndromes, regular school attendance is crucial, because this is a hallmark of normal functioning in this age-group. The dual nature of treatment, targeting both function and pain, needs to be clearly explained to children and their families to outline better the goals by which treatment success will be measured. Indeed, children and families need to be supported in disengaging from the sole pursuit of pain relief and embracing broader treatment goals of improved functioning. Recommended treatment modalities typically include physical and/or occupational therapy, pharmacologic interventions, and cognitive-behavioral and/or other psychotherapeutic interventions. The overarching goal of physical therapy is to improve children's physical function and should emphasize participation in aggressive but graduated aerobic exercise. Pharmacologic interventions should be used judiciously. Low-dose tricyclic antidepressants (amitriptyline, 10-50 mg orally 30 min before bedtime) are indicated for treatment of sleep disturbance; selective serotonin reuptake inhibitors (sertraline, 10-20 mg daily) may prove useful in treating symptoms of depression and anxiety if present. Referral for psychological evaluation is warranted if these symptoms do not resolve with initial treatment efforts or if suicidal ideation is present. Cognitive-behavioral therapy (CBT) and/or other psychotherapeutic interventions are typically designed to teach children and adolescents coping skills for controlling the behavioral, cognitive, and physiologic responses to pain. Specific components often include cognitive restructuring, relaxation, distraction, and problem-solving skills; additional targets of therapy include sleep hygiene and activity scheduling, all with the goal of restoring normal sleep patterns and activities of daily living. Parent education and involvement in the psychological intervention is important to ensure maintenance of progress. More intensive family-based approaches are warranted if barriers to treatment success are identified at the family level. These could include parenting strategies or family dynamics that serve to maintain children's pain complaints, such as overly solicitous responses to the child's pain and maladaptive models for pain coping.

Complications and Prognosis Musculoskeletal pain syndromes can negatively affect the child's development and future role functioning. Worsening pain and the associated symptoms of depression and anxiety can lead to substantial school absences, peer isolation, and developmental delays later in adolescence and early adulthood. Specifically, adolescents with musculoskeletal pain syndromes may fail to achieve the level of autonomy and independence necessary for age-appropriate activities, such as attending college, living away from home, and maintaining a job. Fortunately, not all children and adolescents with musculoskeletal pain syndromes experience this degree of impairment, but many children experience pain that persists for 1 yr or more. Factors that contribute to the persistence of pain are increasingly understood and include female gender, pubertal stage at pain onset, older age of pain onset, increased psychological distress associated with the pain, joint hypermobility, and greater functional impairment. The likelihood of positive health outcomes is increased with multidisciplinary treatment.

193.1

Growing Pains Kelly K. Anthony, Laura E. Schanberg

More appropriately termed benign nocturnal pains of childhood , growing pains affect 10–20% of children, with peak incidence between age 4 and 12 yr. Pain does not occur during periods of rapid growth or at growth sites. The most common cause of recurrent musculoskeletal pain in children, growing pains are intermittent and bilateral, predominantly affecting the anterior thigh, shin, and calf, but not joints. Occasionally, bilateral upper extremity pain may be associated with leg pain; isolated upper extremity pain does not occur. Children typically describe cramping or aching that occurs in the late afternoon or evening. Pain may wake the child from sleep and may last a few minutes to hours, but resolves quickly with massage or analgesics; pain is never present the

following morning (Table 193.3 ). Pain often follows a day with exercise or other physical activities. Physical findings are normal, and gait is not impaired. Table 193.3

Inclusion and Exclusion Criteria for Growing Pains Including Features of Restless Leg Syndromes (RLS) Nature of pain

INCLUSIONS Intermittent; some pain-free days and nights, deep aching, cramping Bilateral

EXCLUSIONS Persistent; increasing intensity, pain during the day

Unilateral Unilateral or bilateral Location Anterior thigh, calf, Articular, back, or groin pain of pain posterior knee—in muscles not the joints Onset of Late afternoon or Pain still present next morning pain evening

Physical findings

Normal

Laboratory Normal findings

RLS FEATURES Urge to move legs often accompanied by unpleasant sensations in legs, but may not be painful

Urge to move and discomfort throughout leg

Worse later in day or night but also present at periods of rest or inactivity throughout the day

Swelling, erythema, tenderness; local trauma or infection; reduced joint range of motion; limping, fever, weight loss, mass Objective evidence of abnormalities; increased erythrocyte sedimentation rate or C-reactive protein; abnormal complete blood count, radiography, bone scan, or MRI

Adapted from Evans AM, Scutter SD: Prevalence of “growing pains” in young children, J Pediatr 145:255–258, 2004; and Walters AS, Gabelia D, Frauscher B: Restless legs syndrome (WillisEkbom disease) and growing pains: are they the same thing? A side-by-side comparison of the diagnostic criteria for both and recommendations for future research, Sleep Med 14:1247–1252, 2013.

Although growing pains are generally considered a benign, time-limited condition, evidence suggests they represent a pain amplification syndrome . Indeed, growing pains persist in a significant percentage of children, with some children developing other pain syndromes such as abdominal pain and headaches. Growing pains are more likely to persist in children with a parent who has a history of a pain syndrome and in children who have lower pain thresholds not just at the site of pain, but throughout their body. Disordered somatosensory testing, lower bone strength, and lower calcium intake have also been shown to be present in children with growing pains. Treatment should also focus on reassurance, education, and healthy sleep

hygiene. Massage during the episode is very effective, and physical therapy and muscle stretching may also be important parts of treatment. NSAIDs agents may be useful for frequent episodes. CBT may be indicated if the pain persists. Restless legs syndrome (RLS , Willis-Ekbom disease), seen more frequently among adolescents and adults, is a sensorimotor disturbance that may be confused with growing pains (see Chapter 31 ). Often familial, RLS is a difficult-to-control urge to move the leg that is exacerbated during rest and at night and is relieved by movement (Table 193.3 ). There is significant overlap in the diagnostic features of growing pains and RLS, leading to diagnostic confusion. Moreover, these conditions can be comorbid, and there is a high incidence of RLS in the parents of children with growing pains. RLS appears to be best distinguished from growing pains by the urge to move the legs, associated uncomfortable leg sensations that may not be described as painful; the worsening with periods of rest; and relief through movement. Iron supplementation may benefit pediatric patients with RLS.

Bibliography Friedland O, Haskes PJ, Jaber L, et al. Decreased bone speed of sound in children with growing pains measured by quantitative ultrasound. J Rheumatol . 2005;32:1354–1357. Hashkes PJ, Friedland O, Jaber L, et al. Decreased pain threshold in children with growing pains. J Rheumatol . 2004;31:610–613. Lowe RM, Hashkes PJ. Growing pains: a noninflammatory pain syndrome of early childhood. Nat Clin Pract Rheumatol . 2008;4:542. Pathiran S, Champion D, Jaaniste T, et al. Somatosensory test responses in children with growing pains. J Pain Res . 2011;4:393–400. Walters AS, Gabelia D, Frauscher B. Restless legs syndrome (Willis-Ekbom disease) and growing pains: are they the same thing? A side-by-side comparison of the diagnostic criteria for both and recommendations for future research. Sleep Med . 2013;14:1247–1252.

193.2

Small Fiber Polyneuropathy Kelly K. Anthony, Laura E. Schanberg

Many patients with juvenile-onset widespread pain syndromes, as well as patients with pediatric fibromyalgia (Chapter 193.3 ), complex regional pain syndrome type I (Chapter 193.4 ), and erythromelalgia (Chapter 193.5 ), have evidence of a small fiber polyneuropathy causing dysfunctional or degeneration of small-diameter unmyelinated C fibers and thinly myelinated A delta fibers that mediate nociception and the autonomic nervous system. Fibromyalgia includes chronic widespread pain , defined as ≥3 mo duration of axial pain that is often bilateral and that also affects the upper and lower extremities. In addition, many patients have associated chronic cardiovascular (dizziness, postural orthostasis syndrome) symptoms, as well as chronic abdominal pain and ileus, headaches, fatigue, and erythromelalgia, suggestive of dysautonomia . There are no typical findings on physical examination or standard laboratory tests. The diagnosis of small fiber polyneuropathy requires distal leg immunolabeled skin biopsy to identify epidermal nociceptive fibers and autonomic function testing to examine cardiovagal, adrenergic, and sudomotor small fiber function. Treatment of patients with small fiber polyneuropathy and isolated juvenileonset widespread pain syndrome, or those subsets of patients with small fiber polyneuropathy and fibromyalgia, complex regional pain syndrome, or erythromelalgia, is evolving and has included prednisone or intravenous immune globulin.

Bibliography Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a smallfiber neuropathy? Ann Neurol . 2009;65:629–638.

Oaklander AL, Herzog ZD, Downs HM, et al. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain . 2013;154:231023–231026. Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained juvenile-onset, widespread pain syndromes. Pediatrics . 2013;131(4):e1091–e1100. Paticoff J, Valovska A, Nedeljkovic SS, et al. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Pain Med . 2007;104:438–441.

193.3

Fibromyalgia Kelly K. Anthony, Laura E. Schanberg

Juvenile primary fibromyalgia syndrome (JPFS) is a common pediatric musculoskeletal pain syndrome. Approximately 25–40% of children with chronic pain syndromes can be diagnosed with JPFS. Although specific diagnostic criteria for JPFS have not been determined, the adult criteria set forth by the American College of Rheumatology (ACR) in 2010 have been shown to have a high degree of sensitivity and specificity in the diagnosis of JPFS (Fig. 193.1 and Table 193.4 ). Previous studies describing children and adolescents with JPFS noted diffuse, multifocal, waxing and waning, and at times migratory musculoskeletal pain in at least 3 areas of the body persisting for at least 3 mo in the absence of an underlying condition. Results of laboratory tests were normal, and physical examination revealed at least 5 well-defined tender points (Fig. 193.2 ). There is considerable overlap among symptoms associated with JPFS and complaints associated with other functional disorders (e.g., irritable bowel

disease, migraines, temporomandibular joint disorder, premenstrual syndrome, mood and anxiety disorders, chronic fatigue syndrome), suggesting that these disorders may be part of a larger spectrum of related syndromes.

FIG. 193.1 Fibromyalgia questionnaire. American College of Rheumatology criteria. IBS, Irritable bowel syndrome. (Adapted from Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 62:600–610, 2010.)

Table 193.4

American College of Rheumatology Fibromyalgia Diagnostic Criteria

The following 3 conditions must be met: 1. Widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3-6 and SS scale score ≥9. 2. Symptoms have been present at a similar level for at least 3 mo. 3. The patient does not have a disorder that would otherwise explain the pain.

Ascertainment of WPI The WPI is the number of areas in which a patient has had pain over the last week. The score will be between 0 and 19: left shoulder girdle left, right shoulder girdle, left upper arm, right upper arm, left lower arm, right lower arm, left hip (buttock, trochanter), right hip (buttock, trochanter), left upper leg, right upper leg, left lower leg, right lower leg, left jaw, right jaw, chest, abdomen, upper back, lower back, and neck.

Ascertainment of Ss Scale Score The SS scale score is the sum of the severity of 3 symptoms (fatigue, waking unrefreshed, and cognitive symptoms) plus the severity of somatic symptoms in general. The final score is between 0 and 12. • For each of the 3 symptoms, the level of severity over the past week is rated using the following scale: 0 = No problem 1 = Slight or mild problems, generally mild or intermittent 2 = Moderate, considerable problems, often present and/or at a moderate level 3 = Severe: pervasive, continuous, life-disturbing problems • Considering somatic symptoms in general, the following scale is used to indicated the number of symptoms: 0 = No symptoms 1 = Few symptoms 2 = Moderate number of symptoms 3 = Great deal of symptoms • Somatic symptoms that can be considered include muscle pain, irritable bowel syndrome, fatigue, thinking problems, muscle weakness, headache, abdominal pain, numbness/tingling, dizziness, insomnia, depression,

constipation, pain in the upper abdomen, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud phenomenon, hives/welts, ringing in ears, vomiting, heartburn, oral ulcers, loss of/change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulties, easy bruising, hair loss, frequent urination, painful urination, and bladder spasms. Adapted from Wolfe F, Clauw DJ, Fitzcharles MA, et al: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity, Arthritis Care Res 62: 600–610, 2010.

FIG. 193.2 Fibromyalgia tender points.

Although the precise cause of JPFS is unknown, there is an emerging understanding that the development and maintenance of JPFS are related both to biologic and psychological factors. JPFS is an abnormality of central pain processing characterized by disordered sleep physiology, enhanced pain perception with abnormal levels of substance P in cerebrospinal fluid, disordered mood, and dysregulation of hypothalamic-pituitary-adrenal and other neuroendocrine axes, resulting in lower tender-point pain thresholds and increased pain sensitivity. Evolving evidence also suggests that up to 50% of patients with fibromyalgia may have a small fiber polyneuropathy (see Chapter

193.2 ), and that patients with JPFS may also have chronotropic incompetence (inability to increase heart rate commensurate with activity) and autonomic dysfunction at diagnosis. Children and adolescents with fibromyalgia often find themselves in a vicious cycle of pain, where symptoms build on one another and contribute to the onset and maintenance of new symptoms (Fig. 193.3 ).

FIG. 193.3 Juvenile primary fibromyalgia syndrome. Vicious cycle promoting symptom maintenance. (Adapted from Anthony KK, Schanberg LE: Juvenile primary fibromyalgia syndrome, Curr Rheumatol Rep 3:167–171, 2001, Fig. 1.)

JPFS has a chronic course that can detrimentally affect child health and development. Adolescents with JPFS who do not receive treatment or who are inadequately treated may withdraw from school and the social milieu, complicating their transition to adulthood. Treatment of JPFS generally follows consensus statements of the American Pain Society. The major goals are to restore function and alleviate pain, as well as improve comorbid mood and sleep disorders. Treatment strategies include parent/child education, pharmacologic interventions, exercise-based interventions, and psychological interventions. Graduated aerobic exercise is the recommended exercise-based intervention, whereas psychological interventions should include training in pain coping skills, stress management skills, emotional support, and sleep hygiene. CBT is particularly effective in reducing symptoms of depression in children and adolescents with JPFS and also helps to reduce functional disability. Drug therapies , although largely unsuccessful in isolation, may include tricyclic antidepressants (amitriptyline, 10-50 mg orally 30 min before bedtime),

selective serotonin reuptake inhibitors (sertraline, 10-20 mg daily), and anticonvulsants. Pregabalin and duloxetine hydrochloride are approved by the U.S. Food and Drug Administration (FDA) for treatment of fibromyalgia in adults (≥18 yr of age). The safety and efficacy of pregabalin in adolescents age 12-17 yr was recently demonstrated in a 15 wk randomized controlled trial and 6 mo open-label study. Safety was consistent with that shown in adults, with preliminary evidence for improvement in secondary pain outcomes, impressions of change, and better sleep. Duloxetine has not been studied in children with JPFS. Muscle relaxants are generally not used in children because they affect school performance.

Bibliography American Pain Society. Guidelines for the management of fibromyalgia syndrome pain in adults and children . American Pain Society: Glenview IL; 2005. Arnold LM, Schikler KN, Bateman L, et al. Safety and efficacy of pregabalin in adolescents with fibromyalgia: a randomized, double-blind, placebo-controlled trial and a 6-month openlabel extension study. Pediatr Rheumatol . 2016;14:46–57. Clauw DJ. Fibromyalgia: a clinical review. JAMA . 2014;311:1547–1554. Derry S, Cording M, Wiffen PJ, et al. Pregabalin for pain in fibromyalgia in adults (review). Cochrane Database Syst Rev . 2016;(9) [CD011790]. Kashikar-Zuck S, Parkins IS, Graham TB, et al. Anxiety, mood, and behavioral disorders among pediatric patients with juvenile fibromyalgia syndrome. Clin J Pain . 2008;24:620– 626. Kashikar-Zuck S, Ting TV, Arnold LM, et al. Cognitivebehavioral therapy for the treatment of juvenile fibromyalgia: a multisite, single-blind, randomized, controlled clinical trial. Arthritis Rheum . 2012;64:297–305. Maia MM, Gualano B, Sa-Pinto AL, et al. Juvenile

fibromyalgia syndrome: blunted heart rate response and cardiac autonomic dysfunction. Semin Arthritis Rheum . 2016;46:338–343. Oaklander AL, Herzog ZD, Downs HM, et al. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain . 2013;154(11):2310–2316. Swain NF, Kashikar-Zuck S, Graham TB, et al. Tender point assessment in juvenile primary fibromyalgia syndrome. Arthritis Rheum . 2005;53:785–787. Ting TV, Barnett K, Lynch-Jordan A, et al. 2010 American College of Rheumatology Adult Fibromyalgia Criteria for use in an adolescent female population with juvenile fibromyalgia. J Pediatr . 2016;169:181–187.

193.4

Complex Regional Pain Syndrome Kelly K. Anthony, Laura E. Schanberg

Complex regional pain syndrome (CRPS) is characterized by ongoing burning limb pain subsequent to an injury, immobilization, or another noxious event affecting the extremity. CRPS1 , formerly called reflex sympathetic dystrophy , has no evidence of nerve injury, whereas CRPS2 , formerly called causalgia , follows a prior nerve injury. Key associated features are pain disproportionate to the inciting event, persisting allodynia (a heightened pain response to normally nonnoxious stimuli), hyperalgesia (exaggerated pain reactivity to noxious stimuli), swelling of distal extremities, and indicators of autonomic dysfunction (cyanosis, mottling, hyperhidrosis). There are currently no gold standard diagnostic criteria for pediatric CPRS;

although in adults, the Budapest criteria have been shown to be more sensitive and specific than previous diagnostic guidelines (Table 193.5 ). The diagnosis requires an initiating noxious event or immobilization; continued pain, allodynia, and hyperalgesia out of proportion to the inciting event; evidence of edema, skin blood flow abnormalities, or sudomotor activity; and exclusion of other disorders. Associated features include atrophy of hair or nails; altered hair growth; loss of joint mobility; weakness, tremor, dystonia; and sympathetically maintained pain.

Table 193.5

Budapest Clinical Diagnostic Criteria for Complex Regional Pain Syndrome All the following criteria must be met: 1. Continuing pain, which is disproportionate to any inciting event 2. Must report at least 1 symptom in each of the following 4 categories: • Sensory : Hyperesthesia and/or allodynia • Vasomotor : Temperature asymmetry, skin color changes, and/or skin color asymmetry • Sudomotor/edema : Edema, sweating changes, and/or sweating asymmetry • Motor/trophic : Decreased range of motion, motor dysfunction (tremor, weakness, dystonia) and/or trophic changes (hair, nail, skin) 3. Must display at least 1 sign at time of evaluation in ≥2 of the following 4 categories: • Sensory : Evidence of hyperesthesia (to pin prick) and/or allodynia (to light touch, temperature sensation, deep somatic pressure, and/or joint movement) • Vasomotor : Evidence of temperature asymmetry (>1°C), skin color changes, and/or skin color asymmetry • Sudomotor/edema : Edema, sweating changes, and/or sweating asymmetry • Motor/trophic : Decreased range of motion, motor dysfunction (tremor, weakness, dystonia) and/or trophic changes (hair, nail, skin) 4. There is no other diagnosis that better explains the signs and symptoms.

Adapted from Harden RN, Bruel S, Stanton-Hicks, et al: Proposed new diagnostic criteria for complex regional pain syndrome, Pain Med 8:326–331, 2007. Although the majority of pediatric patients with CRPS present with a history of minor trauma or repeated stress injury (e.g., caused by competitive sports), a sizable proportion are unable to identify a precipitating event. Usual age of onset is between 8 and 16 yr, and girls outnumber boys with the disease by as much as 6 : 1. Childhood CRPS differs from the adult form in that lower extremities, rather than upper extremities, are most often affected. The incidence of CRPS in children is unknown, largely because it is often undiagnosed or diagnosed late, with the diagnosis frequently delayed by almost 1 yr. Left untreated, CRPS can have severe consequences for children, including bone demineralization, muscle wasting, and joint contractures. An evidence-based approach to the treatment of CRPS continues to suggest a multistage approach. Aggressive physical therapy (PT) should be initiated as soon as the diagnosis is made and CBT added as needed. PT is recommended 34 times/wk, and children may need analgesic premedication at the onset, particularly before PT sessions. PT is initially limited to desensitization and then moves to weight-bearing, range-of-motion, and other functional activities. CBT used as an adjunctive therapy targets psychosocial obstacles to fully participating in PT and provides pain-coping skills training. Sympathetic and epidural nerve blocks should be attempted only under the auspices of a pediatric pain specialist. The goal of both pharmacologic and adjunctive treatments for CRPS is to provide sufficient pain relief to allow the child to participate in aggressive physical rehabilitation. If CRPS is identified and treated early, the majority of children and adolescents can be treated successfully with low-dose amitriptyline (10-50 mg orally 30 min before bedtime), aggressive PT, and CBT interventions. Opioids and anticonvulsants such as gabapentin can also be helpful. Notably, multiple studies have shown that noninvasive treatments, particularly PT and CBT, are at least as efficacious as nerve blocks in helping children with CRPS achieve resolution of their symptoms. There is growing evidence that some patients with CRPS I have a small fiber polyneuropathy (see Chapter 193.2 ).

Bibliography

Barrett MJ, Barnett PLJ. Complex regional pain type 1. Pediatr Emerg Care . 2016;32(3):185–188. Berde C, Lebel A. Complex regional pain syndromes in children and adolescents. Anesthesiology . 2005;102(2):252– 255. Borucki AN, Greco CD. An update on complex regional pain syndromes in children and adolescents. Curr Opin Pediatr . 2015;27:448–452. Goebel A, Baranowski A, Maurer K, et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome. Ann Intern Med . 2010;152:152–158. Goh EL, Chidambaram S. Complex regional pain syndrome: a recent update. Burns Trauma . 2017;5:2. Harden RN, Oaklander AL, Burton AW, et al. Complex regional pain syndrome: practical diagnostic and treatment guidelines. Pain Med . 2013;14:180–229. Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a smallfiber neuropathy. Ann Neurol . 2009;65:629–638. Stanton-Hicks M. Plasticity of complex regional pain syndrome (CRPS) in children. Pain Med . 2010;11:1216–1223. Weissmann R, Uziel Y. Pediatric complex regional pain syndrome: a review. Pediatr Rheumatol . 2016;14:29–39. Wilder RT. Management of pediatric patients with complex regional pain syndrome. Clin J Pain . 2006;22:443–448.

193.5

Erythromelalgia Laura E. Schanberg

Children with erythromelalgia experience episodes of intense pain, erythema, and heat in their hands and feet (Fig. 193.4 ). Less frequently involved are the face, ears, or knees. Symptoms may be triggered by exercise and exposure to heat, lasting for hours and occasionally for days. It is more common in girls and in the teenage years, and diagnosis is often delayed for years. Although most cases are sporadic, an autosomal dominant hereditary form results from mutations of the SCN9A gene on chromosome 2q31-32, causing a painful channelopathy. Secondary erythromelalgia is associated with an array of disorders, including myeloproliferative diseases, peripheral neuropathy, frostbite, hypertension, and rheumatic disease. Treatment includes avoidance of heat exposure and other precipitating situations and utilization of cooling techniques that do not cause tissue damage during attacks. NSAIDs, narcotics, anesthetic agents (lidocaine patch), anticonvulsants (oxcarbazepine, carbamazepine, gabapentin), and antidepressants, as well as biofeedback and hypnosis, may help manage pain. Drugs acting on the vascular system (aspirin, sodium nitroprusside, magnesium, misoprostol) may also be somewhat effective. However, a reliably efficacious treatment is not available, resulting in substantial negative impact on physical and mental health.

FIG. 193.4 Erythromelalgia. Typical redness and edema of the foot. (From Pfund Z, Stankovics J, Decsi T, Illes Z: Childhood steroid-responsive acute erythromelalgia with axonal neuropathy of large myelinated fibers: a dysimmune neuropathy? Neuromuscul Disord 19:49–52, 2009, Fig 1A, p 50.)

There is growing evidence that some patients with erythromelalgia have a small fiber polyneuropathy (see Chapter 193.2 ).

Bibliography Cook-Norris RH, Tollefson MM, Cruz-Inigo AE, et al. Pediatric erythromelalgia: a retrospective review of 32 cases evaluated at Mayo Clinic over a 37-year period. J Am Acad Dermatol . 2011;66:416–423. Dabby R. Pain disorders and erythromelalgia caused by voltagegated sodium channel mutations. Curr Neurol Neurosci Rep . 2012;12:76–83. Davis MDP, Rooke T. Erythromelalgia. Curr Treat Options Cardiovasc Med . 2006;8:153–165. Huh S, Jung K, Eun LY, et al. Erythromelalgia with a linear pattern in a 12-year-old girl. Pediatr Int . 2015;57:706–797. Paticoff J, Valovska A, Nedeljkovic SS, et al. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Pain Med . 2007;104:438–441. Pfund Z, Stankovics J, Decsi T, et al. Childhood steroidresponsive acute erythromelalgia with axonal neuropathy of large myelinated fibers: a dysimmune neuropathy? Neuromuscul Disord . 2009;19:49–52. Thomas J, Maramattom BV, Kuruvilla PM, Varghese J. Subcutaneous panniculitis like T cell lymphoma associated with erythromelalgia. J Postgrad Med . 2014;60(3):335–337. Tang Z, Chen Z, Tang B, Jiang H. Primary erythromelalgia: a review. Orphanet J Rare Dis . 2017;10:127.

Bibliography Anthony KK, Schanberg LE. Assessment and management of pain syndromes and arthritis pain in children and adolescents. Rheum Dis Clin North Am . 2007;33:625–660. Clinch J, Eccleston C. Chronic musculoskeletal pain in children:

assessment and management. Rheumatology (Oxford) . 2009;48:466–474. Connelly MA, Schanberg LE. Evaluating and managing pediatric musculoskeletal pain in primary care. Walco G, Goldschneider K, Berde A. Pain in children: a practical guide for primary care . Humana Press: New York; 2008. Liossi C, Howard RF. Pediatric chronic pain: biopsychosocial assessment and formulation. Pediatrics . 2016;138(5):e20160331. Scharff L, Langan N, Rotter N, et al. Psychological, behavioral, and family characteristics of pediatric patients with chronic pain: a 1-year retrospective study and cluster analysis. Clin J Pain . 2005;21:432–438. Stahl M, Kautiainen H, El-Metwally A, et al. Non-specific neck pain in schoolchildren: prognosis and risk factors for occurrence and persistence—a 4-year follow-up study. Pain . 2008;137:316–322. Tobias JH, Deere K, Palmer S, et al. Joint hypermobility is a risk factor for musculoskeletal pain during adolescence. Arthritis Rheum . 2013;65:1107–1115.

CHAPTER 194

Miscellaneous Conditions Associated With Arthritis Angela Byun Robinson, C. Egla Rabinovich

Relapsing Polychondritis Relapsing polychondritis (RP) is a rare condition characterized by episodic chondritis causing cartilage destruction and deformation of the ears (sparing the earlobes), nose, larynx, and tracheobronchial tree. Antibodies to matrillin-1 and collagen (type II, IX and XI) are present in approximately 60% of patients with RP, suggesting an autoimmune pathogenesis. Patients may experience arthritis, uveitis, and hearing loss resulting from inflammation near the auditory and vestibular nerves. Children may initially relate episodes of intense erythema over the outer ears. Other dermatologic manifestations may include erythema nodosum, maculopapular rash, and purpura. Cardiac involvement, including conduction defects and coronary vasculitis, has been reported. Severe, progressive, and potentially fatal disease resulting from destruction of the tracheobronchial tree and airway obstruction is unusual in childhood. Diagnostic criteria established for adults are useful guidelines for evaluating children with suggestive symptoms (Table 194.1 ). The clinical course of RP is variable; flares of disease are often associated with elevations of acute-phase reactants and may remit spontaneously. Although seen more often in the adult population, RP may coexist with other rheumatic disease (e.g., systemic lupus erythematosus, Sjögren syndrome, Henoch-Schönlein purpura) in up to 30% of patients. The differential diagnosis includes ANCA-associated vasculitis (granulomatosis with polyangiitis) (see Chapter 192.4 ) and Cogan syndrome , which is characterized by auditory nerve inflammation and keratitis but not chondritis. Many children respond to nonsteroidal antiinflammatory drugs, but some require corticosteroids or other immunosuppressive agents (azathioprine, methotrexate,

hydroxychloroquine, colchicine, cyclophosphamide, cyclosporine, and anti– tumor necrosis factor [TNF] agents), as reported in small series and case reports. Table 194.1 Suggested Criteria for Relapsing Polychondritis* MAJOR Typical inflammatory episodes of ear cartilage Typical inflammatory episodes of nose cartilage Typical inflammatory episodes of laryngotracheal cartilage MINOR Eye inflammation (conjunctivitis, keratitis, episcleritis, uveitis) Hearing loss Vestibular dysfunction Seronegative inflammatory arthritis *

The diagnosis is established by the presence of 2 major or 1 major and 2 minor criteria. Histologic examination of affected cartilage is required when the presentation is atypical.

Data from Michet CJ Jr, McKenna CH, Luthra HS, et al: Relapsing polychondritis: survival and predictive role of early disease manifestations, Ann Intern Med 104:74-78, 1986.

Mucha-Habermann Disease/Pityriasis Lichenoides Et Varioliformis Acuta Pityriasis lichenoides et varioliformis acuta (PLEVA ) is a benign, self-limited cutaneous vasculitis characterized by episodes of macules, papules, and papulovesicular lesions that can develop central ulceration, necrosis, and crusting (Fig. 194.1 ). Different stages of development are usually seen at once. PLEVA fulminans or febrile ulceronecrotic Mucha-Habermann disease (FUMHD ) is the severe, life threatening form of PLEVA. Large, coalescing, ulceronecrotic lesions are seen, accompanied by high fever and elevated erythrocyte sedimentation rate (ESR). Systemic manifestations can include interstitial pneumonitis, abdominal pain, malabsorption, arthritis, and neurologic manifestations. PLEVA has a male predominance and occurs more frequently in

childhood. The diagnosis is confirmed by biopsy of skin lesions, which reveals perivascular and intramural lymphocytic inflammation affecting capillaries and venules in the upper dermis that may lead to keratinocyte necrosis. When disease is severe, corticosteroids have been used with questionable effect, and methotrexate has been reported to induce rapid remission in resistant cases. Cyclosporine and anti-TNF agents have also been efficacious in case reports.

FIG. 194.1 Pityriasis lichenoides et varioliformis acuta (PLEVA). Symmetric, oval and round, reddish brown macular, popular, necrotic, and crusted lesions on chest of 9 yr old boy. (From Paller AS, Mancini AJ, editors: Hurwitz clinical pediatric dermatology, ed 5, Philadelphia, 2016, Elsevier, Fig 4-33, p 87.)

Sweet Syndrome Sweet syndrome, or acute febrile neutrophilic dermatosis , is a rare entity in children. It is characterized by fever, elevated neutrophil count, and raised, tender erythematous plaques and nodules over the face, extremities, and trunk. Skin biopsy reveals neutrophilic perivascular infiltration in the upper dermis. Female predominance is seen in the adult population, whereas gender distribution is equal in children. Established criteria are useful for diagnosis (Table 194.2 ). Children can also have arthritis, sterile osteomyelitis, myositis, and other extracutaneous manifestations. Sweet syndrome may be idiopathic or secondary to malignancy (particularly acute myelogenous leukemia), drugs (granulocyte colony-stimulating factor, tretinoin or trimethoprimsulfamethoxazole), or rheumatic diseases (Behçet disease, antiphospholipid

antibody syndrome, systemic lupus erythematosus). The condition usually responds to treatment with corticosteroids, treatment of underlying disease, or removal of associated medication.

Table 194.2

Diagnostic Criteria for Classic Sweet Syndrome* Major Criteria Abrupt onset of painful erythematous plaques or nodules Histopathologic evidence of dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis

Minor Criteria Pyrexia >38°C Association with underlying hematologic or visceral malignancy, inflammatory disease or pregnancy, or preceded by an upper respiratory or gastrointestinal infection or vaccination Excellent response to systemic corticosteroids or potassium iodide Abnormal laboratory values at presentation (3 of 4): Erythrocyte sedimentation rate >20 mm/hr Positive C-reactive protein test result >8,000 leukocytes/mm3 >70% neutrophils/mm3

* The diagnosis is established by the presence of 2 major criteria plus 2 of the 4

minor criteria. Adapted from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazoleassociated acute febrile neutrophilic dermatosis: case report and review of drug induced Sweet's syndrome. J Am Acad Dermatol 34:918–923, 1996.

Hypertrophic Osteoarthropathy Children with chronic disease, especially pulmonary or cardiac disease, can demonstrate clubbing of the terminal phalanges and have associated periosteal reaction and arthritis. These findings characterize the classic presentation of hypertrophic osteoarthropathy. HOA can be primary (idiopathic) or secondary. Although rare, secondary HOA is more common in children and is seen in those with chronic pulmonary disease (cystic fibrosis), congenital heart disease, gastrointestinal disease (malabsorption syndromes, biliary atresia, inflammatory bowel disease), and malignancy (nasopharyngeal sarcoma, osteosarcoma, Hodgkin disease). It may precede diagnosis of cardiopulmonary disease or malignancy. The pathogenesis of secondary HOA is unknown; symptoms often improve if the underlying condition is treated successfully. HOA-related pain can be disabling; in adults, management with bisphosphonates has been reported. Evaluation of children presenting with HOA should include a chest radiograph to evaluate for pulmonary disease or intrathoracic mass. Autosomal recessive mutations in prostaglandin pathway genes have recently been described in primary HOA, also described as pachydermoperiostosis .

Plant Thorn Synovitis A diagnosis of plant thorn synovitis should be considered in children with monoarticular arthritis nonresponsive to antiinflammatory therapy. Acute or chronic arthritis can occur after a plant thorn or other foreign object penetrates a joint. Unlike septic arthritis, children with plant thorn synovitis are usually afebrile. The most common organism seen with plant thorn synovitis is Pantoea agglomerans , although cultures are often negative. The initial injury may be unknown or forgotten, making diagnosis difficult. Ultrasound or MRI can be useful in identifying the foreign body. Removal of the foreign body using arthroscopy, followed by an antibiotic course, is the accepted therapy.

Pigmented Villonodular Synovitis Proliferation of synovial tissue is seen in pigmented villonodular synovitis (PVNS). This proliferation is localized or diffuse and can affect the joint, tendon sheath, or bursa. Macrophages and multinucleated giant cells with brownish

hemosiderin are present histologically. It is unclear if the etiology of PVNS is inflammatory or neoplastic in nature. Although findings are not pathognomonic, MRI with contrast is a useful diagnostic tool by which PVNS can be seen as a mass or bone erosion. Brown or bloody synovial fluid is seen with arthrocentesis, but the diagnosis is made by tissue biopsy. Surgical removal of the affected tissue is the therapeutic modality, and with diffuse disease, a total synovectomy is recommended.

Bibliography Belot A, Duquesne A, Job-Deslandre C, et al. Pediatric-onset relapsing polychondritis: case series and systematic review. J Pediatr . 2010;156:484–489. Emmungil H, Aydin SZ. Relapsing polychondritis. Eur J Rheumatol . 2015;2:155–159. Fernandes NF, Rozdeba PJ, Schwartz RA, et al. Pityriasis lichenoides et varioliformis acuta: a disease spectrum. Int J Dermatol . 2010;49:257–261. Giancane G, Diggle CP, Legger EG, et al. Primary hypertrophic osteoarthropathy: an update on patient features and treatment. J Rheumatol . 2015;42:2211–2214. Jayakar BA, Abelson AG, Yao Q. Treatment of hypertrophic osteoparthropathy with zoledronic acid: case report and review of the literature. Semin Arthritis Rheum . 2011;41:291–296. Duerinckx JF. Case report: subacute synovitis of the knee after a rose thorn injury: unusual clinical picture. Clin Orthop Relat Res . 2008;466:3138–3142. Patel AM, Brown AG, Galambos C, Hirsch R. Pediatric pigmented villonodular synovitis mimicking a septic hip. J Clin Rheumatol . 2010;16:71–73. Uihlein LC, Brandling-Bennett HA, Lio PA, et al. Sweet syndrome in children. Pediatr Dermatol . 2012;29:38–44. Villarreal-Villarreal CD, Ocampo-Candiani J, Villarreal-

Martinez A. Sweet syndrome: a review and update. Actas Dermosifiliogr . 2016;107:369–378.

PA R T X V I

Infectious Diseases OUTLINE Section 1 General Considerations Section 2 Preventive Measures Section 3 Antibiotic Therapy Section 4 Gram-Positive Bacterial Infections Section 5 Gram-Negative Bacterial Infections Section 6 Anaerobic Bacterial Infections Section 7 Mycobacterial Infections Section 8 Spirochetal Infections Section 9 Mycoplasmal Infections Section 10 Chlamydial Infections Section 11 Rickettsial Infections Section 12 Fungal Infections Section 13 Viral Infections Section 14 Antiparasitic Therapy Section 15 Protozoan Diseases Section 16 Helminthic Diseases

SECTION 1

General Considerations OUTLINE Chapter 195 Diagnostic Microbiology Chapter 196 The Microbiome and Pediatric Health

CHAPTER 195

Diagnostic Microbiology Carey-Ann D. Burnham, Gregory A. Storch

Laboratory evidence to support the diagnosis of an infectious disease may be based on one or more of the following: direct examination of specimens using microscopic or antigen detection techniques, isolation of microorganisms in culture, serologic testing, host gene expression patterns, or molecular detection of an organism, resistance determinant, or virulence factor. Some additional roles of the clinical microbiology laboratory include performing antimicrobial susceptibility testing and supporting hospital infection prevention in the detection and characterization of pathogens associated with nosocomial infections.

Specimen Collection The success of a diagnostic microbiology assay, that is, detection of a pathogen if present, is directly linked to specimen collection techniques. In general, this means collecting the correct specimen type for the disease or condition in question and promptly transporting the specimen to the laboratory for analysis. Although swab specimens may be necessary for some conditions, in general a swab is a suboptimal specimen. A swab is only able to hold a very small amount of specimen (approximately 100 µL), and, using a traditional swab, only a small fraction of organisms that are absorbed onto a swab will be released back into the culture. Flocked swabs coupled with transport medium improve organism recovery. However, when possible, fluid or tissue should be submitted to the laboratory for analysis. If anaerobic infection is suspected, the sample should be transported in appropriate medium to preserve viability of anaerobic bacteria. For the recovery of some organism types, such as viruses and Neisseria gonorrhoeae , specific transport media may be required. Considerations specific

to the collection of blood cultures are addressed in the blood culture section.

Laboratory Diagnosis of Bacterial and Fungal Infections Although the scope and availability of molecular methods for detection of bacterial and fungal pathogens have increased rapidly, the diagnosis of many of these infections depends on microscopic detection of organisms or cultivation of organisms on culture media .

Microscopy The Gram stain is an extremely valuable diagnostic technique to provide rapid and inexpensive information regarding the absence or presence of inflammatory cells and organisms in clinical specimens. For some specimen types, the presence of inflammatory and epithelial cells is used to judge the suitability of a specimen for culture. For example, the presence of >10 epithelial cells per lowpower field in a sputum specimen is highly suggestive of a specimen contaminated with oral secretions. In addition, a preliminary assessment of the etiologic agent can be made based on the morphology (e.g., cocci vs rods) and stain reaction (e.g., gram-positive isolates are purple; gram-negative isolates are red) of the microorganisms. However, a negative Gram stain does not rule out infection, since 104 to 105 microorganisms per milliliter (mL) in the specimen are required for detection by this method. In addition to the Gram stain, many other stains are used in microbiology, both to detect organisms and to help infer their identity (Table 195.1 ). Table 195.1

Stains Used for Microscopic Examination TYPE OF STAIN Gram stain Potassium hydroxide (KOH) Calcofluor

CLINICAL USE Stains bacteria (with differentiation of gram-positive and gram-negative organisms), fungi, leukocytes, and epithelial cells. A 10% solution dissolves cellular and organic debris and facilitates detection of fungal elements in clinical specimens. Nonspecific fluorochrome that binds to cellulose and chitin in fungal cell walls, can be combined

white stain Ziehl-Neelsen and Kinyoun stains

Auraminerhodamine stain Acridine orange stain

Lugol iodine stain Wright and Giemsa stains Trichrome stain Direct fluorescentantibody stain

with 10% KOH to dissolve cellular material. Acid-fast stains, using basic carbolfuchsin, followed by acid-alcohol decolorization and methylene blue counterstaining. Acid-fast organisms (e.g., Mycobacterium ) resist decolorization and stain pink. A weaker decolorizing agent is used for partially acid-fast organisms (e.g., Nocardia, Cryptosporidium, Cyclospora, Isospora ). Acid-fast stain using fluorochromes that bind to mycolic acid in mycobacterial cell walls and resist acid-alcohol decolorization; usually performed directly on clinical specimens. Acid-fast organisms stain orange-yellow against a black background. Fluorescent dye that intercalates into DNA, used to aid in differentiation of organisms from debris during direct specimen examination, and also for detection of organisms that are not visible with Gram stain. Bacteria and fungi stain orange, and background cellular material stains green. Added to wet preparations of fecal specimens for ova and parasites to enhance contrast of the internal structures (nuclei, glycogen vacuoles). Primarily for detecting blood parasites (Plasmodium, Babesia, and Leishmania ), detection of amoeba in preparations of cerebrospinal fluid, and fungi in tissues (yeasts, Histoplasma ) Stains stool specimens for identification of protozoa. Used for direct detection of a variety of organisms in clinical specimens by using specific fluorescein-labeled antibodies (e.g., Pneumocystis jiroveci, many viruses).

Isolation and Identification The approach to isolation of microorganisms in a clinical specimen will vary depending on the body site and pathogen suspected. For body sites that are usually sterile, such as cerebrospinal fluid, nutrient-rich media such as sheep blood agar and chocolate agar are used to aid in the recovery of fastidious pathogens. In contrast, stool specimens contain abundant amounts of commensal bacteria, and thus to isolate pathogens, selective and differential media must be used. Selective media will inhibit the growth of some organisms to aid in isolation of suspect pathogens; differential media rely on growth characteristics or carbohydrate assimilation characteristics to impart a growth pattern that differentiates organisms. MacConkey agar supports growth of gram-negative rods while suppressing gram-positive organisms, and a color change in the media from clear to pink distinguishes lactose-fermenting organisms from other gram-negative rods. Special media, such as Sabouraud dextrose agar and inhibitory mold agar, are used to recover fungi in clinical specimens. Many pathogens, including Bartonella , Bordetella pertussis , Legionella , Mycoplasma , some Vibrio spp., and certain fungal pathogens such as Malassezia furfur , require specialized growth media or incubation conditions. Consultation with the laboratory is advised when these pathogens are suspected. Once an organism is recovered in culture, additional testing is performed to

identify the isolate. Confirmation of microbial identity has classically been performed using tests that rely on the phenotypic properties of an isolate; examples include coagulase activity, carbohydrate assimilation patterns, indole production, and motility. However, phenotypic methods are not able to resolve all organisms to species level, and they require incubation time. In some instances, sequence-based identification may be necessary. For bacteria, this is usually based on sequence analysis of the bacterial 16S rRNA gene. This gene is a molecular chronometer that is highly conserved within a species but variable between species; as such, it is an excellent resource for organism identification. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS ) is a rapid and accurate technique that is based on generating a protein fingerprint of an organism and comparing that fingerprint to a library of known organisms to produce an identification. This method can identify bacteria or yeast that have been recovered in culture within minutes, and the consumable costs for these analyses are minimal. However, this methodology currently lacks the ability to resolve polymicrobial samples, and the biomass required for successful MALDI-TOF MS analysis generally precludes analysis directly from clinical specimens.

Blood Culture The detection of microbes in blood culture specimens of patients with bloodstream infection is one of the most important functions of the clinical microbiology laboratory. Most blood cultures are performed by collecting blood into bottles of nutrient-rich broth to facilitate the growth of bacteria or yeast. Blood cultures are frequently submitted as a set that includes an aerobic and an anaerobic bottle, although in children, especially neonates, typically only an aerobic bottle is used. Some blood culture media contain resins or other agents to help neutralize antibiotics that may be present in the patients’ blood. Blood culture bottles are then placed into an automated blood culture incubator that will monitor the blood culture bottle at regular intervals for evidence of growth. Once the instrument detects evidence of microbial growth, an alarm alerts the laboratory. Approximately 80% of blood cultures that will ultimately be positive are identified within the 1st 24 hr of incubation. A portion of broth from a blood culture bottle that has signaled positive is then gram-stained and subsequently inoculated onto appropriate growth media so that the organism can be isolated and identified. Numerous preanalytical variables can influence the accuracy of blood culture results. To facilitate accurate interpretation of a positive blood

culture, a minimum of 2 blood cultures drawn from different sites should be collected whenever possible. Growth of an organism that is part of the normal skin flora from a single blood culture raises concern that the isolate resulted from contamination of the culture. To maximize detection of bloodstream infection, up to 4 blood cultures should be collected over 24 -hr. Proper skin antisepsis is essential before blood collection. Chlorhexidine is frequently used for this purpose, but alcohol is also used. If blood is collected through an indwelling line, proper antisepsis before collection is also important. The practice of obtaining blood for culture from intravascular catheters without accompanying peripheral venous blood cultures should be discouraged, because it is difficult to determine the significance of coagulase-negative staphylococci and other skin flora or environmental organisms isolated from blood obtained from line cultures. Differential time to positivity of 2 hr or more between paired blood cultures drawn simultaneously from a catheter and peripheral vein has been cited as an indicator of catheterrelated bloodstream infection. The volume of blood collected is also an important factor in the recovery of bloodstream pathogens, especially as the number of organisms per milliliter of blood in sepsis may be low (1,800 trials, including many in the pediatric population, probiotics reduced CDAD by 64% with RR of 0.36 (95% CI, 0.26-0.51). A pediatric subgroup was analyzed across relevant studies, revealing benefit in pediatric patients and a well-child subgroup (RR, 0.37; 95% CI, 0.23-0.60). A number of probiotics were used, including different Lactobacillus strains and S. boulardii . More than 15 trials have been performed to study the effect of probiotic administration during pregnancy and to infants to prevent atopic dermatitis. Meta-analysis suggests a modest benefit from probiotic administration to prevent the development of atopic dermatitis. Trials have primarily involved the administration of Lactobacillus rhamnosus. Studies included administration to the pregnant mother, or the infant, or both. The overall RR of 0.79 (95% CI, 0.71-0.88) was generally consistent regardless of the treatment of the mother, child, or both. The duration was generally >6 mo; apparently, however, duration did not significantly alter the effect. The RR was similar for the prevention of IgE- and non–IgE-associated atopic dermatitis.

Synbiotics are combinations of a probiotic and a prebiotic that is specifically used by the probiotic. A large, double-blind placebo-controlled trial of >4,500 infants in India demonstrated that a daily oral symbiotic preparation of Lactobacillus plantarum and fructooligosaccharide given through the neonatal period produced significant reductions in sepsis, pneumonia, skin infections, and all-cause mortality.

Bibliography Albenberg L, Kelsen J. Advances in gut mictobione research and relevance to pediatric diseases. J Pediatr . 2016;178:16– 23. Amenyogbe N, Kollmann TR, Ben-Othman R. Early-life host– microbiome interphase: the key frontier for immune development. Front Pediatr . 2017;5:111. Arrieta M-C, Stiemsma LT, Amenyogbe N, et al. The intestinal microbiome in early life: health and disease. Front Immunol . 2014;5:427. Brumbaugh DE, De Zoeten EF, Pyo-Twist A, et al. An intragastric fecal microbiota transplantation program for treatment of recurrent Clostridium difficile in children is efficacious, safe, and inexpensive. J Pediatr . 2018;194:123– 127.e1. Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol . 2018;16(3):143–155. Fettweis JM, Brooks JP, Serrano MG, et al. Differences in vaginal microbiome in African American women versus women of European ancestry. Microbiology . 2014;160:2272– 2782. Foster JA, Rinaman L, Cryan JF. Stress and the gut-brain axis: regulation by the microbiome. Neurobiol Stress . 2017;11:291–301. Gaufin T, Tobin NH, Aldrovandi GM. The importance of the microbiome in pediatrics and pediatric infectious diseases.

Curr Opin Pediatr . 2018;30:117–124. McCann JR, Mason SN, Auten RL, et al. Early-life intranasal colonization with nontypeable Haemophilus influenzae exacerbates juvenile airway disease in mice. Infect Immun . 2016;84:2022–2030. Nash MJ, Frank DN, Friedman JE. Early microbes modify immune system development and metabolic homeostasis— the “restaurant” hypothesis revisited. Front Endocrinol (Lausanne) . 2017;8:349. Nishida A, Inoue R, Inatomi O, et al. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol . 2018;11(1):1–10. Panigrahi P, Parida S, Nanda NC, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature . 2017;548:407–412.

SECTION 2

Preventive Measures OUTLINE Chapter 197 Immunization Practices Chapter 198 Infection Prevention and Control Chapter 199 Childcare and Communicable Diseases Chapter 200 Health Advice for Children Traveling Internationally Chapter 201 Fever Chapter 202 Fever Without a Focus in the Neonate and Young Infant Chapter 203 Fever in the Older Child Chapter 204 Fever of Unknown Origin Chapter 205 Infections in Immunocompromised Persons Chapter 206 Infection Associated With Medical Devices

CHAPTER 197

Immunization Practices Henry H. Bernstein, Alexandra Kilinsky, Walter A. Orenstein

Immunization is one of the most beneficial and cost-effective disease-prevention measures available. As a result of effective and safe vaccines, smallpox has been eradicated, polio is close to worldwide eradication, and measles and rubella are no longer endemic in the United States. However, cases of vaccine-preventable diseases, including measles, mumps, and pertussis, continue to occur in the United States. Incidence of most vaccine-preventable diseases of childhood has been reduced by ≥99% from representative 20th century annual morbidity, usually before development of the corresponding vaccines (Table 197.1a ), with most of the newer vaccines not achieving quite the same percentage decrease (Table 197.1b ). An analysis of effective prevention measures recommended for widespread use by the U.S. Preventive Services Task Force (USPSTF) reported that childhood immunization received a perfect score based on clinically preventable disease burden and cost-effectiveness. Table 197.1a

Comparison of 20th Century Annual Morbidity and Current Morbidity: Vaccine-Preventable Diseases 20TH CENTURY ANNUAL MORBIDITY* Smallpox 29,005 Diphtheria 21,053 Measles 530,217 Mumps 162,344 Pertussis 200,752 Polio (paralytic) 16,316 Rubella 47,745 Congenital rubella syndrome 152 Tetanus 580 DISEASE

2016 REPORTED CASES † 0 0 122 5,629 15,808 0 9 2 31

PERCENT DECREASE 100% 100% >99% 96% 92% 100% >99% 99% 95%

Haemophilus influenzae type b (Hib)

20,000

22 ‡

>99%

* Data from Roush SW, Murphy TV, Vaccine-Preventable Disease Table Working Group: Historical

comparisons of morbidity and mortality for vaccine-preventable diseases in the United States, JAMA 298(18):2155–2163, 2007. †

Data from Centers for Disease Control and Prevention: Notifiable diseases and mortality tables, MMWR 66(52):ND-924–ND-941, 2018. ‡

Hib 40–50% do not confer a substantially longer protection time for children and are not recommended. Picaridin is fragrance-free, effective, and generally well tolerated on exposed skin and faces. It has similar efficacy to DEET but with less inhalational or dermal irritation. Picaridin at concentrations of 20% or higher provides adequate protection against Anopheles mosquitoes that have potential to transmit malaria. When applying sunscreen and insect repellent, sunscreen should be applied first, followed by DEET or picaridin. Spraying or treating clothing with permethrin , a synthetic pyrethroid, is a safe and effective method of further reducing insect bites in children. Permethrin can be applied directly to clothing, bed nets, shoes, and hats and should be allowed to dry fully before use. As an insecticide, permethrin should never be applied to skin. Permethrin-treated garments retain both repellency and insecticidal activity, even with repeated laundering. Clothing will eventually need to be re-treated to maintain repellency, according to the product label. Bed nets, particularly permethrin-impregnated bed nets, also decrease the risk of insect bites, and their use is highly recommended in malarial areas.

Malaria Chemoprophylaxis Malaria, a mosquito-borne infection, is the leading parasitic cause of death in

children worldwide (see Chapter 314 ). Of the 5 Plasmodium species that infect humans, Plasmodium falciparum causes the greatest morbidity and mortality. Each year, >8 million U.S. citizens visit parts of the world where malaria is endemic (sub-Saharan Africa, Central and South America, India, Southeast Asia, Oceania). Children accounted for 15–20% of imported malaria cases in a WHO study in Europe. Given the major resurgence of malaria and increased travel among families with young children, physicians in industrialized countries are increasingly required to give advice on prevention, diagnosis, and treatment of malaria. Risk factors for severe malaria and death include inadequate adherence to chemoprophylaxis, delay in seeking medical care, delay in diagnosis, and nonimmune status, but the case fatality rate of imported malaria remains 3040 kg: 3 pediatric tablets once daily Weight >40 kg: 1 adult tablet once daily 8.3 mg/kg salt (5 mg/kg base) weekly

* Chloroquine and mefloquine should be started 1-2 wk before departure and continued for 4 wk

after last exposure. † Mefloquine resistance exists in western Cambodia and along the Thailand–Cambodia and

Thailand–Myanmar borders. Travelers to these areas should take doxycycline or atovaquoneproguanil. See text for precautions about mefloquine use. ‡ Doxycycline should be started 1-2 days before departure and continued for 4 wk after last

exposure. Do not use in children 30 days after completion of travel) Few days to 2-3 wk Causative species vary by region 3-14 days Widespread in Latin America, endemic through much of Africa, Southeast Asia, and Pacific Islands See above incubation periods for relevant diseases. Weeks to months 28-30 days (15-50 days) 26-42 days (2-9 wk) 4-8 wk

See above distribution for relevant diseases. Most common in resource-poor countries Most common in resource-poor countries Widespread Most common in sub-Saharan Africa

See above incubation periods for relevant diseases. 90 days (60-150 days) 2-10 mo (10 days to years)

See above distribution for relevant diseases. Widespread Asia, Africa, Latin America, southern Europe, and the Middle East Global distribution, rates, and levels of resistance vary widely.

Primary, weeks; reactivation, years

From Wilson ME: Post-travel evaluation. In CDC Yellow Book , Chapter 5 (Table 5.3 ). https://wwwnc.cdc.gov/travel/yellowbook/2018/post-travel-evaluation/fever-in-returned-travelers .

Among all persons returning from travel (children and adults), 3 major patterns of illness have been noted (Table 200.5 ). The etiology of each of these disease presentations in part depends on the country or geographic region visited

(see Table 200.3 ). Table 200.6 provides suggestive clues to a diagnosis. Table 200.5

Patterns of Illness in Returning International Travelers SYSTEMIC FEBRILE ILLNESS Malaria Dengue Zika Enteric fever (typhoid/paratyphoid) Chikungunya virus Spotted-fever rickettsiae Hepatitis A Acute HIV Leptospirosis Measles Infectious mononucleosis Respiratory causes (pneumonia, influenza) Undetermined fever source ACUTE DIARRHEA Campylobacter Shigella spp. Salmonella spp. Diarrheagenic Escherichia coli (enterotoxigenic E. coli , enteroadherent E. coli —not tested for by routine stool culture methods) Giardiasis (acute, persistent, or recurrent) Entamoeba histolytica Cryptosporidium spp. Cyclospora cayetanensis Presumed viral enteritis DERMATOLOGIC MANIFESTATIONS Rash with fever (dengue) Arthropod-related dermatitis (insect bites) Cutaneous larva migrans (Ancylostoma braziliense ) Bacterial skin infections—pyoderma, impetigo, ecthyma, erysipelas Myiasis (tumbu and botfly) Scabies Tungiasis Superficial mycosis Animal bites Leishmaniasis Rickettsial diseases Marine envenomation/dermatitis Photoallergic dermatitis and phytophotodermatitis

Table 200.6 Common Clinical Findings and Associated Infections COMMON CLINICAL

INFECTIONS TO CONSIDER AFTER TROPICAL TRAVEL

FINDINGS Fever and rash Fever and abdominal pain Undifferentiated fever and normal or low white blood cell count Fever and hemorrhage Fever and arthralgia or myalgia, sometimes persistent Fever and eosinophilia

Dengue, chikungunya, Zika, rickettsial infections, enteric fever (skin lesions may be sparse or absent), acute HIV infection, measles Enteric fever, amebic liver abscess Dengue, malaria, rickettsial infection, enteric fever, chikungunya, Zika

Viral hemorrhagic fevers (dengue and others), meningococcemia, leptospirosis, rickettsial infections Chikungunya, dengue, Zika

Acute schistosomiasis, drug hypersensitivity reaction, fascioliasis and other parasitic infections (rare) Fever and pulmonary Common bacterial and viral pathogens, legionellosis, acute schistosomiasis, Q infiltrates fever, leptospirosis Fever and altered mental Cerebral malaria, viral or bacterial meningoencephalitis, African trypanosomiasis, status scrub typhus Mononucleosis syndrome Epstein-Barr virus (EBV) infection, cytomegalovirus (CMV) infection, toxoplasmosis, acute HIV infection Fever persisting >2 wk Malaria, enteric fever, EBV infection, CMV infection, toxoplasmosis, acute HIV infection, acute schistosomiasis, brucellosis, tuberculosis, Q fever, visceral leishmaniasis (rare) Fever with onset >6 wk after Plasmodium vivax or P. ovale malaria, acute hepatitis (B, C, or E), tuberculosis, travel amebic liver abscess

From Wilson ME: Post-travel evaluation. In CDC Yellow Book, Chapter 5 (Table 5.6). https://wwwnc.cdc.gov/travel/yellowbook/2018/post-travel-evaluation/fever-in-returned-travelers .

Fever is a particularly worrisome symptom. Children with a febrile/systemic illness following recent travel to a malarial destination should be promptly evaluated for malaria, especially if having traveled to sub-Saharan Africa and Papua New Guinea. P. falciparum malaria will generally present within 1-2 mo after return from travel to a malaria-endemic area, but can occur within the 1st yr after return. In contrast, symptoms of P. vivax or P. ovale malaria are typically later in onset following travel (i.e., several months), are milder in disease severity, and may occur in a relapsing pattern if undiagnosed or improperly untreated. Other symptoms of malaria can be nonspecific and include chills, malaise, headache, myalgias, vomiting, diarrhea, cough, and possible seizures. Children are more likely than adults to have higher fevers and also gastrointestinal symptoms, hepatomegaly, splenomegaly, and severe anemia. Thrombocytopenia (without increased bleeding) and fever in a child returning from an endemic area are highly suggestive of malaria. Thick and thin blood smears need to be performed for diagnosis if malaria is clinically suspected. If results are negative initially, 2 or more additional smears should be done 12-24 hr after the initial smears. Rapid malaria antigen tests (BinaxNOW Malaria) are FDA-approved and sensitive for diagnosing

falciparum malaria. Treatment should be initiated immediately once the diagnosis is confirmed or empirically if presentation is severe with suspected malaria. Treatment should be determined in consultation with a pediatric infectious disease specialist and/or the CDC for updated information on the drugs of choice, which are similar to those for adults (see Chapter 314 ). Great caution should be used with young children, nonimmune patients, and pregnant patients with falciparum malaria, and hospitalization of these patients should be strongly considered until reliable improvement is observed. Enteric (typhoid) fever should be considered in children with persistent or recurrent fevers following return from the Indian subcontinent. Multiple blood cultures and a stool culture may both be necessary to diagnosis enteric fever. Dengue is another cause of fever and systemic illness in ill travelers, particularly when returning from Southeast Asia, the Caribbean, Central and South America, or the Indian subcontinent. Many bacterial and protozoal causes of acute traveler's diarrhea may also result in fever and systemic symptoms in children. Additional travel-associated febrile, diarrheal, and dermatologic illnesses exist, of which the most common etiologies can be found in Tables 200.5 and 200.6 .

The Adolescent Traveler The preparation of an adolescent interested in traveling abroad can pose a challenge for most clinicians. Study abroad, gap year, humanitarian volunteer work, adventure, and tourism are among many reasons for travel to countries with limited resources. While many travel-related problems discussed in this chapter are relevant to this group, other high-risk activities such as sexual intercourse, alcohol consumption, driving, use of illicit drugs, and adventure travel (mountain climbing, white water rafting, kayaking, biking) require special attention and discussion with the traveler and parents/guardians. Topics such as HIV exposure, sexually transmitted infections, sexual assault, and unplanned pregnancy may require specific preventive strategies such as condom use, contraception, and postexposure HIV prophylaxis.

Bibliography Ashkenazi S, Schwartz E, O'Ryan M. Travelers’ diarrhea in children: what have we learnt? Pediatr Infect Dis J .

2016;35:698–700. Barnett E. Pediatric travel medicine: challenges for the primary care and travel medicine specialist. Curr Infect Dis Rep . 2013;15:216–222. Centers for Disease Control and Prevention (CDC). International travel with infants and children, Yellow Book 2016. Weinberg N, Weinberg M, Maloney SA: Traveling safely with infants & children . http://wwwnc.cdc.gov/travel/yellowbook/2016/chapter-7international-travel-infants-children/traveling-safely-withinfants-and-children . Dagan R, Amir J, Mijalovsky A, et al. Immunization against hepatitis A in the first year of life: priming despite the presence of maternal antibody. Pediatr Infect Dis J . 2000;19:1045–1052. Fhogartaigh CN, Sanford C, Behrens RH. Preparing young travelers for low resource destinations. BMJ . 2012;345:e7179. Hagmann S, LaRocque RC, Rao SR, et al. Pre-travel health preparation of pediatric international travelers: analysis from the Global TravEpiNet Consortium. J Pediatr Infect Dis Soc . 2013;2:327–334. Hagmann S, Neugebauer R, Schwartz E, et al. Illness in children after international travel: analysis from the GeoSentinel Surveillance Network. Pediatrics . 2010;125(5):e1072–e1080. Han P, Yanni E, Jentes ES, et al. Health challenges of young travelers visiting friends and relative compared with those traveling for other purposes. Pediatr Infect Dis J . 2012;31:915–919. Harvey K, Esposito DH, Han P, Centers for Disease Control and Prevention, et al. Surveillance for travel-related disease— GeoSentinel surveillance system, United States, 1997–2011.

MMWR Surveill Summ . 2013;62:1–23. Hendel-Paterson B, Swanson SJ. Pediatric travelers visiting friends and relatives (VFR) abroad: illnesses, barriers and pre-travel recommendations. Travel Med Infect Dis . 2011;9(4):192–203. Kantele A, Lääveri T, Mero S, et al. Antimicrobials increase travelers’ risk of colonization by extended-spectrum betalactamase-producing Enterobacteriaceae. Clin Infect Dis . 2015;60:837–846. Ladhani S, Aibara RJ, Riordan FA, et al. Imported malaria in children: a review of clinical studies. Lancet Infect Dis . 2007;7:349–357. Leder K, Torresi J, Brownstein JS, et al. Travel-associated illness trends and clusters, 2000–2010. Emerg Infect Dis . 2013;19:1049–1057. Leder K, Torresi J, Libman M, et al. GeoSentinel surveillance of illness in returned travelers, 2007–2011. Ann Intern Med . 2013;158(6):456–468. Mackell S. Traveler's diarrhea in the pediatric population: etiology and impact. Clin Infect Dis . 2005;41:S547–S552. The Medical Letter. Advice for travelers. Med Lett . 2015;57(1466):52–58. The Medical Letter. Vaccines for travelers. Med Lett . 2014;56(1456):115–120. The Medical Letter on Drugs and Therapeutics. Insect repellents. JAMA . 2016;316:766–767. Myers AL, Christenson JC. Approach to immunization for the traveling child. Infect Dis Clin North Am . 2015;29:745–757. Nelson NP, Link-Gelles R, Hofmeister MG, et al. Update: recommendations of the Advisory Committee on Immunization Practices for use of hepatitis A vaccine for postexposure prophylaxis and for preexposure prophylaxis for international travel. MMWR . 2018;67:1216–1220.

Neumann K. Family travel: an overview. Travel Med Infect Dis . 2006;4:202–217. Nield LS. Health implications of adolescent travel. Pediatr Ann . 2011;40:358–361. Nuorti JP, Whitney CG, Centers for Disease Control and Prevention. Prevention of pneumococcal disease among infants and children: use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. MMWR Recomm Rep . 2010;59(RR– 11):1–18. Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler's diarrhea in infants and children. Pediatr Infect Dis J . 1991;10(10):719–723. Rupprecht CE, Briggs D, Brown CM, Centers for Disease Control and Prevention, et al. Use of reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep . 2010;59(RR–2):1–9. Stauffer W, Christenson JC, Fischer PR. Preparing children for international travel. Travel Med Infect Dis . 2008;6:101–113. Strysko JP, Mony V, Cleveland J, et al. International travel is a risk factor for extended-spectrum β-lactamase-producing Enterobacteriaceae acquisition in children: a case-control study in an urban US hospital. Traved Med Infect Dis . 2016;14:568–571. Thwaites GE, Day NPJ. Approach to fever in the returning traveler. N Engl J Med . 2017;376:548–560. Wilson ME, Weld LH, Bogglid A, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis . 2007;4(12):1560–1568. Zafren K. Prevention of high altitude illness. Travel Med Infect Dis . 2014;12:29–39.

* See the map at http://wwwnc.cdc.gov/travel/yellowbook/2016/chapter-3-

infectious-diseases-related-to-travel/meningococcal-disease .

CHAPTER 201

Fever Linda S. Nield, Deepak Kamat

Fever is defined as a rectal temperature ≥38°C (100.4°F), and a value >40°C (104°F) is called hyperpyrexia . Traditionally, body temperature fluctuates in a defined normal range (36.6-37.9°C [97.9-100.2°F] rectally), so that the highest point is reached in early evening and the lowest point is reached in the morning. Any abnormal rise in body temperature should be considered a symptom of an underlying condition. The range of normal temperature is broad, 35.5-37.7°C (96-100°F); if 37°C (98.6°F) is considered normal, many cluster around this temperature (36.1-37.5°C [97-99.5°F]).

Pathogenesis Body temperature is regulated by thermosensitive neurons located in the preoptic or anterior hypothalamus that respond to changes in blood temperature, as well as by cold and warm receptors located in skin and muscles. Thermoregulatory responses include redirecting blood to or from cutaneous vascular beds, increased or decreased sweating, regulation of extracellular fluid (ECF) volume by arginine vasopressin, and behavioral responses, such as seeking a warmer or cooler environmental temperature. Three different mechanisms can produce fever: pyrogens, heat production exceeding heat loss, and defective heat loss. The 1st mechanism involves endogenous and exogenous pyrogens that raise the hypothalamic temperature set point. Endogenous pyrogens include the cytokines interleukin (IL)-1 and IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-β and IFN-γ. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens. The best-studied lipid mediator is prostaglandin E2, which attaches to the prostaglandin receptors in the hypothalamus to produce the new temperature

set point. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens. Some substances produced within the body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigenantibody complexes in the presence of complement, complement components, lymphocyte products, bile acids, and androgenic steroid metabolites. Exogenous pyrogens come from outside the body and consist of mainly infectious pathogens and drugs. Microbes, microbial toxins, or other products of microbes are the most common exogenous pyrogens, which stimulate macrophages and other cells to produce endogenous pyrogens. Endotoxin is one of the few substances that can directly affect thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release. Many drugs cause fever, and the mechanism for increasing body temperature varies with the class of drug. Drugs that are known to cause fever include vancomycin, amphotericin B, and allopurinol. Heat production exceeding heat loss is the 2nd mechanism that leads to fever; examples include salicylate poisoning and malignant hyperthermia. Defective heat loss , the 3rd mechanism, may occur in children with ectodermal dysplasia or victims of severe heat exposure.

Etiology The causes of fever can be organized into 4 main categories: infectious, inflammatory, neoplastic, and miscellaneous. Self-limited viral infections (common cold, influenza, gastroenteritis) and uncomplicated bacterial infections (otitis media, pharyngitis, sinusitis) are the most common causes of acute fever. The body temperature rarely rises above potentially lethal levels (42°C [107.6°F]) in the neurologically intact child unless extreme hyperthermic environmental conditions are present or other extenuating circumstances exist, such as underlying malignant hyperthermia or thyrotoxicosis. The pattern of the fever can provide clues to the underlying etiology. Viral infections typically are associated with a slow decline of fever over 1 wk, whereas bacterial infections are often associated with a prompt resolution of fever after effective antimicrobial treatment. Although antimicrobials can result in rapid elimination of bacteria, if tissue injury has been extensive, the inflammatory response and fever can continue for days after all microbes have been eradicated.

Intermittent fever is an exaggerated circadian rhythm that includes a period of normal temperatures on most days; extremely wide fluctuations may be termed septic or hectic fever . Sustained fever is persistent and does not vary by >0.5°C (0.9°F)/day. Remittent fever is persistent and varies by >0.5°C/day. Relapsing fever is characterized by febrile periods separated by intervals of normal temperature; tertian fever occurs on the 1st and 3rd days (malaria caused by Plasmodium vivax ), and quartan fever occurs on the 1st and 4th days (malaria caused by Plasmodium malariae ). Diseases characterized by relapsing fevers should be distinguished from infectious diseases that have a tendency to relapse (Table 201.1 ). Biphasic fever indicates a single illness with 2 distinct periods (camelback fever pattern); poliomyelitis is the classic example. A biphasic course is also characteristic of other enteroviral infections, leptospirosis, dengue fever, yellow fever, Colorado tick fever, spirillary rat-bite fever (Spirillum minus), and the African hemorrhagic fevers (Marburg, Ebola, and Lassa fevers). The term periodic fever is used narrowly to describe fever syndromes with a regular periodicity (cyclic neutropenia and periodic fever, aphthous stomatitis, pharyngitis, adenopathy) or more broadly to include disorders characterized by recurrent episodes of fever that do not follow a strictly periodic pattern (familial Mediterranean fever, TNF receptor–associated periodic syndrome [Hibernian fever], hyper-IgD syndrome, Muckle-Wells syndrome) (see Chapter 188 ). Factitious fever , or self-induced fever, may be caused by intentional manipulation of the thermometer or injection of pyrogenic material. Table 201.1

Fevers Prone to Relapse INFECTIOUS CAUSES Relapsing fever (Borrelia recurrentis ) Q fever (Coxiella burnetii ) Typhoid fever (Salmonella typhi ) Syphilis (Treponema pallidum ) Tuberculosis Histoplasmosis Coccidioidomycosis Blastomycosis Melioidosis (Pseudomonas pseudomallei ) Lymphocytic choriomeningitis (LCM) infection Dengue fever Yellow fever Chronic meningococcemia

Colorado tick fever Leptospirosis Brucellosis Oroya fever (Bartonella bacilliformis ) Acute rheumatic fever Rat-bite fever (Spirillum minus ) Visceral leishmaniasis Lyme disease (Borrelia burgdorferi ) Malaria Babesiosis Noninfluenza respiratory viral infection Epstein-Barr virus infection NONINFECTIOUS CAUSES Behçet disease Crohn disease Weber-Christian disease (panniculitis) Leukoclastic angiitis syndromes Sweet syndrome Systemic lupus erythematosus and other autoimmune disorders PERIODIC FEVER SYNDROMES (see Chapter 188 ) Familial Mediterranean fever Cyclic neutropenia Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) Hyper–immunoglobulin D syndrome Hibernian fever (tumor necrosis factor superfamily immunoglobulin A–associated syndrome [TRAPS]) Muckle-Wells syndrome Others

The double quotidian fever (or fever that peaks twice in 24 hr) is classically associated with inflammatory arthritis. In general, a single isolated fever spike is not associated with an infectious disease. Such a spike can be attributed to the infusion of blood products and some drugs, as well as some procedures, or to manipulation of a catheter on a colonized or infected body surface. Similarly, temperatures in excess of 41°C (105.8°F) are most often associated with a noninfectious cause. Causes for very high temperatures (>41°C [105.8°F]) include central fever (resulting from central nervous system dysfunction involving the hypothalamus or spinal cord injury), malignant hyperthermia, malignant neuroleptic syndrome, drug fever, or heat stroke. Temperatures that are lower than normal (2 mo old. Relative tachycardia, when the pulse rate is elevated disproportionately to the temperature, is usually caused by noninfectious diseases or infectious diseases in which a toxin is responsible for the clinical manifestations. Relative bradycardia (temperature-pulse dissociation), when the pulse rate remains low in the presence of fever, can accompany typhoid fever, brucellosis, leptospirosis, or drug fever. Bradycardia in the presence of fever also may be a result of a conduction defect resulting from cardiac involvement with acute rheumatic fever, Lyme disease, viral myocarditis, or infective endocarditis.

Evaluation Most acute febrile episodes in a normal host can be diagnosed by a careful history and physical examination and require few, if any, laboratory tests. Because infection is the most likely etiology of the acute fever, the evaluation should initially be geared to discovering an underlying infectious cause (Table 201.2 ). The details of the history should include the onset and pattern of fever and any accompanying signs and symptoms. The patient often displays signs or symptoms that provide clues to the cause of the fever. Exposures to other ill persons at home, daycare, and school should be noted, along with any recent travel or medications. The past medical history should include information about underlying immune deficiencies or other major illnesses and receipt of childhood vaccines. Table 201.2

Evaluation of Acute Fever

Thorough history: onset, other symptoms, exposures (daycare, school, family, pets, playmates), travel, medications, other underlying disorders, immunizations Physical examination: complete, with focus on localizing symptoms Laboratory studies on a case-by-case basis: • Rapid antigen testing • Nasopharyngeal: respiratory viruses by polymerase chain reaction • Throat: group A streptococcus • Stool: NAAT for enteric pathogens, calprotectin • Blood: complete blood count, blood culture, C-reactive protein, sedimentation rate, procalcitonin • Urine: urinalysis, culture • Cerebrospinal fluid: cell count, glucose, protein, Gram stain, culture • Chest radiograph or other imaging studies on a case-by-case basis

NAAT, Nucleic acid amplification test.

Physical examination should begin with a complete evaluation of vital signs, which should include pulse oximetry because hypoxia may indicate lower respiratory infection. In the acutely febrile child, the physical examination should focus on any localized complaints, but a complete head-to-toe screen is recommended, because clues to the underlying diagnosis may be found. For example, palm and sole lesions may be discovered during a thorough skin examination and provide a clue for infection with coxsackievirus . If a fever has an obvious cause, then laboratory evaluation may not be required, and management is tailored to the underlying cause with as-needed reevaluation. If the cause of the fever is not apparent, further diagnostic evaluation should be considered on a case-by-case basis. The history of presentation and abnormal physical examination findings guide the evaluation. The child with respiratory symptoms and hypoxia may require a chest radiograph or rapid antigen testing for respiratory syncytial virus or influenza . The child with pharyngitis can benefit from rapid antigen detection testing for group A streptococcus and a throat culture. Dysuria, back pain, or a history of vesicoureteral reflux should prompt a urinalysis and urine culture, and bloody diarrhea should prompt a stool culture. A complete blood count and blood culture should be considered in the ill-appearing child, along with cerebrospinal fluid studies if the child has neck stiffness or if the possibility of meningitis is considered. Well-defined high-risk groups require a more extensive evaluation on the basis of age, associated disease, or immunodeficiency status and might warrant prompt antimicrobial therapy before a pathogen is identified. Fever in neonates and young infants (0-3 mo old), fever in older children, and fever of unknown origin are discussed in Chapters 202 , 203 , and 204 , respectively.

Management Although fever is a common parental worry, no evidence supports the belief that high fever can result in brain damage or other bodily harm, except in rare instances of febrile status epilepticus and heat stroke. Treating fever in selflimiting illnesses for the sole reason of bringing the body temperature back to normal is not necessary in the otherwise healthy child . Most evidence suggests that fever is an adaptive response and should be treated only in select circumstances. In humans, increased temperatures are associated with decreased microbial replication and an increased inflammatory response. Although fever can have beneficial effects, it also increases oxygen consumption, carbon dioxide production, and cardiac output and can exacerbate cardiac insufficiency in patients with heart disease or chronic anemia (e.g., sickle cell disease), pulmonary insufficiency in patients with chronic lung disease, and metabolic instability in patients with diabetes mellitus or inborn errors of metabolism. Children between 6 mo and 5 yr of age are at increased risk for simple febrile seizures. The focus of the evaluation and treatment of febrile seizures is aimed at determining the underlying cause of the fever. Children with idiopathic epilepsy also often have an increased frequency of seizures associated with a fever. High fever during pregnancy may be teratogenic. Fever with temperatures 41°C [105.8°F]) indicates high probability of hypothalamic disorders or central nervous system hemorrhage and should be treated with antipyretics. Some studies show that hyperpyrexia may be associated with a significantly increased risk of serious bacterial infection, but other studies have not substantiated this relationship. The most common antipyretics are acetaminophen, 10-15 mg/kg/dose every 4 hr, and ibuprofen in children >6 mo old at 5-10 mg/kg/dose every 8 hr. Antipyretics reduce fever by

reducing production of prostaglandins. If used appropriately, antipyretics are safe; potential adverse effects include liver damage (acetaminophen) and gastrointestinal or kidney disturbances (ibuprofen). To reduce fever most safely, the caregiver should choose 1 type of medication and clearly record the dose and time of administration so that overdosage does not occur, especially if multiple caregivers are involved in the management. Physical measures such as tepid baths and cooling blankets are not considered effective to reduce fever. Evidence is also scarce for the use of complementary and alternative medicine interventions. Fever caused by specific underlying etiologies resolves when the condition is properly treated. Examples include administration of intravenous immunoglobulin to treat Kawasaki disease or the administration of antibiotics to treat bacterial infections.

Bibliography Adam H. Fever: measuring and managing. Pediatr Rev . 2013;34:368. American Academy of Pediatrics Subcommittee on Febrile Seizures. Febrile seizures: guideline for the neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics . 2011;127:38. Avner JR. Acute fever. Pediatr Rev . 2009;30:5–13. Biondi EA, Byington CL. Evaluation and management of febrile, well-appearing young infants. Infect Dis Clin North Am . 2015;29:575–585. Blatteis CM. The onset of fever: new insights into its mechanism. Prog Brain Res . 2007;162:3–14. Caspe WB, Nucci AT, Cho S. Extreme hyperpyrexia in childhood: prevention similar to hemorrhagic shock and encephalopathy. Clin Pediatr (Phila) . 1989;28(2):76–80. Chiappini E, Venturini E, Remashi G, et al. 2016 update of the Italian Pediatric Society guidelines for management of fever in children. J Pediatr . 2017;180:177–183.

Cunha BA. The clinical significance of fever patterns. Infect Dis Clin North Am . 1996;1:33–44. Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res . 2004;10(4):201–222. Filha EM, de Carvalho WB. Current management of occult bactermia in infants. J Pediatr (Rio J) . 2015;91:561–566. Gomez B, Bressan S, Mintegi S, et al. Diagnostic value of procalcitonin in well-appearing young febrile infants. Pediatrics . 2012;130:815–822. Hanna CM, Greene DS. How much tachycardia in infants can be attributed to fever? Ann Emerg Med . 2004;43(6):699–705. Purssell E, While AE. Does the use of antipyretics in children who have acute infections prolong febrile illness? A systematic review and meta-analysis. J Pediatr . 2013;163:822–827. Sherman JM, Sood SK. Current challenges in the diagnosis and management of fever. Curr Opin Pediatr . 2012;24:400–406. Trautner BW, Caviness AC, Gerlacher GR, et al. Prospective evaluation of the risk of serious bacterial infection in children who present to the emergency department with hyperpyrexia (temperatures of 106°F or higher). Pediatrics . 2006;118:34– 40. Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ . 2011;342:d3082. Wang D. Complementary, holistic and integrative medicine: fever. Pediatr Rev . 2009;30:75–78.

CHAPTER 202

Fever Without a Focus in the Neonate and Young Infant Laura Brower, Samir S. Shah

Fever is a common reason for neonates and young infants to undergo medical evaluation in the hospital or ambulatory setting. For this age-group (0-3 mo), fever without a focus refers to a rectal temperature of 38°C (100.4°F) or greater, without other presenting signs or symptoms. The evaluation of these patients can be challenging because of the difficulty distinguishing between a serious infection (bacterial or viral) and a self-limited viral illness. The etiology and evaluation of fever without a focus depend on the age of the child. Three agegroups are typically considered: neonates 0-28 days, young infants 29-90 days, and children 3-36 mo. This chapter focuses on neonates and young infants.

Etiology and Epidemiology Serious bacterial infection (SBI) occurs in 7% to 13% of neonates and young infants with fever. In this group, the most common SBIs are urinary tract infection (UTI; 5–13%), bacteremia (1–2%) and meningitis (0.2–0.5%). Escherichia coli is the most common organism causing SBI, followed by group B streptococcus (GBS). The decrease in GBS infections is related to increased screening of pregnant women and use of intrapartum antibiotic prophylaxis. Other, less common organisms include Klebsiella spp., Enterococcus spp., Streptococcus pneumoniae , Neisseria meningitidis , and Staphylococcus aureus (Table 202.1 ). Listeria monocytogenes is a rare cause of neonatal infections, potentially related to changes in public health education and improvements in food safety. Additional details about specific bacteria are available in the following chapters: Escherichia coli (Chapter 227 ), GBS (Chapter 211 ),

Streptococcus pneumoniae (Chapter 209 ), Neisseria meningitidis (Chapter 218 ), Staphylococcus aureus (Chapter 208.1 ), and Listeria monocytogenes (Chapter 215 ). Specific bacterial infections that can present with fever in this age-group, although often with symptoms other than isolated fever, include pneumonia (Chapter 428 ), gastroenteritis (Chapter 366 ), osteomyelitis (Chapter 704 ), septic arthritis (Chapter 705 ), omphalitis (Chapter 125 ), cellulitis, and other skin and soft tissue infections (Chapter 685 ). Table 202.1

Bacterial Pathogens in Neonates and Young Infants With Urinary Tract Infection, Bacteremia, or Meningitis FREQUENCY Common Less common

Rare

URINARY TRACT INFECTION Escherichia coli Klebsiella spp. Enterococcus spp. Group B streptococcus Staphylococcus aureus Pseudomonas aeruginosa Enterobacter spp. Citrobacter spp. Proteus mirabilis

BACTEREMIA AND MENINGITIS Escherichia coli Group B streptococcus Streptococcus pneumoniae Staphylococcus aureus Klebsiella spp. Listeria monocytogenes Neisseria meningitidis Salmonella spp. Enterobacter spp. Enterococcus spp. Cronobacter sakazakii

Herpes simplex virus (HSV ) infections (Chapter 279 ) should also be considered in febrile neonates 180 beats/min, delayed capillary refill >3 sec, weak or bounding pulses), abnormal abdominal examination, abnormal neurologic examination (lethargy, irritability, alterations in tone), or abnormal skin examination (rash, petechiae, cyanosis). Infants with septic arthritis or osteomyelitis may appear well except for signs around the involved joint or bone or may only manifest with pseudoparalysis (disuse) and paradoxical irritability (pain when attempting to comfort the child).

Diagnosis No consensus exists on the diagnosis and empirical treatment of febrile neonates and young infants. Traditionally, all neonates 6 mo is uncommon in children and suggests granulomatous, autoinflammatory, or autoimmune disease. Repeat interval evaluation is required, including history, physical examination, laboratory evaluation, and imaging studies. Historically, 90% of pediatric FUO cases in the United States had an identifiable cause: approximately 50% infectious, 10–20% collagen vascular, and 10% oncologic. Later studies from the 1990s had variable results: 20–44% infectious, 0–7% collagen vascular, 2–3% oncologic, and up to 67% undiagnosed. The reason for the paradoxical increase in undiagnosed cases of FUO ironically is likely caused by improved infectious and autoimmune diagnostic techniques. The advent of polymerase chain reaction (PCR), improved culture techniques, and better understanding of atypical viral and bacterial pathogenesis and autoimmune processes likely contribute to earlier diagnosis of these conditions and fewer children with these conditions advancing to the category of FUO. By contrast, causes of FUO remain primarily infectious in developing settings where there is a higher infectious disease burden, and advanced diagnostics techniques are more limited.

Diagnosis The evaluation of FUO requires a thorough history and physical examination supplemented by a few screening laboratory tests and additional laboratory and imaging evaluation informed by the history or abnormalities on examination or initial screening tests (see Table 204.2 ). Occasionally the fever pattern helps make a diagnosis (Fig. 204.1 ). Nonetheless, most diseases causing an FUO do not have a typical fever pattern.

FIG. 204.1 Distinctive fever patterns. A, Malaria. B, Typhoid fever (demonstrating relative bradycardia). C, Hodgkin disease (Pel-Ebstein fever pattern). D, Borreliosis (relapsing fever pattern). (From Woodward TE: The fever pattern as a clinical diagnostic aid. In Mackowiak PA, editor: Fever: basic mechanisms and management , ed 2, Philadelphia, 1997, Lippincott-Raven, pp 215–236.)

History A detailed fever history should be obtained, including onset, frequency, duration, response or nonresponse to therapy, recurrence, and associated symptoms. Repetitive chills and temperature spikes are common in children with septicemia (regardless of cause), particularly when associated with kidney disease, liver or biliary disease, infective endocarditis, malaria, brucellosis, ratbite fever, or a loculated collection of pus. The age of the patient is helpful in evaluating FUO. Children >6 yr old often have a respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis), JIA, or rarely, leukemia. Adolescent patients are more likely to have IBD, autoimmune processes, lymphoma, or tuberculosis, in addition to the causes of FUO found in younger children. A history of exposure to wild or domestic animals should be solicited. The incidence of zoonotic infections in the United States is increasing, and these infections are often acquired from pets that are not overtly ill. Immunization of dogs against specific disorders such as leptospirosis can prevent canine disease but does not always prevent the animal from carrying and shedding leptospires, which may be transmitted to household contacts. A history of ingestion of rabbit or squirrel meat might provide a clue to the diagnosis of oropharyngeal, glandular, or typhoidal tularemia . A history of tick bite or travel to tick- or parasite-infested areas should be obtained. Any history of pica should be elicited. Ingestion of dirt is a particularly important clue to infection with Toxocara canis (visceral larva migrans) or

Toxoplasma gondii (toxoplasmosis). A history of unusual dietary habits or travel as early as the birth of the child should be sought. Tuberculosis, malaria, histoplasmosis, and coccidioidomycosis can reemerge years after visiting or living in an endemic area. It is important to identify prophylactic immunizations and precautions taken by the patient against ingestion of contaminated water or food during foreign travel. Rocks, dirt, and artifacts from geographically distant regions that have been collected and brought into the home as souvenirs can serve as vectors of disease. A medication history should be pursued rigorously. This history should elicit information about nonprescription preparations and topical agents, including eyedrops, that may be associated with atropine-induced fever. The genetic background of a patient also is important. Descendants of the Ulster Scots may have FUO because they are afflicted with nephrogenic diabetes insipidus. Familial dysautonomia (Riley-Day syndrome), a disorder in which hyperthermia is recurrent, is more common among Jews than among other population groups. Ancestry from the Mediterranean region should suggest familial Mediterranean fever . Both familial Mediterranean fever and hyperIgD syndrome are inherited as autosomal recessive disorders. Tumor necrosis factor receptor–associated periodic syndrome and Muckle-Wells syndrome are inherited as autosomal dominant traits. Pseudo-FUO is defined as successive episodes of benign, self-limited infections with fever that the parents perceive as 1 prolonged fever episode. This needs to be carefully ruled out before undertaking an unnecessary evaluation. Usually, pseudo-FUO starts with a well-defined infection (frequently viral) that resolves but is followed by other febrile viral illnesses that may be less well defined. Diagnosis of pseudo-FUO usually requires a careful history, focusing on identifying afebrile periods between febrile episodes. If pseudo-FUO is suspected and the patient does not appear ill, keeping a fever diary can be helpful.

Physical Examination A complete physical examination is essential to search for any clues to the underlying diagnosis, and often it is worthwhile to repeat a detailed examination on different days to detect signs that may have changed or been missed (Tables 204.3 and 204.4 ). The child's general appearance, including sweating during fever, should be noted. The continuing absence of sweat in the presence of an

elevated or changing body temperature suggests dehydration caused by vomiting, diarrhea, or central or nephrogenic diabetes insipidus. It also should suggest anhidrotic ectodermal dysplasia, familial dysautonomia, or exposure to atropine. The general activity of the patient and the presence or absence of rashes should also be noted. Table 204.3

Subtle Physical Findings with Special Significance in Patients with Fever of Unknown Origin BODY SITE Head Temporal artery Oropharynx

Fundi or conjunctivae Thyroid Heart

Abdomen

Rectum Genitalia Spine Lower extremities Upper or lower extremities Skin and nails

PHYSICAL FINDING Sinus tenderness Nodules, reduced pulsations Ulceration

DIAGNOSIS Sinusitis Temporal arteritis Disseminated histoplasmosis, SLE, IBD, Behçet syndrome, periodic fever syndromes Tender tooth Periapical abscess, sinus referred pain Choroid tubercle Disseminated granulomatosis* Petechiae, Roth spots Endocarditis Enlargement, tenderness Thyroiditis Murmur Infective or marantic endocarditis Relative bradycardia Typhoid fever, malaria, leptospirosis, psittacosis, central fever, drug fever Enlarged iliac crest lymph nodes, Lymphoma, endocarditis, disseminated splenomegaly granulomatosis* Audible abdominal aortic or renal artery Large vessel vasculitis such as Takayasu arteritis bruit Costovertebral tenderness Chronic pyelonephritis, perinephric abscess Perirectal fluctuance, tenderness Abscess Prostatic tenderness, fluctuance Abscess Testicular nodule Periarteritis nodosa, cancer Epididymal nodule Disseminated granulomatosis Spinal tenderness Vertebral osteomyelitis Paraspinal tenderness Paraspinal collection Deep venous tenderness Thrombosis or thrombophlebitis Pseudoparesis

Syphilitic bone disease

Petechiae, splinter hemorrhages, subcutaneous nodules, clubbing

Vasculitis, endocarditis

* Includes tuberculosis, histoplasmosis, coccidioidomycosis, sarcoidosis, granulomatosis with

polyangiitis, and syphilis. Adapted from Mackowak PA, Durack DT: Fever of unknown origin. In Mandell GL, Bennett, JE, Dolin R, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 7, Philadelphia, 2010, Elsevier (Table 51-8).

Table 204.4 Examples of Potential Diagnostic Clues to Infections Presenting as Fever of Unknown Origin ETIOLOGY Anaplasmosis

HISTORICAL CLUES Transmitted by bite of Ixodes tick in association with outdoor activity in northern-central and eastern United States Transmitted by bite of Ixodes tick in association with outdoor activity in northeastern United States

PHYSICAL CLUES Fever, headache, arthralgia, myalgia, pneumonitis, thrombocytopenia, lymphopenia, elevated liver enzymes Babesiosis Arthralgias, myalgias, relative bradycardia, hepatosplenomegaly, anemia, thrombocytopenia, elevated liver enzymes Bartonellosis Recent travel to Andes Mountains (Oroya fever; Conjunctivitis, retroorbital pain, Bartonella bacilliformis ), association with anterior tibial bone pain, macular rash, homelessness in urban settings (Bartonella nodular plaque lesions, regional quintana ) or scratch of infected kitten or feral cat lymphadenopathy (Bartonella henselae ) Blastomycosis Contact with soil adjacent to Mississippi and Ohio Arthritis, atypical pneumonia, River valleys, Saint Lawrence River in New York pulmonary nodules, and/or fulminant and Canada, and North American Great Lakes or adult respiratory distress syndrome; exposure to infected dogs verrucous, nodular, or ulcerative skin lesions; prostatitis Brucellosis Associated with contact or consumption of Arthralgias, hepatosplenomegaly, products from infected goats, pigs, camels, yaks, suppurative musculoskeletal lesions, buffalo, or cows and with abattoir work sacroiliitis, spondylitis, uveitis, hepatitis, pancytopenia Coccidioidomycosis Exposure to soil or dust in southwestern United Arthralgias, pneumonia, pulmonary States cavities, pulmonary nodules, erythema multiforme, erythema nodosum Ehrlichiosis Transmitted by bite of Amblyomma, Dermacentor, Pneumonitis, hepatitis, or Ixodes tick in association with outdoor activity thrombocytopenia, lymphopenia in midwestern and southeastern United States Enteric fever Recent travel to a low- or middle-income country Headache, arthritis, abdominal pain, (Salmonella (LMIC) with consumption of potentially relative bradycardia, enterica serovar contaminated food or water hepatosplenomegaly, leukopenia typhi ) Histoplasmosis Exposure to bat or blackbird excreta in roosts, Headache, pneumonia, pulmonary chicken houses, or caves in region surrounding cavities, mucosal ulcers, adenopathy, Ohio and Mississippi River valleys erythema nodosum, erythema multiforme, hepatitis, anemia, leukopenia, thrombocytopenia Leptospirosis Occupational exposure among workers in sewers, Bitemporal and frontal headache, calf rice and sugarcane fields, and abattoirs; and lumbar muscle tenderness, recreational water sports and exposure to conjunctival suffusion, hepatic and contaminated waters or infected dogs renal failure, hemorrhagic pneumonitis Leishmaniasis Associated with recent travel to areas endemic for Hepatosplenomegaly, (visceral disease) sand flies lymphadenopathy, and hyperpigmentation of face, hand, foot, and abdominal skin (kala-azar) Malaria

Recent travel to endemic areas in Asia, Africa, and Fever, headaches, nausea, emesis, Central/South America diarrhea, hepatomegaly, splenomegaly, anemia

Psittacosis Associated with contact with birds, especially (Chlamydia psittaci psittacine birds )

Q fever (Coxiella burnetii ) Rat-bite fever (Streptobacillus moniliformis ) Relapsing fever (Borrelia recurrentis ) Rocky Mountain spotted fever Tuberculosis

Tularemia

Whipple disease (Tropheryma whipplei )

Fever, pharyngitis, hepatosplenomegaly, pneumonia, blanching maculopapular eruptions; erythema multiforme, marginatum, and nodosum Associated with farm, veterinary, or abattoir work; Atypical pneumonia, hepatitis, consumption of unpasteurized milk; contact with hepatomegaly, relative bradycardia, infected sheep, goats, or cattle splenomegaly Recent bite or scratch by rat, mouse, or squirrel; Headaches, myalgias, polyarthritis, and ingestion of food or water contaminated by rat maculopapular, morbilliform, petechial, excrement vesicular, or pustular rash over the palms, soles, and extremities Associated with poverty, crowding, and poor High fever with rigors, headache, sanitation (louse-borne), or with camping (tickdelirium, arthralgias, myalgias, and borne), particularly in the Grand Canyon hepatosplenomegaly Associated with outdoor activity in the South Headache, petechial rash involving the Atlantic or southeastern United States and extremities, palms, and soles exposure to Dermacentor tick bites Recent contact with tuberculosis; recent Night sweats, weight loss, atypical immigration from endemic country; work or pneumonia, cavitary pulmonary lesions residence in homeless shelters, correctional facilities, or healthcare facilities Associated with bites by Amblyomma or Ulcerated skin lesions at a bite site, Dermacentor ticks, deer flies, and mosquitoes or pneumonia, relative bradycardia, direct contact with tissues of infected animals such lymphadenopathy, conjunctivitis as rabbits, squirrels, deer, raccoons, cattle, sheep, and swine Potential association with exposure to sewage Chronic diarrhea, arthralgia, weight loss, malabsorption, malnutrition

Adapted from Wright WF, Mackowiak PA: Fever of unknown origin. In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier (Table 56-9).

A careful ophthalmic examination is important. Red, weeping eyes may be a sign of connective tissue disease, particularly polyarteritis nodosa. Palpebral conjunctivitis in a febrile patient may be a clue to measles, coxsackievirus infection, tuberculosis, infectious mononucleosis, lymphogranuloma venereum, or cat-scratch disease. In contrast, bulbar conjunctivitis in a child with FUO suggests Kawasaki disease or leptospirosis. Petechial conjunctival hemorrhages suggest infective endocarditis. Uveitis suggests sarcoidosis, JIA, SLE, Kawasaki disease, Behçet disease, and vasculitis. Chorioretinitis suggests CMV, toxoplasmosis, and syphilis. Proptosis suggests an orbital tumor, thyrotoxicosis, metastasis (neuroblastoma), orbital infection, Wegener granulomatosis (granulomatosis with polyangiitis), or pseudotumor. The ophthalmoscope should also be used to examine nail-fold capillary abnormalities that are associated with connective tissue diseases such as juvenile dermatomyositis and systemic scleroderma. Immersion oil or lubricating jelly is

placed on the skin adjacent to the nail bed, and the capillary pattern is observed with the ophthalmoscope set on +40. FUO is sometimes caused by hypothalamic dysfunction . A clue to this disorder is failure of pupillary constriction because of absence of the sphincter constrictor muscle of the eye. This muscle develops embryologically when hypothalamic structure and function also are undergoing differentiation. Fever resulting from familial dysautonomia may be suggested by lack of tears, an absent corneal reflex, or a smooth tongue with absence of fungiform papillae. Tenderness to tapping over the sinuses or the upper teeth suggests sinusitis. Recurrent oral candidiasis may be a clue to various disorders of the immune system, especially involving the T lymphocytes. Hyperactive deep tendon reflexes can suggest thyrotoxicosis as the cause of FUO. Hyperemia of the pharynx, with or without exudate, suggests streptococcal infection, Epstein-Barr virus infection, CMV infection, toxoplasmosis, salmonellosis, tularemia, Kawasaki disease, gonococcal infection, or leptospirosis. The muscles and bones should be palpated carefully. Point tenderness over a bone can suggest occult osteomyelitis or bone marrow invasion from neoplastic disease. Tenderness over the trapezius muscle may be a clue to subdiaphragmatic abscess. Generalized muscle tenderness suggests dermatomyositis, trichinosis, polyarteritis, Kawasaki disease, or mycoplasma or arboviral infection. Rectal examination can reveal perirectal lymphadenopathy or tenderness, which suggests a deep pelvic abscess, iliac adenitis, or pelvic osteomyelitis. A guaiac test should be obtained; occult blood loss can suggest granulomatous colitis or ulcerative colitis as the cause of FUO.

Laboratory Evaluation The laboratory evaluation of the child with FUO and whether inpatient or outpatient are determined on a case-by-case basis. Hospitalization may be required for laboratory or imaging studies that are unavailable or impractical in an ambulatory setting, for more-careful observation, or for temporary relief of parental anxiety. The tempo of diagnostic evaluation should be adjusted to the tempo of the illness; haste may be imperative in a critically ill patient, but if the illness is more chronic, the evaluation can proceed in a systematic manner and can be carried out in an outpatient setting. If there are no clues in the patient's history or on physical examination that suggest a specific infection or area of

suspicion, it is unlikely that diagnostic studies will be helpful. In this common scenario, continued surveillance and repeated reevaluations of the child should be employed to detect any new clinical findings. Although ordering a large number of diagnostic tests in every child with FUO according to a predetermined list is discouraged, certain studies should be considered in the evaluation. A complete blood cell count (CBC) with a white blood cell (WBC) differential and a urinalysis should be part of the initial laboratory evaluation. An absolute neutrophil count (ANC) of 10,000/µL or a nonsegmented PMN count of >500/µL, a severe bacterial infection is highly likely. Direct examination of the blood smear with Giemsa or Wright stain can reveal organisms of malaria, trypanosomiasis, babesiosis, or relapsing fever. An erythrocyte sedimentation rate (ESR) >30 mm/hr indicates inflammation and the need for further evaluation for infectious, autoimmune, autoinflammatory, or malignant diseases, tuberculosis, Kawasaki disease, or autoimmune disease. A low ESR does not eliminate the possibility of infection or JIA. C-reactive protein (CRP) is another acute-phase reactant that becomes elevated and returns to normal more rapidly than the ESR. Experts recommend checking either ESR or CRP, because there is no evidence that measuring both in the same patient with FUO is clinically useful. Blood cultures should be obtained aerobically. Anaerobic blood cultures have an extremely low yield and should be obtained only if there are specific reasons to suspect anaerobic infection. Multiple or repeated blood cultures may be required to detect bacteremia associated with infective endocarditis, osteomyelitis, or deep-seated abscesses. Polymicrobial bacteremia suggests factitious or self-induced infection or GI pathology. The isolation of leptospires, Francisella, or Yersinia requires selective media or specific conditions not routinely used. Therefore, it is important to inform the laboratory what organisms are suspected in a particular case. Urine culture should be obtained in all cases. Tuberculin skin testing (TST) should be performed with intradermal placement of 5 units of purified protein derivative that has been kept appropriately refrigerated. In children >2 yr old, it is reasonable to test for tuberculosis using an interferon-γ release assay (IGRA). Imaging studies of the chest, sinuses, mastoids, or GI tract may be indicated

by specific historical or physical findings. Radiographic evaluation of the GI tract for IBD may be helpful in evaluating selected children with FUO and no other localizing signs or symptoms. Examination of the bone marrow can reveal leukemia; metastatic neoplasm; mycobacterial, fungal, or parasitic infections; histiocytosis; hemophagocytosis; or storage diseases. If a bone marrow aspirate is performed, cultures for bacteria, mycobacteria, and fungi should be obtained. Serologic tests can aid in the diagnosis of EBV infection, CMV infection, toxoplasmosis, salmonellosis, tularemia, brucellosis, leptospirosis, cat-scratch disease, Lyme disease, rickettsial disease, and on some occasions JIA. The clinician should be aware that the reliability and the sensitivity and specificity of these tests vary; for example, serologic tests for Lyme disease outside of reference laboratories have been generally unreliable. Radionuclide scans may be helpful in detecting abdominal abscesses as well as osteomyelitis, especially if the focus cannot be localized to a specific limb or multifocal disease is suspected. Gallium citrate localizes inflammatory tissues (leukocytes) associated with tumors or abscesses. Technetium-99m phosphate is useful for detecting osteomyelitis before plain radiographs demonstrate bone lesions. Granulocytes tagged with indium or iodinated IgG may be useful in detecting localized pyogenic processes. 18 F-fluorodeoxyglucose positron emission tomography (PET) is a helpful imaging modality in adults with an FUO and can contribute to an ultimate diagnosis in 30–60% of patients. Echocardiograms can demonstrate vegetation on the leaflets of heart valves, suggesting infective endocarditis. Ultrasonography (US) can identify intraabdominal abscesses of the liver, subphrenic space, pelvis, or spleen. Total body CT or MRI (both with contrast) is usually the first imaging study of choice; both permit detection of neoplasms and collections of purulent material without the use of surgical exploration or radioisotopes. CT and MRI are helpful in identifying lesions of the head, neck, chest, retroperitoneal spaces, liver, spleen, intraabdominal and intrathoracic lymph nodes, kidneys, pelvis, and mediastinum. CT or US-guided aspiration or biopsy of suspicious lesions has reduced the need for exploratory laparotomy or thoracotomy. MRI is particularly useful for detecting osteomyelitis or myositis if there is concern about a specific limb. Diagnostic imaging can be very helpful in confirming or evaluating a suspected diagnosis. With CT scans, however, the child is exposed to large amounts of radiation. PET-CT or MRI may help localize an occult tumor. Biopsy is occasionally helpful in establishing a diagnosis of FUO.

Bronchoscopy, laparoscopy, mediastinoscopy, and GI endoscopy can provide direct visualization and biopsy material when organ-specific manifestations are present. When employing any of the more invasive testing procedures, the risk/benefit ratio for the patient must always be considered before proceeding further.

Management The ultimate treatment of FUO is tailored to the underlying diagnosis. Fever and infection in children are not synonymous, and antimicrobial agents should only be used when there is evidence of infection, with avoidance of empirical trials of medication. An exception may be the use of antituberculous treatment in critically ill children with suspected disseminated tuberculosis. Empirical trials of other antimicrobial agents may be dangerous and can obscure the diagnosis of infective endocarditis, meningitis, parameningeal infection, or osteomyelitis. After a complete evaluation, antipyretics may be indicated to control fever associated with adverse symptoms.

Prognosis Children with FUO have a better prognosis than adults. The outcome in a child depends on the primary disease process. In many cases, no diagnosis can be established, and fever abates spontaneously. In as many as 25% of children in whom fever persists, the cause of the fever remains unclear, even after thorough evaluation. In a series of 69 patients referred for “prolonged” unexplained fever, 10 were not actually having fever, and 11 had diagnoses that were readily apparent at the initial visit. The remaining 48 were classified as having FUO. The median duration of reported fever for these patients was 30 days. Fifteen received a diagnosis, and 10 (67%) had confirmed infections: acute EBV or CMV infection (n = 5; with 1 patient developing hemophagocytic lymphohistiocytosis); catscratch disease (3); and histoplasmosis (2). The other 5 patients had inflammatory conditions (systemic JIA, 2; IBD, 1), central fever (1), or malignancy (acute lymphoblastic leukemia, 1).

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procalcitonin in well-appearing young febrile infants. Pediatrics . 2012;130:815. Gómez B, Mintegi S, Benito J, et al. Blood culture and bacteremia predictors in infants less than three months of age with fever without source. Pediatr Infect Dis J . 2010;29:43– 47. Greenhow TL, Hung YY, Herz AM. Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics . 2012;129:e590–e596. Horowitz HW. Fever of unknown origin or fever of too many origins? N Engl J Med . 2013;368:197–199. Huppler AR, Eickhoff JC, Wald ER. Performance of low-risk criteria in the evaluation of young infants with fever: review of the literature. Pediatrics . 2010;125:228–233. Mahajan P, Ramilo O, Kuppermann N. The future possibilities of diagnostic testing for the evaluation of febrile infants. JAMA Pediatr . 2013;167:888–898. Naik JD, Sathiyaseelan SRK, Vasudev NS. Febrile neutropenia. BMJ . 2011;342:103–104. Oliveira CF, Botoni FA, Oliveira CRA, et al. Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial. Crit Care Med . 2013;41:2336– 2343. Segal I, Ehrlichman M, Urbach J, Bar-Meir M. Use of time from fever onset improves the diagnostic accuracy of Creactive protein in identifying bacterial infections. Arch Dis Child . 2014;99:974–978. Statler VA, Marshall GS. Characteristics of patients referred to a pediatric infectious diseases clinic with unexplained fever. J Pediatr Infect Dis . 2016;5:249–256. Thompson MJ, van den Bruel A. Diagnosing serious bacterial infection in young febrile children. BMJ . 2010;340:c2062. Van den Bruel A, Haj-Hassan T, Thompson M, et al. Diagnostic

value of clinical features at presentation to identify serious infection in children in developed countries: a systematic review. Lancet . 2010;375:834–844. Vidwan G, Geis G. Evaluation, management, and outcome of focal bacterial infections (FBIs) in nontoxic infants under two months of age. J Hosp Med . 2010;5:76–82. Yo CH, Hsieh PS, Lee SH, et al. Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis. Ann Emerg Med . 2012;60:591– 600.

CHAPTER 205

Infections in Immunocompromised Persons Marian G. Michaels, Hey Jin Chong, Michael Green

Infection and disease develop when the host immune system fails to protect adequately against potential pathogens. In individuals with an intact immune system, infection occurs in the setting of naïveté to the microbe and absence of or inadequate preexisting microbe-specific immunity, or when protective barriers of the body such as the skin have been breached. Healthy children are able to meet the challenge of most infectious agents with an immunologic armamentarium capable of preventing significant disease. Once an infection begins to develop, an array of immune responses is set into action to control the disease and prevent it from reappearing. In contrast, immunocompromised children might not have this same capability. Depending on the level and type of immune defect, the affected child might not be able to contain the pathogen or develop an appropriate immune response to prevent recurrence. General practitioners are likely to see children with an abnormal immune system in their practice because increasing numbers of children survive with primary immunodeficiencies or receive immunosuppressive therapy for treatment of malignancy, autoimmune disorders, or transplantation. Primary immunodeficiencies are compromised states that result from genetic defects affecting one or more arms of the immune system. Acquired, or secondary, immunodeficiencies may result from infection (e.g., infection with HIV), from malignancy, or as an adverse effect of immunomodulating or immunosuppressing medications. The latter include medications that affect T cells (corticosteroids, calcineurin inhibitors, tumor necrosis factor [TNF] inhibitors, chemotherapy), neutrophils (myelosuppressive agents, idiosyncratic or immune-mediated neutropenia), specific immunoregulatory cells (TNF blockers, interleukin-2 inhibitors), or all immune cells (chemotherapy).

Perturbations of the mucosal and skin barriers or the normal microbial flora can also be characterized as secondary immunodeficiencies, predisposing the host to infections, if only temporarily. The major pathogens causing infections among immunocompetent hosts are also the main pathogens responsible for infections among children with immunodeficiencies. In addition, less virulent organisms, including normal skin flora, commensal bacteria of the oropharynx or gastrointestinal (GI) tract, environmental fungi, and common community viruses of low-level pathogenicity, can cause severe, life-threatening illnesses in immunocompromised patients (Table 205.1 ). For this reason, close communication with the diagnostic laboratory is critical to ensure that the laboratory does not disregard normal flora and organisms normally considered contaminants as being unimportant. Table 205.1

Most Common Causes of Infections in Immunocompromised Children BACTERIA, AEROBIC Acinetobacter Bacillus Burkholderia cepacia Citrobacter Corynebacterium Enterobacter spp. Enterococcus faecalis Enterococcus faecium Escherichia coli Klebsiella spp. Listeria monocytogenes Mycobacterium spp. Neisseria meningitidis Nocardia spp. Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus, coagulase-negative Streptococcus pneumoniae Streptococcus, viridans group BACTERIA, ANAEROBIC Bacillus Clostridium Fusobacterium Peptococcus Peptostreptococcus Propionibacterium Veillonella

FUNGI Aspergillus Candida albicans Other Candida spp. Cryptococcus neoformans Fusarium spp. Pneumocystis jiroveci Zygomycoses (Mucor, Rhizopus, Rhizomucor) VIRUSES Adenoviruses Cytomegalovirus Epstein-Barr virus Herpes simplex virus Human herpesvirus 6 Polyomavirus (BK) Respiratory and enteric community-acquired viruses Varicella-zoster virus PROTOZOA Cryptosporidium parvum Giardia lamblia Toxoplasma gondii

205.1

Infections Occurring With Primary Immunodeficiencies Marian G. Michaels, Hey Jin Chong, Michael Green

Currently, more than 300 genes involving inborn errors of immunity have been identified, accounting for a wide array of diseases presenting with susceptibility to infection, allergy, autoimmunity, and autoinflammation, as well as malignancy.

Abnormalities of the Phagocytic System Children with abnormalities of the phagocytic and neutrophil system have problems with bacteria as well as environmental fungi. Disease manifests as

recurrent infections of the skin, mucous membranes, lungs, liver, and bones. Dysfunction of this arm of the immune system can be a result of inadequate numbers, abnormal movement properties, or aberrant function of neutrophils (see Chapter 153 ). Neutropenia is defined as an absolute neutrophil count (ANC) of 180 days); most infections present in the 1st 180 days after transplantation. Table 205.4 should be used as a general guideline to the types of infections encountered but may be modified with the introduction of newer immunosuppressive therapies and by the use of prophylaxis. Table 205.4

Timing of Infectious Complications After Solid-Organ Transplantation EARLY PERIOD (0-30 DAYS) Bacterial Infections Gram-negative enteric bacilli • Small bowel, liver, neonatal heart Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes • Cystic fibrosis lung Gram-positive organisms • All transplant types Fungal Infections • All transplant types Viral Infections

Herpes simplex virus • All transplant types Nosocomial respiratory viruses • All transplant types MIDDLE PERIOD (1-6 MO) Viral Infections Cytomegalovirus • All transplant types • Seronegative recipient of seropositive donor Epstein-Barr virus • All transplant types (small bowel the highest-risk group) • Seronegative recipient Varicella-zoster virus • All transplant types • Opportunistic infections Pneumocystis jiroveci • All transplant types Toxoplasma gondii • Seronegative recipient of cardiac transplant from a seropositive donor Bacterial Infections Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes • Cystic fibrosis lung Gram-negative enteric bacilli • Small bowel LATE PERIOD (>6 MO) Viral Infections Epstein-Barr virus • All transplant types, but less risk than middle period Varicella-zoster virus • All transplant types Community-acquired viral infections • All transplant types Bacterial Infections Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes • Cystic fibrosis lung • Lung transplants with chronic rejection Gram-negative bacillary bacteremia • Small bowel Fungal Infections Aspergillus • Lung transplants with chronic rejection

Adapted from Green M, Michaels MG: Infections in solid organ transplant recipients. In Long SS, Prober C, Fisher M, editors: Principles and practice of pediatric infectious disease , ed 5, Philadelphia, 2018, Elsevier (Table 95-1).

Early infections are usually the result of a complication of the transplant surgery itself, the unexpected acquisition of a bacterial or fungal pathogen from the donor, or the presence of an indwelling catheter. In contrast, infections during the intermediate period typically result from a complication of the immunosuppression, which tends to be at its greatest intensity during the 1st 6 mo after transplantation. This is the period of greatest risk for infections caused by opportunistic pathogens such as CMV, EBV, and P. jiroveci. Anatomic

abnormalities, such as bronchial stenosis and biliary stenosis, that develop as a result of the transplant surgery can also predispose to recurrent infection in this period. Infections developing late after transplantation typically result from uncorrected anatomic abnormalities, chronic rejection, or exposure to community-acquired pathogens. Augmented immunosuppression as treatment for late, acute cellular rejection or chronic rejection can increase the risk for late presentations with CMV, EBV, and other potential opportunistic infections. Acquisition of infection from community-acquired pathogens such as RSV can result in severe infection secondary to the immunocompromised state of the transplant recipient during the early and intermediate periods. Compared with the earlier periods, community-acquired infections in the late period are usually benign, because immunosuppression is typically maintained at significantly lower levels. However, certain pathogens such as VZV and EBV may be associated with severe disease even at this late period.

Bacterial and Fungal Infections Although there are important graft-specific considerations for bacterial and fungal infections following transplantation, some principles are generally applicable to all transplant recipients. Bacterial and fungal infections after organ transplantation are usually a direct consequence of the surgery, a breach in an anatomic barrier, a foreign body, or an abnormal anatomic narrowing or obstruction. With the exception of infections related to the use of indwelling catheters, sites of bacterial infection tend to occur at or near the transplanted organ. Infections following abdominal transplantation (liver, intestine, or renal) usually occur in the abdomen or at the surgical wound. The pathogens are typically enteric gram-negative bacteria, Enterococcus, and occasionally Candida. Infections after thoracic transplantation (heart, lung) usually occur in the lower respiratory tract or at the surgical wound. Pathogens associated with these infections include S. aureus and gram-negative bacteria. Patients undergoing lung transplantation for cystic fibrosis experience a particularly high rate of infectious complications, because they are often colonized with P. aeruginosa or Aspergillus before transplantation. Even though the infected lungs are removed, the sinuses and upper airways remain colonized with these pathogens, and subsequent reinfection of the transplanted lungs can occur. Children receiving organ transplants are often hospitalized for long periods and receive many antibiotics; thus recovery of bacteria with multiple antibiotic

resistance patterns is common after all types of organ transplantation. Infections caused by Aspergillus are less common but occur after all types of organ transplantation and are associated with high rates of morbidity and mortality.

Viral Infections Viral pathogens, especially herpesviruses, are a major source of morbidity and mortality following solid-organ transplantation. In addition, BK virus is a major cause of renal disease after kidney transplantation. The patterns of disease associated with individual viral pathogens are generally similar among all organ transplant recipients. However, the incidence, mode of presentation, and severity differ according to type of organ transplanted and, for many viral pathogens, pretransplant serologic status of the recipient. Viral pathogens can be generally categorized as latent pathogens, which cause infection through reactivation in the host or acquisition from the donor (e.g., CMV, EBV) or as community-acquired viruses (e.g., RSV). For CMV and EBV, primary infection occurring after transplantation is associated with the greatest degree of morbidity and mortality. The highest risk is seen in a naïve host who receives an organ from a donor who previously was infected with one of these viruses. This mismatched state is frequently associated with severe disease. However, even if the donor is negative for CMV and EBV, primary infection can be acquired from a close contact or through blood products. Secondary infections (reactivation of a latent strain within the host or superinfection with a new strain) tend to result in milder illness unless the patient is highly immunosuppressed, which can occur in the setting of treatment of significant rejection. CMV is one of the most commonly recognized transplant viral pathogens. Disease from CMV has decreased significantly with the use of preventive strategies, including antiviral prophylaxis as well as viral load monitoring to inform preemptive antiviral therapy. Some centers have implemented a hybrid approach where surveillance viral load monitoring follows a relatively short period (2-4 wk) of chemoprophylaxis. Clinical manifestations of CMV disease can range from a syndrome of fatigue and fever to tissue invasive disease that most often affects the liver, lungs, and GI tract. Infection caused by EBV is another important complication of solid-organ transplantation. Clinical symptoms range from a mild mononucleosis syndrome to disseminated posttransplant lymphoproliferative disorder . Posttransplant lymphoproliferative disorder is more common among children than adults,

because primary EBV infection in the immunosuppressed host is more likely to lead to uncontrolled proliferative disorders, including posttransplant lymphoma. Other viruses, such as adenovirus, also have the capacity to be donor associated, but appear to be less common. The unexpected development of donor-associated viral pathogens, including hepatitis B virus, hepatitis C virus, and HIV, is rare today because of intensive donor screening. However, the changing epidemiology of some viruses (e.g., dengue, chikungunya, Zika) raises concerns for the donor-derived transmission of these emerging viral pathogens. Community-acquired viruses, including those associated with respiratory tract infection (RSV, influenza virus, adenovirus, parainfluenza virus) and GI infection (enteroviruses, norovirus, and rotavirus), can cause important disease in children after organ transplantation. In general, risk factors for more severe infection include young age, acquisition of infection early after transplantation, and augmented immune suppression. Infection in the absence of these risk factors frequently results in a clinical illness that is comparable to that seen in immunocompetent children. However, some community-acquired viruses, such as adenovirus, can be associated with graft dysfunction even when acquired late after transplantation.

Opportunistic Pathogens Children undergoing solid-organ transplantation are also at risk for symptomatic infections from pathogens that do not usually cause clinical disease in immunocompetent hosts. Although these typically present in the intermediate period, these infections can also occur late in patients, requiring prolonged and high levels of immunosuppression. P. jiroveci is a well-recognized cause of pneumonia after solid-organ transplantation, although routine prophylaxis has essentially eliminated this problem. T. gondii can complicate cardiac transplantations because of tropism of the organism for cardiac muscle and risk for donor transmission; less often it complicates other types of organ transplantation.

Bibliography Blumberg EA, Danziger-Isakov L, Kumar D, et al. Infectious diseases guidelines, ed 3. [editors] Am J Transplant . 2013;13(Suppl 4):1–371.

Castagnola E, Fontana V, Caviglia I, et al. A prospective study on the epidemiology of febrile episodes during chemotherapy induced neutropenia in children with cancer or after hematopoietic stem cell transplantation. Clin Infect Dis . 2007;45:1296–1304. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis . 2011;52:e56–e93. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol . 2012;30:4427–4438. Palazzi DL. The use of antimicrobial agents in children with fever during chemotherapy-induced neutropenia. Pediatr Infect Dis J . 2011;30:887–890. Phillips R, Hancock B, Graham J, et al. Prevention and management of neutropenic sepsis in patients with cancer: summary of NICE guidance. BMJ . 2012;345:47–49. Pizzo PA, Robichaud KJ, Wesley R, et al. Fever in the pediatric and young adult patient with cancer: a prospective study of 1001 episodes. Medicine (Baltimore) . 1982;61:153–165.

205.3

Prevention of Infection in Immunocompromised Persons Marian G. Michaels, Hey Jin Chong, Michael Green

Although infections cannot be completely prevented in children who have defects in one or more arms of their immune system, measures can be taken to decrease the risks for infection. Replacement immunoglobulin is a benefit to children with primary B cell deficiencies. Interferon (IFN)-γ, TMP-SMX, and oral antifungal agents have long been used to reduce the number of infections occurring in children with CGD, although the relative benefit of INF-γ has been questioned. Children who have depressed cellular immunity resulting from primary diseases, advanced HIV infection, or immunosuppressive medications benefit from prophylaxis against P. jiroveci. Immunizations prevent many infections and are particularly important for children with compromised immune systems who do not have a contraindication or inability to respond. For children rendered immunocompromised because of medication or splenectomy, immunizations should be administered before treatment. This timing allows for superior response to vaccine antigens, avoids the risk of live vaccines, which may be contraindicated depending on the immunosuppression, and importantly provides protection before the immune system is compromised. Although immunodeficient children are a heterogeneous group, some principles of prevention are generally applicable. The use of inactivated vaccines does not lead to an increased risk for adverse effects, although their efficacy may be reduced because of an impaired immune response. In most cases, children with immunodeficiencies should receive all the recommended inactivated vaccines. Live-attenuated vaccinations can cause disease in some children with immunologic defects, and therefore alternative immunizations should be used whenever possible, such as inactivated influenza vaccine rather than liveattenuated influenza vaccine or inactivated typhoid vaccine rather than the oral live typhoid vaccine for travelers. In general, live-virus vaccines should not be used in children with primary T cell abnormalities; efforts should be made to ensure that close contacts are all immunized to decrease the risk of exposure. In some patients in whom wild-type viral infection can be severe, immunizations, even with live-virus vaccine, are warranted in the immunosuppressed child. For example, children with HIV infection and a CD4 level of >15% should receive vaccinations against measles and varicella. Some vaccines should be given to children with immunodeficiencies in addition to routine vaccinations. As an example, children with asplenia or splenic dysfunction should receive meningococcal vaccine and both the conjugate and the polysaccharide pneumococcal vaccines. Influenza vaccination is recommended for all individuals >6 mo old and should be emphasized for immunocompromised

children as well as all household contacts, to minimize risk for transmission to the immunocompromised child.

Bibliography Blumberg EA, Danziger-Isakov L, Kumar D, et al. Infectious diseases guidelines, ed 3. [editors] Am J Transplant . 2013;13(Suppl 4):1–371. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis . 2011;52:e56–e93. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol . 2012;30:4427–4438.

CHAPTER 206

Infection Associated With Medical Devices Joshua Wolf, Patricia M. Flynn

Use of implanted synthetic and prosthetic devices has revolutionized pediatric practice by providing long-term venous access, limb-salvage surgery, and successful treatment of hydrocephalus, urinary retention, and renal failure. However, infectious complications of these devices remain a major concern. These infections are related to the development of biofilms , organized communities of microorganisms on the device surface protected from the immune system and from antimicrobial therapy. A number of factors are important to the development of infection, including host susceptibility, device composition, duration of implantation, and exposure to colonizing organisms.

Intravascular Access Devices Intravascular access devices range from short, stainless steel needles or plastic cannulae inserted for brief periods to multilumen implantable synthetic plastic catheters that are expected to remain in use for years. Infectious complications include local skin and soft tissue infections such as exit-site, tunnel-tract, and device-pocket infections, and catheter-related bloodstream infections (CRBSIs) . The use of central venous devices has improved the quality of life of high-risk patients but has also increased the risk of infection.

Catheter Types Short-term peripheral cannulae are most often used in pediatric patients, and infectious complications occur infrequently. The rate of peripheral CRBSIs in

children is 70%), although some case reports of cure with antimicrobial lock therapy are promising. Other indications for removing a long-term catheter include severe sepsis, suppurative thrombophlebitis, and endocarditis. Prolonged therapy (4-6 wk) is indicated for persistent bacteremia or fungemia despite catheter removal, since this may represent unrecognized infective endocarditis or thrombophlebitis. The decision to attempt catheter salvage should weigh the risk and clinical impact of persistent or relapsed infection against the risk of surgical intervention. CRBSI may be complicated by other intravascular infections such as septic

thrombophlebitis or endocarditis. Presence of these conditions may be suggested by preexisting risk factors (e.g., congenital heart disease), signs and symptoms, or persistent bacteremia or fungemia 72 hr after device removal and appropriate therapy. Screening for these complications in otherwise low-risk children, even those with S. aureus infection, is not recommended, because the overall frequency is low and the tests can be difficult to interpret and may lead to inappropriate therapy.

Prevention of Infection Catheters should routinely be removed as soon as they are no longer needed. Although prevalence of infection increases with prolonged duration of catheter use, routine replacement of a required CVC, either at a new site or over a guidewire, results in significant morbidity and is not recommended. Optimal prevention of infections related to long-term vascular access devices includes “bundles” of interventions, including meticulous aseptic surgical insertion technique in an operating room–like environment, avoidance of bathing or swimming (except with totally implantable devices), and careful catheter care. Use of antibiotic, taurolidine, or ethanol lock solutions; heparin with preservatives; and alcohol-impregnated caps, as well as antimicrobialimpregnated/coated catheters, all reduce the risk of CRBSIs and may be appropriate in high-risk populations. There is no evidence that routine replacement of short-term peripheral catheters prevents phlebitis or other complications in children, so they should only be replaced when clinically indicated (e.g., phlebitis, dysfunction, dislodgment).

Cerebrospinal Fluid Shunts Cerebrospinal fluid (CSF) shunting is required for the treatment of many children with hydrocephalus . The usual procedure uses a silicone rubber device with a proximal portion inserted into the ventricle, a unidirectional valve, and a distal segment that diverts the CSF from the ventricles to either the peritoneal cavity (ventriculoperitoneal [VP] shunt) or right atrium (ventriculoatrial [VA] shunt). The incidence of shunt infection ranges from 1–20% (average, 10%). The highest rates are reported in young infants, patients with prior shunt infections, and certain etiologies of hydrocephalus. Most infections result from intraoperative contamination of the surgical wound by skin flora. Accordingly,

coagulase-negative staphylococci are isolated in more than half the cases. S. aureus is isolated in approximately 20% and gram-negative bacilli in 15% of cases. Four distinct clinical syndromes have been described: colonization of the shunt, infection associated with wound infection, distal infection with peritonitis, and infection associated with meningitis. The most common type of infection is colonization of the shunt , with nonspecific symptoms that reflect shunt malfunction as opposed to frank infection. Symptoms associated with colonized VP shunts include lethargy, headache, vomiting, a full fontanel, and abdominal pain. Fever is common but may be 30 days develop bacteriuria. The organism burden in catheterassociated urinary tract infection (UTI) is typically ≥10,000 colony-forming units/mL. Lower thresholds may be used where there is a high index of suspicion, but these episodes may represent colonization rather than infection. Urine culture should only be performed in catheterized patients when infection is suspected, because asymptomatic colonization is ubiquitous and may lead to overtreatment and subsequent development of bacterial resistance. Gramnegative bacilli and Enterococcus spp. are the predominant organisms isolated in catheter-related UTI; coagulase-negative staphylococci are implicated in approximately 15% of cases. Symptomatic UTIs should be treated with antibiotics and catheter removal. Catheter colonization with Candida spp. is common but rarely leads to invasive infection, and treatment does not have a long-term impact on colonization. Treatment for asymptomatic candiduria or bacteriuria is not recommended, except in neonates, immunocompromised

patients, and those with urinary tract obstruction.

Prevention of Infection All urinary catheters introduce a risk for infection, and their casual use should be avoided. When in place, their duration of use should be minimized. Technologic advances have led to development of silver- or antibiotic-impregnated urinary catheters that are associated with lower rates of infection. Prophylactic antibiotics do not significantly reduce the infection rates for long-term catheters but clearly increase the risk for infection with antibiotic-resistant organisms.

Peritoneal Dialysis Catheters During the 1st yr of peritoneal dialysis for end-stage renal disease, 65% of children will have 1 or more episodes of peritonitis. Bacterial entry comes from luminal or periluminal contamination of the catheter or by translocation across the intestinal wall. Hematogenous infection is rare. Infections can be localized at the exit site or associated with peritonitis, or both. Organisms responsible for peritonitis include coagulase-negative staphylococci (30–40%), Staphylococcus aureus (10–20%), streptococci (10–15%), Escherichia coli (5-10%), Pseudomonas spp. (5–10%), other gram-negative bacteria (5–15%), Enterococcus spp. (3–6%), and fungi (2–10%). S. aureus is more common in localized exit-site or tunnel-tract infections (42%). Most infectious episodes are caused by a patient's own flora, and carriers of S. aureus have increased rates of infection compared with noncarriers. The clinical manifestations of peritonitis may be subtle and include low-grade fever with mild abdominal pain or tenderness. Cloudy peritoneal dialysis fluid may be the first and predominant sign. With peritonitis, the peritoneal fluid cell count is usually >100 white blood cells/µL. When peritonitis is suspected, the effluent dialysate should be submitted for a cell count, Gram stain, and culture. The Gram stain is positive in up to 40% of cases of peritonitis. Patients with cloudy fluid and clinical symptoms should receive empirical therapy, preferably guided by results of a Gram stain. If no organisms are visualized, vancomycin and either an aminoglycoside or a third- or fourthgeneration cephalosporin with antipseudomonal activity should be given by the intraperitoneal route. Blood levels should be measured for glycopeptides and aminoglycosides. Patients without cloudy fluid and with minimal symptoms may

have therapy withheld pending culture results. Once the cause is identified by culture, changes in the therapeutic regimen may be needed. Oral rifampin may be added as adjunctive therapy for S. aureus infections, but drug interactions must be considered. Candidal peritonitis should be treated with catheter removal and intraperitoneal or oral fluconazole or an intravenous echinocandin such as caspofungin or micafungin, depending on the Candida spp. Catheter retention has been associated with almost inevitable relapse and higher risk of mortality in adult studies. The duration of therapy is a minimum of 14 days, with longer treatment of 21-28 days for episodes of S. aureus , Pseudomonas spp., and resistant gram-negative bacteria and 28-42 days for fungi. Repeat episodes of peritonitis with the same organism within 4 wk of previous therapy should lead to consideration of catheter removal or attempt at salvage with administration of a fibrinolytic agent and a longer a course of up to 6 wk of antibiotic therapy. In all cases, if the infection fails to clear following appropriate therapy, or if a patient's condition is deteriorating, the catheter should be removed. Exit-site and tunnel-tract infections may occur independently of peritonitis or may precede it. Appropriate antibiotics should be administered on the basis of Gram stain and culture findings and are typically given systemically only, unless peritonitis is also present. Some experts recommend that the peritoneal catheter be removed if Pseudomonas spp. or fungal organisms are isolated.

Prevention of Infection In addition to usual hygienic practices, regular application of mupirocin or gentamicin cream to the catheter exit site reduces exit-site infections and peritonitis. Some practitioners recommend against the use of gentamicin cream because of the risk of infection with gentamicin-resistant bacteria. Systemic antibiotic prophylaxis should be considered at catheter insertion, if there is accidental contamination, and at dental procedures. Antifungal prophylaxis with oral nystatin or fluconazole should be considered during antibiotic therapy to prevent fungal infection.

Orthopedic Prostheses Orthopedic prostheses are used infrequently in children. Infection most often follows introduction of microorganisms at surgery through airborne contamination or direct inoculation, hematogenous spread, or contiguous spread

from an adjacent infection. Early postoperative infection occurs within 2-4 wk of surgery, with manifestations typically including fever, pain, and local symptoms of wound infection. Rapid assessment, including isolation of the infecting organism by joint aspiration or intraoperative culture, operative debridement, and antimicrobial treatment, may allow salvage of the implant if the duration of symptoms is 1 mo after surgery and is often caused by organisms of low virulence that contaminated the implant at surgery or by failure of wound healing. Typical manifestations include pain and deterioration in function. Local symptoms such as erythema, swelling, or drainage may also occur. These infections respond poorly to antibiotic treatment and usually require removal of the implant using a 1- or 2-stage procedure. Surgical irrigation and debridement of the site with retention of the prosthesis and longterm suppressive antibiotic therapy may be considered, but eradication of infection appears uncommon. Acute hematogenous infections are most often observed ≥2 yr after surgery. Retention of the prosthesis is sometimes attempted, but inadequate long-term data exist to determine the success rate. If salvage therapy is attempted, prompt debridement and appropriate antibiotic therapy are recommended. As with other long-term implanted devices, the most common organisms are coagulase-negative staphylococci and S. aureus . With prior antibiotic therapy, the prosthesis culture may be negative; in these situations, molecular techniques to identify the organism are available, but sensitivity and specificity are poorly understood. Systemic antibiotic prophylaxis, antibiotic-containing bone cement, and operating rooms fitted with laminar airflow have been proposed to reduce infection. To date, results from clinical studies are conflicting.

Bibliography Chopra V, Saint S. Vascular catheter infections: time to get technical. Lancet . 2015;386:2034–2036. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev . 2002;15:167–193. Downes KJ, Metlay JP, Bell LM, et al. Polymicrobial bloodstream infections among children and adolescents with

central venous catheters evaluated in ambulatory care. Clin Infect Dis . 2008;46:387–394. Fulkerson DH, Sivaganesan A, Hill JD, et al. Progression of cerebrospinal fluid cell count and differential over a treatment course of shunt infection. J Neurosurg Pediatr . 2011;8:613– 619. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis . 2010;50:625–663. Marsh N, Webster J, Mihala G, Rickard CM. Devices and dressings to secure peripheral venous catheters: a Cochrane systematic review and meta-analysis. Int J Nurs Stud . 2017;67:12–19. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis . 2009;49:1–45. Mimoz O, Lucet JC, Kerforne T, et al. Skin antisepsis with chlorhexidine-alcohol versus povidone iodine-alcohol, with and without skin scrubbing, for prevention of intravascularcatheter-related infection (CLEAN): two-by-two factorial trial. Lancet . 2015;386:2069–2077. O'Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control . 2011;39:S1–S34. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis . 2013;56:e1–e25. Prusseit J, Simon M, von der Brelie C, et al. Epidemiology, prevention and management of ventriculoperitoneal shunt

infections in children. Pediatr Neurosurg . 2009;45:325–336. Shenep MA, Tanner MR, Sun Y, et al. Catheter-related complications in children with cancer receiving parenteral nutrition: change in risk is moderated by catheter type. JPEN J Parenter Enteral Nutr . 2017;41(6):1063–1071. Simon TD, Hall M, Riva-Cambrin J, et al. Infection rates following initial cerebrospinal fluid shunt placement across pediatric hospitals in the United States. J Neurosurg Pediatr . 2009;4:156–165. Sobel JD, Kauffman CA, McKinsey D, et al. Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis . 2000;30:19–24. Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America's clinical practice guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis . 2017;64(6):e34–e65. Warady BA, Bakkaloglu S, Newland J, et al. Consensus guidelines for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update. Perit Dial Int . 2012;32(Suppl 2):S32–S86. Wolf J, Curtis N, Worth LJ, et al. Treatment of central-line associated bloodstream infections in children: an update. Pediatr Infect Dis J . 2013;32:905–910. Zegers B, Uiterwaal C, Kimpen J, et al. Antibiotic prophylaxis for urinary tract infections in children with spina bifida on intermittent catheterization. J Urol . 2011;186:2365–2370.

SECTION 3

Antibiotic Therapy OUTLINE Chapter 207 Principles of Antibacterial Therapy

CHAPTER 207

Principles of Antibacterial Therapy Mark R. Schleiss

Antibacterial therapy in infants and children presents many challenges. A daunting problem is the paucity of pediatric data regarding pharmacokinetics and optimal dosages; as a consequence, pediatric recommendations are frequently extrapolated from adult studies. A 2nd challenge is the need for the clinician to consider important differences among pediatric age-groups with respect to the pathogenic species most often responsible for bacterial infections. Ageappropriate antibiotic dosing and toxicities must be considered, taking into account the developmental status and physiology of infants and children. Finally, the style of how a pediatrician uses antibiotics in children, particularly young infants, has some important differences compared with how antibiotics are used adult patients. Specific antibiotic therapy is optimally driven by a microbiologic diagnosis , predicated on isolation of the pathogenic organism from a sterile body site, and supported by antimicrobial susceptibility testing. However, given the inherent difficulties that can arise in collecting specimens from pediatric patients, and given the high risk of mortality and disability associated with serious bacterial infections in very young infants, much of pediatric infectious diseases practice is based on a clinical diagnosis with empirical use of antibacterial agents, administered before or even without eventual identification of the specific pathogen. Although there is increasing emphasis on the importance of using empirical therapy sparingly (so as to not select for resistant organisms), there are some settings in which antimicrobials must be administered before the presence of a specific bacterial pathogen is proven. This is particularly relevant to the care of the febrile or ill-appearing neonate or young infant under 30 days of age. Several key considerations influence decision-making regarding appropriate empirical use of antibacterial agents in infants and children. It is important to

know the age-appropriate differential diagnosis with respect to likely pathogens. This information affects the choice of antimicrobial agent and also the dose, dosing interval, and route of administration (oral vs parenteral). A complete history and physical examination, combined with appropriate laboratory and radiographic studies, are necessary to identify specific diagnoses, information that in turn affects the choice, dosing, and degree of urgency of administration of antimicrobial agents. The vaccination history may confer reduced risk for some invasive infections (i.e., Haemophilus influenzae type b, Streptococcus pneumoniae , Neisseria meningitidis ), but not necessarily elimination of risk. The risk of serious bacterial infection in pediatric practice is also affected by the child's immunologic status, which may be compromised by immaturity (neonates), underlying disease, and associated treatments (see Chapter 205 ). Infections in immunocompromised children may result from bacteria that are not considered pathogenic in immunocompetent children. The presence of foreign bodies (medical devices) also increases the risk of bacterial infections (see Chapter 206 ). The likelihood of central nervous system (CNS) involvement must be considered in all pediatric patients with serious bacterial infections, because many cases of bacteremia in childhood carry a significant risk for hematogenous spread to the CNS. The patterns of antimicrobial resistance in the community and for the potential causative pathogen being empirically covered must also be considered. Resistance to penicillin and cephalosporins is commonplace among strains of S. pneumoniae, often necessitating the use of other classes of antibiotics. Similarly, the striking emergence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA ) infections has complicated antibiotic choices for this pathogen. Extended-spectrum β-lactamase (ESBL )–producing gramnegative bacteria (Enterobacteriaceae) have reduced the effectiveness of penicillins and cephalosporins. Furthermore, carbapenem-resistant Enterobacteriaceae are an increasing problem among hospitalized patients, particularly in children with an epidemiologic connection to regions of the world, such as India, where such strains are frequently encountered. Antimicrobial resistance occurs through many modifications of the bacterial genome (Tables 207.1 and 207.2 ). Mechanisms include enzyme inactivation of the antibiotic, decreased cell membrane permeability to intracellularly active antibiotics, efflux of antibiotics out of the bacteria, protection or alteration of the antibiotic target site, excessive production of the target site, and bypassing the antimicrobial site of action.

Table 207.1

Mechanisms of Resistance to β-Lactam Antibiotics I. Alter target site (PBP) A. Decrease affinity of PBP for β-lactam antibiotic 1. Modify existing PBP a. Create mosaic PBP (1) Insert nucleotides obtained from neighboring bacteria (e.g., penicillin-resistant Streptococcus pneumoniae ) (2) Mutate structural gene of PBP(s) (e.g., ampicillin-resistant β-lactamase–negative Haemophilus influenzae ) 2. Import new PBP (e.g., mecA in methicillin-resistant Staphylococcus aureus ) II. Destroy β-lactam antibiotic A. Increase production of β-lactamases, carbapenemases 1. Acquire more efficient promoter a. Mutate existing promoter b. Import new promoter 2. Deregulate control of β-lactamase production a. Mutate regulator genes (e.g., ampD in “stably derepressed” Enterobacter cloacae ) B. Modify structure of resident β-lactamase 1. Mutate structural gene (e.g., ESBLs in Klebsiella pneumoniae ) C. Import new β-lactamase(s) with different spectrum of activity III. Decrease concentration of β-lactam antibiotic inside cell A. Restrict its entry (loss of porins) B. Pump it out (efflux mechanisms)

ESBLs, Extended-spectrum β-lactamases; PBP, Penicillin-binding protein. Adapted from Opal SM, Pop-Vicas A: Molecular mechanisms of antibiotic resistance in bacteria. In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier (Table 18-4).

Table 207.2

Aminoglycoside-Modifying Enzymes* ENZYMES USUAL ANTIBIOTICS MODIFIED PHOSPHORYLATION APH(2″) K, T, G APH(3′)-I K APH(3′)-III K ± A ACETYLATION AAC(2′) G AAC(3)-I ±T, G AAC(3)-III, -IV, or -V K, T, G AAC(6′) K, T, A ADENYLATION ANT(2″) K, T, G ANT(4′) K, T, A BIFUNCTIONAL ENZYMES

COMMON GENERA SA, SR E, PS, SA, SR E, PS, SA, SR PR E, PS E, PS E, PS, SA E, PS SA

AAC(6′)-APH(2″) AAC(6′)-lbcr

G, Ar G, K, T, FQ*

SA, Ent E

* Aminoglycoside-modifying enzymes confer antibiotic resistance through 3 general reactions: N-

acetylation, O-nucleotidylation, and O-phosphorylation. For each of these general reactions, there are several different enzymes that attack a specific amino or hydroxyl group. A, Amikacin; AAC, aminoglycoside acetyltransferase; ANT, aminoglycoside nucleotidyltransferase; APH, aminoglycoside phosphotransferase; cr, ciprofloxacin resistance; Ar, arbekacin, E, Enterobacteriaceae; Ent, enterococci, FQ, fluoroquinolone (acetylates the piperazine ring in some fluoroquinolones), G, gentamicin; K, kanamycin; PR, Providencia-Proteus ; PS, pseudomonads; SA, staphylococci; SR, streptococci; T, tobramycin. Adapted from Opal SM, Pop-Vicas A: Molecular mechanisms of antibiotic resistance in bacteria. In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier (Table 18-5).

Antimicrobial resistance has reached crisis proportions , driven by the emergence of new resistance mechanisms (e.g., carbapenemases, including Klebsiella pneumoniae –associated carbapenemases, or KPCs ) and by overuse of antibiotics, both in healthcare and in other venues, such as agribusiness and animal husbandry. This increase in antibiotic resistance has rendered some bacterial infections encountered in clinical practice virtually untreatable. Accordingly, there is an urgent need to develop new antimicrobials, as well as rediscover some older antibiotics that have been out of use in recent decades but still retain activity against resistant organisms. It is vital that practitioners use antibiotics only as necessary, with the narrowest feasible antimicrobial spectrum, to help thwart emergence of resistance. In addition, advocacy for vaccines , particularly conjugate pneumococcal vaccine, can also decrease the selective pressure that excessive antimicrobial use exerts on resistance. Effective antibiotic action requires achieving therapeutic levels of the drug at the site of infection. Although measuring the level of antibiotic at the site of infection is not always possible, one may measure the serum level and use this level as a surrogate marker for achievement of the desired effect at the tissue level. Various target serum levels are appropriate for different antibiotic agents and are assessed by the peak and trough serum levels and the area under the therapeutic drug level curve (Fig. 207.1 ). These levels in turn are a reflection of the route of administration, drug absorption (IM, PO), volume of distribution, and drug elimination half-life, as well as of drug-drug interactions that might enhance or impede enzymatic inactivation of an antibiotic or result in antimicrobial synergism or antagonism (Fig. 207.2 ).

FIG. 207.1 Area under the curve (AUC; shaded area ) for different antibiotics. The AUC provides a measure of antibiotic exposure to bacterial pathogens. The greatest exposure comes with antibiotics that have a long serum half-life and are administered parenterally (upper left panel, antibiotic A). The lowest exposure occurs with oral administration (lower right panel, antibiotic C). Dosing of antibiotic B once a day (upper right panel) provides far less exposure than dosing the same antibiotic every 6 hr (lower left panel). MIC, Minimal inhibitory concentration. (From Pong AL, Bradley JS: Guidelines for the selection of antibacterial therapy in children, Pediatr Clin North Am 52:869–894, 2005.)

FIG. 207.2 Antibacterial effects of antibiotic combinations. A, Combination of antibiotics 1 and 2 is indifferent ; killing by antibiotic 2 is unchanged when antibiotic 1 is added. B, Combination of antibiotics 1 and 2 results in synergy ; killing by antibiotic

2 is significantly enhanced when antibiotic 1 is added at a subinhibitory concentration. C, Combination of antibiotics 1 and 2 is antagonistic ; killing by antibiotic 2 is diminished in the presence of antibiotic 1. (From Eliopoulos GM, Moellering RC Jr: Principles of anti-infective therapy. In Bennett JF, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett's principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Elsevier, Fig 17-1.)

Age- and Risk-Specific Use of Antibiotics in Children Neonates The causative pathogens associated with neonatal infections are typically acquired around the time of delivery. Thus, empirical antibiotic selection must take into account the importance of these organisms (see Chapter 129 ). Among the causes of neonatal sepsis in infants, group B streptococcus (GBS) is the most common. Although intrapartum antibiotic prophylaxis administered to women at increased risk for transmission of GBS to the infant has greatly decreased the incidence of this infection in neonates, particularly with respect to early-onset disease, GBS infections are still frequently encountered in clinical practice (see Chapter 211 ). Gram-negative enteric organisms acquired from the maternal birth canal, in particular Escherichia coli, are also common causes of neonatal sepsis. Although less common, Listeria monocytogenes is an important pathogen to consider, insofar as the organism is intrinsically resistant to cephalosporin antibiotics, which are often used as empirical therapy for serious bacterial infections in young children. Salmonella bacteremia and meningitis on a global basis is a well-recognized infection in infants. All these organisms can be associated with meningitis in the neonate; therefore lumbar puncture should always be considered with bacteremic infections in this age-group, and if meningitis cannot be excluded, antibiotic management should include agents capable of crossing the blood-brain barrier.

Older Children Antibiotic choices in toddlers and young children were once driven by the high risk of this age-group to invasive disease caused by H. influenzae type b (Hib ; see Chapter 221 ). With the advent of conjugate vaccines against Hib, invasive disease has declined dramatically. However, outbreaks still occur, and have been

observed in the context of parental refusal of vaccines. Therefore, it is still important to use antimicrobials that are active against Hib in many clinical settings, particularly if meningitis is a consideration. Other important pathogens to consider in this age-group include E. coli , S. pneumoniae, N. meningitidis, and S. aureus . Strains of S. pneumoniae that are resistant to penicillin and cephalosporin antibiotics are frequently encountered in clinical practice. Similarly, MRSA is highly prevalent in children in the outpatient setting. Resistance of S. pneumoniae as well as MRSA is a result of mutations that confer alterations in penicillin-binding proteins, the molecular targets of penicillin and cephalosporin activity (see Table 207.1 ). Depending on the specific clinical diagnosis, other pathogens encountered among older children include Moraxella catarrhalis, nontypeable (nonencapsulated) strains of H. influenzae, and Mycoplasma pneumoniae, which cause upper respiratory tract infections and pneumonia; group A streptococcus, which causes pharyngitis, skin and soft tissue infections, osteomyelitis, septic arthritis, and rarely, bacteremia with toxic shock syndrome; Kingella kingae, which causes bone and joint infections; viridians group streptococci and Enterococcus, which cause endocarditis; and Salmonella spp., which cause enteritis, bacteremia, osteomyelitis, and septic arthritis. Vector-borne bacterial infections, including Borrelia burgdorferi , Rickettsia rickettsii , and Anaplasma phagocytophilum , are increasingly recognized in certain regions, with an evolving epidemiology triggered by climate change. These complexities underscore the importance of formulation of a complete differential diagnosis in children with suspected severe bacterial infections, including an assessment of the severity of the infection undertaken in parallel with consideration of local epidemiological disease trends, including knowledge of the antimicrobial susceptibility patterns in the community.

Immunocompromised and Hospitalized Patients It is important to consider the risks associated with immunocompromising conditions (malignancy, solid-organ or hematopoietic stem cell transplantation) and the risks conferred by conditions leading to prolonged hospitalization (intensive care, trauma, burns). Serious viral infections, particularly influenza, can also predispose to invasive bacterial infections, especially those caused by S. aureus . Immunocompromised children are predisposed to develop a wide range of bacterial, viral, fungal, or parasitic infections. Prolonged hospitalization can

lead to nosocomial infections, often associated with indwelling lines and catheters and caused by highly antibiotic-resistant gram-negative enteric organisms. In addition to bacterial pathogens already discussed, Pseudomonas aeruginosa and enteric organisms, including E. coli, K. pneumoniae, Enterobacter, and Serratia , are important opportunistic pathogens in these settings. Selection of appropriate antimicrobials is challenging because of the diverse causes and scope of antimicrobial resistance exhibited by these organisms. Many strains of enteric organisms have resistance because of ESBLs (see Table 207.1 ). Class B metallo-β-lactamases (also known as New Delhi metallo-β-lactamases) that hydrolyze all β-lactam antibiotics except aztreonam are increasingly being described, as well as KPCs that confer resistance to carbapenems. Reports of carbapenemases are increasingly being described for Enterobacteriaceae. Carbapenemase-producing Enterobacteriaceae are different from other multidrug-resistant microorganisms in that they are susceptible to few (if any) antibacterial agents. Other modes of antimicrobial resistance are being increasingly recognized. P. aeruginosa encodes proteins that function as efflux pumps to eliminate multiple classes of antimicrobials from the cytoplasm or periplasmic space. In addition to these gram-negative pathogens, infections caused by Enterococcus faecalis and E. faecium are inherently difficult to treat. These organisms may cause urinary tract infection (UTI) or infective endocarditis in immunocompetent children and may be responsible for a variety of syndromes in immunocompromised patients, especially in the setting of prolonged intensive care. The emergence of infections caused by vancomycin-resistant enterococcus (VRE) has further complicated antimicrobial selection in high-risk patients and has necessitated the development of newer antimicrobials that target these highly resistant grampositive bacteria.

Infections Associated With Medical Devices A special situation affecting antibiotic use is the presence of an indwelling medical device, such as venous catheter, ventriculoperitoneal shunts, stents, or other catheters (see Chapter 206 ). In addition to S. aureus, coagulase-negative staphylococci are also a major consideration. Coagulase-negative staphylococci seldom cause serious disease in the absence of risk factors such as indwelling catheters. Empirical antibiotic regimens must take this risk into consideration. In addition to appropriate antibiotic therapy, removal or replacement of the

colonized prosthetic material is usually required for cure.

Antibiotics Commonly Used in Pediatric Practice Table 207.3 lists antibiotic medications and pediatric indications. Table 207.3 Selected Antibacterial Medications (Antibiotics)* DRUG (TRADE NAMES, FORMULATIONS) Amikacin sulfate Amikin Injection: 50 mg/mL, 250 mg/mL

INDICATIONS (MECHANISM OF ACTION) COMMENTS AND DOSING Aminoglycoside antibiotic active against Cautions: Anaerobes, gram-negative bacilli, especially Streptococcus (including Escherichia coli, Klebsiella, Proteus, S. pneumoniae ) are Enterobacter, Serratia, and Pseudomonas resistant. May cause Neonates: Postnatal age ≤7 days, weight ototoxicity and 1,200-2,000 g: 7.5 mg/kg q12-18h IV or IM; nephrotoxicity. Monitor weight >2,000 g: 10 mg/kg q12h IV or IM; renal function. Drug postnatal age >7 days, weight 1,200-2,000 g: eliminated renally. 7.5 mg/kg q8-12h IV or IM; weight >2,000 g: Administered IV over 10 mg/kg q8h IV or IM 30-60 min Children: 15-25 mg/kg/24 hr divided q8-12h Drug interactions: May IV or IM potentiate other ototoxic Adults: 15 mg/kg/24 hr divided q8-12h IV or and nephrotoxic drugs IM Target serum concentrations: Peak 25-40 mg/L; trough 2,000 g: 75 mg/kg/24 hr divided q8h IV or IM (meningitis: 150 mg/kg/24 hr divided q8h IV or IM). Postnatal age >7 days weight 2,000 g: 100 mg/kg/24 hr divided q6h IV or IM (meningitis: 200 mg/kg/24 hr divided q6h IV or IM) Children: 100-200 mg/kg/24 hr divided q6h IV or IM (meningitis: 200-400 mg/kg/24 hr divided q4-6h IV or IM) Adults: 250-500 mg q4-8h IV or IM β-Lactam (ampicillin) and β-lactamase inhibitor (sulbactam) enhances ampicillin activity against penicillinase-producing bacteria: S. aureus, H. influenzae, M. catarrhalis, E. coli, Klebsiella, B. fragilis Children: 100-200 mg/kg/24 hr divided q4-8h IV or IM Adults: 1-2 g q6-8h IV or IM (max daily dose: 8 g)

penicillintolerant/resistant S. pneumoniae Cautions: Less bioavailable than amoxicillin, causing greater diarrhea Drug interaction: Probenecid

Azithromycin Zithromax Tablet: 250 mg Suspension: 100 mg/5 mL, 200 mg/5 mL

Azalide antibiotic with activity against S. aureus, Streptococcus, H. influenzae, Mycoplasma, Legionella, Chlamydia trachomatis, Babesia microti Children: 10 mg/kg PO on day 1 (max dose: 500 mg) followed by 5 mg/kg PO q24h for 4 days Group A streptococcus pharyngitis: 12 mg/kg/24 hr PO (max dose: 500 mg) for 5 days Adults: 500 mg PO day 1 followed by 250 mg for 4 days Uncomplicated C. trachomatis infection: single 1 g dose PO

Cautions: Drug dosed on ampicillin component. May cause diarrhea, rash. Drug eliminated renally Note: Higher dose may be active against penicillintolerant/resistant S. pneumoniae Drug interaction: Probenecid Note: Very long half-life permitting once-daily dosing. No metabolic-based drug interactions (unlike erythromycin and clarithromycin), limited GI distress. Shorter-course regimens (e.g., 1-3 days) under investigation. 3 day, therapy (10 mg/kg/24 hr × 3 days) and single-dose therapy (30 mg/kg): use with increasing frequency (not for streptococcus pharyngitis)

Aztreonam Azactam Injection

β-Lactam (monobactam) antibiotic with activity against gram-negative aerobic bacteria, Enterobacteriaceae, and Pseudomonas aeruginosa Neonates: Postnatal age ≤7 days weight ≤2,000 g: 60 mg/kg/24 hr divided q12h IV or

Cautions: Rash, thrombophlebitis, eosinophilia. Renally eliminated Drug interaction: Probenecid

Ampicillin-sulbactam Unasyn Injection

Cefadroxil Generic Capsule: 500 mg Tablet: 1,000 mg Suspension: 125 mg/5 mL, 250 mg/5 mL, 500 mg/5 mL Cefazolin Ancef, Kefzol Injection

Cefdinir Omnicef Capsule: 300 mg Oral suspension: 125 mg/5 mL

IM; weight >2,000 g: 90 mg/kg/24 hr divided q8h IV or IM; postnatal age >7 days weight 2,000 g: 120 mg/kg/24 hr divided q6-8h IV or IM Children: 90-120 mg/kg/24 hr divided q6-8h IV or IM. For cystic fibrosis, up to 200 mg/kg/24 hr IV Adults: 1-2 g IV or IM q8-12h (max dose: 8 g/24 hr) First-generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella , and Proteus Children: 30 mg/kg/24 hr divided q12h PO (max dose: 2 g) Adults: 250-500 mg q8-12h PO

First-generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella , and Proteus Neonates: Postnatal age ≤7 days 40 mg/kg/24 hr divided q12h IV or IM; >7 days 40-60 mg/kg/24 hr divided q8h IV or IM Children: 50-100 mg/kg/24 hr divided q8h IV or IM Adults: 0.5-2g q8h IV or IM (max dose: 12 g/24 hr) Extended-spectrum, semisynthetic cephalosporin Children 6 mo-12 yr: 14 mg/kg/24 hr in 1 or 2 doses PO (max dose: 600 mg/24 hr) Adults: 600 mg q24h PO

Cefepime Maxipime Injection

Expanded-spectrum, fourth-generation cephalosporin active against many grampositive and gram-negative pathogens, including P. aeruginosa and many multidrug-resistant pathogens Children: 100-150 mg/kg/24 hr q8-12h IV or IM Adults: 2-4 g/24 hr q12h IV or IM

Cefixime Suprax Tablet: 200, 400 mg Suspension: 100 mg/5 mL

Third-generation cephalosporin active against streptococci, H. influenzae, M. catarrhalis, Neisseria gonorrhoeae, Serratia marcescens , and Proteus vulgaris . No

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Long halflife permits q12-24h dosing Drug interaction: Probenecid Caution: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Does not adequately penetrate CNS Drug interaction: Probenecid

Cautions: Reduce dosage in renal insufficiency (creatinine clearance 7 days: weight 1,200 g: 150 mg/kg/24 hr divided q8h IV or IM Children: 150 mg/kg/24 hr divided q6-8h IV or IM (meningitis: 200 mg/kg/24 hr divided q6-8h IV) Adults: 1-2 g q8-12h IV or IM (max dose: 12 g/24 hr) Second-generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, Klebsiella, Proteus , and Bacteroides . Inactive against Enterobacter Children: 40-80 mg/kg/24 hr divided q12h IV or IM Adults: 2-4 g/24 hr divided q12h IV or IM (max dose: 6 g/24 hr) Second-generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, Klebsiella, Proteus , and Bacteroides . Inactive against Enterobacter Neonates: 70-100 mg/kg/24 hr divided q812h IV or IM Children: 80-160 mg/kg/24 hr divided q6-8h IV or IM Adults: 1-2 g q6-8h IV or IM (max dose: 12 g/24 hr) Third-generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, M. catarrhalis, N. gonorrhoeae, E. coli, Klebsiella , and Proteus . No antipseudomonal activity Children: 10 mg/kg/24 hr divided q12h PO Adults: 200-800 mg/24 hr divided q12h PO

adequately penetrate CNS Drug interaction: Probenecid Cautions: Highly protein-bound cephalosporin with limited potency reflected by weak antipseudomonal activity. Variable Grampositive activity. Primarily hepatically eliminated in bile Drug interaction: Disulfiram-like reaction with alcohol Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Each gram of drug contains 2.2 mEq sodium. Active metabolite Drug interaction: Probenecid

Cautions: Highly proteinbound cephalosporin, poor CNS penetration; β-lactam safety profile (rash, eosinophilia), disulfiram-like reaction with alcohol. Renally eliminated (~20% in bile) Cautions: Poor CNS penetration; β-lactam safety profile (rash, eosinophilia). Renally eliminated. Painful given intramuscularly Drug interaction: Probenecid

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Does not adequately penetrate CNS. Increased bioavailability when

(max dose: 800 mg/24 hr) Uncomplicated gonorrhea: 200 mg PO as single-dose therapy

Ceftaroline fosamil Teflaro Injection

Cefprozil Cefzil Tablet: 250, 500 mg Suspension: 125 mg/5 mL, 250 mg/5 mL

Fifth-generation cephalosporin active against S. aureus (including MRSA when used for skin and soft tissue infection), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, H. influenzae, and Klebsiella oxytoca Children: skin/skin structure infections or community-acquired pneumonia, 24 mg/kg/24 hr divided q8h IV (2-23 mo old) ×5-14 days; 36 mg/kg/24 hr divided q8h IV (weight ≤33 kg) ×5-14 days; 400 mg q8h IV (weight >33 kg) Adults: 600 mg q12h IV Second-generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, M. catarrhalis, Klebsiella , and Proteus spp. Children: 30 mg/kg/24 hr divided q8-12h PO Adults: 500-1,000 mg/24 hr divided q12h PO (max dose: 1.5 g/24 hr)

Ceftazidime Fortaz, Ceptaz, Tazicef, Tazidime Injection

Third-generation cephalosporin active against gram-positive and gram-negative pathogens, including P. aeruginosa Neonates: Postnatal age ≤7 days: 100 mg/kg/24 hr divided q12h IV or IM; >7 days weight ≤1,200 g: 100 mg/kg/24 hr divided q12h IV or IM; weight >1,200 g: 150 mg/kg/24 hr divided q8h IV or IM Children: 150 mg/kg/24 hr divided q8h IV or IM (meningitis: 150 mg/kg/24 hr IV divided q8h) Adults: 1-2 g q8-12h IV or IM (max dose: 812 g/24 hr)

Ceftizoxime Cefizox Injection

Third-generation cephalosporin active against gram-positive and gram-negative pathogens. No antipseudomonal activity Children: 150 mg/kg/24 hr divided q6-8h IV or IM Adults: 1-2 g q6-8h IV or IM (max dose: 12 g/24 hr) Third-generation cephalosporin widely active against gram-positive and gramnegative pathogens. No antipseudomonal activity Neonates: 50-75 mg/kg q24h IV or IM

Ceftriaxone sodium Rocephin Injection

taken with food Drug interaction: Probenecid; antacids and H2 receptor antagonists may decrease absorption Caution: β-Lactam safety profile (rash, eosinophilia) Drug interaction: Probenecid

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Good bioavailability; food does not affect bioavailability Drug interaction: Probenecid Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Increasing pathogen resistance developing with longterm, widespread use Drug interaction: Probenecid

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated Drug interaction: Probenecid Cautions: β-Lactam safety profile (rash, eosinophilia). Eliminated via kidney (33–65%) and bile; can

Children: 50-75 mg/kg q24h IV or IM (meningitis: 75 mg/kg dose once then 80-100 mg/kg/24 hr divided q12-24h IV or IM) Adults: 1-2 g q24h IV or IM (max dose: 4 g/24 hr)

Cefuroxime (cefuroxime axetil for oral administration) Ceftin, Kefurox, Zinacef Injection Suspension: 125 mg/5 mL Tablet: 125, 250, 500 mg

Cephalexin Keflex, Keftab Capsule: 250, 500 mg Tablet: 500 mg, 1 g Suspension: 125 mg/5 mL, 250 mg/5 mL, 100 mg/mL drops

Second-generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, M. catarrhalis, Klebsiella , and Proteus Neonates: 40-100 mg/kg/24 hr divided q12h IV or IM Children: 200-240 mg/kg/24 hr divided q8h IV or IM; PO administration: 20-30 mg/kg/24 hr divided q8-12h PO Adults: 750-1,500 mg q8h IV or IM (max dose: 6 g/24 hr) First-generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella , and Proteus Children: 25-100 mg/kg/24 hr divided q6-8h PO Adults: 250-500 mg q6h PO (max dose: 4 g/24 hr)

cause sludging. Long half-life and dosedependent protein binding favors q24h rather than q12h dosing. Can add 1% lidocaine for IM injection Drug interaction: Probenecid. In neonates, co-administration with calcium-containing products can result in severe precipitation and attendant embolic complications Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated. Food increases PO bioavailability Drug interaction: Probenecid

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated Drug interaction: Probenecid

Cephradine Velosef Capsule: 250, 500 mg Suspension: 125 mg/5 mL, 250 mg/5 mL

First-generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella , and Proteus Children: 50-100 mg/kg/24 hr divided q6-12h PO Adults: 250-500 mg q6-12h PO (max dose: 4 g/24 hr)

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated Drug interaction: Probenecid

Ciprofloxacin Cipro Tablet: 100, 250, 500, 750 mg Injection Ophthalmic solution and ointment Otic suspension Oral suspension: 250 and 500 mg/5 mL

Quinolone antibiotic active against P. aeruginosa, Serratia, Enterobacter, Shigella, Salmonella, Campylobacter, N. gonorrhoeae, H. influenzae, M. catarrhalis, some S. aureus , and some Streptococcus Neonates: 10 mg/kg q 12 hr PO or IV Children: 15-30 mg/kg/24 hr divided q12h PO or IV; cystic fibrosis: 20-40 mg/kg/24 hr divided q8-12h PO or IV Adults: 250-750 mg q12h; 200-400 mg IV q12h PO (max dose: 1.5 g/24 hr)

Cautions: Concerns of joint destruction in juvenile animals not seen in humans; tendonitis, superinfection, dizziness, confusion, crystalluria, some photosensitivity Drug interactions: Theophylline; magnesium-, aluminum, or calcium-containing antacids; sucralfate;

Clarithromycin Biaxin Tablet: 250, 500 mg Suspension: 125 mg/5 mL, 250 mg/5 mL

Macrolide antibiotic with activity against S. aureus, Streptococcus, H. influenzae, Legionella, Mycoplasma, and C. trachomatis Children: 15 mg/kg/24 hr divided q12h PO Adults: 250-500 mg q12h PO (max dose: 1 g/24 hr)

Clindamycin Cleocin Capsule: 75, 150, 300 mg Suspension: 75 mg/5 mL Injection Topical solution, lotion, and gel Vaginal cream

Protein synthesis inhibitor active against most gram-positive aerobic and anaerobic cocci except Enterococcus Neonates: Postnatal age ≤7 days weight 2,000 g: 15 mg/kg/24 hr divided q8h IV or IM; >7 days weight 2,000 g: 20 mg/kg/24 hr divided q8h IV or IM Children: 10-40 mg/kg/24 hr divided q6-8h IV, IM, or PO Adults: 150-600 mg q6-8h IV, IM, or PO (max dose: 5 g/24 hr IV or IM or 2 g/24 hr PO) Penicillinase-resistant penicillin active against S. aureus and other gram-positive cocci except Enterococcus and coagulasenegative staphylococci Children: 50-100 mg/kg/24 hr divided q6h PO Adults: 250-500 mg q6h PO (max dose: 4 g/24 hr)

Cloxacillin sodium Tegopen Capsule: 250, 500 mg Suspension: 125 mg/5 mL

Colistin (Colistimethate sodium; polymyxin E) Injection Inhalation

Treatment of multidrug resistant gramnegative organisms (Enterobacteriaceae including extended-spectrum beta lactamase and carbapenemase-producing strains) Children: 2.5-5 mg/kg/day divided in 2-4 divided doses IV Adults: 300 mg/day in 2-4 divided doses IV

probenecid; warfarin; cyclosporine Cautions: Adverse events less than erythromycin; GI upset, dyspepsia, nausea, cramping Drug interactions: Same as erythromycin: astemizole carbamazepine, terfenadine, cyclosporine, theophylline, digoxin, tacrolimus Cautions: Diarrhea, nausea, Clostridium difficile – associated colitis, rash. Administer slow IV over 3060 min. Topically active as an acne treatment

Cautions: β-Lactam safety profile (rash, eosinophilia). Primarily hepatically eliminated; requires dose reduction in renal disease. Food decreases bioavailability Drug interaction: Probenecid Cautions: Nephrotoxicity (~3% in young children; higher rates in adolescents and adults); adjust dose for renal insufficiency; neurotoxicity (headaches, paresthesia, ataxia) Drug interactions: Should not be administered concomitantly with polymyxins or aminoglycosides

Co-trimoxazole (trimethoprimsulfamethoxazole; TMPSMX) Bactrim, Cotrim, Septra, Sulfatrim Tablet: SMX 400 mg and TMP 80 mg Tablet DS: SMX 800 mg and TMP 160 mg Suspension: SMX 200 mg and TMP 40 mg/5 mL Injection

Antibiotic combination with sequential antagonism of bacterial folate synthesis with broad antibacterial activity: Shigella, Legionella, Nocardia, Chlamydia, Pneumocystis jiroveci. Dosage based on TMP component Children: 6-20 mg TMP/kg/24 hr or IV divided q12h PO Pneumocystis carinii pneumonia: 15-20 mg TMP/kg/24 hr divided q12h PO or IV P. carinii prophylaxis: 5 mg TMP/kg/24 hr or 3 times/wk PO Adults: 160 mg TMP q12h PO

Daptomycin Cubicin

Disrupts bacterial cell membrane function, causing depolarization leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death. Active against enterococci (including glycopeptide-resistant strains), staphylococci (including MRSA), streptococci, and corynebacteria. Approved for skin and soft tissue infections. Acceptable for bacteremia and right-sided endocarditis with susceptible strains Adults: In skin and soft tissue infections, 4 mg/kg daptomycin IV once daily. For S. aureus bacteremia or right-sided endocarditis, 6 mg/kg IV once daily Children: For skin/skin structure infections, 12-23 mo, 10 mg/kg IV q24h; 2-6 yr, 9 mg/kg IV q24h; 7-11 yr, 7 mg/kg q24h; 12-17 yr, 5 mg/kg q24h, all for up to 14 days. For staphylococcal bacteremia, 1-6 yr, 12 mg/kg q24h; 7-11 yr, 9 mg/kg q24h; 12-17 yr, 7 mg/kg q24h; all for up to 42 days. For staphylococcal endocarditis, 1-5 yr, 10 mg/kg IV q24h for at least 6 wk; ≥6 yr, 6 mg/kg IV q24h for at least 6 wk

Demeclocycline Declomycin Tablet: 150, 300 mg Capsule: 150 mg

Tetracycline active against most grampositive cocci except Enterococcus , many gram-negative bacilli, anaerobes, Borrelia burgdorferi (Lyme disease), Mycoplasma, and Chlamydia Children: 8-12 mg/kg/24 hr divided q6-12h PO Adults: 150 mg PO q6-8h Syndrome of inappropriate antidiuretic hormone secretion: 900-1,200 mg/24 hr or 13-15 mg/kg/24 hr divided q6-8h PO with dose reduction based on response to 600-900 mg/24 hr

Cautions: Drug dosed on TMP (trimethoprim) component. Sulfonamide skin reactions: rash, erythema multiforme, Stevens-Johnson syndrome, nausea, leukopenia. Renal and hepatic elimination; reduce dose in renal failure Drug interactions: Protein displacement with warfarin, possibly phenytoin, cyclosporine Cautions: Should not be used for pneumonia because drug inactivated by surfactants. Associated with rash, renal failure, anemia, and headache. Is reported to cause myopathy, rhabdomyolysis, and eosinophilic pneumonia Drug interactions: Should not be administered with statins

Cautions: Teeth staining, possibly permanent (if administered 7 days weight 1,200 g: 30 mg/kg/24 hr divided q8h PO (give as 5 mg/kg/dose q6h to improve feeding intolerance) Children: Usual max dose: 2 g/24 hr Base: 30-50 mg/kg/24 hr divided q6-8h PO Estolate: 30-50 mg/kg/24 hr divided q8-12h PO Stearate: 20-40 mg/kg/24 hr divided q6h PO

milk, dairy products may decrease absorption Cautions: β-Lactam safety profile (rash, eosinophilia). Primarily renally (65%) and bile (30%) elimination. Food may decrease bioavailability Drug interaction: Probenecid Cautions: β-Lactam safety profile; does not undergo hepatic metabolism. Renal elimination (70–75%); dose adjustment for renal failure Drug interactions: Valproic acid, probenecid Cautions: Teeth staining, possibly permanent (2,000 g: 2.5 mg/kg q8h IV or IM Children: 2.5 mg/kg/24 hr divided q8-12h IV or IM. Alternatively, may administer 5-7.5 mg/kg/24 hr IV once daily Intrathecal: Preservative-free preparation for intraventricular or intrathecal use: neonate: 1 mg/24 hr; children: 1-2 mg/24 hr intrathecal; adults: 4-8 mg/24 hr Adults: 3-6 mg/kg/24 hr divided q8h IV or IM Carbapenem antibiotic with broadspectrum activity against gram-positive cocci and gram-negative bacilli, including P. aeruginosa and anaerobes. No activity against Stenotrophomonas maltophilia Neonates: Postnatal age ≤7 days weight 1,200 g: 40 mg/kg divided q12h IV or IM; postnatal age >7 days weight 1,2002,000 g: 40 mg/kg q12h IV or IM; weight >2,000 g: 60 mg/kg q8h IV or IM Children: 60-100 mg/kg/24 hr divided q6-8h IV or IM Adults: 2-4 g/24 hr divided q6-8h IV or IM (max dose: 4 g/24 hr)

Imipenem-cilastatin Primaxin Injection

Linezolid Zyvox Tablet: 400, 600 mg Oral suspension: 100 mg/5 mL Injection: 100 mg/5 mL

Oxazolidinone antibiotic active against gram-positive cocci (especially drugresistant organisms), including Staphylococcus, Streptococcus, E. faecium, and Enterococcus faecalis . Interferes with protein synthesis by binding to 50S ribosome subunit Children: 10 mg/kg q12h IV or PO Adults: Pneumonia: 600 mg q12h IV or PO;

treatment of acne Drug interactions: Antagonizes hepatic CYP 3A4 activity: astemizole, carbamazepine, terfenadine, cyclosporine, theophylline, digoxin, tacrolimus, carbamazepine Cautions: Anaerobes, S. pneumoniae, and other Streptococcus are resistant. May cause ototoxicity and nephrotoxicity. Monitor renal function. Drug eliminated renally. Administered IV over 30-60 min Drug interactions: May potentiate other ototoxic and nephrotoxic drugs Target serum concentrations: Peak 612 mg/L; trough >2 mg/L with intermittent daily dose regimens only Cautions: β-Lactam safety profile (rash, eosinophilia), nausea, seizures. Cilastatin possesses no antibacterial activity; reduces renal imipenem metabolism. Primarily renally eliminated Drug interaction: Possibly ganciclovir

Adverse events: Myelosuppression, pseudomembranous colitis, nausea, diarrhea, headache Drug interaction: Probenecid

Loracarbef Generic Capsule: 200 mg Suspension: 100 mg/5 mL, 200 mg/5 mL

Meropenem Merrem Injection

Metronidazole Flagyl, Metro I.V., Topical gel, vaginal gel Injection Tablet: 250, 500 mg

skin infections: 400 mg q12h IV or PO Carbacephem very closely related to cefaclor (second-generation cephalosporin) active against S. aureus, Streptococcus, H. influenzae, M. catarrhalis, E. coli, Klebsiella , and Proteus Children: 30 mg/kg/24 hr divided q12h PO (max dose: 2 g) Adults: 200-400 mg q12h PO (max dose: 800 mg/24 hr) Carbapenem antibiotic with broadspectrum activity against gram-positive cocci and gram-negative bacilli, including P. aeruginosa and anaerobes. No activity against S. maltophilia Children: 60 mg/kg/24 hr divided q8h IV meningitis: 120 mg/kg/24 hr (max dose: 6 g/24 hr) q8h IV Adults: 1.5-3 g q8h IV Highly effective in the treatment of infections caused by anaerobes. Oral therapy of C. difficile colitis Neonates: weight 7 days: 225 mg/kg divided q8h IV Children: 200-300 mg/kg/24 hr divided q4-6h IV; cystic fibrosis 300-450 mg/kg/24 hr IV Adults: 2-4 g/dose q4-6h IV (max dose: 12 g/24 hr)

Mupirocin Bactroban Ointment

Topical antibiotic active against Staphylococcus and Streptococcus Topical application: Nasal (eliminate nasal carriage) and to the skin 2-4 times daily Penicillinase-resistant penicillin active

Nafcillin sodium

Cautions: β-Lactam safety profile (rash, eosinophilia). Renally eliminated Drug interaction: Probenecid

Cautions: β-Lactam safety profile; appears to possess less CNS excitation than imipenem. 80% renal elimination Drug interaction: Probenecid Cautions: Dizziness, seizures, metallic taste, nausea, disulfiram-like reaction with alcohol. Administer IV slow over 30-60 min. Adjust dose with hepatic impairment Drug interactions: Carbamazepine, rifampin, phenobarbital may enhance metabolism; may increase levels of warfarin, phenytoin, lithium Cautions: β-Lactam safety profile (rash, eosinophilia); painful given intramuscularly; each gram contains 1.8 mEq sodium. Interferes with platelet aggregation with high doses; increases noted in liver function test results. Renally eliminated. Inactivated by βlactamase enzyme Drug interaction: Probenecid Caution: Minimal systemic absorption because drug metabolized within the skin Cautions: β-Lactam

Nafcil, Unipen Injection Capsule: 250 mg Tablet: 500 mg

Nalidixic acid NegGram Tablet: 250, 500, 1,000 mg Suspension: 250 mg/5 mL

Neomycin sulfate Mycifradin Tablet: 500 mg Topical cream, ointment Solution: 125 mg/5 mL

Nitrofurantoin Furadantin, Furan, Macrodantin Capsule: 50, 100 mg Extended-release capsule: 100 mg Macrocrystal: 50, 100 mg Suspension: 25 mg/5 mL Ofloxacin Ocuflox 0.3% ophthalmic solution: 1, 5, 10 mL Floxin 0.3% otic solution: 5, 10 mL

against S. aureus and other gram-positive cocci, except Enterococcus and coagulasenegative staphylococci Neonates: Postnatal age ≤7 days weight 1,200-2,000 g: 50 mg/kg/24 hr divided q12h IV or IM; weight >2,000 g: 75 mg/kg/24 hr divided q8h IV or IM; postnatal age >7 days weight 1,200-2,000 g: 75 mg/kg/24 hr divided q8h; weight >2,000 g: 100 mg/kg/24 hr divided q6-8h IV (meningitis: 200 mg/kg/24 hr divided q6h IV) Children: 100-200 mg/kg/24 hr divided q4-6h IV Adults: 4-12 g/24 hr divided q4-6h IV (max dose: 12 g/24 hr) First-generation quinolone effective for short-term treatment of lower UTIs caused by E. coli, Enterobacter, Klebsiella , and Proteus Children: 50-55 mg/kg/24 hr divided q6h PO; suppressive therapy: 25-33 mg/kg/24 hr divided q6-8h PO Adults: 1 g q6h PO; suppressive therapy: 500 mg q6h PO Aminoglycoside antibiotic used for topical application or orally before surgery to decrease GI flora (nonabsorbable) and hyperammonemia Infants: 50 mg/kg/24 hr divided q6h PO Children: 50-100 mg/kg/24 hr divided q6-8h PO Adults: 500-2,000 mg/dose q6-8h PO

Effective in treatment of lower UTIs caused by gram-positive and gramnegative pathogens Children: 5-7 mg/kg/24 hr divided q6h PO (max dose: 400 mg/24 hr); suppressive therapy 1-2.5 mg/kg/24 hr divided q12-24h PO (max dose: 100 mg/24 hr) Adults: 50-100 mg/24 hr divided q6h PO Quinolone antibiotic for treatment of conjunctivitis or corneal ulcers (ophthalmic solution) and otitis externa or chronic suppurative otitis media (otic solution) caused by susceptible grampositive, gram-negative, anaerobic bacteria, or C. trachomatis Child >1-12 yr: Conjunctivitis: 1-2 drops in affected eye(s)

safety profile (rash, eosinophilia), phlebitis; painful given intramuscularly; oral absorption highly variable and erratic (not recommended) Adverse effect: Neutropenia

Cautions: Vertigo, dizziness, rash. Not for use in systemic infections Drug interactions: Liquid antacids

Cautions: In patients with renal dysfunction because small amount absorbed may accumulate Adverse events: Primarily related to topical application, abdominal cramps, diarrhea, rash Aminoglycoside ototoxicity and nephrotoxicity if absorbed Cautions: Vertigo, dizziness, rash, jaundice, interstitial pneumonitis. Do not use with moderate to severe renal dysfunction Drug interactions: Liquid antacids Adverse events: Burning, stinging, eye redness (ophthalmic solution), dizziness with otic solution if not warmed

Oxacillin sodium Prostaphlin Injection Capsule: 250, 500 mg Suspension: 250 mg/5 mL

Penicillin G Injection Tablets

q2-4h for 2 days, then 1-2 drops qid for 5 days Corneal ulcers: 1-2 drops q 30 min while awake and at 4 hr intervals at night for 2 days, then 1-2 drops hourly for 5 days while awake, then 1-2 drops q6h for 2 days Otitis externa (otic solution): 5 drops into affected ear bid for 10 days Chronic suppurative otitis media: treat for 14 days Child >12 yr and adults: Ophthalmic solution doses same as for younger children. Otitis externa (otic solution): Use 10 drops bid for 10 or 14 days as for younger children Penicillinase-resistant penicillin active against S. aureus and other gram-positive cocci, except Enterococcus and coagulasenegative staphylococci Neonates: Postnatal age ≤7 days weight 1,200-2,000 g: 50 mg/kg/24 hr divided q12h IV; weight >2,000 g: 75 mg/kg/24 hr IV divided q8h IV; postnatal age >7 days weight 2,000 g: 100 mg/kg/24 hr IV divided q6h IV Infants: 100-200 mg/kg/24 hr divided q4-6h IV Children: PO 50-100 mg/kg/24 hr divided q46h IV Adults: 2-12 g/24 hr divided q4-6h IV (max dose: 12 g/24 hr) Penicillin active against most grampositive cocci; S. pneumoniae (resistance is increasing), group A streptococcus, and some gram-negative bacteria (e.g., N. gonorrhoeae, N. meningitidis ) Neonates: Postnatal age ≤7 days weight 1,200-2,000 g: 50,000 units/kg/24 hr divided q12h IV or IM (meningitis: 100,000 U/kg/24 hr divided q12h IV or IM); weight >2,000 g: 75,000 U/kg/24 hr divided q8h IV or IM (meningitis: 150,000 U/kg/24 hr divided q8h IV or IM); postnatal age >7 days weight ≤1,200 g: 50,000 U/kg/24 hr divided q12h IV (meningitis: 100,000 U/kg/24 hr divided q12h IV); weight 1,200-2,000 g: 75,000 U/kg/24 hr q8h IV (meningitis: 225,000 U/kg/24 hr divided q8h IV); weight >2,000 g: 100,000 U/kg/24 hr divided q6h IV (meningitis: 200,000 U/kg/24 hr divided q6h IV) Children: 100,000-250,000 units/kg/24 hr divided q4-6h IV or IM (max dose: 400,000 U/kg/24 hr)

Cautions: β-Lactam safety profile (rash, eosinophilia) Moderate oral bioavailability (35– 65%) Primarily renally eliminated Drug interaction: Probenecid Adverse effect: Neutropenia

Cautions: β-Lactam safety profile (rash, eosinophilia), allergy, seizures with excessive doses particularly in patients with marked renal disease. Substantial pathogen resistance. Primarily renally eliminated Drug interaction: Probenecid

Penicillin G, benzathine Bicillin Injection

Penicillin G, procaine Crysticillin Injection

Penicillin V Pen VK, V-Cillin K Tablet: 125, 250, 500 mg Suspension: 125 mg/5 mL, 250 mg/5 mL

Piperacillin Pipracil Injection

Adults: 2-24 million units/24 hr divided q46h IV or IM Long-acting repository form of penicillin effective in treatment of infections responsive to persistent, low penicillin concentrations (1-4 wk), e.g., group A streptococcus pharyngitis, rheumatic fever prophylaxis Neonates weight >1,200 g: 50,000 units/kg IM once Children: 300,000-1.2 million units/kg q 3-4 wk IM (max dose: 1.2-2.4 million units/dose) Adults: 1.2 million units IM q 3-4 wk Repository form of penicillin providing low penicillin concentrations for 12 hr Neonates weight >1,200 g: 50,000 units/kg/24 hr IM Children: 25,000-50,000 units/kg/24 hr IM for 10 days (max dose: 4.8 million units/dose) Gonorrhea: 100,000 units/kg (max dose: 4.8 million units/24 hr) IM once with probenecid 25 mg/kg (max dose: 1 g) Adults: 0.6-4.8 million units q12-24h IM Preferred oral dosing form of penicillin, active against most gram-positive cocci; S. pneumoniae (resistance is increasing), other streptococci, and some gramnegative bacteria (e.g., N. gonorrhoeae, N. meningitidis ) Children: 25-50 mg/kg/24 hr divided q4-8h PO Adults: 125-500 mg q6-8h PO (max dose: 3 g/24 hr)

Extended-spectrum penicillin active against E. coli, Enterobacter, Serratia, P. aeruginosa, and Bacteroides Neonates: Postnatal age ≤7 days 150 mg/kg/24 hr divided q8-12h IV; >7 days; 200 mg/kg divided q6-8h IV Children: 200-300 mg/kg/24 hr divided q4-6h IV; cystic fibrosis: 350-500 mg/kg/24 hr IV Adults: 2-4 g/dose q4-6h (max dose: 24 g/24 hr) IV

Cautions: β-Lactam safety profile (rash, eosinophilia), allergy. Administer by IM injection only. Substantial pathogen resistance. Primarily renally eliminated Drug interaction: Probenecid Cautions: β-Lactam safety profile (rash, eosinophilia) allergy. Administer by IM injection only. Substantial pathogen resistance. Primarily renally eliminated Drug interaction: Probenecid Cautions: β-Lactam safety profile (rash, eosinophilia), allergy, seizures with excessive doses particularly in patients with renal disease. Substantial pathogen resistance. Primarily renally eliminated. Inactivated by penicillinase Drug interaction: Probenecid Cautions: β-Lactam safety profile (rash, eosinophilia); painful given intramuscularly; each gram contains 1.9 mEq sodium. Interferes with platelet aggregation/serum sickness–like reaction with high doses; increases in liver function test results. Renally eliminated. Inactivated by penicillinase Drug interaction: Probenecid

Piperacillin-tazobactam Zosyn Injection

Extended-spectrum penicillin (piperacillin) combined with a β-lactamase inhibitor (tazobactam) active against S. aureus, H. influenzae, E. coli, Enterobacter, Serratia, Acinetobacter, P. aeruginosa, and Bacteroides Children: 300-400 mg/kg/24 hr divided q6-8h IV or IM Adults: 3.375 g q6-8h IV or IM

Quinupristin/dalfopristin Synercid IV injection: powder for reconstitution, 10 mL contains 150 mg quinupristin, 350 mg dalfopristin Sulfadiazine Tablet: 500 mg

Streptogramin antibiotic (quinupristin) active against vancomycin-resistant E. faecium (VRE) and methicillin-resistant S. aureus (MRSA). Not active against E. faecalis Children and adults: VRE: 7.5 mg/kg q8h IV for VRE; skin infections: 7.5 mg/kg q12h IV Sulfonamide antibiotic primarily indicated for treatment of lower UTIs caused by E. coli, P. mirabilis, and Klebsiella Toxoplasmosis: Neonates: 100 mg/kg/24 hr divided q12h PO with pyrimethamine 1 mg/kg/24 hr PO (with folinic acid) Children: 120-200 mg/kg/24 hr divided q6h PO with pyrimethamine 2 mg/kg/24 hr divided q12h PO ≥3 days, then 1 mg/kg/24 hr (max dose: 25 mg/24 hr) with folinic acid Rheumatic fever prophylaxis: weight ≤30 kg: 500 mg/24 hr q24h PO; weight >30 kg: 1 g/24 hr q24h PO

Sulfamethoxazole Gantanol Tablet: 500 mg Suspension: 500 mg/5 mL

Sulfonamide antibiotic used for treatment of otitis media, chronic bronchitis, and lower UTIs caused by susceptible bacteria Children: 50-60 mg/kg/24 hr divided q12h PO Adults: 1 g/dose q12h PO (max dose: 3 g/24 hr)

Sulfisoxazole Gantrisin Tablet: 500 mg Suspension: 500 mg/5 mL Ophthalmic solution,

Sulfonamide antibiotic used for treatment of otitis media, chronic bronchitis, and lower UTIs caused by susceptible bacteria Children: 120-150 mg/kg/24 hr divided q4-6h PO (max dose: 6 g/24 hr)

Cautions: β-Lactam safety profile (rash, eosinophilia); painful given intramuscularly; each gram contains 1.9 mEq sodium Interferes with platelet aggregation, serum sickness–like reaction with high doses, increases in liver function test results. Renally eliminated Drug interaction: Probenecid Adverse events: Pain, edema, or phlebitis at injection site, nausea, diarrhea Drug interactions : Synercid is a potent inhibitor of CYP 3A4 Cautions: Rash, Stevens-Johnson syndrome, nausea, leukopenia, crystalluria. Renal and hepatic elimination; avoid use with renal disease. Halflife: ~10 hr Drug interactions: Protein displacement with warfarin, phenytoin, methotrexate

Cautions: Rash, Stevens-Johnson syndrome, nausea, leukopenia, crystalluria. Renal and hepatic elimination; avoid use with renal disease. Halflife: ~12 hr. Initial dose often a loading dose (doubled) Drug interactions: Protein displacement with warfarin, phenytoin, methotrexate Cautions: Rash, Stevens-Johnson syndrome, nausea, leukopenia, crystalluria. Renal and hepatic

ointment

Adults: 4-8 g/24 hr divided q4-6h PO

Tigecycline Tygacil Injection

Tetracycline-class antibiotic (glycylcycline) active against Enterobacteriaceae, including extended spectrum β-lactamase producers; streptococci (including VRE); staphylococci (including MRSA); and anaerobes Children: unknown Adults: 100 mg loading dose followed by 50 mg q12h IV

Tobramycin Nebcin, Tobrex Injection Ophthalmic solution, ointment

Aminoglycoside antibiotic active against gram-negative bacilli, especially E. coli, Klebsiella, Enterobacter, Serratia, Proteus, and Pseudomonas Neonates: Postnatal age ≤7 days, weight 1,200-2,000 g: 2.5 mg/kg q12-18h IV or IM; weight >2,000 g: 2.5 mg/kg q12h IV or IM; postnatal age >7 days, weight 1,200-2,000 g: 2.5 mg/kg q8-12h IV or IM; weight >2,000 g: 2.5 mg/kg q8h IV or IM Children: 2.5 mg/kg/24 hr divided q8-12h IV or IM. Alternatively, may administer 5-7.5 mg/kg/24 hr IV. Preservative-free preparation for intraventricular or intrathecal use: neonate, 1 mg/24 hr; children, 1-2 mg/24 hr; adults, 4-8 mg/24 hr Adults: 3-6 mg/kg/24 hr divided q8h IV or IM

Trimethoprim Proloprim, Trimpex Tablet: 100, 200 mg

Folic acid antagonist effective in prophylaxis and treatment of E. coli, Klebsiella, P. mirabilis, and Enterobacter UTIs; P. carinii pneumonia Children: For UTI: 4-6 mg/kg/24 hr divided q12h PO Children >12 yr and adults: 100-200 mg q12h PO. P. carinii pneumonia (with dapsone): 1520 mg/kg/24 hr divided q6h for 21 days PO Glycopeptide antibiotic active against most gram-positive pathogens including staphylococci (including MRSA and coagulase-negative staphylococci), S. pneumoniae including penicillin-resistant strains, Enterococcus (resistance is increasing), and C. difficile –associated colitis Neonates: Postnatal age ≤7 days, weight

Vancomycin Vancocin, Lyphocin Injection Capsule: 125 mg, 250 mg Suspension

elimination; avoid use with renal disease. Halflife: ~7-12 hr. Initial dose often a loading dose (doubled) Drug interactions: Protein displacement with warfarin, phenytoin, methotrexate Cautions: Pregnancy; children 90% of all staphylococci isolated, regardless of source, are resistant to these agents. Addition of a β-lactamase inhibitor (clavulanic acid, sulbactam, tazobactam) to a penicillin-based drug also confers antistaphylococcal activity but has no effect on MRSA. The spectrum of these agents (which includes gram-negative bacteria) can be an advantage when broad empirical coverage is needed, but narrower coverage should be selected once S. aureus is identified. Antistaphylococcal penicillins and most cephalosporins do not provide activity against MRSA. For initial treatment for penicillin-allergic individuals and those with suspected serious infections caused by MRSA, vancomycin is the preferred therapy. Serum levels of vancomycin should be monitored, with serum trough concentrations of 10-20 µg/mL, depending on the location and severity of infection. Rare vancomycin intermediate and vancomycin-resistant strains of S. aureus have also been reported, mostly in patients being treated with vancomycin. For critically ill patients with suspected S. aureus , empirical therapy with both vancomycin and nafcillin should be considered until cultures results are available. Initial treatment with IV clindamycin, followed by a transition to oral clindamycin, has been effective in bone, joint, and soft tissue

infection; however, not all strains of MSSA or MRSA are susceptible to clindamycin. Inducible clindamycin resistance in isolates initially reported as susceptible must be ruled out by D-test or molecular methods. Clindamycin is bacteriostatic and should not be used to treat endocarditis, persistent bacteremia, or CNS infections caused by S. aureus. Given that the mechanism of action of clindamycin involves inhibition or protein synthesis, many experts use clindamycin to treat S. aureus toxin–mediated illnesses (e.g., TSS) to inhibit toxin production. Although the very-broad- spectrum carbapenems (meropenem, ertapenem, and imipenem) have activity against MSSA, they have no activity against MRSA. As a result, carbapenems are rarely used for empirical therapy of possible staphylococcal infection and are too broad in most cases for use in identified MSSA infections. Quinolone antibiotics have unpredictable activity against MSSA and no activity against MRSA. Linezolid and daptomycin are useful for serious S. aureus infections, particularly those caused by MRSA, when treatment with vancomycin is ineffective or not tolerated.(Table 208.1 ). A number of novel antistaphylococcal antibiotics have emerged for use in resistant or refractory MSSA and MRSA infection in adults that may be required for pediatric therapy in select patients under the guidance of a pediatric infectious disease specialist. These include ceftaroline , a broad-spectrum antistaphylococcal cephalosporin, and oritavancin and dalbavancin , lipoglycopeptides structurally related to vancomycin with very long half-lives and broad activity against gram-positive organisms. Rifampin or gentamicin may be added to a β-lactam or vancomycin for synergy in serious infections such as endocarditis, particularly when prosthetic valve material is involved. Table 208.1

Parenteral Antimicrobial Agent(s) for Treatment of Serious Staphylococcus aureus Infections SUSCEPTIBILITY ANTIMICROBIALS COMMENTS I. INITIAL EMPIRICAL THERAPY (ORGANISM OF UNKNOWN SUSCEPTIBILITY) Drugs of choice: Vancomycin + For life-threatening infections (e.g., septicemia, nafcillin or oxacillin endocarditis, CNS infection); linezolid could be substituted if the patient has received several recent courses of vancomycin Vancomycin

For non–life-threatening infection without signs of severe sepsis (e.g., skin infection, cellulitis, osteomyelitis, pyarthrosis) when rates of MRSA colonization and

Cefazolin or nafcillin

infection in the community are substantial For non–life-threatening infection when low likelihood of MRSA is suspected

Clindamycin

For non–life-threatening infection without signs of severe sepsis when rates of MRSA colonization and infection in the community are substantial and prevalence of clindamycin resistance is low II. METHICILLIN-SUSCEPTIBLE, PENICILLIN-RESISTANT S. aureus Drugs of choice: Nafcillin* Alternatives (depending on Cefazolin susceptibility results): Clindamycin Only for patients with a serious penicillin allergy and clindamycin-susceptible strain Vancomycin Only for penicillin- and cephalosporin-allergic patients Ampicillin + When broader coverage, including gram-negative sulbactam organisms is required III. METHICILLIN-RESISTANT S. aureus (MRSA) Drugs of choice: Vancomycin* Alternatives: susceptibility Clindamycin (if testing results available susceptible) before alternative drugs are Daptomycin † used Linezolid † Trimethoprimsulfamethoxazole * One of the adjunctive agents, gentamicin or rifampin, should be added to the therapeutic

regimen for life-threatening infections such as endocarditis or central nervous system (CNS) infection. Consultation with an infectious diseases specialist should be considered to determine which agent to use and duration of use. † Linezolid and daptomycin are agents with activity in vitro and efficacy with multidrug-resistant,

gram-positive organisms, including S. aureus . Because experience with these agents in children is limited, consultation with an infectious diseases specialist should be considered before use. Daptomycin is ineffective for treatment of pneumonia.

In many infections, oral antimicrobials may be substituted to complete the course of treatment, after an initial period of parenteral therapy and determination of antimicrobial susceptibilities, or can be used as initial treatment in less severe infections. Dicloxacillin (50-100 mg/kg/24 hr divided 4 times daily PO) and cephalexin (25-100 mg/kg/24 hr divided 3-4 times daily PO) are absorbed well orally (PO) and are effective against MSSA. Amoxicillinclavulanate (40-80 mg amoxicillin/kg/24 hr divided 3 times daily PO) is also effective when a broader spectrum of coverage is required. Clindamycin (30-40 mg/kg/24 hr divided 3-4 times daily PO) is highly absorbed from the intestinal tract and is frequently used for empirical coverage when both MRSA and MSSA are possible, as well as for susceptible MRSA infections or for MSSA in penicillin/cephalosporin-allergic patients. Compliance with oral clindamycin may be limited in small children because of poor palatability of oral

formulations. Trimethoprim-sulfamethoxazole (TMP-SMX) may be an effective oral antibiotic for many strains of both MSSA and MRSA. Oral linezolid is an option for severe MRSA infections that have improved but require ongoing therapy when more common options are not tolerated or are ineffective due to resistance patterns. Despite in vitro susceptibility of S. aureus to ciprofloxacin and other quinolone antibiotics, these agents should not be used in serious staphylococcal infections, because their use is associated with rapid development of resistance. The duration of oral therapy depends on the response, as determined by the clinical response and in some cases, radiologic and laboratory findings.

Prognosis Untreated S. aureus septicemia is associated with a high fatality rate, which has been reduced significantly by appropriate antibiotic treatment. S. aureus pneumonia can be fatal at any age but is more likely to be associated with high morbidity and mortality in young infants or in patients whose therapy has been delayed. Prognosis also may be influenced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. In most cases with abscess formation, surgical drainage is necessary.

Prevention S. aureus infection is transmitted primarily by direct contact. Strict attention to hand hygiene is the most effective measure for preventing the spread of staphylococci from between individuals (see Chapter 198 ). Use of a hand wash containing chlorhexidine or alcohol is recommended. In hospitals or other institutional settings, all persons with acute S. aureus infections should be isolated until they have been treated adequately. There should be constant surveillance for nosocomial S. aureus infections within hospitals. When MRSA is recovered, strict isolation of affected patients has been shown to be the most effective method for preventing nosocomial spread of infection. When hospitalacquired infections do occur, clusters of nosocomial cases may be defined by molecular typing, and if associated with a singular molecular strain, it may also be necessary to identify colonized hospital personnel and attempt to eradicate

carriage in affected individuals. A number of protocols are aimed at decolonization in patients with recurrent S. aureus skin infection, particularly in individuals colonized with MRSA. These often involve various combinations of decontaminating baths (hypochlorite, 1 tsp common bleach solution per gallon of water, or chlorhexidine 4% soap used weekly), an appropriate oral antibiotic, nasal mupirocin twice daily for 1 wk, and cleaning of household linens in hot water. Although success is not universal, recurrent infections may be reduced, particularly when eradication is done in both the patient and frequent or household contacts. Most cases of mild, recurrent disease will resolve in time without these measures. Because of the potential severity of infections with S. aureus and concerns about emerging resistance, much work has focused on developing a staphylococcal vaccine for use in high-risk patients, but to date, clinical trials have been disappointing. Because S. aureus is frequently a co-infection in severe influenza infections, an indirect preventive impact against staphylococcal pneumonia and tracheitis may be achieved though annual influenza vaccination. Food poisoning may be prevented by excluding individuals with S. aureus infections of the skin from the preparation and handling of food. Prepared foods should be eaten immediately or refrigerated appropriately to prevent multiplication of S. aureus that may have contaminated the food (see Chapter 366 ).

Bibliography Brade KD, Rybak JM, Rybak MJ. Oritavancin: a new lipoglycopeptide antibiotic in the treatment of gram-positive infections. Infect Dis Ther . 2016;5:1–15. Bradley J, Glasser C, Patino H, et al. Daptomycin for complicated skin infections: a randomized trial. Pediatrics . 2017;139(3). Fritz SA, Hogan PG, Hayek G, et al. Household versus individual approaches to eradication of communityassociated Staphylococcus aureus in children: a randomized trial. Clin Infect Dis . 2012;54:743–751. Hamdy RF, Hsu AJ, Stockmann C, et al. Epidemiology of

methicillin-resistant Staphylococcus aureus bacteremia in children. Pediatrics . 2017;139(6):e20170183. Hersh AL, Lee BR, Hedican EB, et al. Linezolid use in hospitalized children. Pediatr Infect Dis J . 2014;33:e14–e18. Holland TL, Fowler VG Jr. Rifampicin for Staphylococcus aureus bacteraemia: give it ARREST. Lancet . 2018;391:634–636. Iwamoto M, Mu Y, Lynfield R, et al. Trends in invasive methicillin-resistant Staphylococcus aureus infections. Pediatrics . 2013;132(4):e817–e824. Jackson KA, Bohm MK, Brooks JT, et al. Invasive methicillinresistant Staphylococcus aureus infections among persons who inject drugs: six sites, 2005–2016. MMWR Morb Mortal Wkly Rep . 2018;67(22):625–628. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis . 2011;52(3):e18–e55. Missiakas D, Schneewind O. Staphylococcus aureus vaccines: deviating from the carol. J Exp Med . 2016;213:1645–1653. Oestergaard LB, Christiansen MN, Schmiegelow MD, et al. Familial clustering of Staphylococcus aureus bacteremia in first-degree relatives. Ann Intern Med . 2016;165(6):390–398. Ray SM. Preventing methicillin-resistant Staphylococcus aureus (MRSA) disease in urban US hospitals—now for the hard part: more evidence pointing to the community as the source of MRSA acquisition. J Infect Dis . 2017;215:1631–1633. Smith JR, Roberts KD, Rybak MJ. Dalbavancin: a novel lipoglycopeptide antibiotic with extended activity against gram-positive infections. Infect Dis Ther . 2015;4(3):245– 258. Walrath JJ, Hennrikus WL, Zalonis C, et al. The prevalence of

MRSA nasal carriage in preoperative pediatric orthopaedic patients. Adv Orthop . 2016;2016:5646529. Zervou FN, Zacharioudakis IM, Ziakas PD, Mylonakis E. MRSA colonization and risk of infection in the neonatal and pediatric ICU: a meta-analysis. Pediatrics . 2014;133(4):e1015–e1023.

208.2

Toxic Shock Syndrome James T. Gaensbauer, James K. Todd

Toxic shock syndrome (TSS) is an acute and potentially severe illness characterized by fever, hypotension, erythematous rash with subsequent desquamation on the hands and feet, and multisystem involvement, including vomiting, diarrhea, myalgias, nonfocal neurologic abnormalities, conjunctival hyperemia, and strawberry tongue.

Etiology TSS is caused by TSST-1–producing and some enterotoxin-producing strains of S. aureus, which may colonize the vagina or cause focal sites of staphylococcal infection.

Epidemiology TSS continues to occur in the United States in men, women, and children, with highest rates in menstruating women 15-25 yr of age. Nonmenstrual TSS is associated with S. aureus infected nasal packing and wounds, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary

bacteremia. Most strains of S. aureus associated with TSS are methicillin susceptible because USA300, the predominant isolate of community-acquired MRSA in the United States, does not contain genes expressing the most common TSS superantigens.

Pathogenesis The primary toxin associated with TSS is TSST-1, although a significant proportion of nonmenstrual TSS is caused by one or more staphylococcal enterotoxins. These toxins act as a superantigens , which trigger cytokine release causing massive loss of fluid from the intravascular space and end-organ cellular injury. Epidemiologic and in vitro studies suggest that these toxins are selectively produced in a clinical environment consisting of a neutral pH, a high PCO 2 , and an aerobic PO 2 , which are the conditions found in abscesses and the vagina with tampon use during menstruation. The risk factors for symptomatic disease include a nonimmune host colonized with a toxin-producing organism, which is exposed to focal growth conditions (menstruation plus tampon use or abscess) that induce toxin production. Some hosts may have a varied cytokine response to exposure to TSST-1, helping to explain a spectrum of severity of TSS that may include staphylococcal scarlet fever. The overall mortality rate of treated patients is 3–5% with early treatment. Approximately 90% of adults have antibody to TSST-1 without a history of clinical TSS, suggesting that most individuals are colonized at some point with a toxin-producing organism at a site (anterior nares) where low-grade or inactive toxin exposure results in an immune response without disease.

Clinical Manifestations The diagnosis of TSS is based on clinical manifestations (Table 208.2 ). Milder cases and those with incomplete clinical characteristics may be common, particularly if the nidus of infection is addressed quickly (e.g., removal of a tampon). The onset of classic TSS is abrupt, with high fever, vomiting, and diarrhea, and is accompanied by sore throat, headache, and myalgias. A diffuse erythematous macular rash (sunburn-like or scarlatiniform) appears within 24 hr and may be associated with hyperemia of pharyngeal, conjunctival, and vaginal mucous membranes. A strawberry tongue is common. Symptoms may include

alterations in the level of consciousness, oliguria, and hypotension, which in severe cases may progress to shock and disseminated intravascular coagulation. Complications, including acute respiratory distress syndrome (ARDS), myocardial dysfunction, and renal failure, are commensurate with the degree of shock. Recovery occurs within 7-10 days and is associated with desquamation, particularly of palms and soles; hair and nail loss have also been observed after 1-2 mo. Immunity to the toxins is slow to develop, so recurrences can occur, especially if there is inadequate antibiotic treatment and/or recurrent tampon use. Many cases of apparent scarlet fever without shock may be caused by TSST-1– producing S. aureus strains. Table 208.2

Diagnostic Criteria of Staphylococcal Toxic Shock Syndrome MAJOR CRITERIA (ALL REQUIRED) Acute fever; temperature >38.8°C (101.8°F) Hypotension (orthostatic, shock; blood pressure below age-appropriate norms) Rash (erythroderma with convalescent desquamation) MINOR CRITERIA (ANY 3 OR MORE) Mucous membrane inflammation (vaginal, oropharyngeal or conjunctival hyperemia, strawberry tongue) Vomiting, diarrhea Liver abnormalities (bilirubin or transaminase greater than twice the upper limit of normal) Renal abnormalities (blood urea nitrogen or creatinine greater than twice the upper limit of normal, or greater than 5 white blood cells per high-power field) Muscle abnormalities (myalgia or creatinine phosphokinase greater than twice the upper limit of normal) Central nervous system abnormalities (alteration in consciousness without focal neurologic signs) Thrombocytopenia (≤100,000/mm3 ) EXCLUSIONARY CRITERIA Absence of another explanation Negative blood cultures (except occasionally for Staphylococcus aureus )

Data from Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red book: 2015 report of the Committee on Infectious Diseases , ed 30, Elk Grove Village, IL, 2015, American Academy of Pediatrics.

Diagnosis There is no specific laboratory test, and diagnosis depends on meeting certain clinical and laboratory criteria in the absence of an alternate diagnosis (see Fig. 208.2 ). Appropriate tests reveal involvement of multiple organ systems, including the hepatic, renal, muscular, gastrointestinal, cardiopulmonary, and

central nervous systems. Bacterial cultures of the associated focus (vagina, abscess) before administration of antibiotics usually yield S. aureus, although this is not a required element of the definition.

Differential Diagnosis Group A streptococci can cause a similar TSS-like illness, termed streptococcal TSS (see Chapter 210 ), which is often associated with severe streptococcal sepsis or a focal streptococcal infection such as cellulitis, necrotizing fasciitis, or pneumonia. Kawasaki disease closely resembles TSS clinically but is usually not as severe or rapidly progressive. Both conditions are associated with fever unresponsive to antibiotics, hyperemia of mucous membranes, and an erythematous rash with subsequent desquamation. However, many of the clinical features of TSS are rare in Kawasaki disease, including diffuse myalgia, vomiting, abdominal pain, diarrhea, azotemia, hypotension, ARDS, and shock (see Chapter 191 ). Kawasaki disease typically occurs in children 1 blood culture is positive with the same CoNS strain, cultures from both line and peripheral sites are positive, and clinical and laboratory signs and symptoms compatible with CoNS sepsis are present and subsequently resolve with appropriate therapy. No blood culture that is positive for CoNS in a neonate or patient with an intravascular catheter should be considered contaminated without careful assessment of the foregoing criteria and examination of the patient. Before initiating presumptive antimicrobial therapy in such patients, it is always prudent to draw 2 separate blood cultures to facilitate subsequent interpretation if CoNS is grown. Increasingly, PCR techniques can allow rapid identification of CoNS in positive blood cultures; use of such methods may prevent unnecessary antibiotic exposure.

Treatment Because most CoNS strains are resistant to methicillin, vancomycin is the initial drug of choice. The addition of rifampin to vancomycin may increase antimicrobial efficacy due to good penetration of this antibiotic into biofilms on indwelling medical devices. Other antibiotics with good in vitro activity against CoNS may be considered in certain circumstances. These include linezolid, quinupristin-dalfopristin, and daptomycin. Antibiotics with potential activity include teicoplanin, clindamycin, levofloxacin, and TMP-SMX. Removal of an infected catheter is ideal. However, this is not always possible because of the therapeutic requirements of the underlying disease (e.g., nutrition for short bowel syndrome, chemotherapy for malignancy). A trial of IV vancomycin (potentially with addition of rifampin) is indicated to attempt to preserve the use of the central line, as long as systemic manifestations of infection are not severe. Antibiotic therapy given through an infected CVC (alternating lumens if multiple) and the use of antibiotic locks in conjunction with systemic therapy may increase the likelihood of curing CoNS line sepsis without line removal. Prosthetic heart valves and CSF shunts usually need to be removed to treat the infection adequately. Peritonitis caused by S. epidermidis in patients on continuous ambulatory peritoneal dialysis is an infection that may be treated with IV or intraperitoneal antibiotics without removing the dialysis catheter. If the organism is resistant to methicillin, vancomycin adjusted for renal function is appropriate therapy. Unlike most CoNS, S. saprophyticus is usually methicillin susceptible, and UTI can typically be treated with a first-generation cephalosporin (cephalexin), amoxicillin–clavulanic acid, or TMP-SMX.

Prognosis Most episodes of CoNS bacteremia respond successfully to antibiotics and removal of any foreign body that is present. Poor prognosis is associated with malignancy, neutropenia, and infected prosthetic or native heart valves. CoNS increases morbidity, duration of hospitalization, and mortality among patients with underlying complicated illnesses.

Prevention

Iatrogenic morbidity and resource utilization caused by contaminated blood cultures can be reduced by using gloves, good skin preparatory techniques, and trained, dedicated personnel to draw blood cultures. Prevention of CoNS infection of indwelling lines includes basic techniques such as central line care “bundles,” which incorporate good hand hygiene, decontamination of hubs and ports before access, minimizing frequency of access, and frequent replacement of external connections and infusion materials. In a recent large randomized controlled trial in children, antibiotic-impregnated catheters significantly reduced rates of central line–associated bloodstream infections.

Bibliography German GJ, Wang B, Bernard K, et al. Staphylococcus lugdunensis : low prevalence and clinical significance in a pediatric microbiology laboratory. Pediatr Infect Dis J . 2013;32:87–89. Gkentzi D, Kolyva S, Spiliopoulou I, et al. Treatment options for persistent coagulase negative staphylococcal bacteremia in neonates. Curr Pediatr Rev . 2016;12:199–208. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis . 2009;49:1–45. Pogorzelska-Maziarz M. The use and effectiveness of bundles for prevention of central line-associated bloodstream infections in neonates: a review of the literature. J Perinat Neonatal Nurs . 2016;30:148–159. Pardo J, Klinker KP, Borgert SJ, et al. Clinical and economic impact of antimicrobial stewardship interventions with the FilmArray blood culture identification panel. Diagn Microbiol Infect Dis . 2016;84:159–164.

CHAPTER 209

Streptococcus pneumoniae (Pneumococcus) Kacy A. Ramirez, Timothy R. Peters

Streptococcus pneumoniae (pneumococcus) is an important pathogen that kills more than 1 million children each year. Childhood pneumococcal disease is prevalent and typically severe, causes numerous clinical syndromes, and is a major cause of life-threatening pneumonia, bacteremia, and meningitis. Antimicrobial resistance in pneumococcus is a major public health problem, with 15–30% of isolates worldwide classified as multidrug resistant (MDR ; resistant to ≥3 classes of antibiotics). Pneumococcal polysaccharide-protein conjugate vaccines (PCVs ) developed for infants have been highly successful in the control of disease caused by virulent vaccine-specific serotypes. Epidemiologic surveillance reveals a dynamic pneumococcal ecology with emergence of highly virulent, MDR serotypes. Ongoing vaccine development and distribution efforts remain the best approach to control this threat to childhood health.

Etiology Streptococcus pneumoniae is a gram-positive, lancet-shaped, polysaccharide encapsulated diplococcus, occurring occasionally as individual cocci or in chains; >90 serotypes have been identified by type-specific capsular polysaccharides. Antisera to some pneumococcal polysaccharides cross-react with other pneumococcal types, defining serogroups (e.g., 6A and 6B). Encapsulated strains cause most serious disease in humans. Capsular polysaccharides impede phagocytosis. Virulence is related in part to capsular size, but pneumococcal types with capsules of the same size can vary widely in

virulence. On solid media, S. pneumoniae forms unpigmented, umbilicated colonies surrounded by a zone of incomplete (α) hemolysis. S. pneumoniae is bile soluble (i.e., 10% deoxycholate) and optochin sensitive. S. pneumoniae is closely related to the viridans groups of Streptococcus mitis , which typically overlap phenotypically with pneumococci. The conventional laboratory definition of pneumococci continues to rely on bile and optochin sensitivity, although considerable confusion occurs in distinguishing pneumococci and other αhemolytic streptococci. Pneumococcal capsules can be microscopically visualized and typed by exposing organisms to type-specific antisera that combine with their unique capsular polysaccharide, rendering the capsule refractile (Quellung reaction). Specific antibodies to capsular polysaccharides confer protection on the host, promoting opsonization and phagocytosis. Additionally, CD4+ T cells have a direct role in antibody-independent immunity to pneumococcal nasopharyngeal colonization. Conjugated PCVs promote T-cell immunity and protect against pneumococcal colonization, in contrast to the pneumococcal polysaccharide vaccine (PPSV23) that is used in adults and certain high-risk pediatric populations and that does not affect nasopharyngeal colonization.

Epidemiology Most healthy individuals carry various S. pneumoniae serotypes in their upper respiratory tract; >90% of children between 6 mo and 5 yr of age harbor S. pneumoniae in the nasopharynx at some time. A single serotype usually is carried by a given individual for an extended period (45 days to 6 mo). Carriage does not consistently induce local or systemic immunity sufficient to prevent later reacquisition of the same serotype. Rates of pneumococcal carriage peak during the 1st and 2nd yr of life and decline gradually thereafter. Carriage rates are highest in institutional setting and during the winter, and rates are lowest in summer. Nasopharyngeal carriage of pneumococci is common among young children attending out-of-home care, with rates of 21–59% in point prevalence studies. Before the introduction of heptavalent pneumococcal conjugate vaccine (PCV7 ) in 2000, serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F caused most invasive childhood pneumococcal infections in the United States. The introduction of PCVs resulted in a marked decrease in invasive pneumococcal

infections (IPIs) in children. By 2005, however, IPIs began to increase slightly because of an increase in non-PCV7 serotypes, particularly serotype 19A. Serotype replacement can result from expansion of existing nonvaccine serotypes, as well as from vaccine-type pneumococci acquiring the polysaccharide capsule of a nonvaccine serotype (serotype switching ). Since the introduction of PCV13 in 2010 in the United States, there has been a decline in IPIs caused by new vaccine serotypes, including 19A. Nonetheless, 19A remains an important cause of meningitis. Indirect protection of unvaccinated persons has occurred since PCV introduction, and this herd protection is likely a result of decreases in nasopharyngeal carriage of virulent pneumococcal vaccine serotypes. S. pneumoniae is the most frequent cause of bacteremia, bacterial pneumonia, otitis media, and bacterial meningitis in children. The decreased ability in children 15,000/µL. In severe cases of pneumococcal disease, WBC count may be low. Pneumococci can be identified in body fluids as gram-positive, lancet-shaped diplococci. Early in the course of pneumococcal meningitis, many bacteria may be seen in relatively acellular CSF. With current methods of continuously monitored blood culture systems, the average time to isolation of pneumococcal organisms is 14-15 hr. Pneumococcal latex agglutination tests for urine or other body fluids suffer from poor sensitivity and add little to gram-stained fluids and standard cultures. Multiplex real-time polymerase chain reaction (PCR) assays are specific and more sensitive than culture of pleural fluid, CSF, and blood, particularly in patients who have recently received antimicrobial therapy.

Additional investigational assays, including serotype-specific urinary antigen detection, have not been validated.

Treatment Antimicrobial resistance among S. pneumoniae continues to be a serious healthcare concern, especially for the widely used β-lactams, macrolides, and fluoroquinolones. Serotypes 6A, 6B, 9V, 14, 19A, 19F, and 23F are the most common serotypes associated with resistance to penicillin. Consequently, the introduction of the 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13 ) has altered antimicrobial resistance patterns. Resistance in pneumococcal organisms to penicillin and the extendedspectrum cephalosporins cefotaxime and ceftriaxone is defined by the minimum inhibitory concentration (MIC), as well as clinical syndrome. Pneumococci are considered susceptible, intermediate, or resistant to various antibacterial agents based on specific MIC breakpoints. For patients with pneumococcal meningitis, penicillin-susceptible strains have MIC ≤0.06 µg/mL, and penicillin-resistant strains have MIC ≥0.12 µg/mL. For patients with nonmeningeal pneumococcal infections, breakpoints are higher; in particular, penicillin-susceptible strains have MIC ≤2 µg/mL, and penicillin resistant strains have MIC ≥8 µg/mL. For patients with meningitis, cefotaxime- and ceftriaxone-susceptible strains have MIC ≤0.5 µg/mL, and resistant strains have MIC ≥2.0 µg/mL. For patients with nonmeningeal pneumococcal disease, breakpoints are higher, and cefotaximeand ceftriaxone-susceptible strains have MIC ≤1 µg/mL, and resistant strains have MIC ≥4 µg/mL. In cases when the pneumococcus is resistant to erythromycin but sensitive to clindamycin, a D-test should be performed to determine whether clindamycin resistance can be induced; if the D-test is positive, clindamycin should not be used to complete treatment of the patient. More than 30% of pneumococcal isolates are resistant to trimethoprimsulfamethoxazole (TMP-SMX); levofloxacin resistance is low but has also been reported. All isolates from children with severe infections should be tested for antibiotic susceptibility, given widespread pneumococcal MDR strains. Resistance to vancomycin has not been seen at this time, but vancomycintolerant pneumococci that are killed at a slower rate have been reported, and these tolerant pneumococci may be associated with a worse clinical outcome. Linezolid is an oxazolidinone antibacterial with activity against MDR grampositive organisms, including pneumococcus, and has been used in the treatment

of MDR pneumococcal pneumonia, meningitis, and severe otitis. Despite early favorable studies, use of this drug is limited by myelosuppression and high cost, and linezolid resistance in pneumococcus is reported. Children ≥1 mo old with suspected pneumococcal meningitis should be treated with combination therapy using vancomycin (60 mg/kg/24 hr divided every 6 hr IV), and high-dose cefotaxime (300 mg/kg/24 hr divided every 8 hr IV) or ceftriaxone (100 mg/kg/24 hr divided every 12 hr IV). Proven pneumococcal meningitis can be treated with penicillin alone, or cefotaxime or ceftriaxone alone, if the isolate is penicillin susceptible. If the organism is nonsusceptible (i.e., intermediate or full resistance) to penicillin but susceptible to cefotaxime and ceftriaxone, pneumococcal meningitis can be treated with cefotaxime or ceftriaxone alone. However, if the organism is nonsusceptible to penicillin and to cefotaxime or ceftriaxone, pneumococcal meningitis should be treated with combination vancomycin plus cefotaxime or ceftriaxone, not with vancomycin alone, and consideration should be given to the addition of rifampin . Some experts recommend use of corticosteroids in pneumococcal meningitis early in the course of disease, but data demonstrating clear benefit in children are lacking. The 2011 Infectious Diseases Society of America guidelines recommend amoxicillin as first-line therapy for previously healthy, appropriately immunized infants and preschool children with mild to moderate, uncomplicated community-acquired pneumonia. Ampicillin or penicillin G may be administered to the fully immunized infant or school-age child admitted to a hospital ward with uncomplicated community-acquired pneumonia, when local epidemiologic data document lack of substantial high-level penicillin resistance for invasive S. pneumoniae . Empirical therapy with a parenteral thirdgeneration cephalosporin (ceftriaxone or cefotaxime) should be prescribed for hospitalized infants and children who are not fully immunized, in regions where local epidemiology of invasive pneumococcal strains documents widespread penicillin resistance, or for infants and children with life-threatening infection, including those with empyema. Non–β-lactam agents, such as vancomycin, have not been shown to be more effective than third-generation cephalosporins in the treatment of pneumococcal pneumonia, given the degree of drug resistance currently seen in the United States. Higher doses of amoxicillin (80-100 mg/kg/24 hr) have been successful in the treatment of otitis media caused by penicillin-nonsusceptible strains. If the patient has failed initial antibiotic therapy, alternative agents should be active

against penicillin-nonsusceptible pneumococcus as well as β-lactamase– producing Haemophilus influenzae and Moraxella catarrhalis . These include high-dose oral amoxicillin-clavulanate (in the 14 : 1 formulation to reduce risk of diarrhea), oral cefdinir, cefpodoxime, or cefuroxime; or a 3-day course of intramuscular (IM) ceftriaxone if patients fail oral therapy. Empirical treatment of pneumococcal disease should be based on knowledge of susceptibility patterns in specific communities. For individuals with a non–type I allergic reaction to penicillin, cephalosporins (standard dosing) can be used. For type I allergic reactions (immediate, anaphylactic) to β-lactam antibiotics, clindamycin and levofloxacin are preferred alternatives depending on the site of infection (e.g., clindamycin may be effective for pneumococcal infections other than meningitis). TMP-SMX may also be considered for susceptible strains, but erythromycin (or related macrolides; e.g., azithromycin, clarithromycin) should be avoided given high rates of resistance.

Prognosis Prognosis depends on the integrity of host defenses, virulence and numbers of the infecting organism, age of the host, site and extent of the infection, and adequacy of treatment. The mortality rate for pneumococcal meningitis is approximately 10% in most studies. Pneumococcal meningitis results in sensorineural hearing loss in 20–30% of patients and can cause other serious neurologic sequelae, including paralysis, epilepsy, blindness, and intellectual deficits.

Prevention The highly successful PCVs have resulted in a marked decrease in IPIs in children. PCVs provoke protective antibody responses in 90% of infants given these vaccines at 2, 4, and 6 mo of age, and greatly enhanced responses (e.g., immunologic memory) are apparent after vaccine doses given at 12-15 mo of age (Table 209.2 ). In a large clinical trial, PCV7 was shown to reduce invasive disease caused by vaccine serotypes by up to 97% and to reduce invasive disease caused by all serotypes, including serotypes not in the vaccine, by 89%. Children who received PCV7 had 7% fewer episodes of acute otitis media and underwent

20% fewer tympanostomy tube placements than unvaccinated children. Following PCV13, a 64% reduction in IPIs caused by vaccine serotypes has been seen, particularly in children 60 lb, every 4 wk* or Penicillin V 250 mg, twice daily or Sulfadiazine or 0.5 g, once daily for patients weighing ≤60 lb sulfisoxazole 1.0 g, once daily for patients weighing >60 lb For People Who Are Allergic to Penicillin and Sulfonamide Drugs Macrolide or azalide Variable

ROUTE Intramuscular

Oral Oral

Oral

* In high-risk situations, administration every 3 wk is recommended.

Adapted from Gerber MA, Baltimore RS, Eaton CB, et al: Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, Circulation 119:1541–1551, 2009.

Table 210.5 Duration of Prophylaxis for People Who Have Had Acute Rheumatic Fever: AHA

Recommendations CATEGORY Rheumatic fever without carditis Rheumatic fever with carditis but without residual heart disease (no valvular disease* ) Rheumatic fever with carditis and residual heart disease (persistent valvular disease* )

DURATION 5 yr or until 21 yr of age, whichever is longer 10 yr or until 21 yr of age, whichever is longer 10 yr or until 40 yr of age, whichever is longer; sometimes lifelong prophylaxis

* Clinical or echocardiographic evidence.

Adapted from Gerber MA, Baltimore RS, Eaton CB, et al: Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association (AHA) Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, Circulation 119:1541–1551, 2009.

Patients who did not have carditis with their initial episode of acute RF have a relatively low risk for carditis with recurrences. Antibiotic prophylaxis should continue in these patients until the patient reaches 21 yr of age or until 5 yr have elapsed since the last rheumatic fever attack, whichever is longer. The decision to discontinue prophylactic antibiotics should be made only after careful consideration of potential risks and benefits and of epidemiologic factors such as the risk for exposure to GAS infections. The regimen of choice for secondary prevention is a single intramuscular injection of benzathine penicillin G (600,000 IU for children weighing ≤60 lb and 1.2 million IU for those >60 lb) every 4 wk (Table 210.4 ). In certain highrisk patients, and in certain areas of the world where the incidence of rheumatic fever is particularly high, use of benzathine penicillin G every 3 wk may be necessary because serum concentrations of penicillin may decrease to marginally effective levels after 3 wk. In the United States, administration of benzathine penicillin G every 3 wk is recommended only for those who have recurrent acute RF despite adherence to a 4 wk regimen. In compliant patients, continuous oral antimicrobial prophylaxis can be used. Penicillin V (250 mg twice daily) and sulfadiazine or sulfisoxazole (500 mg for those weighing ≤60 lb or 1,000 mg for those >60 lb, once daily) are equally effective when used in such patients. For the exceptional patient who is allergic to both penicillin and sulfonamides, a macrolide (erythromycin or clarithromycin) or azalide (azithromycin) may be used. Table 210.5 notes the duration of secondary prophylaxis.

Bibliography

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C H A P T E R 2 11

Group B Streptococcus Catherine S. Lachenauer, Michael R. Wessels

Group B streptococcus (GBS ), or Streptococcus agalactiae, is a major cause of neonatal bacterial sepsis in the United States. Although advances in prevention strategies have led to a decline in the incidence of neonatal disease, GBS remains a major pathogen for neonates, pregnant women, and nonpregnant adults.

Etiology Group B streptococci are facultative anaerobic gram-positive cocci that form chains or diplococci in broth and small, gray-white colonies on solid medium. GBS is definitively identified by demonstration of the Lancefield group B carbohydrate antigen, such as with latex agglutination techniques widely used in clinical laboratories. Presumptive identification can be established on the basis of a narrow zone of β-hemolysis on blood agar, resistance to bacitracin and trimethoprim-sulfamethoxazole (TMP-SMX), lack of hydrolysis of bile esculin, and elaboration of CAMP factor (named for the discoverers, Christie, Atkins, and Munch-Petersen), an extracellular protein that, in the presence of the β toxin of Staphylococcus aureus, produces a zone of enhanced hemolysis on sheep blood agar. Individual GBS strains are serologically classified according to the presence of 1 of the structurally distinct capsular polysaccharides, which are important virulence factors and stimulators of antibody-associated immunity. Ten GBS capsular types have been identified: types Ia, Ib, II, III, IV, V, VI, VII, VIII, and IX.

Epidemiology

GBS emerged as a prominent neonatal pathogen in the late 1960s. For the next 2 decades, the incidence of neonatal GBS disease remained fairly constant, affecting 1.0-5.4 per 1,000 liveborn infants in the United States. Two patterns of disease were seen: early-onset disease , which presents at 50% of cases of late-onset disease and of meningitis associated with early- or late-onset disease. The serotype distribution of colonizing and invasive isolates from pregnant women is similar to that from infected newborns. In Japan, serotypes VI and VIII have been reported as common maternal colonizing serotypes, and case reports indicate that type VIII strains may cause neonatal disease indistinguishable from that caused by other serotypes.

Pathogenesis A major risk factor for the development of early-onset neonatal GBS infection is maternal vaginal or rectal colonization by GBS. Infants acquire GBS by ascending infection or during passage through the birth canal. Fetal aspiration of infected amniotic fluid may occur. The incidence of early-onset GBS infection increases with the duration of rupture of membranes. Infection may also occur through seemingly intact membranes. In cases of late-onset infection, GBS may

be vertically transmitted or acquired later from maternal or nonmaternal sources. Several bacterial factors are implicated in the pathophysiology of invasive GBS disease, primarily the type-specific capsular polysaccharide . Strains that are associated with invasive disease in humans elaborate more capsular polysaccharide than do colonizing isolates. All GBS capsular polysaccharides are high-molecular-weight polymers composed of repeating oligosaccharide subunits that include a short side chain terminating in N -acetylneuraminic acid (sialic acid ). Studies in type III GBS show that the sialic acid component of the capsular polysaccharide prevents activation of the alternative complement pathway in the absence of type-specific antibody. Sialylated capsular polysaccharide on the GBS surface also interacts with sialic acid–binding lectins or siglecs on human leukocytes to dampen inflammatory gene activation. Thus, the capsular polysaccharide appears to exert a virulence effect by protecting the organism from opsonophagocytosis in the nonimmune host and by downregulating leukocyte activation. In addition, type-specific virulence attributes are suggested by the fact that type III strains are implicated in most cases of late-onset neonatal GBS disease and meningitis. Type III strains are taken up by brain endothelial cells more efficiently in vitro than are strains of other serotypes, although studies using acapsular mutant strains demonstrate that it is not the capsule itself that facilitates cellular invasion. A single clone of type III GBS is highly associated with late-onset disease and meningitis. This clonal group, ST-17, produces a surface-anchored protein called hypervirulent GBS adhesin (HvgA ) that is not present in other GBS isolates. HvgA contributes to GBS adherence to intestinal and endothelial cells and mediates invasion into the central nervous system (CNS) in an experimental infection model in mice. Other putative GBS virulence factors include GBS surface proteins, which may play a role in adhesion to host cells; C5a peptidase, which is postulated to inhibit the recruitment of polymorphonuclear cells into sites of infection; β-hemolysin, which has been associated with cell injury in vitro; and hyaluronidase, which has been postulated to act as a spreading factor in host tissues. In a classic study of pregnant women colonized with type III GBS, those who gave birth to healthy infants had higher levels of capsular polysaccharide– specific antibody than those who gave birth to infants who developed invasive disease. In addition, there is a high correlation of antibody titer to GBS type III in mother–infant paired sera. These observations indicate that transplacental transfer of maternal antibody is critically involved in neonatal immunity to GBS. Optimal immunity to GBS also requires an intact complement system. The

classical complement pathway is an important component of GBS immunity in the absence of specific antibody; in addition, antibody-mediated opsonophagocytosis may proceed by the alternative complement pathway. These and other results indicate that anticapsular antibody can overcome the prevention of C3 deposition on the bacterial surface by the sialic acid component of the type III capsule. The precise steps between GBS colonization and invasive disease remain unclear. In vitro studies showing GBS entry into alveolar epithelial cells and pulmonary vasculature endothelial cells suggest that GBS may gain access to the bloodstream by invasion from the alveolar space, perhaps following intrapartum aspiration of infected fluid. β-Hemolysin/cytolysin may facilitate GBS entry into the bloodstream following inoculation into the lungs. However, highly encapsulated GBS strains, which enter eukaryotic cells poorly in vitro compared with capsule-deficient organisms, are associated with virulence clinically and in experimental infection models. GBS induces the release of proinflammatory cytokines. The group B antigen and the peptidoglycan component of the GBS cell wall are potent inducers of tumor necrosis factor-α release in vitro, whereas purified type III capsular polysaccharide is not. Even though the capsule plays a central role in virulence through avoidance of immune clearance, the capsule does not directly contribute to cytokine release and the resultant inflammatory response. The complete genome sequences of hundreds of GBS strains have been reported, emphasizing a genomic approach to better understanding GBS. Analysis of these sequences shows that GBS is closely related to Streptococcus pyogenes and Streptococcus pneumoniae. Many known and putative GBS virulence genes are clustered in pathogenicity islands that also contain mobile genetic elements, suggesting that interspecies acquisition of genetic material plays an important role in genetic diversity.

Clinical Manifestations Two syndromes of neonatal GBS disease are distinguishable on the basis of age at presentation, epidemiologic characteristics, and clinical features (Table 211.1 ). Early-onset neonatal GBS disease presents within the 1st 6 days of life and is often associated with maternal obstetric complications, including chorioamnionitis, prolonged rupture of membranes, and premature labor. Infants may appear ill at the time of delivery, and most infants become ill within 24 hr of

birth. In utero infection may result in septic abortion or immediate distress after birth. More than 80% of early-onset GBS disease presents as sepsis; pneumonia and meningitis are other common manifestations. Asymptomatic bacteremia is uncommon but can occur. In symptomatic patients, nonspecific signs such as hypothermia or fever, irritability, lethargy, apnea, and bradycardia may be present. Respiratory signs are prominent regardless of the presence of pneumonia and include cyanosis, apnea, tachypnea, grunting, flaring, and retractions. A fulminant course with hemodynamic abnormalities, including tachycardia, acidosis, and shock, may ensue. Persistent fetal circulation may develop. Clinically and radiographically, pneumonia associated with early-onset GBS disease is difficult to distinguish from respiratory distress syndrome . Patients with meningitis often present with nonspecific findings, as described for sepsis or pneumonia, with more specific signs of CNS involvement initially absent. Table 211.1 Characteristics of Early- and Late-Onset Group B Streptococcus Disease

Age at onset Increased risk after obstetric complications Common clinical manifestations Common serotypes Case fatality rate

EARLY-ONSET DISEASE 0-6 days Yes Sepsis, pneumonia, meningitis Ia, Ib, II, III, V 4.7%

LATE-ONSET DISEASE 7-90 days No Bacteremia, meningitis, osteomyelitis, other focal infections III predominates 2.8%

Adapted from Schrag SJ, Zywicki S, Farley MM, et al: Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis, N Engl J Med 342:15–20, 2000.

Late-onset neonatal GBS disease presents at ≥7 days of life (may be seen in 1st 2-3 mo) and usually manifests as bacteremia (45–65%) and meningitis (25– 35%). Focal infections involving bone and joints, skin and soft tissue, the urinary tract, or lungs may also be seen. Cellulitis and adenitis are often localized to the submandibular or parotid regions. In contrast to early-onset disease, maternal obstetric complications are not risk factors for the development of late-onset GBS disease. Infants with late-onset disease are often less severely ill on presentation than infants with early-onset disease, and the disease is often less fulminant. Invasive GBS disease in children beyond early infancy is uncommon.

Bacteremia without a focus is the most common syndrome associated with childhood GBS disease beyond early infancy. Focal infections may include meningitis, pneumonia, endocarditis, and bone and joint infections.

Diagnosis A major challenge is distinguishing between respiratory distress syndrome and invasive neonatal GBS infection in preterm infants because the 2 illnesses share clinical and radiographic features. Severe apnea, early onset of shock, abnormalities in the peripheral leukocyte count, and greater lung compliance may be more likely in infants with GBS disease. Other neonatal pathogens, including Escherichia coli and Listeria monocytogenes, may cause illness that is clinically indistinguishable from that caused by GBS. The diagnosis of invasive GBS disease is established by isolation and identification of the organism from a normally sterile site, such as blood, urine, or cerebrospinal fluid (CSF). Isolation of GBS from gastric or tracheal aspirates or from skin or mucous membranes indicates colonization and is not diagnostic of invasive disease. CSF should be examined in all neonates suspected of having sepsis, because specific CNS signs are often absent in the presence of meningitis, especially in early-onset disease. Antigen detection methods that use group B polysaccharide–specific antiserum, such as latex particle agglutination, are available for testing of urine, blood, and CSF, but these tests are less sensitive than culture. Moreover, antigen is often detected in urine samples collected by bag from otherwise healthy neonates who are colonized with GBS on the perineum or rectum.

Laboratory Findings Frequently present are abnormalities in the peripheral white blood cell count, including an increased or decreased absolute neutrophil count, elevated band count, increased ratio of bands to total neutrophils, or leukopenia. Elevated Creactive protein level has been investigated as a potential early marker of GBS sepsis but is unreliable. Findings on chest radiograph are often indistinguishable from those of respiratory distress syndrome and may include reticulogranular patterns, patchy infiltrates, generalized opacification, pleural effusions, or increased interstitial markings.

Treatment Penicillin G is the treatment of choice of confirmed GBS infection. Empirical therapy of neonatal sepsis that could be caused by GBS generally includes ampicillin and an aminoglycoside, both for the need for broad coverage pending organism identification and for synergistic bactericidal activity. Once GBS has been definitively identified and a good clinical response has occurred, therapy may be completed with penicillin alone. Especially in patients with meningitis, high doses of penicillin (450,000-500,000 units/kg/day) or ampicillin (300 mg/kg/day) are recommended because of the relatively high mean inhibitory concentration (MIC) of penicillin for GBS as well as the potential for a high initial CSF inoculum. The duration of therapy varies according to the site of infection and should be guided by clinical circumstances (Table 211.2 ). Extremely ill near-term patients with respiratory failure have been successfully treated with extracorporeal membrane oxygenation. Table 211.2 Recommended Duration of Therapy for Manifestations of Group B Streptococcus Disease TREATMENT Bacteremia without a focus Uncomplicated meningitis Ventriculitis Septic arthritis or osteomyelitis

DURATION 10 days 14 days At least 4 wk 3-4 wk

Data from the American Academy of Pediatrics: Group B streptococcal infections. In Kimberlin DW, Brady MT, Jackson MA, Long SS, editors: Red book: 2015 report of the Committee on Infectious Diseases , ed 30. Elk Grove Village, IL, 2015, American Academy of Pediatrics, pp 746–747.

In patients with GBS meningitis, some experts recommend that additional CSF be sampled at 24-48 hr to determine whether sterility has been achieved. Persistent GBS growth may indicate an unsuspected intracranial focus or an insufficient antibiotic dose. For recurrent neonatal GBS disease , standard intravenous antibiotic therapy followed by attempted eradication of GBS mucosal colonization has been suggested. This suggestion is based on the findings in several studies that invasive isolates from recurrent episodes are usually identical to each other and to colonizing isolates from the affected infant. Rifampin has most frequently been used for this purpose, but one report demonstrates that eradication of GBS

colonization in infants is not reliably achieved by rifampin therapy. Optimal management of this uncommon situation remains unclear.

Prognosis Studies from the 1970s and 1980s showed that up to 30% of infants surviving GBS meningitis had major long-term neurologic sequelae, including developmental delay, spastic quadriplegia, microcephaly, seizure disorder, cortical blindness, or deafness; less severe neurologic complications may be present in other survivors. A study of infants who survived GBS meningitis diagnosed from 1998 through 2006 found that 19% had severe neurologic impairment and 25% had mild to moderate impairment at long-term follow-up. Periventricular leukomalacia and severe developmental delay may result from GBS disease and accompanying shock in premature infants, even in the absence of meningitis. The outcome of focal GBS infections outside the CNS, such as bone or soft tissue infections, is generally favorable. In the 1990s, the case fatality rates associated with early- and late-onset neonatal GBS disease were 4.7% and 2.8%, respectively. Mortality is higher in premature infants; one study reported a case fatality rate of 30% in infants at gestational age 2,000 µg/mL, a result of modification or inactivation of aminoglycoside agents. Strains demonstrating high-level resistance and even some moderately resistant isolates are not affected synergistically by aminoglycosides and cell wall–active antibiotics. Resistance to almost all other antibiotic classes, including tetracyclines, macrolides, and chloramphenicol, has been described among the enterococci, necessitating individual susceptibility testing for these antibiotics when their use is considered. Despite apparent susceptibility in vitro, trimethoprimsulfamethoxazole (TMP-SMX) has poor activity in vivo and should not be used as the primary agent against Enterococcus infections. Whereas ampicillin and vancomycin continue to have reliable activity against E. faecalis , resistance to both antibiotics is prevalent among E. faecium . Resistance to vancomycin, defined as MIC >32 µg/mL, and other glycopeptides, including teicoplanin, occurs in >30% of invasive E. faecium infections. Rates of vancomycin-resistant Enterococcus (VRE ) have increased >2-fold since 2000 and have become a major challenge in the care of hospitalized patients. Mortality in patients with VRE bloodstream infections is considerable, and treatment is complicated by frequent resistance of VRE to most other antibiotic classes. Both high- and moderate-level resistance are described in E. faecalis and E. faecium. High-level resistance (MIC ≥64 µg/mL) can be transferred by way of conjugation and usually results from plasmid-mediated transfer of the vanA gene. High-level resistance is most common among E. faecium but is increasingly seen among E. faecalis isolates. Moderate-level resistance (MIC 8256 µg/mL) results from a chromosomal homolog of vanA, known as vanB. Isolates that harbor the vanB gene are only moderately resistant to vancomycin and initially demonstrate susceptibility to teicoplanin, although resistance can emerge during therapy. Resistance to newer agents, including linezolid and daptomycin, is rare thus far. Linezolid resistance is a result of mutations in the 26S ribosomal subunit, whereas daptomycin resistance is associated with mutations in genes required for membrane synthesis and repair.

Clinical Manifestations Enterococcus infections traditionally occurred predominantly in newborn infants; however, infection in older children is increasingly common. Most

Enterococcus infections occur in patients with breakdown of normal physical barriers such as the GI tract, skin, or urinary tract. Other risk factors for Enterococcus infection include cancer chemotherapy, prolonged hospitalization, indwelling vascular catheters, prior use of antibiotics, and compromised immunity.

Neonatal Infections Enterococcus accounts for up to 15% of all neonatal bacteremia and septicemia. As with group B streptococcus infections, Enterococcus infections are seen in 2 distinct settings in neonatal patients. Early-onset infection (90%, including cases of bacteremia and sepsis, and this antibiotic has become the preferred agent in treatment of VRE infections in many institutions. Anecdotal reports reveal the success of linezolid in treating meningitis caused by VRE. Unfortunately, as seen with other antibiotics, linezolid resistance is documented, and nosocomial spread of these organisms can occur. Linezolid frequently causes reversible bone marrow suppression after prolonged use and is associated with rare occurrences of lactic acidosis and irreversible peripheral neuropathy. Serotonin syndrome may be seen in patients taking concomitant selective serotonin reuptake inhibitor antidepressants. Oxazolidinones in development include tedizolid , which has better in vitro activity against enterococci and appears to have favorable pharmacokinetic and toxicity profiles compared to linezolid. Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against a broad range of gram-positive organisms. This antibiotic inserts into the bacterial cell wall, causing membrane depolarization and cell death. It has been approved for the treatment of adults with serious skin and soft tissue infections, right-sided endocarditis, and bacteremia caused by susceptible organisms. Most strains of VRE (both E. faecium and E. faecalis ) are susceptible to daptomycin in vitro, and its efficacy in adult patients with VRE appears to be similar to that of linezolid. Experience with daptomycin in children is limited, particularly in the setting of Enterococcus infections. However, based on the experience with adult patients, daptomycin may be an alternative to linezolid when resistance or side effects limit utility of that antibiotic. Daptomycin dosages may need to be higher in children than adults because of more rapid renal clearance. The antibiotic has unreliable activity in the lung and therefore should not be used as a sole agent to treat pneumonia. Resistance of both Staphylococcus aureus and Enterococcus to daptomycin has rarely been described, sometimes arising during therapy. Quinupristin-dalfopristin is a combined streptogramin antibiotic that inhibits bacterial protein synthesis at 2 different stages. It has activity against most E. faecium strains, including those with high-level vancomycin resistance. Approximately 90% of E. faecium strains are susceptible to quinupristin-

dalfopristin in vitro. Notably, it is inactive against E. faecalis and therefore should not be used as the sole agent against gram-positive organisms until culture results exclude the presence of E. faecalis . Studies in children suggest that this antibiotic is effective and generally well tolerated, although episodes of arthralgia and myalgia during therapy are reported. Emergence of resistance to quinupristin-dalfopristin is rare but has been demonstrated. Tigecycline is the first clinically available glycylcycline antibiotic, an expended-spectrum derivative of the tetracycline family. The agent inhibits protein synthesis by binding to the 30S ribosome and is bacteriostatic against susceptible organisms. Tigecycline has broad activity against gram-positive, gram-negative, and anaerobic organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and VRE, and is approved for the treatment of adults with skin and soft tissue infections and intraabdominal infections caused by susceptible organisms. Its efficacy in VRE infections has not yet been demonstrated in clinical trials, and there is little published experience with the use of tigecycline in children thus far. As with other tetracycline antibiotics, tigecycline use may cause discoloration of the teeth, and its use in children 125,000 diphtheria cases, with 10,000 deaths, were reported annually in the United States, with the highest fatality rates among very young and elderly persons. The incidence then began to decrease and, with widespread use of diphtheria toxoid in the United States after World War II, declined steadily through the late 1970s. Since then, ≤5 cases have occurred annually in the United States, with no epidemics of respiratory tract diphtheria. Similar decreases occurred in Europe. Despite the worldwide decrease in disease incidence, diphtheria remains endemic in many developing countries with poor immunization rates against diphtheria. When diphtheria was endemic, it primarily affected children 25 yr old. The largest outbreak of diphtheria in the developed world

since the 1960s occurred from 1990–1996 in the newly independent countries of the former Soviet Union, involving >150,000 cases in 14 countries. Of these, >60% of cases occurred in individuals >14 yr old. Case fatality rates ranged from 3–23% by country. Factors contributing to the epidemic included a large population of underimmunized adults, decreased childhood immunization rates, population migration, crowding, and failure to respond aggressively during early phases of the epidemic. Cases of diphtheria among travelers from these endemic areas were transported to many countries in Europe. Most proven cases of respiratory tract diphtheria in the United States in the 1990s were associated with importation of toxigenic C. diphtheriae, although clonally related toxigenic C. diphtheriae has persisted in this country and Canada for at least 25 yr. World Health Organization (WHO) surveillance reports indicate that most cases of diphtheria worldwide occur in the Southeast Asia and Africa regions. In Europe, increasing reports of respiratory and systemic infections have been attributed to C ulcerans ; animal contact is the predominant risk factor. Cutaneous diphtheria, a curiosity when diphtheria was common, accounted for more than 50% of reported C. diphtheriae isolates in the United States by 1975. This indolent local infection, compared with mucosal infection, is associated with more prolonged bacterial shedding, greater contamination of the environment, and increased transmission to the pharynx and skin of close contacts. Outbreaks are associated with homelessness, crowding, poverty, alcoholism, poor hygiene, contaminated fomites, underlying dermatosis, and introduction of new strains from exogenous sources. It is no longer a tropical or subtropical disease; 1,100 C. diphtheriae infections were documented in a neighborhood in Seattle (site of the last major U.S. outbreak), from 1971–1982; 86% were cutaneous, and 40% involved toxigenic strains. Cutaneous diphtheria is an important source for toxigenic C. diphtheriae in the United States, and its importation is frequently the source for subsequent sporadic cases of respiratory tract diphtheria. Cutaneous diphtheria caused by C. ulcerans from travel to tropical countries or animal contact has been increasingly reported.

Pathogenesis Both toxigenic and nontoxigenic C. diphtheriae cause skin and mucosal infection and can rarely cause focal infection after bacteremia. The organism usually remains in the superficial layers of skin lesions or respiratory tract

mucosa, inducing local inflammatory reaction. The major virulence of the organism lies in its ability to produce a potent polypeptide exotoxin, which inhibits protein synthesis and causes local tissue necrosis and resultant local inflammatory response. Within the first few days of respiratory tract infection (usually in the pharynx), a dense necrotic coagulum of organisms, epithelial cells, fibrin, leukocytes, and erythrocytes forms, initially white and advancing to become a gray-brown, leather-like adherent pseudomembrane (diphtheria is Greek for leather). Removal is difficult and reveals a bleeding edematous submucosa. Paralysis of the palate and hypopharynx is an early local effect of diphtheria toxin. Toxin absorption can lead to systemic manifestations: kidney tubule necrosis, thrombocytopenia, cardiomyopathy, and demyelination of nerves. Because the latter 2 complications can occur 2-10 wk after mucocutaneous infection, the pathophysiology in some cases is suspected to be immunologically mediated.

Clinical Manifestations The manifestations of C. diphtheriae infection are influenced by the anatomic site of infection, the immune status of the host, and the production and systemic distribution of toxin.

Respiratory Tract Diphtheria In a classic description of 1,400 cases of diphtheria in California (1954), the primary focus of infection was the tonsils or pharynx (94%), with the nose and larynx the next 2 most common sites. After an average incubation period of 2-4 days (range 1-10 days), local signs and symptoms of inflammation develop. Infection of the anterior nares is more common among infants and causes serosanguineous, purulent, erosive rhinitis with membrane formation. Shallow ulceration of the external nares and upper lip is characteristic. In tonsillar and pharyngeal diphtheria , sore throat is the universal early symptom. Only half of patients have fever, and fewer have dysphagia, hoarseness, malaise, or headache. Mild pharyngeal injection is followed by unilateral or bilateral tonsillar membrane formation, which can extend to involve the uvula (which may cause toxin-mediated paralysis), soft palate, posterior oropharynx, hypopharynx, or glottic areas (Fig. 214.1 ). Underlying soft tissue edema and enlarged lymph nodes can cause a bull-neck appearance. The degree of local extension correlates

directly with profound prostration, bull-neck appearance, and fatality due to airway compromise or toxin-mediated complications (Fig. 214.2 ).

FIG. 214.1 Tonsillar diphtheria. (Courtesy of Franklin H. Top, MD, Professor and Head of the Department of Hygiene and Preventive Medicine, State University of Iowa, College of Medicine, Iowa City, IA; and Parke, Davis & Company's Therapeutic Notes.)

FIG. 214.2 Diphtheria. Bull-neck appearance of diphtheritic cervical lymphadenopathy. (Courtesy of the Centers for Disease Control and Prevention.)

The characteristic adherent membrane, extension beyond the faucial area, dysphagia, and relative lack of fever help differentiate diphtheria from exudative pharyngitis caused by Streptococcus pyogenes or Epstein-Barr virus. Vincent angina, infective phlebitis with thrombosis of the jugular veins (Lemierre syndrome), and mucositis in patients undergoing cancer chemotherapy are usually differentiated by the clinical setting. Infection of the larynx, trachea, and bronchi can be primary or a secondary extension from the pharyngeal infection. Hoarseness, stridor, dyspnea, and croupy cough are clues. Differentiation from bacterial epiglottitis, severe viral laryngotracheobronchitis, and staphylococcal or streptococcal tracheitis hinges partially on the relative paucity of other signs and symptoms in patients with diphtheria and primarily on visualization of the adherent pseudomembrane at laryngoscopy and intubation. Patients with laryngeal diphtheria are at significant risk for suffocation because of local soft tissue edema and airway obstruction by the diphtheria membrane, a dense cast of respiratory epithelium, and necrotic coagulum. Establishment of an artificial airway and resection of the pseudomembrane can be lifesaving, but further obstructive complications are common, and systemic toxic complications are inevitable.

Cutaneous Diphtheria Classic cutaneous diphtheria is an indolent, nonprogressive infection

characterized by a superficial, ecthyma-like, nonhealing ulcer with a gray-brown membrane. Diphtheria skin infections cannot always be differentiated from streptococcal or staphylococcal impetigo, and these conditions frequently coexist. In most cases, a primary process, such as dermatosis, laceration, burn, bite, or impetigo, becomes secondarily infected with C. diphtheriae. Extremities are more often affected than the trunk or head. Pain, tenderness, erythema, and exudate are typical. Local hyperesthesia or hypesthesia is unusual. Respiratory tract colonization or symptomatic infection with toxic complications occurs in the minority of patients with cutaneous diphtheria. Among infected adults in the Seattle outbreak, 3% with cutaneous infections and 21% with symptomatic nasopharyngeal infection, with or without skin involvement, demonstrated toxic myocarditis, neuropathy, or obstructive respiratory tract complications. All had received at least 20,000 units of equine antitoxin at the time of hospitalization.

Infection at Other Sites C. diphtheriae occasionally causes mucocutaneous infections at other sites, such as the ear (otitis externa), the eye (purulent and ulcerative conjunctivitis), and the genital tract (purulent and ulcerative vulvovaginitis). The clinical setting, ulceration, membrane formation, and submucosal bleeding help differentiate diphtheria from other bacterial and viral causes. Rare cases of septicemia are described and are universally fatal. Sporadic cases of endocarditis occur, and clusters among intravenous drug users have been reported in several countries; skin was the probable portal of entry, and almost all strains were nontoxigenic. Sporadic cases of pyogenic arthritis, mainly from nontoxigenic strains, have been reported in adults and children. Diphtheroids isolated from sterile body sites should not be routinely dismissed as contaminants without careful consideration of the clinical setting.

Diagnosis Specimens for culture should be obtained from the nose and throat and any other mucocutaneous lesion. A portion of membrane should be removed and submitted for culture along with underlying exudate. The laboratory must be notified to use selective medium. C. diphtheriae survives drying. If obtained in a remote area, a dry swab specimen can be placed in a silica gel pack and sent to the laboratory. Evaluation of a direct smear using Gram stain or specific fluorescent antibody is

unreliable. Culture isolates of coryneform organisms should be identified to the species level, and toxigenicity and antimicrobial susceptibility tests should be performed for C. diphtheriae isolates. It is recommended that all isolates be sent to a reference laboratory. In the United States, the Centers for Disease Control and Prevention (CDC) Pertussis and Diphtheria Laboratory provides support to local and state health departments needing assistance with isolation, identification, and subtyping of C. diphtheriae and C. ulcerans.

Complications Respiratory tract obstruction by pseudomembranes may require bronchoscopy or intubation and mechanical ventilation. Two other tissues usually remote from sites of C. diphtheriae infection can be significantly affected by diphtheritic toxin : the heart and the nervous system.

Toxic Cardiomyopathy Toxic cardiomyopathy occurs in 10–25% of patients with respiratory diphtheria and is responsible for 50–60% of deaths. Subtle signs of myocarditis can be detected in most patients, especially the elderly, but the risk for significant complications correlates directly with the extent and severity of exudative local oropharyngeal disease, as well as delay in administration of antitoxin. The first evidence of cardiac toxicity characteristically occurs during the 2nd and 3rd wk of illness as the pharyngeal disease improves, but can appear acutely as early as the 1st wk of illness, a poor prognostic sign, or insidiously as late as the 6th wk. Tachycardia disproportionate to fever is common and may be evidence of cardiac toxicity or autonomic nervous system dysfunction. A prolonged P-R interval and changes in the ST-T wave on an electrocardiographic tracing are relatively frequent findings; dilated and hypertrophic cardiomyopathy detected by echocardiogram has been described. Single or progressive cardiac dysrhythmias can occur, including first-, second-, and third-degree heart block. Temporary transvenous pacing may improve outcomes. Atrioventricular dissociation and ventricular tachycardia are also described, the latter having a high associated mortality. Heart failure may appear insidiously or acutely. Elevation of the serum aspartate transaminase concentration closely parallels the severity of myonecrosis. Severe dysrhythmia portends death. Histologic postmortem findings are variable: little or diffuse myonecrosis with acute

inflammatory response. Recovery from toxic myocardiopathy is usually complete, although survivors of more severe dysrhythmias can have permanent conduction defects.

Toxic Neuropathy Neurologic complications parallel the severity of primary infection and are multiphasic in onset. Acutely or 2-3 wk after onset of oropharyngeal inflammation, hypesthesia and local paralysis of the soft palate typically occur. Weakness of the posterior pharyngeal, laryngeal, and facial nerves may follow, causing a nasal quality in the voice, difficulty in swallowing, and risk for aspiration. Cranial neuropathies characteristically occur in the 5th wk, leading to oculomotor and ciliary paralysis, which can cause strabismus, blurred vision, or difficulty with accommodation. Symmetric demyelinating polyneuropathy has onset 10 days to 3 mo after oropharyngeal infection and causes principally motor deficits with diminished deep tendon reflexes. Nerve conduction velocity studies and cerebrospinal fluid findings in diphtheritic polyneuropathy are indistinguishable from those of Guillain-Barré syndrome. Paralysis of the diaphragm may ensue. Complete neurologic recovery is likely, but rarely vasomotor center dysfunction 2-3 wk after onset of illness can cause hypotension or cardiac failure. Recovery from myocarditis and neuritis is often slow but usually complete. Corticosteroids do not diminish these complications and are not recommended.

Treatment Specific antitoxin is the mainstay of therapy and should be administered on the basis of clinical diagnosis. Because it neutralizes only free toxin, antitoxin efficacy diminishes with elapsed time after the onset of mucocutaneous symptoms. Equine diphtheria antitoxin is available in the United States only from the CDC. Physicians treating a case of suspected diphtheria should contact the CDC Emergency Operations Center (770-488-7100 at all times). Antitoxin is administered as a single empirical dose of 20,000-100,000 units based on the degree of toxicity, site and size of the membrane, and duration of illness. Skin testing must be performed before administration of antitoxin. Patients with positive sensitivity testing or with a history of hypersensitivity reaction to horse equine protein should be desensitized. Antitoxin is probably of no value for local

manifestations of cutaneous diphtheria, but its use is prudent because toxic sequelae can occur. Commercially available intravenous immunoglobulin preparations contain low titers of antibodies to diphtheria toxin; their use for therapy of diphtheria is not proved or approved. Antitoxin is not recommended for asymptomatic carriers. The role of antimicrobial therapy is to halt toxin production, treat localized infection, and prevent transmission of the organism to contacts. C. diphtheriae is usually susceptible to various agents in vitro, including penicillins, erythromycin, clindamycin, rifampin, and tetracycline. Resistance to erythromycin is common in populations if the drug has been used broadly, and resistance to penicillin has also been reported. Only erythromycin or penicillin is recommended; erythromycin is marginally superior to penicillin for eradication of nasopharyngeal carriage. Appropriate therapy is erythromycin (40-50 mg/kg/day divided every 6 hr by mouth [PO] or intravenously [IV]; maximum 2 g/day), aqueous crystalline penicillin G (100,000-150,000 units/kg/day divided every 6 hr IV or intramuscularly [IM]), or procaine penicillin (300,000 units every 12 hr IM for those ≤10 kg in weight; 600,000 units every 12 hr IM for those >10 kg in weight) for 14 days. Once oral medications are tolerated, oral penicillin V (250 mg four times daily) may be used. Antibiotic therapy is not a substitute for antitoxin therapy. Some patients with cutaneous diphtheria have been treated for 7-10 days. Elimination of the organism should be documented by negative results of at least 2 successive cultures of specimens from the nose and throat (or skin) obtained 24 hr apart after completion of therapy. Treatment with erythromycin is repeated if either culture yields C. diphtheriae.

Supportive Care Droplet precautions are instituted for patients with pharyngeal diphtheria; for patients with cutaneous diphtheria, contact precautions are observed until the results of cultures of specimens taken after cessation of therapy are negative. Cutaneous wounds are cleaned thoroughly with soap and water. Bed rest is essential during the acute phase of disease, usually for ≥2 wk until the risk for symptomatic cardiac damage has passed, with return to physical activity guided by the degree of toxicity and cardiac involvement.

Prognosis

The prognosis for patients with diphtheria depends on the virulence of the organism (subspecies gravis has the highest fatality rate), patient age, immunization status, site of infection, and speed of administration of the antitoxin. Mechanical obstruction from laryngeal diphtheria or bull-neck diphtheria and the complications of myocarditis account for most diphtheriarelated deaths. The case fatality rate of almost 10% for respiratory tract diphtheria has not changed in 50 yr; the rate was 8% in a Vietnamese series described in 2004. At recovery, administration of diphtheria toxoid is indicated to complete the primary series or booster doses of immunization, because not all patients develop antibodies to diphtheria toxin after infection.

Prevention Protection against serious disease caused by imported or indigenously acquired C. diphtheriae depends on immunization. In the absence of a precisely determined minimum protective level for diphtheria antitoxin, the presumed minimum is 0.01-0.10 IU/mL. In outbreaks, 90% of individuals with clinical disease have had antibody values 0.1 IU/mL. In serosurveys in the United States and Western Europe, where almost universal immunization during childhood has been achieved, 25% to >60% of adults lack protective antitoxin levels, with typically very low levels in elderly persons. All suspected diphtheria cases should be reported to local and state health departments. Investigation is aimed at preventing secondary cases in exposed individuals and at determining the source and carriers to halt spread to unexposed individuals. Reported rates of carriage in household contacts of case patients are 0–25%. The risk for development of diphtheria after household exposure to a case is approximately 2%, and the risk after similar exposure to a carrier is 0.3%.

Asymptomatic Case Contacts All household contacts and people who have had intimate respiratory or habitual physical contact with a patient are closely monitored for illness for 7 days. Cultures of the nose, throat, and any cutaneous lesions are performed. Antimicrobial prophylaxis is presumed effective and is administered regardless of immunization status, using a single injection of benzathine penicillin G

(600,000 units IM for patients 6 yr old) or erythromycin (40-50 mg/kg/day divided qid PO for 10 days; max 2 g/day). Diphtheria toxoid vaccine, in age-appropriate form, is given to immunized individuals who have not received a booster dose within 5 yr. Children who have not received their 4th dose should be vaccinated. Those who have received fewer than 3 doses of diphtheria toxoid or who have uncertain immunization status should be immunized with an age-appropriate preparation on a primary schedule.

Asymptomatic Carriers When an asymptomatic carrier is identified, antimicrobial prophylaxis is given for 10-14 days and an age-appropriate preparation of diphtheria toxoid is administered immediately if a booster has not been given within 1 yr. Droplet precautions (respiratory tract colonization) or contact precautions (cutaneous colonization only) are observed until at least 2 subsequent cultures obtained 24 hr apart after cessation of therapy have negative results. Repeat cultures are performed about 2 wk after completion of therapy for cases and carriers; if results are positive, an additional 10-day course of oral erythromycin should be given and follow-up cultures performed. Susceptibility testing of isolates should be performed, as erythromycin resistance is reported. Neither antimicrobial agent eradicates carriage in 100% of individuals. In one report, a single course of therapy failed in 21% of carriers. Transmission of diphtheria in modern hospitals is rare. Only those who have an unusual contact with respiratory or oral secretions should be managed as contacts. Investigation of the casual contacts of patients and carriers or persons in the community without known exposure has yielded extremely low carriage rates and is not routinely recommended.

Vaccine Universal immunization with diphtheria toxoid throughout life, to provide constant protective antitoxin levels and to reduce severity of C. diphtheriae disease, is the only effective control measure. Although immunization does not preclude subsequent respiratory or cutaneous carriage of toxigenic C. diphtheriae, it decreases local tissue spread, prevents toxic complications, diminishes transmission of the organism, and provides herd immunity when at

least 70–80% of a population is immunized. Diphtheria toxoid is prepared by formaldehyde treatment of toxin, standardized for potency, and adsorbed to aluminum salts, enhancing immunogenicity. Two preparations of diphtheria toxoids are formulated according to the limit of flocculation (Lf) content, a measure of the quantity of toxoid. The pediatric (6 mo to 6 yr) preparations (i.e., DTaP [diphtheria and tetanus toxoids with acellular pertussis vaccine], DT [diphtheria and tetanus toxoids vaccine]) contain 6.7-25.0 Lf units of diphtheria toxoid per 0.5 mL dose; the adult preparation (Td; 10% of pediatric diphtheria toxoid dose, Tdap [diphtheria and tetanus toxoids with acellular pertussis vaccine]) contain no more than 2-2.5 Lf units of toxoid per 0.5 mL dose. The higher-potency (D) formulation of toxoid is used for primary series and booster doses for children through 6 yr of age because of superior immunogenicity and minimal reactogenicity. For individuals ≥7 yr old, Td is recommended for the primary series and booster doses because the lower concentration of diphtheria toxoid is adequately immunogenic and increasing the content of diphtheria toxoid heightens reactogenicity with increasing age. For children 6 wk to 6 yr of age, five 0.5 mL doses of diphtheria-containing (D) vaccine (DTaP preferred) are given in the primary series, including doses at 2, 4, and 6 mo of age, and a 4th dose, an integral part of the primary series, at 15-18 mo. A booster dose is given at 4-6 yr of age (unless the 4th primary dose was administered at ≥4 yr). For persons ≥7 yr old not previously immunized for diphtheria, three 0.5 mL doses of lower-level diphtheria-containing (d) vaccine are given in a primary series of 2 doses at least 4 wk apart and a 3rd dose 6 mo after the 2nd dose. The 1st dose should be Tdap, and subsequent doses should be Td. The only contraindication to tetanus and diphtheria toxoid is a history of neurologic or severe hypersensitivity reaction after a prior dose. For children 39.4°C (103°F) after a dose of Td usually has high serum tetanus antitoxin levels and should not be given Td more frequently than every 10 yr, even if the patient sustains a significant tetanus-prone injury. The DT or Td preparation can be given concurrently with other vaccines. Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal conjugate vaccines containing diphtheria toxoid (PRP-D) or the variant of diphtheria toxin, CRM197 protein, are not substitutes for diphtheria toxoid immunization and do not affect reactogenicity.

Bibliography Both L, Collins S, De Zoysa A, et al. Molecular and epidemiological review of toxigenic diphtheria infections in England between 2007 and 2013. J Clin Microbiol . 2015;53(2):567–572. Chagina IA, Borisova O, Mel'nikov VG, et al. [Sensitivity of Corynebacterium diphtheriae strains to antibacterial preparations]. Zh Mikrobiol Epidemiol Immunobiol . 2014;4:8–13. De Zoysa A, Efstratiou A, Mann G, et al. Development, validation and implementation of a quadruplex real-time PCR assay for identification of potentially toxigenic corynebacteria. J Med Microbiol . 2016;65(12):1521–1527. FitzGerald RP, Rosser AJ, Perera DN. Non-toxigenic penicillinresistant cutaneous C. diphtheriae infection: a case report and review of the literature. J Infect Public Health . 2015;8(1):98–100. Hacker E, Antunes CA, Mattos-Guaraldi AL, et al. Corynebacterium ulcerans , an emerging human pathogen. Future Microbiol . 2016;11(9):1191–1208. Manikyamba D, Satyavani A, Deepa P. Diphtheritic

polyneuropathy in the wake of resurgence of diphtheria. J Pediatr Neurosci . 2015;10(4):331–334. May MLA, McDougall RJ, Robson JM. Corynebacterium diphtheriae and the returned tropical traveler. J Travel Med . 2014;21(1):39–44. Moore LS, Leslie A, Meltzer M, et al. Corynebacterium ulcerans cutaneous diphtheria. Lancet Infect Dis . 2015;15(9):1100. Mothershed EA, et al. Development of a real-time fluorescence PCR assay for rapid detection of the diphtheria toxin gene. J Clin Microbiol . 2002;40(12):4713–4719. 2011. Notes from the field: respiratory diphtheria-like illness caused by toxigenic Corynebacterium ulcerans —Idaho, 2010. MMWR Morb Mortal Wkly Rep . 2011;60(3):77. Schuhegger R, et al. Detection of toxigenic Corynebacterium diphtheriae and Corynebacterium ulcerans strains by a novel real-time PCR. J Clin Microbiol . 2008;46(8):2822–2823. Sing A, et al. Rapid detection and molecular differentiation of toxigenic Corynebacterium diphtheriae and Corynebacterium ulcerans strains by LightCycler PCR. J Clin Microbiol . 2011;49(7):2485–2489.

Websites Centers for Disease Control and Prevention, Pertussis and Diphtheria Laboratory. https://www.cdc.gov/diphtheria/laboratory.html . World Health Organization Diphtheria reported cases . http://www.who.int/topics/diphtheria/en/ .

CHAPTER 215

Listeria monocytogenes Thomas S. Murray, Robert S. Baltimore

Listeriosis in humans is caused principally by Listeria monocytogenes, 1 of 6 species of the genus Listeria that are widely distributed in the environment and throughout the food chain. Human infections can usually be traced to an animal reservoir. Infection usually occurs at the extremes of age. In the pediatric population, perinatal infections predominate and usually occur secondary to maternal infection or colonization. Outside the newborn period, disease is most often encountered in immunosuppressed (usually T-cell deficiencies) children and adults and in elderly persons. For most people the major risk for infection with Listeria is food-borne transmission . In the United States, food-borne outbreaks are caused by improperly processed dairy products and contaminated vegetables and principally affect the same individuals at risk for sporadic disease.

Etiology Members of the genus Listeria are facultatively anaerobic, non–spore-forming, motile, gram-positive bacilli that are catalase positive. In the laboratory, Listeria can be distinguished from other gram-positive bacilli by their characteristic tumbling motility and growth at cold temperature (4-10°C [39.2-50°F]). The 6 Listeria spp. are divided into 2 genomically distinct groups on the basis of DNADNA hybridization studies. One group contains the species Listeria grayi, considered nonpathogenic. The 2nd group contains 5 species: the nonhemolytic species Listeria innocua and L. welshimeri and the hemolytic species Listeria monocytogenes, L. seeligeri, and L. ivanovii. Listeria ivanovii is pathogenic primarily in animals, and the vast majority of both human and animal disease is

caused by L. monocytogenes. Subtyping of L. monocytogenes isolates for epidemiologic purposes has been attempted with the use of heat-stable somatic O and heat-labile flagellar H antigens, phage typing, pulsed-field gel electrophoresis, ribotyping, and multilocus enzyme electrophoresis. Electrophoretic typing demonstrates the clonal structure of populations of L. monocytogenes as well as the sharing of populations between human and animal sources. Subtyping is an important component of determining whether cases are connected or sporadic but usually requires collaboration with a specialized laboratory. Selected biochemical tests, together with the demonstration of tumbling motility , umbrella-type formation below the surface in semisolid medium, hemolysis, and a typical cyclic adenosine monophosphate test, are usually sufficient to establish a presumptive identification of L. monocytogenes.

Epidemiology Listeria monocytogenes is widespread in nature, has been isolated throughout the environment, and is associated with epizootic disease and asymptomatic carriage in >42 species of wild and domestic animals and 22 avian species. Epizootic disease in large animals (e.g., sheep, cattle) is associated with abortion and “circling disease,” a form of basilar meningitis. L. monocytogenes is isolated from sewage, silage, and soil, where it survives for >295 days. Human-to-human transmission rarely occurs except in maternal-fetal transmission. The annual incidence of listeriosis decreased by 36% between 1996 and 2004 and has remained level since then. However, food-borne outbreaks continue to occur. In 2011, 84 cases and 15 deaths in 19 states were traced to cantaloupes from a single source. The cases were connected by use of pulsed-field gel electrophoresis, which showed that 4 different strains traced to the same source. The rate of Listeria infections varies among states. Epidemic human listeriosis has been associated with food-borne transmission in several large outbreaks, especially in association with aged soft cheeses; improperly pasteurized milk and milk products; contaminated raw and ready-to-eat beef, pork, and poultry, and packaged meats and salads; and vegetables both fresh and frozen harvested from farms where the ground is contaminated with the feces of colonized animals. Food-borne outbreaks in 2016 included raw milk, packaged salads, and frozen vegetables. The ability of L. monocytogene s to grow at temperatures as low as 4°C (39.2°F) increases the risk for transmission from aged soft cheeses and

stored contaminated food. Listeriosis is an uncommon but important recognized etiology of neonatal sepsis and meningitis. Small clusters of nosocomial personto-person transmission have occurred in hospital nurseries and obstetric suites. Sporadic endemic listeriosis is less well characterized. Likely routes include food-borne infection and zoonotic spread. Zoonotic transmission with cutaneous infections occurs in veterinarians and farmers who handle sick animals. Reported cases of listeriosis are clustered at the extremes of age. Some studies show higher rates in males and a seasonal predominance in the late summer and fall in the Northern hemisphere. Outside the newborn period and during pregnancy, disease is usually reported in patients with underlying immunosuppression, with a 100-300 times increased risk in HIV-infected persons and in the elderly population (Table 215.1 ). In a recent surveillance study from England, malignancies accounted for one third of cases, with special risk associated with cancer in elderly persons. Table 215.1

Types of Listeria monocytogenes Infections Listeriosis in pregnancy Neonatal listeriosis Early onset Late onset Food-borne outbreaks/febrile gastroenteritis Listeriosis in normal children and adults (rare) Focal Listeria infections (e.g., meningitis, endocarditis, pneumonia, liver abscess, osteomyelitis, septic arthritis) Listeriosis in immunocompromised persons Lymphohematogenous malignancies Collagen vascular diseases Diabetes mellitus HIV infection Transplantation Renal failure with peritoneal dialysis Listeriosis in elderly persons

The incubation period, which is defined only for common-source food-borne disease, is 21-30 days but in some cases may be longer. Asymptomatic carriage and fecal excretion are reported in 1–5% of healthy persons and 5% of abattoir workers, but duration of excretion, when studied, is short (14 days) can lead to malnutrition , a potentially mortality-associated outcome of EPEC infection in infants in the developing world. Studies show that breastfeeding is protective against diarrhea caused by EPEC. EPEC colonization causes blunting of intestinal villi, local inflammatory

changes, and sloughing of superficial mucosal cells; EPEC-induced lesions extend from the duodenum through the colon. EPEC induces a characteristic attaching and effacing histopathologic lesion, which is defined by the intimate attachment of bacteria to the epithelial surface and effacement of host cell microvilli. Factors responsible for the attaching and effacing lesion formation are encoded by the locus of enterocyte effacement (LEE), a pathogenicity island with genes for a type III secretion system, the translocated intimin receptor (Tir) and intimin, and multiple effector proteins such as the E. coli –secreted proteins (EspA-B-D). Some strains adhere to the host intestinal epithelium in a pattern known as localized adherence , a trait that is mediated in part by the type IV bundle-forming pilus (Bfp) encoded by a plasmid (the EAF plasmid). After initial contact, proteins are translocated through filamentous appendages forming a physical bridge between the bacteria and the host cell; bacterial effectors (EspB, EspD, Tir) are translocated through these conduits. Tir moves to the surface of host cells, where it is bound by a bacterial outer membrane protein intimin (encoded by the eae gene). Intimin-Tir binding triggers polymerization of actin and other cytoskeletal components at the site of attachment. These cytoskeletal changes result in intimate bacterial attachment to the host cell, enterocyte effacement, and pedestal formation. Other LEE-encoded effectors include Map, EspF, EspG, EspH, and SepZ. Various other effector proteins are encoded outside the LEE and secreted by the type III secretion system (the non–LEE-encoded proteins, or Nle). The contribution of these putative effectors (NleA/EspI, NleB, NleC, NleD, etc.) to virulence is still under investigation. The presence and expression of virulence genes vary among EPEC strains. The eae (intimin) and bfp A genes are useful for identifying EPEC and for subdividing this group of bacteria into typical and atypical strains. E. coli strains that are eae + /bfp A+ are classified as “typical” EPEC; most of these strains belong to common O:H serotypes. E. coli strains that are eae + /bfp A− are classified as “atypical” EPEC. Typical EPEC has been considered for many years to be a leading cause of infantile diarrhea in developing countries and was considered rare in industrialized countries. However, current data suggest that atypical EPEC are more prevalent than typical EPEC in both developed and developing countries, even in persistent diarrhea cases. Determining which of these heterogeneous strains are true pathogens remains a work in progress. In the GEMS, typical EPEC was the main pathogen associated with increased risk of mortality, particularly in infants in Africa.

The classic EPEC serogroups include strains of 12 O serogroups: O26, O55, O86, O111, O114, O119, O125, O126, O127, O128, O142, and O158. However, various E. coli strains defined as EPEC based on the presence of the intimin gene belong to nonclassic EPEC serogroups, especially the atypical strains.

Shiga Toxin–Producing Escherichia coli STEC causes a broad spectrum of diseases. STEC infections may be asymptomatic. Patients who develop intestinal symptoms can have mild diarrhea or severe hemorrhagic colitis. Abdominal pain with initially watery diarrhea that may become bloody over several days characterizes STEC illness. Infrequent fever differentiates STEC disease from the otherwise similar appearance of shigellosis or EIEC disease. Most persons with STEC recover from the infection without further complication. However, 5–10% of children with STEC hemorrhagic colitis go on within a few days to develop systemic complications such as hemolytic-uremic syndrome (HUS), characterized by acute kidney failure, thrombocytopenia, and microangiopathic hemolytic anemia (see Chapter 538 ). Severe illness occurs most often among children 6 mo to 10 yr old. Young children with STEC-associated bloody diarrhea and neutrophilic leukocytosis in the early course of their diarrhea are at risk for HUS progression. Older individuals can also develop HUS or thrombotic thrombocytopenic purpura. STEC is transmitted person to person (e.g., in families and daycare centers) as well as by food and water; ingestion of a small number of organisms is sufficient to cause disease with some strains. Poorly cooked hamburger is a common cause of food-borne outbreaks, although many other foods (apple cider, lettuce, spinach, mayonnaise, salami, dry fermented sausage, and unpasteurized dairy products) have also been incriminated in STEC transmission. STEC affects the colon most severely. These organisms adhere to intestinal cells, and most strains that affect humans produce attaching-effacing lesions such as those seen with EPEC and contain related genes (e.g., intimin, Tir, EspAD ). Unlike EPEC, STEC produces Shiga toxins (Stx; previously called verotoxins and Shiga- like) as key virulence factors. There are 2 major Shiga toxin families, Stx1 and Stx2, with multiple subtypes identified by letters (e.g., Stx2a, Stx2c). Some STEC produce only Stx1, and others produce only 1 of the variants of Stx2; many STEC have genes for several toxins. Stx1 is essentially identical to Shiga toxin, the protein synthesis–inhibiting exotoxin of Shigella dysenteriae serotype 1. Stx2 and variants of Stx2 are more distantly related to

Shiga toxin, although they share conserved sequences. These ETEC Shiga toxins are composed of a single A subunit noncovalently associated with a pentamer composed of identical B subunits. The B subunits bind to globotriaosylceramide (Gb3 ), a glycosphingolipid receptor on host cells. The A subunit is taken up by endocytosis. The toxin target is the 28S rRNA, which is depurated by the toxin at a specific adenine residue, causing protein synthesis to cease and affected cells to die. These toxins are carried on bacteriophages that are normally inactive (lysogenic) in the bacterial chromosome; when the phages are induced to replicate (e.g., by the stress induced by many antibiotics), they cause lysis of the bacteria and release of large amounts of toxin. Toxin translocation across the intestinal epithelium into the systemic circulation can lead to damage of vascular endothelial cells, resulting in activation of the coagulation cascade, formation of microthrombi, intravascular hemolysis, and ischemia. The clinical outcome of an STEC infection depends on a strain-specific combination of epithelial attachment and the toxin factors. The Stx2 family of toxins is associated with a higher risk of causing HUS. Strains that make only Stx1 often cause only watery diarrhea and are infrequently associated with HUS. The most common STEC serotypes are E. coli O157:H7, E. coli O111:NM, and E. coli O26:H11, although several hundred other STEC serotypes have also been described. E. coli O157:H7 is the most virulent serotype and the serotype most frequently associated with HUS; however, other non-O157 serotypes also cause this illness.

Enteroaggregative Escherichia coli EAEC is associated with (1) acute, prolonged and persistent pediatric diarrhea in developing countries, most prominently in children 200 serogroups, only serogroups O1 and O139 have been associated with epidemics, although some non-O1, non-O139 V. cholerae strains (e.g., O75, O141) are pathogenic and can cause small outbreaks. A flagellar H antigen is present but is not used for species identification. The O1 serogroup is further divided into classical and the El Tor biotypes based on its biochemical characteristics. Since the turn of the 21st century, only O1 El Tor has been reported; hybrids and variants of V. cholerae O1 El Tor possessing classical genes have been reported worldwide. These hybrid and variant strains have been associated with more severe disease. Each biotype of V. cholerae can be further subdivided into Inaba, Ogawa, and Hikojima serotypes based on the antigenic determinants on the O antigen. Inaba strains have A and C antigenic determinants, whereas Ogawa strains have A and B antigenic determinants. Hikojima strains produce all 3 antigenic determinants but are unstable and rare. Recent studies reveal that serotype switching results from a selection process as yet unidentified.

Epidemiology The 1st 6 cholera pandemics originated in the Indian subcontinent and were caused by classical O1 V. cholerae . The 7th pandemic is the most extensive of all and is caused by V. cholerae O1 El Tor. This pandemic began in 1961 in Sulawesi, Indonesia, and has spread to the Indian subcontinent, Southeast Asia, Africa, Oceania, Southern Europe, and the Americas. In 1991, V. cholerae O1 El Tor first appeared in Peru before rapidly spreading in the Americas. Cholera becomes endemic in areas following outbreaks when a large segment of the population develops immunity to the disease after recurrent exposure. The disease is now endemic in parts of Africa and Asia and in Haiti. In 1992 the first non-O1 V. cholerae that resulted in epidemics was identified in India and Bangladesh and was designated V. cholerae O139 . From 1992– 1994, this organism replaced O1 as the predominant cause of cholera in South Asia but has since been an uncommon etiologic agent. The hybrid El Tor strains were first identified sporadically in Bangladesh. In 2004, during routine surveillance in Mozambique, isolates of V. cholerae O1 El Tor carrying classical genes were identified. Since then, hybrid and variant El Tor strains have been reported in other parts of Asia and Africa and have caused outbreaks in India and Vietnam. Although the classical biotype has virtually disappeared, its genes remain within the El Tor biotype. The current circulating strain in Haiti is closely related to the South Asian strain. Humans are the only known hosts for V. cholerae, but free-living and plankton-associated V. cholerae exist in the marine environment. The organism thrives best in moderately salty water but can survive in rivers and fresh water if nutrient levels are high, as occurs when there is organic pollution such as human feces. The formation of a biofilm on abiotic surfaces and the ability to enter a viable but nonculturable state have been hypothesized as factors that allow V. cholerae to persist in the environment. Surface sea temperature, pH, chlorophyll content, the presence of iron compounds and chitin, and climatic conditions such as amount of rainfall and sea level rise are all important environmental factors that influence the survival of V. cholerae in the environment and the expression of cholera toxin, an important virulence determinant. Consumption of contaminated water and ingestion of undercooked shellfish are the main modes of transmission, with the latter more often seen in developed countries. In cholera-endemic areas, the incidence is highest among children 108 colony-forming units) are required for severe cholera to occur; however, for persons whose gastric barrier is disrupted, a much lower dose (105 CFUs) is required. After ingestion of V. cholerae from the environment, several changes occur in the vibrios as they traverse the human intestine: increased expression of genes required for nutrient acquisition, downregulation of chemotactic response, and expression of motility factors. Together these changes allow the vibrios to reach a hyperinfectious state, leading to lower infectious doses required to secondarily infect other persons. This hyperinfectivity may remain for 5-24 hr after excretion and is believed to be the predominant pathway for person-to-person transmission during epidemics. If the vibrios survive gastric acidity, they colonize the small intestine through various factors such as toxin–co-regulated pili and motility, leading to efficient delivery of cholera toxin (Fig. 228.1 ). The cholera toxin consists of 5 binding B subunits and 1 active A subunit. The B subunits are responsible for binding to the GM1 ganglioside receptors located in the small intestinal epithelial cells. After binding, the A subunit is released into the cell, where it stimulates adenylate cyclase and initiates a cascade of events. An increase in cyclic adenosine monophosphate leads to an increase in chloride secretion by the crypt cells, which in turn leads to inhibition of absorption of sodium and chloride by the microvilli. These events eventually lead to massive purging of electrolyte rich isotonic fluid in the small intestine that exceeds the absorptive capacity of the colon, resulting in rapid dehydration and depletion of electrolytes, including sodium, chloride, bicarbonate, and potassium. Metabolic acidosis and hypokalemia then ensue.

FIG. 228.1 Cholera pathogenesis and cholera toxin action. After ingestion, Vibrio cholerae colonize the small intestine and secrete cholera toxin, which has a doughnutlike structure with a central enzymatic toxic-active A (CTA-1 + CTA-2) subunit associated with a pentameric B subunit (CTB). After binding to GM1 ganglioside receptors on small intestinal epithelial cells, which are mainly localized in lipid rafts on the cell surface, the cholera toxin is endocytosed and transported to the degradosome via the endoplasmic reticulum (ER) by a retrograde pathway, which, dependent on cell type, may or may not involve passage through the Golgi apparatus. In the ER, CTA dissociates from CTB, allowing CTA-1 to reach the cytosol by being translocated through the degradosome pathway. In the cytosol, CTA-1 subunits rapidly refold and bind to the Gsα subunit of adenylate cyclase (AC) in the cell membrane; on binding, CTA-1 adenosine diphosphate (ADP)-ribosylates the Gsα subunit, which stimulates AC activity, leading to an increase in intracellular concentration of cyclic adenosine monophosphate (cAMP), activation of protein kinase A (PKA), phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel, and extracellular secretion of chloride ions (Cl− ) and water. Cholera toxin– induced Cl− (and bicarbonate ion) secretion is particularly pronounced in intestinal crypt cells, whereas the increased intracellular cAMP concentrations in villus cells mainly inhibit the uptake of sodium chloride (NaCl) and water. (Adapted from Clemens J, Shin S, Sur D, et al: New-generation vaccines against cholera, Nat Rev Gastroenterol Hepatol 8:701–710, 2011; by permission of Nature Publishing Group.)

Clinical Manifestations Most cases of cholera are mild or inapparent. Among symptomatic individuals, approximately 20% develop severe dehydration that can rapidly lead to death. Following an incubation period of 1-3 days (range: several hours to 5 days), acute watery diarrhea and vomiting ensue. The onset may be sudden, with profuse watery diarrhea, but some patients have a prodrome of anorexia and abdominal discomfort and the stool may initially be brown. Diarrhea can progress to painless purging of profuse rice-water stools (suspended flecks of mucus) with a fishy smell, which is the hallmark of the disease (Figs. 228.2 and

228.3 ). Vomiting with clear watery fluid is usually present at the onset of the disease.

FIG. 228.2 Rice-water stool in a patient with cholera. (Modified from Harris JB, LaRocque RC, Qadri F: Cholera, Lancet 379:2466–2474, 2012.)

FIG. 228.3 A child, lying on a cholera cot, showing typical signs of severe dehydration from cholera. The patient has sunken eyes, lethargic appearance, and poor skin turgor, but within 2 hr was sitting up, alert, and eating normally. (From Sack DA, Sack RB, Nair GB, et al: Cholera, Lancet 363:223–233, 2004.)

Cholera gravis , the most severe form of the disease, results when purging rates of 500-1,000 mL/hr occur. This purging leads to dehydration manifested by decreased urine output, a sunken fontanel (in infants), sunken eyes, absence of tears, dry oral mucosa, shriveled hands and feet (“washerwoman's hands”), poor skin turgor, thready pulse, tachycardia, hypotension, and vascular collapse (Fig. 228.3 ). Patients with metabolic acidosis can present with typical Kussmaul breathing. Although patients may be initially thirsty and awake, they rapidly progress to obtundation and coma. If fluid losses are not rapidly corrected, death can occur within hours.

Laboratory Findings Findings associated with dehydration such as elevated urine specific gravity and hemoconcentration are evident. Hypoglycemia is a common finding that is caused by decreased food intake during the acute illness. Serum potassium may be initially normal or even high in the presence of metabolic acidosis; however, as the acidosis is corrected, hypokalemia may become evident. Metabolic acidosis due to bicarbonate loss is a prominent finding in severe cholera. Serum sodium and chloride levels may be normal or decreased, depending on the severity of the disease.

Diagnosis and Differential Diagnosis In children who have acute watery diarrhea with severe dehydration residing in a cholera-endemic area or who have recently traveled to an area known to have cholera, the disease may be suspected pending laboratory confirmation. Cholera differs from other diarrheal diseases in that it often occurs in large outbreaks affecting both adults and children. Treatment of dehydration should begin as soon as possible. Diarrhea caused by other etiologic causes (e.g., enterotoxigenic Escherichia coli or rotavirus) may be difficult to distinguish from cholera clinically. Microbiologic isolation of V. cholerae remains the gold standard for diagnosis. Although definitive diagnosis is not required for treatment to be initiated, laboratory confirmation is necessary for epidemiologic surveillance. V. cholerae may be isolated from stools, vomitus, or rectal swabs. Specimens may be transported on Cary-Blair media if they cannot be processed immediately. Selective media such as thiosulfate-citrate–bile salts sucrose agar that inhibit normal flora should be used. Because most laboratories in industrialized countries do not routinely culture for V. cholerae , clinicians should request appropriate cultures for clinically suspected cases. Stool examination reveals few fecal leukocytes and erythrocytes because cholera does not cause inflammation. Dark-field microscopy may be used for rapid identification of typical darting motility in wet mounts of rice-water stools, a finding that disappears once specific antibodies against V. cholerae O1 or O139 are added. Rapid diagnostic tests are currently available and may be especially useful in areas with limited laboratory capacity, allowing early identification of cases at the onset of an outbreak and facilitating a timely response. Molecular identification with the use of polymerase chain reaction and DNA probes is available but often not used in areas where cholera exists.

Complications Delayed initiation of rehydration therapy or inadequate rehydration often leads to complications. Renal failure from prolonged hypotension can occur. Unless potassium supplementation is provided, hypokalemia can lead to nephropathy and focal myocardial necrosis. Hypoglycemia is common among children and can lead to seizures unless it is appropriately corrected.

Treatment Rehydration is the mainstay of therapy (see Chapter 69 ). Effective and timely case management decreases mortality considerably. Children with mild or moderate dehydration may be treated with oral rehydration solution (ORS) unless the patient is in shock, is obtunded, or has intestinal ileus. Vomiting is not a contraindication to ORS. Severely dehydrated patients require intravenous fluid, ideally with lactated Ringer solution. When available, rice-based ORS should be used during rehydration, because this fluid has been shown to be superior to standard ORS in children and adults with cholera. Close monitoring is necessary, especially during the 1st 24 hr of illness, when large amounts of stool may be passed. After rehydration, patients should be reassessed every 1-2 hr, or more frequently if profuse diarrhea is ongoing. Feeding should not be withheld during diarrhea. Frequent, small feedings are better tolerated than less frequent, large feedings. Antibiotics should only be given in patients with moderately severe to severe dehydration (Table 228.1 ). As soon as vomiting stops (usually within 4-6 hr after initiation of rehydration therapy), an antibiotic to which local V. cholerae strains are sensitive must be administered. Antibiotics shorten the duration of illness, decrease fecal excretion of vibrios, decrease the volume of diarrhea, and reduce the fluid requirement during rehydration. Single-dose antibiotics increase compliance; doxycycline, ciprofloxacin, and azithromycin are effective against cholera. There are increasing reports of resistance to tetracyclines, trimethoprimsulfamethoxazole, and other drugs. Because of these multidrug-resistant strains, antibiotic treatment must be tailored based on available susceptibility results from the area. The 2013 WHO guidelines recommend cotrimoxazole (4 mg trimethoprim/kg and 20 mg/kg sulfamethoxazole/kg twice daily) and chloramphenicol (20 mg/kg IM every 6 hr for 3 days) as possible alternative antibiotics for treatment. A recent systematic review, however, recommended the use of single-dose azithromycin (20 mg/kg) due to widespread antimicrobial resistance. Cephalosporins and aminoglycosides are not clinically effective against cholera and therefore should not be used, even if in vitro tests show strains to be sensitive. Table 228.1

Recommended Antimicrobials for Cholera*

RECOMMENDING BODY WHO † (antibiotics recommended for cases with severe dehydration)

ANTIBIOTIC OF CHOICE ALTERNATIVE Adults Adults Doxycycline, 300 mg given as a Erythromycin, 250 mg 4 times a day single dose orally (PO) × 3 days PO or Tetracycline, 500 mg 4 times a day × 3 days PO Children Children Tetracycline, 12.5 mg/kg/dose 4 Erythromycin, 12.5 mg/kg/dose 4 times a day × 3 days (up to 500 times a day × 3 days (up to 250 mg mg/dose × 3 days) PO 4 times a day × 3 days) PO PAHO ‡ (antibiotics Adults Adults Doxycycline, 300 mg PO given Ciprofloxacin, 1 g PO single dose recommended for cases with as a single dose or moderate to severe dehydration) Azithromycin, 1 g PO single dose (first line for pregnant women) Children Children Erythromycin, 12.5 mg/kg/dose Ciprofloxacin, 20 mg/kg PO as a 4 times a day × 3 days (up to single dose 500 mg/dose × 3 days) or or Doxycycline, 2-4 mg/kg PO as a Azithromycin, 20 mg/kg as a single dose single dose (up to 1 g) * Antibiotic selection must be based on sensitivity patterns of strains of Vibrio cholerae O1 or

O139 in the area. † Adapted from World Health Organization: The treatment of diarrhea: a manual for physicians

and other senior health workers , 4th revision, Geneva, 2005, WHO. ‡ Adapted from Pan American Health Organization: Recommendations for clinical management of

cholera, Washington, DC, 2010. http://new.paho.org/hq/index.php? option=com_docman&task=doc_download&gid=10813&Itemid= .

Zinc should be given as soon as vomiting stops . Zinc deficiency is common among children in many developing countries. Zinc supplementation in children 6 yr old: 2 doses, 1-6 wk apart

Adults and children ≥1 yr old: 2 doses, 2 wk apart

V. cholerae O139-600 EU of Formalin-killed strain 4260B * WHO-prequalified vaccines.

Oral cholera vaccines have been available for >2 decades, and with the WHO declaration, countries are now using oral cholera vaccines in mass vaccination campaigns where cholera remains a substantial problem. A cholera vaccine stockpile, established by WHO, is now available and can be accessed by countries at risk for cholera, supplementing efforts to lessen the impact of this ongoing cholera scourge.

Bibliography Ali M, Nelson AR, Lopez AL, Sack DA. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis . 2015;9(6):e0003832. Clemens JD, Nair GB, Ahmed T, et al. Cholera. Lancet . 2017;390:1539–1548. Desai SN, Pezzoli L, Martin S, et al. A second affordable oral cholera vaccine: implications for the global vaccine stockpile. Lancet Glob Health . 2016;4(4):e223–e224. Hall V, Medus C, Wahl G, et al. Vibrio cholerae serogroup O1, serotype Inaba—Minnesota, August 2016. MMWR Morb Mortal Wkly Rep . 2017;66(36):961–962. Qadri F, Islam T, Clemons JD. Cholera in Yemen: an old foe rearing its ugly head. N Engl J Med . 2017;377(21):2005– 2007. Sauvageot D, Njanpop-Lafourcade B-M, Akilimali L, et al. Cholera incidence and mortality in sub-Saharan African sites during multi-country surveillance. PLoS Negl Trop Dis . 2016;10(5):e0004679. UNICEF. Cholera toolkit . [New York, 20123, UNICEF] https://www.unicef.org/cholera/index_71222.html . Williams PCM, Berkley JA. Guidelines for the management of paediatric cholera infection: a systematic review of the

evidence. Paediatr Int Child Health . 2018;38:S16–S31.

CHAPTER 229

Campylobacter Ericka V. Hayes

Campylobacter , typically Campylobacter jejuni and Campylobacter coli , are found globally and are among the most common causes of human intestinal infections. Clinical presentation varies by age and underlying conditions.

Etiology Twenty-six species and 9 subspecies of Campylobacter are recognized (as of December 2014). Most of these have been isolated from humans, and many are considered pathogenic. The most significant of these are C. jejuni and C. coli, which are believed to cause the majority of human enteritis. More than 100 serotypes of C. jejuni have been identified. C. jejuni has been subspeciated into C. jejuni subsp. jejuni and C. jejuni subsp. doylei. Although C. jejuni subsp. doylei has been isolated from humans, it is much less common, less hardy, and more difficult to isolate. Other species, including Campylobacter fetus, Campylobacter lari, and Campylobacter upsaliensis, have been isolated from patients with diarrhea, although much less frequently (Table 229.1 ). Emerging Campylobacter spp. have been implicated in acute gastroenteritis, inflammatory bowel disease, and peritonitis, including C. concisus , and C. ureolyticus . Additional Campylobacter spp. have been isolated from clinical specimens, but their roles as pathogens have not been established. Table 229.1 Campylobacter Species Associated With Human Disease SPECIES C. jejuni

DISEASES IN HUMANS Gastroenteritis, bacteremia, Guillain-Barré

COMMON SOURCES Poultry, raw milk, cats, dogs, cattle, swine,

C. coli C. fetus

syndrome Gastroenteritis, bacteremia Bacteremia, meningitis, endocarditis, mycotic aneurysm, diarrhea Diarrhea, bacteremia, proctitis

C. hyointestinalis C. lari Diarrhea, colitis, appendicitis, bacteremia, UTI C. upsaliensis Diarrhea, bacteremia, abscesses, enteritis, colitis, hemolytic-uremic syndrome C. concisus Diarrhea, gastritis, enteritis, periodontitis C. sputorum Diarrhea, bedsores, abscesses, periodontitis C. rectus Periodontitis C. mucosalis Enteritis C. jejuni Diarrhea, colitis, appendicitis, bacteremia, UTI subsp. doylei C. curvus Gingivitis, alveolar abscess C. gracilis C. cryaerophila

monkeys, water Poultry, raw milk, cats, dogs, cattle, swine, monkeys, oysters, water Sheep, cattle, birds, dogs Swine, cattle, deer, hamsters, raw milk, oysters Seagulls, water, poultry, cattle, dogs, cats, monkeys, oysters, mussels Cats, dogs, other domestic pets Human oral cavity, dogs Human oral cavity, cattle, swine, dogs Swine, dogs Swine

Poultry, raw milk, cats, dogs, cattle, swine, monkeys, water, human oral cavity Head and neck abscesses, abdominal abscesses, Dogs empyema Diarrhea Swine

UTI, Urinary tract infection.

Campylobacter organisms are gram-negative, curved, thin (0.2-0.8 µm wide), non–spore-forming rods (0.5-5 µm long) that usually have tapered ends. They are smaller than most other enteric bacterial pathogens and have variable morphology, including short, comma-shaped or S -shaped organisms and long, multispiraled, filamentous, seagull-shaped organisms. Individual organisms are usually motile with a flagellum at one or both poles depending on the species. Such morphology enables these bacteria to colonize the mucosal surfaces of both the gastrointestinal (GI) and respiratory tracts and move through them in a spiraling motion. Most Campylobacter organisms are microaerophilic, occasionally partially anaerobic, and oxidase positive. Most can transform into coccoid forms under adverse conditions, especially oxidation.

Epidemiology Worldwide, Campylobacter enteritis is a leading cause of acute diarrhea. Efforts to reduce Campylobacter contamination and use of safe handling practices have led to decreased incidence. Campylobacter infections can be both food-borne and water-borne and most frequently result from ingestion of contaminated poultry (chicken, turkey) or raw milk . Less often, the bacteria come from

drinking water, household pets (cats, dogs, hamsters), and farm animals. Infections are more common in resource-limited settings, are prevalent yearround in tropical areas, and can exhibit seasonal peaks in temperate regions (late spring with a peak midsummer in most of the United States, with a smaller secondary peak in late fall). In industrialized countries, Campylobacter infections peak in early childhood and again in young adulthood (15-44 yr). This 2nd peak is not seen with Salmonella and Shigella infections. In developing countries, repeated infections are common in childhood, leading to increased immunity and rare disease in adulthood. Each year in the United States, there are an estimated 2.5 million cases of Campylobacter infection. Of these, death is rare, with 50-150 reports annually. In The Netherlands, medical record review shows that on average each resident acquires asymptomatic Campylobacter colonization every 2 yr, progressing to symptomatic infection in approximately 1% of colonized people. Food-borne infection is most common and can be seen with the consumption of raw or undercooked meat, as well as by cross-contamination of other foods. Although chickens are the classic source of Campylobacter, many animal sources of human food can also harbor Campylobacter, including seafood. C. coli has been linked to swine. Poultry is more likely to be heavily contaminated, whereas red meats often have fewer organisms. Unpasteurized milk products are also a documented source. Additionally, many pets can carry Campylobacter, and flies inhabiting contaminated environments can acquire the organism. Shedding from animals can contaminate water sources. Humans can acquire infection from water, although much less frequently than from contaminated food. Airborne (droplet) transmission of Campylobacter has occurred in poultry workers. Use of antimicrobials in animal foods may increase the prevalence of antibiotic-resistant Campylobacter isolated from humans. Human infection can result from exposure to as few as 500 bacteria, although a higher dose (>9,000 bacteria) is often needed to cause illness reproducibly. Inoculum effectiveness is dependent on host factors, including immune status and stomach acidification. C. jejuni and C. coli spread person to person, perinatally, and at childcare centers where diapered toddlers are present. People infected with C. jejuni usually shed the organism for weeks, but some can shed for months, with children tending toward longer shedding. Handwashing is critical to preventing spread in these environments.

Pathogenesis Most Campylobacter isolates are acid sensitive and should, in theory, be eradicated in the stomach. Therefore, models for the pathogenesis of C. jejuni enteritis include mechanisms to transit the stomach, adhere to intestinal mucosal cells, and initiate intestinal lumen fluid accumulation. Host conditions associated with reduced gastric acidity, such as proton pump inhibitor use, and foods capable of shielding organisms in transit through the stomach may help allow Campylobacter to reach the intestine. Once there, Campylobacter is able to adhere to and invade intestinal mucosal cells through motility, including use of flagellae, as well as by the use of surface proteins (e.g., PEB1, CadF), large plasmids (e.g., pVir), surface adhesins (e.g., JIpA), and chemotactic factors. Lumen fluid accumulation is associated with direct damage to mucosal cells resulting from bacterial invasion and potentially from an enterotoxin and other cytotoxins. Additionally, C. jejuni has mechanisms that enable transit away from the mucosal surface. The factors used depend on the species involved. Campylobacter spp. differ from other enteric bacterial pathogens in that they have both N - and O -linked glycosylation capacities. N -linked glycosylation is associated with molecules expressed on the bacterial surface, and O -linked glycosylation appears limited to flagellae. Slipped-strand mispairing in glycosylation loci results in modified, antigenically distinct surface structures. It is hypothesized that antigenic variation provides a mechanism for immune evasion. C. fetus possesses a high-molecular-weight S-layer protein that mediates highlevel resistance to serum-mediated killing and phagocytosis and is therefore thought to be responsible for the propensity to produce bacteremia. C. jejuni and C. coli are generally sensitive to serum-mediated killing, but serum-resistant variants exist. Some suggest these serum-resistant variants may be more capable of systemic dissemination. Campylobacter infections can be followed by Guillain-Barré syndrome , reactive arthritis , and erythema nodosum . Such complications are thought to be from molecular mimicry between nerve, joint, and dermal tissue and Campylobacter surface antigens. Most Campylobacter infections are not followed by immunoreactive complications, indicating that host conditions as well as other factors, in addition to molecular mimicry, are required for these complications. It is proposed that low-grade inflammation caused by Campylobacter, below the threshold that can be detected by endoscopy, results in

crosstalk with gut nerves, leading to symptoms.

Clinical Manifestations There are a variety of clinical presentations of Campylobacter infections, depending on host factors such as age, immunocompetence, and underlying conditions. Infection presents most often as gastroenteritis, but also as bacteremia, neonatal infections, and, less often, extraintestinal infections.

Acute Gastroenteritis Acute gastroenteritis with diarrhea is usually caused by C. jejuni (90–95%) or C. coli, and rarely by C. lari, C. hyointestinalis, or C. upsaliensis. Infections with C. jejuni and C. coli are indistinguishable by clinical presentation. The average incubation period is 3 days (range: 1-7 days). One third of symptomatic patients can have a prodrome with fever, headache, dizziness, and myalgias; 1-3 days later, they develop cramping abdominal pain and loose, watery stools, or, less frequently, mucus-containing bloody stools. In severe cases (approximately 15%), blood appears in the stools 2-4 days after the onset of symptoms. In younger children, >50% may develop blood in their stools. Some patients do not develop diarrhea at all, most often children who are 6-15 yr old. Fever may be the only manifestation initially and is most pronounced in patients >1 yr old. From 60–90% of older children also complain of abdominal pain. The abdominal pain is most frequently periumbilical and sometimes persists after the stools return to normal. The abdominal pain can mimic appendicitis, colitis, or intussusception. Nausea is common, with up to 25% of adults developing vomiting. Vomiting tends to be more common the younger the patient and is most frequent in infants. Infection with species other than C. jejuni and C. coli may have milder symptoms. Diarrhea lasts approximately 7 days and will resolve spontaneously. More mild disease can last 1-2 days; 20–30% of patients will have symptoms for 2 wk, and 5–10% are symptomatic for >2 wk. Relapse can occur in 5–10% of patients. Persistent or recurrent Campylobacter gastroenteritis has been reported in immunocompetent patients, in patients with hypogammaglobulinemia (both congenital and acquired), and in patients with AIDS. Persistent infection can mimic chronic inflammatory bowel disease (IBD); therefore Campylobacter infection should also be considered when evaluating for IBD. Some evidence

supports that Campylobacter infection may also be the trigger for development of IBD. Fecal shedding of the organisms in untreated patients usually lasts for 23 wk, with a range from a few days to several months. Shedding tends to occur longer in young children. Acute appendicitis, mesenteric lymphadenitis, and ileocolitis have been reported in patients who have had appendectomy during C. jejuni infection.

Bacteremia Transient bacteremia has been shown in early acute infection in 0.1–1% of patients. With the exception of bacteremia caused by C. fetus , bacteremia with Campylobacter occurs most often among patients with chronic illnesses or immunodeficiency (e.g., HIV), severe malnutrition, and in extremes of age. However, bacteremia is also well described in patients without underlying disease. The majority of cases of bacteremia are asymptomatic. C. fetus causes bacteremia in adults with or without identifiable focal infection, usually in the setting of underlying conditions such as malignancy, immunodeficiency, or diabetes mellitus. When symptomatic, C. jejuni bacteremia is associated with fever, headache, malaise, and abdominal pain. Relapsing or intermittent fever is associated with night sweats, chills, and weight loss when the illness is prolonged. Lethargy and confusion can occur, but focal neurologic signs are unusual without cerebrovascular disease or meningitis. Moderate leukocytosis with left shift may be found. Variable presentations have been described, including transient asymptomatic bacteremia, rapidly fatal septicemia, and prolonged bacteremia of 8-13 wk.

Focal Extraintestinal Infections Focal infections caused by C. jejuni are rare and occur mainly among neonates and immunocompromised patients. Multiple sites have been reported, including meningitis, pneumonia, thrombophlebitis, pancreatitis, cholecystitis, ileocecitis, urinary tract infection, arthritis, peritonitis, ileocecitis, pericarditis, and endocarditis. C. fetus shows a predilection for vascular endothelium, leading to endocarditis, pericarditis, thrombophlebitis, and mycotic aneurysms. C. hyointestinalis has been associated with proctitis, C. upsaliensis with breast abscesses, and C. rectus with periodontitis.

Perinatal Infections Perinatal infections are most often acquired at birth from a mother infected with or shedding Campylobacter. Maternal C. fetus and C. jejuni infections may be asymptomatic and can result in abortion, stillbirth, premature delivery, or neonatal infection with sepsis and meningitis. Severe perinatal infections are uncommon and are caused most often by C. fetus and rarely by C. jejuni . Neonatal infection with C. jejuni is associated with diarrhea that may be bloody. Nosocomial infections in nurseries have also been described.

Diagnosis The clinical presentation of Campylobacter enteritis can be similar to that of enteritis caused by other bacterial pathogens. The differential diagnosis includes Shigella, Salmonella, Escherichia coli , Yersinia enterocolitica, Aeromonas, Vibrio parahaemolyticus, and amebiasis. Fecal leukocytes are found in as many as 75% of cases, and fecal blood is present in 50% of cases (higher in pediatric patients). Campylobacter should be considered in patients with bloody stools, fever, and abdominal pain. The diagnosis of Campylobacter enteritis is usually confirmed by identification of the organism in cultures of stool or rectal swabs. Isolation is most likely from selective media such as CAMPY-agar grown in microaerophilic conditions (5–10% oxygen), 1–10% carbon dioxide, with some hydrogen. Some C. jejuni grow best at 42°C (107.6°F). Growth on solid media results in small (0.5-1.0 mm), slightly raised, smooth colonies. Organisms can be identified from stool microscopically in approximately 50% of known Campylobacter cases. Gram stain is even less sensitive. Stool culture is >90% sensitive and is the standard method of diagnosis. Visible growth on stool culture is most often present in 1-2 days. Visible growth in blood cultures is often not apparent until 5-14 days after inoculation. Routine culture may be adequate for isolation of C. jejuni because of the large numbers of bacteria that are often present. However, because Campylobacter organisms grow more slowly under routine conditions than do other enteric bacteria, routine culture can result in failure because of overgrowth of other enteric bacteria. Campylobacter culture can be enhanced, when necessary, with selective media. However, selective culture media developed to enhance isolation of C. jejuni may inhibit the growth of other Campylobacter spp.

Filtration methods are available and can preferentially enrich for Campylobacter by selecting for their small size. These methods allow subsequent culture of the enriched sample on antibiotic-free media, enhancing rates of isolation of Campylobacter organisms inhibited by the antibiotics included in standard selective media. Isolation of Campylobacter from normally sterile sites does not require enhancement procedures. Clinically, it is not necessary to speciate Campylobacter, because clinical disease is the same. Speciation can be done, when needed, and specialized laboratories can perform strain typing when required for epidemiologic purposes. For rapid diagnosis of Campylobacter enteritis, direct carbolfuchsin stain of fecal smear, indirect fluorescence antibody test, dark-field microscopy, or latex agglutination were used historically. Polymerase chain reaction testing is more specific and sensitive and is becoming more widely available for rapid testing, often grouped with testing for other bacterial, viral, and parasitic stool pathogens in a multiplex assay. At this time, the recommendation remains to confirm all positive rapid tests with culture, which also allows for susceptibility testing and epidemiologic investigations. Serologic diagnosis is also possible and is most helpful in patients with late-onset reactive arthritis or Guillain-Barré syndrome, since these patients may have negative stool cultures by the time of presentation with these late complications.

Complications Severe, prolonged C. jejuni infection can occur in patients with immunodeficiencies, including hypogammaglobulinemia, malnutrition, and acquired immunodeficiency syndrome (AIDS). In patients with AIDS, increased frequency and severity of C. jejuni infection occurs; severity correlates inversely with CD4 count. Complications can include acute complications, as described earlier, and late-onset complications that may present after the acute infection has resolved. The most common late-onset complications include reactive arthritis and Guillain-Barré syndrome.

Reactive Arthritis Reactive arthritis can accompany Campylobacter enteritis in adolescents and adults, especially in patients who are positive for HLA-B27 (see Chapter 182 ). Reactive arthritis occurs in up to 3% of patients, although up to 13% may have

joint symptoms. This manifestation usually appears 1-2 wk after the onset of diarrhea but has been seen 5-40 days later. It involves mainly large joints and resolves without sequelae. The arthritis is typically migratory and occurs without fever. Synovial fluid lacks bacteria. The arthritis responds well to nonsteroidal antiinflammatory drugs and typically resolves after 1 wk to several months. Reactive arthritis with conjunctivitis, urethritis, and rash (including erythema nodosum) also occurs but is less common.

Guillain-Barré Syndrome Guillain-Barré syndrome (GBS) is an acute demyelinating disease of the peripheral nervous system characterized clinically by acute flaccid paralysis and is the most common cause of neuromuscular paralysis worldwide (see Chapter 634 ). GBS carries a mortality rate of approximately 2%, and approximately 20% of patients develop major neurologic sequelae. C. jejuni has been identified as the trigger in up to 40% of patients with GBS and is most closely linked to the serotypes Penner O19 and O41. It has been reported 1-12 wk after C. jejuni gastroenteritis in 1 of every 1,000 C. jejuni infections. Stool cultures obtained from patients with GBS at the onset of neurologic symptoms have yielded C. jejuni in >25% of the cases. Serologic studies suggest that 20–45% of patients with GBS have evidence of recent C. jejuni infection. Molecular mimicry between nerve tissue GM1 ganglioside and Campylobacter surface antigens may be the triggering factor in Campylobacter -associated GBS. The Miller-Fisher variant, which more often affects cranial nerves, is characterized by ataxia, areflexia, and ophthalmoplegia and is linked to cross-reacting antibodies to the GQ1b ganglioside found in cranial nerve myelin; the most common serotype for this variant is Penner O2. When associated with Campylobacter, GBS is more likely to be the axonal form and has a worse prognosis with slower recovery and more neurologic disability. The management of GBS includes supportive care, intravenous immunoglobulin, and plasma exchange.

Other Complications Immunoglobulin A nephropathy and immune complex glomerulonephritis with C. jejuni antigens in the kidneys have been reported. Campylobacter infection has also been associated with hemolytic anemia and hemolytic-uremic syndrome.

Treatment Fluid replacement, correction of electrolyte imbalance, and supportive care are the mainstays of treatment of children with Campylobacter gastroenteritis. Antimotility agents are contraindicated because they can cause prolonged or fatal disease. The need for antibiotic therapy in healthy patients with uncomplicated gastroenteritis is controversial. Data suggest a shortened duration of symptoms (by an average of 1.3 days) and intestinal shedding of organisms if antibiotics are initiated early in the disease. Antibiotics are recommended for patients with bloody stools, high fever, or a severe course, as well as for children who are immunosuppressed or have underlying diseases, and individuals at high risk of developing severe disease (e.g., pregnancy). Extraintestinal infections (e.g., bacteremia) should also be treated with antibiotics. Most Campylobacter isolates are susceptible to macrolides, fluoroquinolones, aminoglycosides, chloramphenicol, tetracyclines, and clindamycin (though there is no clinical efficacy data for these last three agents, only in vitro data) and are resistant to cephalosporins, penicillins, and trimethoprim. Resistance to tetracyclines, macrolides, and more often fluoroquinolones has been described. Antibiotic resistance among C. jejuni has become a serious worldwide problem. Macrolide resistance is increased in areas such as Thailand and Ireland, whereas fluoroquinolone resistance has been reported in Spain, Hungary, and multiple developing countries in >50% of cultured Campylobacter . Fluoroquinolone resistance continues to increase in the United States and is related to the use of quinolones in veterinary medicine and food products, as well as acquisition from travelers. Erythromycin-resistant Campylobacter isolates are uncommon in the United States; therefore, azithromycin is the drug of choice if therapy is required, particularly in pediatric patients. Drug sensitivities should be determined for patients who do not respond to therapy or any patient with invasive or extraintestinal infection. Sepsis is treated with parenteral antibiotics such as meropenem or imipenem, with or without an aminoglycoside. For extraintestinal infection caused by C. fetus , prolonged therapy is advised. C. fetus isolates resistant to erythromycin and fluoroquinolones have been reported; therefore empirical therapy for serious C. fetus infection should avoid these agents pending susceptibilities.

Prognosis

Although Campylobacter gastroenteritis is usually self-limited, immunosuppressed children (including children with AIDS) can experience a protracted or severe course. Septicemia in newborns and immunocompromised hosts has a poor prognosis, with an estimated mortality rate of 30–40%. Additional prognosis is based on the secondary sequelae that may develop.

Prevention Most human Campylobacter infections are sporadic and are acquired from infected animals or contaminated foods or water. Interventions to minimize transmission include cooking meats thoroughly, preventing recontamination after cooking by not using the same surfaces, utensils, or containers for both uncooked and cooked food, and avoiding unpasteurized dairy products. Also, it is important to ensure that water sources are not contaminated and that water is kept in clean containers. Contact with infected animals should be avoided. No specific isolation is required; standard precautions are sufficient, although in a hospital or clinic setting with an incontinent child, contact precautions are indicated. However, children in diapers should be kept out of daycare until the diarrhea resolves. Breastfeeding appears to decrease symptomatic Campylobacter disease but does not reduce colonization. Several approaches at immunization have been studied, including the use of live-attenuated organisms, subunit vaccines, and killed–whole cell vaccines. No vaccine is currently available.

Bibliography Ben-Shimol S, Carmi A, Greenberg D. Demographic and clinical characteristics of Campylobacter bacteremia in children with and without predisposing factors. Pediatr Infect Dis J . 2013;32:e414–e418. Burakoff A, Brown K, Knutsen J, et al. Outbreak of fluoroquinolone-resistant Campylobacter jejuni infections associated with raw milk consumption from a herdshare dairy —Colorado, 2016. MMWR . 2018;67(5):146–148. Buss SN, Leber A, Chapin K, et al. Multicenter evaluation of

the BioFire FilmArray gastrointestinal panel for etiologic diagnosis of infectious gastroenteritis. J Clin Microbiol . 2015;53(3):915–925. Centers for Disease Control and Prevention. Multistate outbreak of Campylobacter jejuni infections associated with undercooked chicken livers—Northeastern United States, 2012. MMWR . 2013;62:874–876. Feodoroff B, Lauhio A, Ellström P, et al. A nationwide study of Campylobacter jejuni and Campylobacter coli bacteremia in Finland over a 10-year period, 1998–2007, with special reference to clinical characteristics and antimicrobial susceptibility. Clin Infect Dis . 2011;53(8):e99–e106. Glashower D, Snyder J, Welch D, McCarthy S. Outbreak of Campylobacter jejuni associated with consuming undercooked chicken liver mousse—Clark County, Washington, 2016. MMWR . 2017;66(38):1027–1028. Kaakoush NO, Castano-Rodriguez N, Mitchel HM, Man SM. Global epidemiology of Campylobacter infection. Clin Microbiol Rev . 2015;28(3):687–720. Kaira V, Chaudhry R, Dua T, et al. Association of Campylobacter jejuni infection with childhood GuillainBarré syndrome: a case-control study. J Child Neurol . 2009;24(6):664–668. Man SM. The clinical importance of emerging Campylobacter species. Nat Rev Gastroenterol Hepatol . 2011;8:669–985. Su CP, de Perio MA, Fagan K, et al. Occupational distribution of campylobacteriosis and salmonellosis cases—Maryland, Ohio, and Virginia, 2014. MMWR . 2017;66(32):850–853. World Health Organization Media Centre. Campylobacter: Factsheet No 255, 2016 . http://www.who.int/mediacentre/factsheets/fs255/en/ .

CHAPTER 230

Yersinia Ericka V. Hayes

The genus Yersinia is a member of the family Enterobacteriaceae and comprises more than 14 named species, 3 of which are established as human pathogens. Yersinia enterocolitica is by far the most common Yersinia species causing human disease and produces fever, abdominal pain that can mimic appendicitis, and diarrhea. Yersinia pseudotuberculosis is most often associated with mesenteric lymphadenitis. Yersinia pestis is the agent of plague and typically causes an acute febrile lymphadenitis (bubonic plague) and less often occurs as septicemic, pneumonic, pharyngeal, or meningeal plague. Other Yersinia species are uncommon causes of infections of humans, and their identification is often an indicator of immunodeficiency. Yersinia is enzootic and can colonize pets. Infections in humans are incidental and most often result from contact with infected animals or their tissues; ingestion of contaminated water, milk, or meat; or for Y. pestis, the bite of infected fleas or inhalation of respiratory droplets (human, dog, cat). Association with human disease is less clear for Yersinia frederiksenii, Yersinia intermedia, Yersinia kristensenii , Yersinia aldovae, Yersinia bercovieri, Yersinia mollaretii, Yersinia rohdei, and Yersinia ruckeri. Some Yersinia isolates replicate at low temperatures (1-4°C [33.8-39.2°F]) or survive at high temperatures (50-60°C [122-140°F]). Thus, common food preparation and storage and common pasteurization methods might not limit the number of bacteria. Most are sensitive to oxidizing agents.

230.1

Yersinia enterocolitica Ericka V. Hayes

Keywords abdominal pain appendicitis bacteremia blood products chitterlings diarrhea enterocolitis food-borne infection iron overload mesenteric lymphadenitis pharyngitis pig pork water-borne infection

Etiology Yersinia enterocolitica is a large, gram-negative coccobacillus that exhibits little or no bipolarity when stained with methylene blue and carbolfuchsin. It ferments glucose and sucrose but not lactose, is oxidase negative, and reduces nitrate to nitrite. These facultative anaerobes grow well on common culture media and are motile at 22°C (71.6°F) but not 37°C (98.6°F). Optimal growth temperature is 25-28°C (77-82.4°F); however, the organism can grow at refrigerator temperature. Y. enterocolitica includes pathogenic and nonpathogenic members. It has 6 different biotypes (1A, 1B, and 2-5). Y. enterocolitica relies on other bacteria for iron uptake, and conditions associated with iron overload increase risk of infection.

Epidemiology Y. enterocolitica is transmitted to humans through food, water, animal contact, and contaminated blood products. Transmission can occur from mother to newborn. Y. enterocolitica appears to have a global distribution but is seldom a cause of tropical diarrhea. In 2014, incidence of culture-confirmed Y. enterocolitica infection in the United States was 0.28 per 100,000 population (52% decrease from incidence in 1996–1998). Infection may be more common in Northern Europe. Most infections occur among children 50% of cases occur in California, Florida, and Texas; hunting feral swine in these states is a recently recognized risk factor. All age-groups can be infected by Brucella, and infections are more common in males, likely because of more frequent occupational and environmental exposures.

Pathogenesis Modes of transmission for these organisms include inoculation through cuts or abrasions in the skin, inoculation of the conjunctiva, inhalation of infectious aerosols, or ingestion of contaminated meat or dairy products. Infected livestock are the most common source of human infection. In children the primary means of infection is through eating or drinking unpasteurized or raw dairy products. Individuals in endemic areas with occupational exposures to animals, such as farmers and veterinarians, are at highest risk. Laboratory workers are more often exposed to infected aerosols. The risk for infection depends on the nutritional and immune status of the host, the route of inoculum, and the species of Brucella. For reasons that remain unclear, it has been suggested that B. melitensis and B. suis are more virulent than B. abortus or B. canis. The major virulence factor for Brucella appears to be its cell wall lipopolysaccharide (LPS). Strains containing smooth LPS have been demonstrated to have greater virulence and are more resistant to killing by polymorphonuclear leukocytes. These organisms are facultative intracellular pathogens that can survive and replicate within the mononuclear phagocytic cells (monocytes, macrophages) of the reticuloendothelial system. Even though Brucella spp. are chemotactic for entry of leukocytes into the body, the leukocytes are less efficient at killing these organisms than other bacteria despite the assistance of serum factors such as complement. Brucella spp. possess multiple strategies to evade immune responses and establish and maintain chronic infection. Specifically, during chronic stages of infection, organisms

persist within the liver, spleen, lymph nodes, and bone marrow and result in granuloma formation. Antibodies are produced against the LPS and other cell wall antigens, providing a means of diagnosis and probably playing a role in long-term immunity. The major factor in recovery from infection appears to be development of a cell-mediated response, resulting in macrophage activation and enhanced intracellular killing. Specifically, sensitized T lymphocytes release cytokines (e.g., interferon-γ, tumor necrosis factor-α), which activate the macrophages and enhance their intracellular killing capacity.

Clinical Manifestations Brucellosis is a systemic illness that can be very difficult to diagnose in children. Symptoms can be acute or insidious in nature and are usually nonspecific. The incubation period is generally 2-4 wk but may be shorter with B. melitensis . Fever is present in >75% of cases, and the fever pattern can vary widely. The most common physical complaints are arthralgia, myalgia, and back pain. Systemic symptoms, such as fatigue, sweats, chills, anorexia, headache, weight loss, and malaise, are reported in the majority of adult cases but are less frequent in children. Other associated symptoms include abdominal pain, diarrhea, rash, vomiting, cough, and pharyngitis. The most common physical manifestation of brucellosis is hepatic and splenic enlargement, which is present in approximately half of cases. Whereas arthralgia is common, arthritis occurs in a minority of cases. Arthritis is typically monoarticular and most often involves the knee or hip in children and the sacroiliac joint in adolescents and adults. A number of skin lesions have been described with brucellosis, but there is no typical rash for this infection. Epididymo-orchitis is more common in adolescents and adults. In endemic countries, Brucella spp. are an important cause of occult bacteremia in young children. Because of the organism's ability to establish chronic infection, hepatic and splenic abscesses may develop. Serious manifestations of brucellosis include endocarditis, meningitis, osteomyelitis, and spondylitis. Although headache, mental inattention, and depression may be demonstrated in patients with uncomplicated brucellosis, invasion of the nervous system occurs in only 1–4% of cases. Neonatal and congenital infections with these organisms have also been described, resulting from transplacental transmission, breast milk, and blood transfusions. The signs and symptoms

associated with congenital/neonatal brucellosis are nonspecific. Hematologic abnormalities are common with brucellosis; thrombocytopenia, leukopenia, anemia, or pancytopenia may occur. Hemolytic complications can include microangiopathic hemolytic anemia, thrombotic microangiopathy, and autoimmune hemolytic anemia. Elevations of liver enzymes occur in approximately half of cases.

Diagnosis A definitive diagnosis of brucellosis is established by recovering the organisms from the blood, bone marrow, or other tissues. Unfortunately, cultures are insensitive and positive only in a minority of cases. Isolation of the organism may require as long as 4 wk from a blood culture sample unless the laboratory is using an automated culture system such as the lysis-centrifugation method, where the organism can be recovered in 5-7 days. Therefore, it is prudent to alert the clinical microbiology laboratory that brucellosis is suspected so that cultures can be held longer. Bone marrow cultures may be superior to blood cultures when evaluating patients who have received previous antimicrobial therapy. Because of the low yield of cultures, various serologic tests have been applied to the diagnosis of brucellosis. The serum agglutination test is the most widely used and detects antibodies against B. abortus, B. melitensis, and B. suis. This method does not detect antibodies against B. canis because this species lacks the smooth LPS; B. canis –specific antigen is required to diagnose this species. No single titer is ever diagnostic, but most patients with acute infections have titers of ≥1 : 160. Antibodies can generally be detected within 2-4 wk after infection. Low titers may be found early in the course of the illness, requiring the use of acute and convalescent sera testing to confirm the diagnosis: 4-fold increase in titers drawn ≥2 wk apart. Because patients with active infection have both an immunoglobulin M (IgM) and an IgG response and the serum agglutination test measures the total quantity of agglutinating antibodies, the total quantity of IgG is measured by treatment of the serum with 2-mercaptoethanol. This fractionation is important in determining the significance of the antibody titer, because low levels of IgM can remain in the serum for weeks to months after the infection has been treated. IgG titers decrease with effective therapy, and a negative 2-mercaptoethanol test after treatment indicates a favorable response. It is important to remember that all serologic results must be interpreted in light of a patient's history and physical examination. False-positive results from

cross-reacting antibodies to other gram-negative organisms, such as Yersinia enterocolitica, Francisella tularensis, and Vibrio cholerae, can occur. In addition, the prozone effect can give false-negative results in the presence of high titers of antibody. To avoid this issue, serum that is being tested should be diluted to ≥1 : 320. The enzyme immunoassay should only be used for suspected cases with negative serum agglutination tests or for the evaluation of patients in the following situations: (1) complicated cases, (2) suspected chronic brucellosis, or (3) reinfection. Polymerase chain reaction assays have been developed but are not available in most clinical laboratories.

Differential Diagnosis Brucellosis should be considered in the differential diagnosis of fever of unknown origin in endemic areas. It may present similar to other infections such as tularemia, cat-scratch disease, malaria, typhoid fever, histoplasmosis, blastomycosis, and coccidioidomycosis. Infections caused by Mycobacterium tuberculosis, atypical mycobacteria, rickettsiae, and Yersinia can also present similar to brucellosis.

Treatment Many antimicrobial agents are active in vitro against Brucella spp., but the clinical effectiveness does not always correlate with these results. Agents that provide good intracellular killing are required for elimination of Brucella infections. Because of the risk of relapse with monotherapy, combination therapy is generally recommended. In children, doxycycline or trimethoprimsulfamethoxazole (TMP-SMX) in combination with rifampin are most often used for uncomplicated (e.g., nonfocal) infections (Table 234.1 ). While data support that the combination of doxycycline plus an aminoglycoside (streptomycin, gentamicin) is superior to the above oral combination therapies, with fewer treatment failures and relapses, the inconvenience of parenteral therapy may limit this approach in uncomplicated cases, particularly in resourcelimited settings. Fluoroquinolones may be a viable alternative to doxycycline or TMP-SMX but have not been studied in children. For uncomplicated infections, a 6 wk course of therapy is recommended.

Table 234.1

Recommended Therapy for Treatment of Brucellosis AGE/CONDITIONS ≥8 yr

ANTIMICROBIAL AGENT Doxycycline plus Rifampin Alternative: Doxycycline plus Streptomycin or Gentamicin

3 wk.

Etiology Bartonella henselae can be cultured from the blood of healthy cats. B. henselae organisms are the small pleomorphic gram-negative bacilli visualized with Warthin-Starry stain in affected lymph nodes from patients with CSD. Development of serologic tests that showed prevalence of antibodies in 84– 100% of cases of CSD, culturing of B. henselae from CSD nodes, and detection of B. henselae by polymerase chain reaction (PCR) in the majority of lymph node samples and pus from patients with CSD, confirmed the organism as the cause of CSD. Occasional cases of CSD may be caused by other organisms, including Bartonella clarridgeiae, B. grahamii , B. alsatica, and B. quintana .

Epidemiology CSD is common, with >24,000 estimated cases per year in the United States. It is transmitted most frequently by cutaneous inoculation through the bite or scratch of a cat. However, transmission may occur through other routes, such as flea bites. Most patients (87–99%) have had contact with cats, many of which are kittens 50% of patients have a definite history of a cat scratch or bite. Cats have high-level Bartonella bacteremia for months without any clinical symptoms; kittens are more frequently bacteremic than adult cats. Transmission between cats occurs through the cat flea, Ctenocephalides felis. In temperate zones, most cases occur between September and March, perhaps in relation to the seasonal breeding of domestic cats or to the close proximity of family pets in the fall and winter. In tropical zones, there is no seasonal prevalence. Distribution is worldwide, and infection occurs in all races. Cat scratches appear to be more common among children, and males are affected more often than females. CSD is a sporadic illness; usually only 1 family member is affected, even though many siblings play with the same kitten. However, clusters do occur, with family cases within weeks of one another. Anecdotal reports have implicated other sources, such as dog scratches, wood

splinters, fishhooks, cactus spines, and porcupine quills.

Pathogenesis The pathologic findings in the primary inoculation papule and affected lymph nodes are similar. Both show a central avascular necrotic area with surrounding lymphocytes, giant cells, and histiocytes. Three stages of involvement occur in affected nodes, sometimes simultaneously in the same node. The 1st stage consists of generalized enlargement with thickening of the cortex and hypertrophy of the germinal center and with a predominance of lymphocytes. Epithelioid granulomas with Langerhans giant cells are scattered throughout the node. The 2nd stage is characterized by granulomas that increase in density, fuse, and become infiltrated with polymorphonuclear leukocytes, with beginning central necrosis. In the 3rd stage, necrosis progresses with formation of large, pus-filled sinuses. This purulent material may rupture into surrounding tissue. Similar granulomas have been found in the liver, spleen, and osteolytic lesions of bone when those organs are involved.

Clinical Manifestations After an incubation period of 7-12 days (range: 3-30 days), 1 or more 3-5 mm red papules develop at the site of cutaneous inoculation, often reflecting a linear cat scratch. These lesions are often overlooked because of their small size but are found in at least 65% of patients when careful examination is performed (Fig. 236.1 ). Lymphadenopathy is generally evident within 1-4 wk (Fig. 236.2 ). Chronic regional lymphadenitis is the hallmark, affecting the1st or 2nd set of nodes draining the entry site. Affected lymph nodes in order of frequency include the axillary, cervical, submandibular, preauricular, epitrochlear, femoral, and inguinal nodes. Involvement of >1 group of nodes occurs in 10–20% of patients, although at a given site, half the cases involve several nodes.

FIG. 236.1 A child with typical cat-scratch disease demonstrating the original scratch injuries and the primary papule that soon thereafter developed proximal to the middle finger. (Courtesy of Dr. V.H. San Joaquin, University of Oklahoma Health Sciences Center, Oklahoma City.)

FIG. 236.2 Right axillary lymphadenopathy followed the scratches and development of a primary papule in this child with typical cat-scratch disease. (From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases , ed 6, Philadelphia, 2006, Elsevier, p 2737.)

Nodes involved are usually tender and have overlying erythema but without cellulitis. They usually range between 1 and 5 cm in size, although they can become much larger. From 10–40% eventually suppurate. The duration of enlargement is usually 1-2 mo, with persistence up to 1 yr in rare cases. Fever

occurs in approximately 30% of patients, usually 38-39°C (100.4-102.2°F). Other nonspecific symptoms, including malaise, anorexia, fatigue, and headache, affect less than one third of patients. Transient rashes, which may occur in approximately 5% of patients, are mainly truncal maculopapular rashes. Erythema nodosum, erythema multiforme, and erythema annulare are also reported. CSD is usually a self-limited infection that spontaneous resolves within a few weeks to months. The most common ocular presentation of CSD is Parinaud oculoglandular syndrome, which is unilateral conjunctivitis followed by preauricular lymphadenopathy and occurs in 5% of patients with CSD (Fig. 236.3 ). Direct eye inoculation as a result of rubbing with the hands after cat contact is the presumed mode of spread. A conjunctival granuloma may be found at the inoculation site. The involved eye is usually not painful and has little or no discharge but may be quite red and swollen. Submandibular or cervical lymphadenopathy may also occur.

FIG. 236.3 The granulomatous conjunctivitis of Parinaud oculoglandular syndrome is associated with ipsilateral local lymphadenopathy, usually preauricular and less often submandibular. (From Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases , ed 6, Philadelphia, 2006, Elsevier, p 2739.)

More severe, disseminated illness occurs up to 14% of patients and is characterized by presentation with high fever, often persisting for several weeks. Other prominent symptoms include significant abdominal pain and weight loss.

Hepatosplenomegaly may occur, although hepatic dysfunction is rare (Fig. 236.4 ). Granulomatous changes may be seen in the liver and spleen. Another common site of dissemination is bone, with the development of multifocal granulomatous osteolytic lesions, associated with localized pain but without erythema, tenderness, or swelling. Other, uncommon manifestations are neuroretinitis with papilledema and stellate macular exudates, encephalitis, endocarditis, and atypical pneumonia.

FIG. 236.4 In this CT scan of a patient with hepatic involvement of catscratch disease, the absence of enhancement of the multiple lesions after contrast infusion is consistent with the granulomatous inflammation of this entity. Treated empirically with various antibiotics without improvement before establishment of this diagnosis, the patient subsequently recovered fully with no further antimicrobial therapy. (Courtesy of Dr. V.H. San Joaquin, University of Oklahoma Health Sciences Center, Oklahoma City.)

Diagnosis In most cases the diagnosis can be strongly suspected on clinical grounds in a patient with history of exposure to a cat. Serologic testing can be used to confirm the diagnosis. Most patients have elevated IgG antibody titers at presentation. However, the IgM response to B. henselae has frequently resolved by the time testing is considered. There is cross-reactivity among Bartonella spp., particularly B. henselae and B. quintana. If tissue specimens are obtained, bacilli may be visualized with Warthin-Starry

and Brown-Hopps tissue stains. Bartonella DNA can be identified through PCR analysis of tissue specimens. Culturing of the organism is not generally practical for clinical diagnosis.

Differential Diagnosis The differential diagnosis of CSD includes virtually all causes of lymphadenopathy (see Chapter 517 ). The more common entities include pyogenic (suppurative) lymphadenitis, primarily from staphylococcal or streptococcal infections, atypical mycobacterial infections, and malignancy. Less common entities are tularemia, brucellosis, and sporotrichosis. Epstein-Barr virus, cytomegalovirus, and Toxoplasma gondii infections usually cause more generalized lymphadenopathy.

Laboratory Findings Routine laboratory tests are not helpful. The erythrocyte sedimentation rate is often elevated. The white blood cell count may be normal or mildly elevated. Hepatic transaminases are often normal but may be elevated in systemic disease. Ultrasonography or CT may reveal many granulomatous nodules in the liver and spleen; the nodules appear as hypodense, round, irregular lesions and are usually multiple. However, CSD presenting as a solitary splenic lesion has been reported.

Treatment Antibiotic treatment of CSD is not always needed and is not clearly beneficial. For most patients, treatment consists of conservative symptomatic care and observation. Studies show a significant discordance between in vitro activity of antibiotics and clinical effectiveness. For many patients, diagnosis is considered in the context of failure to respond to β-lactam antibiotic treatment of presumed staphylococcal lymphadenitis. A small prospective study of oral azithromycin (500 mg on day 1, then 250 mg on days 2-5; for smaller children, 10 mg/kg/24 hr on day 1 and 5 mg/kg/24 hr on days 2-5) showed a decrease in initial lymph node volume in 50% of patients during the 1st 30 days, but after 30 days there was no difference in

lymph node volume. No other clinical benefit was found. For the majority of patients, CSD is self-limited, and resolution occurs over weeks to months without antibiotic treatment. Azithromycin, clarithromycin, trimethoprimsulfamethoxazole (TMP-SMX), rifampin, ciprofloxacin, and gentamicin appear to be the best agents if treatment is considered. Suppurative lymph nodes that become tense and extremely painful should be drained by needle aspiration , which may need to be repeated. Incision and drainage of nonsuppurative nodes should be avoided because chronic draining sinuses may result. Surgical excision of the node is rarely necessary. Children with hepatosplenic CSD appear to respond well to rifampin at a dose of 20 mg/kg for 14 days, either alone or in combination with a 2nd agent such as azithromycin, gentamicin, or TMP-SMX.

Complications Encephalopathy can occur in as many as 5% of patients with CSD and typically manifests 1-3 wk after the onset of lymphadenitis as the sudden onset of neurologic symptoms, which often include seizures, combative or bizarre behavior, and altered level of consciousness. Imaging studies are generally normal. The cerebrospinal fluid is normal or shows minimal pleocytosis and protein elevation. Recovery occurs without sequelae in almost all patients but may take place slowly over many months. Other neurologic manifestations include peripheral facial nerve paralysis, myelitis, radiculitis, compression neuropathy, and cerebellar ataxia. One patient has been reported to have encephalopathy with persistent cognitive impairment and memory loss. Stellate macular retinopathy is associated with several infections, including CSD. Children and young adults present with unilateral or rarely bilateral loss of vision with central scotoma, optic disc swelling, and macular star formation from exudates radiating out from the macula. The findings usually resolve completely, with recovery of vision, generally within 2-3 mo. The optimal treatment for the neuroretinitis is unknown, although treatment of adults with doxycycline and rifampin for 4-6 wk has had good results. Hematologic manifestations include hemolytic anemia, thrombocytopenic purpura, nonthrombocytopenic purpura, and eosinophilia. Leukocytoclastic vasculitis, similar to Henoch-Schönlein purpura, has been reported in association with CSD in one child. A systemic presentation of CSD with

pleurisy, arthralgia or arthritis, mediastinal masses, enlarged nodes at the head of the pancreas, and atypical pneumonia also has been reported.

Prognosis The prognosis for CSD in a normal host is generally excellent, with resolution of clinical findings over weeks to months. Recovery is occasionally slower and may take as long as 1 yr.

Prevention Person-to-person spread of Bartonella infections is not known. Isolation of the affected patient is not necessary. Prevention would require elimination of cats from households, which is not practical or necessarily desirable. Awareness of the risk of cat (and particularly kitten) scratches should be emphasized to parents. Cat scratches or bites should be washed immediately. Cat flea control is helpful.

Bibliography Amer R, Tugal-Tutkun I. Ophthalmic manifestations of Bartonella infection. Curr Opin Ophthalmol . 2017;28:607– 612. Angelakis E, Rraoult D. Pathogenicity and treatment of Bartonella infections. Int J Antimicrob Agents . 2014;44:16– 25. Anyfantakis D, Kastanakis M, Papdomichelakis A, Bobolakis E. Cat-scratch disease presenting as a solitary splenic abscess in an immunocompetent adult: case report and literature review. Infez Med . 2013;21:130–133. Arisoy ES, Correa AG, Wagner ML, et al. Hepatosplenic catscratch disease in children: selected clinical features and treatment. Clin Infect Dis . 1999;28:778–784. Bass JW, Freitas BC, Freitas AD, et al. Prospective randomized

double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease. Pediatr Infect Dis J . 1998;17:447–452. Batts S, Demers DM. Spectrum and treatment of cat-scratch disease. Pediatr Infect Dis J . 2004;23:1161–1162. Carithers HA, Margileth AM. Cat scratch disease: acute encephalopathy and other neurologic manifestations. Am J Dis Child . 1991;145:98–101. Centers for Disease Control and Prevention. https://www.cdc.gov/bartonella/transmission/index.html ; 2017. Florin TA, Zaoutis TE, Zaoutis LB. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Pediatrics . 2008;121:e1413–e1425. Fournier PE, Lelievre H, Ekyn SJ, et al. Epidemiologic and clinical characteristics of Bartonella quintana and Bartonella henselae endocarditis: a study of 48 patients. Medicine (Baltimore) . 2001;80:245–251. Jacobs R, Schutze G. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis . 1998;26:80–84. Metzkor-Cotter E, Kletter Y, Avidor B, et al. Long-term serological analysis and clinical follow-up of patients with cat scratch disease. Clin Infect Dis . 2003;37:1149–1154. Oksi J, Rantala S, Kilpinen S, et al. Cat scratch disease caused by Bartonella grahamii in an immunocompromised patient. J Clin Microbiol . 2013;51:2781–2784. Ormerod LD, Dailey JP. Ocular manifestations of cat-scratch disease. Curr Opin Ophthalmol . 1999;10:209–216.

236.2

Bartonellosis (Bartonella bacilliformis) Rachel C. Orscheln

Keywords B. bacilliformis Carrión disease hemolytic anemia Oroya fever verruca peruana sandfly The first human Bartonella infection described was bartonellosis , a geographically distinct disease caused by B. bacilliformis. There are 2 predominant forms of illness caused by B. bacilliformis : Oroya fever , a severe, febrile hemolytic anemia, and verruca peruana (verruga peruana), an eruption of hemangioma-like lesions. B. bacilliformis also causes asymptomatic infection. Bartonellosis is also called Carrión disease .

Etiology Bartonella bacilliformis is a small, motile, gram-negative organism with a brush of ≥10 unipolar flagella, which appear to be important components for invasiveness. An obligate aerobe, it grows best at 28°C (82.4°F) in semisolid nutrient agar containing rabbit serum and hemoglobin.

Epidemiology Bartonellosis is a zoonosis found only in mountain valleys of the Andes

Mountains in Peru, Ecuador, Colombia, Chile, and Bolivia at altitudes and environmental conditions favorable for the vector, which is the sandfly , Lutzomyia verrucarum.

Pathogenesis After the sandfly bite, Bartonella organisms enter the endothelial cells of blood vessels, where they proliferate. Found throughout the reticuloendothelial system, they then reenter the bloodstream and parasitize erythrocytes. They bind on the cells, deform the membranes, and then enter intracellular vacuoles. The resultant hemolytic anemia may involve as many as 90% of circulating erythrocytes. Patients who survive this acute phase may or may not experience the cutaneous manifestations, which are nodular hemangiomatous lesions or verrucae ranging in size from a few millimeters to several centimeters.

Clinical Manifestations The incubation period is 2-14 wk. Patients may be totally asymptomatic or may have nonspecific symptoms such as headache and malaise without anemia. Oroya fever is characterized by fever with rapid development of anemia. Clouding of the sensorium and delirium are common symptoms and may progress to overt psychosis. Physical examination demonstrates signs of severe hemolytic anemia, including icterus and pallor, sometimes in association with generalized lymphadenopathy. In the preeruptive stage of verruca peruana (Fig. 236.5 ), patients may complain of arthralgias, myalgias, and paresthesias. Inflammatory reactions such as phlebitis, pleuritis, erythema nodosum, and encephalitis may develop. The appearance of verrucae is pathognomonic of the eruptive phase. Lesions vary greatly in size and number.

FIG. 236.5 A single, large lesion of verruca peruana on the leg of an inhabitant of the Peruvian Andes. Such lesions are prone to superficial ulceration, and their vascular nature may lead to copious bleeding. Ecchymosis of the skin surrounding the lesion is also evident. (Courtesy of Dr. J.M. Crutcher, Oklahoma State Department of Health, Oklahoma City.)

Diagnosis The diagnosis of bartonellosis is established on clinical grounds in conjunction with a blood smear demonstrating organisms or with blood culture. The anemia is macrocytic and hypochromic, with reticulocyte counts as high as 50%. B. bacilliformis may be seen on Giemsa stain preparation as red-violet rods in the erythrocytes. In the recovery phase, organisms change to a more coccoid form and disappear from the blood. In the absence of anemia, the diagnosis depends on blood cultures. In the eruptive phase, the typical verruca confirms the diagnosis. Antibody testing has been used to document infection.

Treatment B. bacilliformis is sensitive to many antibiotics, including rifampin, tetracycline, and chloramphenicol. Treatment is very effective in rapidly diminishing fever and eradicating the organism from the blood. Chloramphenicol (50-75

mg/kg/day) is considered the drug of choice, because it is also useful in the treatment of concomitant infections such as Salmonella. Fluoroquinolones are used successfully as well. Blood transfusions and supportive care are critical in patients with severe anemia. Antimicrobial treatment for verruca peruana is considered when there are >10 cutaneous lesions, if the lesions are erythematous or violaceous, or if the onset of the lesions was 95% since 1947, and deaths from tetanus have declined by >99% in that same period. From 2009 through 2015, a total of 197 cases and 16 deaths from tetanus were reported in the United States. The majority of U.S. childhood cases of tetanus have occurred in unimmunized children whose parents objected to vaccination.

FIG. 238.1 Global elimination status of maternal and neonatal tetanus (MNT). (From World Health Organization: Maternal and neonatal tetanus (MNT) elimination. http://www.who.int/immunization/diseases/MNTE_initiative/en .)

Most non-neonatal cases of tetanus are associated with a traumatic injury, often a penetrating wound inflicted by a dirty object such as a nail, splinter, fragment of glass, or unsterile injection. Tetanus may also occur in the setting of illicit drug injection. The disease has been associated with the use of contaminated suture material and after intramuscular injection of medicines, most notably quinine for chloroquine-resistant falciparum malaria. The disease may also occur in association with animal bites, abscesses (including dental abscesses), ear and other body piercing, chronic skin ulceration, burns, compound fractures, frostbite, gangrene, intestinal surgery, ritual scarification, infected insect bites, and female circumcision. Rarely, cases may present to clinical attention without an antecedent history of trauma.

Pathogenesis Tetanus typically occurs after spores (introduced by traumatic injury) germinate, multiply, and produce tetanus toxin. A plasmid carries the toxin gene. Toxin is produced only by the vegetative cell, not the spore. It is released after the vegetative phase of replication, with replication occurring under anaerobic conditions. The low oxidation-reduction potential of an infected injury site therefore provides an ideal environment for transition from the spore to the vegetative stage of growth. Following bacterial cell death and lysis, tetanospasmin is produced. The toxin has no known function for clostridia in the soil environment where they normally reside. Tetanus toxin is a 150 kDa simple protein consisting of a heavy (100 kDa) and a light (50 kDa) chain joined by a single disulfide bond. Tetanus toxin binds at the neuromuscular junction and enters the motor nerve by endocytosis, after which it undergoes retrograde axonal transport, facilitated by dyneins, to the cytoplasm of the α-motoneuron. In the sciatic nerve, the transport rate was found to be 3.4 mm/hr. The toxin exits the motoneuron in the spinal cord and next enters adjacent spinal inhibitory interneurons, where it prevents release of the neurotransmitters glycine and γaminobutyric acid (GABA). Tetanus toxin thus blocks the normal inhibition of antagonistic muscles on which voluntary coordinated movement depends; as a consequence, affected muscles sustain maximal contraction and cannot relax. This aspect of pathogenesis led to the term lockjaw , classically applied to the clinical manifestations of tetanus in the affected individual. The autonomic nervous system is also rendered unstable in tetanus. The phenomenal potency of tetanus toxin is enzymatic. The 50 kDa light chain (A-chain) of tetanus toxin is a zinc-containing endoprotease whose substrate is synaptobrevin, a constituent protein of the docking complex that enables the synaptic vesicle to fuse with the terminal neuronal cell membrane. The cleavage of synaptobrevin is the final target of tetanus toxin, and even in low doses the neurotoxin will inhibit neurotransmitter exocytosis in the inhibitory interneurons. The blockage of GABA and glycine causes the physiologic effects of tetanus toxin. The 100 kDa heavy chain (B-chain) of the toxin contains its binding and internalization domains. It binds to disialogangliosides (GD2 and GD1b) on the neuronal membrane. The translocation domain aids the movement of the protein across that membrane and into the neuron. Because C. tetani is not an invasive organism, its toxin-producing vegetative

cells remain where introduced into the wound, which may display local inflammatory changes and a mixed bacterial flora.

Clinical Manifestations Tetanus is most often generalized but may also be localized. The incubation period typically is 2-14 days but may be as long as months after the injury. In generalized tetanus the presenting symptom in about half of cases is trismus (masseter muscle spasm, or lockjaw). Headache, restlessness, and irritability are early symptoms, often followed by stiffness, difficulty chewing, dysphagia, and neck muscle spasm. The so-called sardonic smile of tetanus (risus sardonicus ) results from intractable spasms of facial and buccal muscles. When the paralysis extends to abdominal, lumbar, hip, and thigh muscles, the patient may assume an arched posture of extreme hyperextension of the body, or opisthotonos , with the head and the heels bent backward and the body bowed forward. In severe cases, only the back of the head and the heels of the patient are noted to be touching the supporting surface. Opisthotonos is an equilibrium position that results from unrelenting total contraction of opposing muscles, all of which display the typical boardlike rigidity of tetanus. Laryngeal and respiratory muscle spasm can lead to airway obstruction and asphyxiation. Because tetanus toxin does not affect sensory nerves or cortical function, the patient unfortunately remains conscious, in extreme pain, and in fearful anticipation of the next tetanic seizure. The seizures are characterized by sudden, severe tonic contractions of the muscles, with fist clenching, flexion, and adduction of the arms and hyperextension of the legs. Without treatment, the duration of these seizures may range from a few seconds to a few minutes in length with intervening respite periods. As the illness progresses, the spasms become sustained and exhausting. The smallest disturbance by sight, sound, or touch may trigger a tetanic spasm. Dysuria and urinary retention result from bladder sphincter spasm; forced defecation may occur. Fever, occasionally as high as 40°C (104°F), is common and is caused by the substantial metabolic energy consumed by spastic muscles. Notable autonomic effects include tachycardia, dysrhythmias, labile hypertension, diaphoresis, and cutaneous vasoconstriction. The tetanic paralysis usually becomes more severe in the 1st wk after onset, stabilizes in the 2nd wk, and ameliorates gradually over the ensuing 1-4 wk. Neonatal tetanus , the infantile form of generalized tetanus, typically manifests within 3-12 days of birth. It presents as progressive difficulty in

feeding (sucking and swallowing), associated hunger, and crying. Paralysis or diminished movement, stiffness and rigidity to the touch, and spasms, with or without opisthotonos, are characteristic. The umbilical stump, which is typically the portal of entry for the microorganism, may retain remnants of dirt, dung, clotted blood, or serum, or it may appear relatively benign. Localized tetanus results in painful spasms of the muscles adjacent to the wound site and may precede generalized tetanus. Cephalic tetanus is a rare form of localized tetanus involving the bulbar musculature that occurs with wounds or foreign bodies in the head, nostrils, or face. It also occurs in association with chronic otitis media. Cephalic tetanus is characterized by retracted eyelids, deviated gaze, trismus, risus sardonicus, and spastic paralysis of the tongue and pharyngeal musculature.

Diagnosis The picture of tetanus is one of the most dramatic in medicine, and the diagnosis may be established clinically. The typical setting is an unimmunized patient (and/or mother) who was injured or born within the preceding 2 wk, who presents with trismus, dysphagia, generalized muscle rigidity and spasm, and a clear sensorium. Results of routine laboratory studies are usually normal. A peripheral leukocytosis may result from a secondary bacterial infection of the wound or may be stress-induced from the sustained tetanic spasms. The cerebrospinal fluid analysis is normal, although the intense muscle contractions may raise intracranial pressure. Serum muscle enzymes (creatine kinase, aldolase) may be elevated. Neither the electroencephalogram nor the electromyogram shows a characteristic pattern, although EMG may show continuous discharge of motor subunits and shortening, or absence of the silent interval normally observed after an action potential. An assay for antitoxin levels is not readily available, although a serum antitoxin level of ≥0.01 IU/mL is generally considered protective and makes the diagnosis of tetanus less likely. C. tetani is not always visible on Gram stain of wound material and is isolated by culture in only approximately 30% of cases. The spatula test is a simple diagnostic bedside test that involves touching the oropharynx with a spatula or tongue blade. Normally this maneuver will elicit a gag reflex, as the patient tries to expel the spatula (negative test). If tetanus is present, patients develop a reflex spasm of the masseter muscles and bite the spatula (positive test). This bedside diagnostic

maneuver is said to have a high sensitivity and specificity.

Differential Diagnosis Florid and generalized tetanus is typically not mistaken for any other disease. However, trismus may result from parapharyngeal, retropharyngeal, or dental abscesses or rarely from acute encephalitis involving the brainstem. Either rabies or tetanus may follow an animal bite, and rabies may manifest as trismus with seizures. Rabies may be distinguished from tetanus by hydrophobia, marked dysphagia, predominantly clonic seizures, and pleocytosis (see Chapter 300 ). Although strychnine poisoning may result in tonic muscle spasms and generalized seizure activity, it seldom produces trismus, and unlike in tetanus, general relaxation usually occurs between spasms. Hypocalcemia may produce tetany that is characterized by laryngeal and carpopedal spasms, but trismus is absent. Occasionally, epileptic seizures, narcotic withdrawal, or other drug reactions may suggest tetanus.

Treatment Management of tetanus requires eradication of C. tetani , correction of wound environment conditions conducive to its anaerobic replication, neutralization of all accessible tetanus toxin, control of seizures and respiration, palliation, provision of meticulous supportive care, and prevention of recurrences. Surgical wound excision and debridement are often needed to remove the foreign body or devitalized tissue that created the anaerobic growth conditions necessary for vegetative replication. Surgery should be performed promptly after administration of human tetanus immunoglobulin (TIG) and antibiotics. Excision of the umbilical stump in the neonate with tetanus is no longer recommended. Tetanus toxin cannot be neutralized by TIG after it has begun its axonal ascent to the spinal cord. However, TIG should be given as soon as possible, toward the goal of neutralizing toxin that diffuses from the wound into the circulation before the toxin can bind at distant muscle groups. The optimal dose of TIG has not been determined. Some experts recommend a single intramuscular injection of 500 units of TIG to neutralize systemic tetanus toxin, but total doses as high as 3,000-6,000 U are also recommended. Infiltration of part of the dose of TIG into the wound is recommended by the Red Book Committee of the American

Academy of Pediatrics, although the efficacy of this approach has not been proved. If TIG is unavailable, use of human intravenous immunoglobulin may be necessary. IVIG contains 4-90 U/mL of TIG; the optimal dosage of IVIG for treating tetanus is not known, and its use is not approved for this indication. In parts of the world where it is available, another alternative may be equinederived tetanus antitoxin (TAT). This product is no longer available in the United States. A dose of 1,500-3,000 U is recommended and should be administered after appropriate testing for sensitivity and desensitization, since up to 15% of patients given the usual dose of TAT will experience serum sickness. The human-derived immunoglobulins are much preferred because of their longer half-life (30 days) and the virtual absence of allergic and serum sickness adverse effects. Results of studies examining the potential benefit of intrathecal administration of TIG are conflicting. The TIG preparation available for use in the United States is neither licensed nor formulated for intrathecal or intravenous use. Oral (or intravenous) metronidazole (30 mg/kg/day, given at 6 hr intervals; maximum dose, 4 g/day) decreases the number of vegetative forms of C. tetani and is currently considered the antibiotic of choice. Parenteral penicillin G (100,000 U/kg/day, administered at 4-6 hr intervals, with a daily maximum 12 million U) is an alternative treatment. Antimicrobial therapy for a total duration of 7-10 days is recommended. Supportive care and pharmacologic interventions targeted at control of tetanic spasms are of critical importance in the management of tetanus. Toward this goal, all patients with generalized tetanus should receive muscle relaxants . Diazepam provides both relaxation and seizure control. The initial dose of 0.10.2 mg/kg every 3-6 hr intravenously is subsequently titrated to control the tetanic spasms, after which the effective dose is sustained for 2-6 wk before a tapered withdrawal. Magnesium sulfate, other benzodiazepines (midazolam), chlorpromazine, dantrolene, and baclofen are also used. Intrathecal baclofen produces such complete muscle relaxation that apnea often ensues; as with most other agents listed, baclofen should be used only in an intensive care unit setting. Favorable survival rates in generalized tetanus have been described with the use of neuromuscular blocking agents such as vecuronium and pancuronium, which produce a general flaccid paralysis that is then managed by mechanical ventilation. Autonomic instability is regulated with standard α- or β-adrenergic (or both) blocking agents; morphine has also proved useful.

Supportive Care Meticulous supportive care in a quiet, dark, secluded setting is most desirable. Because tetanic spasms may be triggered by minor stimuli, the patient should be sedated and protected from all unnecessary sounds, sights, and touch, and all therapeutic and other manipulations must be carefully scheduled and coordinated. Endotracheal intubation may not be required, but it should be done to prevent aspiration of secretions before laryngospasm develops. A tracheostomy kit should be immediately at hand for unintubated patients. Endotracheal intubation and suctioning easily provoke reflex tetanic seizures and spasms, so early tracheostomy should be considered in severe cases not managed by pharmacologically induced flaccid paralysis. Therapeutic botulinum toxin has been used to overcome trismus. Cardiorespiratory monitoring, frequent suctioning, and maintenance of the patient's substantial fluid, electrolyte, and caloric needs are fundamental. Careful nursing attention to mouth, skin, bladder, and bowel function is needed to avoid ulceration, infection, and obstipation. Prophylactic subcutaneous heparin may be of value, but it must be balanced with the risk of hemorrhage. Enoxaparin would be an alternative for the patient for whom deep vein thrombosis prophylaxis is warranted.

Complications The seizures and the severe, sustained rigid paralysis of tetanus predispose the patient to many complications. Aspiration of secretions with attendant pneumonia is an important complication to consider and may be present at initial diagnosis. Maintaining airway patency often mandates endotracheal intubation and mechanical ventilation with their attendant hazards, including pneumothorax and mediastinal emphysema. The seizures may result in lacerations of the mouth or tongue, in intramuscular hematomas or rhabdomyolysis with myoglobinuria and renal failure, or in long-bone or spinal fractures. Venous thrombosis, pulmonary embolism, gastric ulceration with or without hemorrhage, paralytic ileus, and decubitus ulceration are described as complications. Excessive use of muscle relaxants, which are an integral part of care, may produce iatrogenic apnea. Cardiac arrhythmias, including asystole, unstable blood pressure, and labile temperature regulation reflect disordered autonomic nervous system control that may be aggravated by inattention to maintenance of intravascular

volume needs.

Prognosis Recovery in tetanus occurs through regeneration of synapses within the spinal cord that results in restoration of muscle relaxation. Interestingly, an episode of tetanus does not result in the production of toxin-neutralizing antibodies, presumably because the infinitesimally small amounts of toxin required to cause disease are not sufficient to elicit an immune response. Therefore, active immunization with tetanus toxoid during convalescence and/or at discharge, with provision for completion of the primary vaccine series, is mandatory. The most important factor that influences outcome is the quality of supportive care. Mortality is highest in very young and very old patients. A favorable prognosis is associated with a long incubation period, absence of fever, and localized disease. An unfavorable prognosis is associated with onset of trismus 1:16. Chancroid and herpes simplex virus can be distinguished clinically from LGV by the concurrent presence of painful genital ulcers. Syphilis can be differentiated by serologic tests. However, co-infections can occur.

Treatment

Doxycycline (100 mg PO bid for 21 days) is the recommended treatment. The alternative regimen is erythromycin base (500 mg PO 4 times a day for 21 days). Azithromycin (1 g PO once weekly for 3 wk) may also be effective, but clinical data are lacking. Sex partners of patients with LGV should be treated if they have had sexual contact with the patient during the 30 days preceding the onset of symptoms.

Bibliography Bäcker M, Hammerschlag MR. Case #09011: A teenager with constipation and weight loss. ID Images . [Available from:] http://www.idimages.org/idreview/case/caseid=7 [(Accessed Jan 21, 2019)]. Blank S, Schillinger JA, Harbatkin D. lymphogranuloma venereum in the industrialized world. Lancet . 2005;365:1607–1608. Centers for Disease Control and Prevention (CDC). Recommendations for the Laboratory-Based Detection of Chlamydia trachomatis and Neisseria gonorrhoeae — 2014. MMWR Recomm Rep . 2014;63(RR–#2):1–24. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines 2015. MMWR Recomm Rep . 2015;64(RR–#3):1–140. Leeyaphan C, Ong JJ, Cow EPF, et al. Treatment outcomes for rectal lymphogranuloma venreum in men who have sex with men using doxycycline, azithromycin, or both: a review of clinical cases. Sex Transm Dis . 2017;44:245–248.

CHAPTER 254

Psittacosis (Chlamydia psittaci) Stephan A. Kohlhoff, Margaret R. Hammerschlag

Chlamydia psittaci, the agent of psittacosis (also known as parrot fever and ornithosis ), is primarily an animal pathogen and rarely causes human disease. In birds, C. psittaci infection is known as avian chlamydiosis .

Etiology C. psittaci affects both psittacine birds (e.g., parrots, parakeets, macaws) and nonpsittacine birds (ducks, turkeys); the known host range includes 130 avian species. The life cycle of C. psittaci is the same as for C. pneumoniae (see Chapter 252 ). Strains of C. psittaci have been analyzed by patterns of pathogenicity, inclusion morphology in tissue culture, DNA restriction endonuclease analysis, and monoclonal antibodies, which indicate that there are 7 avian serovars. The organism has also been found in non-avian domestic animals, including cattle, sheep, pigs, goats, and cats. Non-avian C. psittaci has rarely caused disease in humans. Two of the avian serovars, psittacine and turkey, are of major importance in the avian population of the United States. Each is associated with important host preferences and disease characteristics.

Epidemiology From 2005 to 2009 there were 66 reported cases of psittacosis in the United States. Of these, 85% of these cases were associated with exposure to birds, including 70% following exposure to caged pet birds, which were usually psittacine birds, including cockatiels, parakeets, parrots, and macaws. Chlamydiosis among caged nonpsittacine birds occurs most often in pigeons,

doves, and mynah birds. Persons at highest risk for acquiring psittacosis include bird fanciers and owners of pet birds (43% of cases) and pet shop employees (10% of cases). Reported cases most likely underestimate the number of actual infections owing to a lack of awareness. Inhalation of aerosols from feces, fecal dust, and nasal secretions of animals infected with C. psittaci is the primary route of infection. Source birds are either asymptomatic or have anorexia, ruffled feathers, lethargy, and watery green droppings . Psittacosis is uncommon in children, in part because children may be less likely to have close contact with infected birds. One high-risk activity is cleaning the cage. Several major outbreaks of psittacosis have occurred in turkey-processing plants; workers exposed to turkey viscera are at the highest risk for infection.

Clinical Manifestations Infection with C. psittaci in humans ranges from clinically inapparent to severe disease, including pneumonia and multiorgan involvement. The mean incubation period is 15 days after exposure, with a range of 5-21 days. Onset of disease is usually abrupt, with fever, cough, headache, myalgia, and malaise. The fever is high and is often associated with rigors and sweats. The headache can be so severe that meningitis is considered. The cough is usually nonproductive. Gastrointestinal symptoms are occasionally reported. Crackles may be heard on auscultation. Chest radiographs are usually abnormal and are characterized by the presence of variable infiltrates, sometimes accompanied by pleural effusions. The white blood cell count is usually normal but is sometimes mildly elevated. Elevated levels of aspartate aminotransferase, alkaline phosphatase, and bilirubin are common. Nonpulmonary complications include pericarditis, endocarditis, and myocarditis. Mortality occurs in 5% of cases.

Diagnosis Psittacosis can be difficult to diagnose because of the varying clinical presentations. A history of exposure to birds or association with an active case can be important clues, but as many as 20% of patients with psittacosis have no known contact. Person-to-person spread has been suggested but not proved. Other infections that cause pneumonia with high fever, unusually severe

headache, and myalgia include routine bacterial and viral respiratory infections as well as Coxiella burnetii infection (Q fever), Mycoplasma pneumoniae infection, C. pneumoniae infection, tularemia, tuberculosis, fungal infections, and Legionnaires disease. A patient is considered to have a confirmed case of psittacosis if clinical illness is compatible with psittacosis and the case is laboratory confirmed by either isolation of C. psittaci from respiratory specimens (e.g., sputum, pleural fluid, or tissue) or blood, or 4-fold or greater increase in antibody (immunoglobulin G) against C. psittaci by complement fixation or microimmunofluorescence between paired acute- and convalescent-phase serum specimens obtained at least 2-4 wk apart. A patient is considered to have a probable case of psittacosis if the clinical illness is compatible with psittacosis and 1 of the 2 following laboratory results is present: supportive serology (e.g., C. psittaci antibody titer [Immunoglobulin M] ≥ 32 in at least 1 serum specimen obtained after onset of symptoms), or detection of C. psittaci DNA in a respiratory specimen (e.g., sputum, pleural fluid, or tissue) via amplification of a specific target by polymerase chain reaction assay. Although microimmunofluorescence has greater specificity to C. psittaci than complement fixation, cross reactions with other Chlamydia species can occur. Therefore acute- and convalescent-phase serum specimens should be analyzed at the same time in the same laboratory. False-negative microimmunofluorescence results can occur in acutely ill patients. Early treatment of psittacosis with tetracycline can abrogate the antibody response. Although C. psittaci will grow in the same culture systems used for isolation of Chlamydia trachomatis and C. pneumoniae, very few laboratories culture for C. psittaci, mainly because of the potential biohazard. Real-time polymerase chain reaction assays have been developed for use in the detection of C. psittaci in respiratory specimens. These assays can distinguish C. psittaci from other chlamydial species and identify different C. psittaci genotypes. However, polymerase chain reaction–based tests have not been cleared by the FDA for use as diagnostic tests in human samples.

Treatment Recommended treatment regimens for psittacosis are doxycycline (100 mg PO twice daily) or tetracycline (500 mg PO 4 times a day) for at least 10-14 days after the fever abates. The initial treatment of severely ill patients is doxycycline

hyclate (4.4 mg/kg/day divided every 12 hr IV; maximum: 100 mg/dose). Erythromycin (500 mg PO 4 times a day) and azithromycin (10 mg/kg PO day 1, not to exceed 500 mg, followed by 5 mg/kg PO on days 2-5, not to exceed 250 mg) are alternative drugs if tetracyclines are contraindicated (e.g., children < 8 yr of age and pregnant women) but may be less effective. Remission is usually evident within 48-72 hr. Initial infection does not appear to be followed by longterm immunity. Reinfection and clinical disease can develop within 2 mo of treatment.

Prognosis The mortality rate of psittacosis is 15–20% with no treatment but is 50%) include fever, rash (frequently involving the palms or soles), nausea and vomiting, and headache, and less often (50%, 3-5–fold greater than that of acyclovir. Plasma concentrations approach those observed

with intravenous acyclovir. Valacyclovir is available only for oral administration. A suspension formulation is not commercially available, but an oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg caplets for use in pediatric patients for whom a solid dosage form is not appropriate. Suppressive therapy with valacyclovir is commonly prescribed in the 2nd and 3rd trimesters of pregnancy in women who have a clinical history of recurrent genital herpes. It is important to be aware that perinatal transmission of HSV can occur, leading to symptomatic disease in spite of maternal antenatal antiviral prophylaxis. In such settings, the possibility of emergence of acyclovirresistant virus should be considered.

Penciclovir and Famciclovir Penciclovir is an acyclic nucleoside analog that, like acyclovir, inhibits the viral DNA polymerase following phosphorylation to its active form. Compared with acyclovir, penciclovir has a substantially longer intracellular half-life, which in theory can confer superior antiviral activity at the intracellular level; however, there is no evidence that this effect confers clinical superiority. Penciclovir is licensed only as a topical formulation (1% penciclovir cream), and this formulation is indicated for therapy of cutaneous HSV infections. Topical therapy for primary or recurrent herpes labialis or cutaneous HSV infection is an appropriate use of penciclovir in children older than 2 yr of age. Famciclovir is the prodrug formulation (diacetyl ester) of penciclovir. In contrast to penciclovir, famciclovir may be administered orally and has bioavailability of approximately 70%. Following oral administration, famciclovir is deacetylated to the parent drug, penciclovir. The efficacy of famciclovir for HSV and VZV infections appears equivalent to that of acyclovir, although the pharmacokinetic profile is more favorable. Famciclovir is indicated for oral therapy of HSV and VZV infections. There is currently no liquid or suspension formulation available, and experience with pediatric use is very limited. The toxicity profile is identical to that of acyclovir. In a clinical trial, valacyclovir was found to be superior to famciclovir in prevention of reactivation and reduction of viral shedding in the setting of recurrent genital HSV infection.

Ganciclovir and Valganciclovir

Ganciclovir is a nucleoside analog with structural similarity to acyclovir. Like acyclovir, ganciclovir must be phosphorylated for antiviral activity, which is targeted against the viral polymerase. The gene responsible for ganciclovir phosphorylation is not TK but rather the virally encoded UL97 phosphotransferase gene. Antiviral resistance in CMV can be observed with prolonged use of nucleoside antivirals, and resistance should be considered in patients on long-term therapy who appear to fail to respond clinically and virologically. Ganciclovir is broadly active against many herpesviruses, including HSV and VZV, but is most valuable for its activity against CMV. Ganciclovir was the first antiviral agent licensed specifically to treat and prevent CMV infection. It is indicated for prophylaxis against and therapy of CMV infections in high-risk patients, including HIV-infected patients and SOT or HSCT recipients. Of particular importance is the use of ganciclovir in the management of CMV retinitis, a sight-threatening complication of HIV infection. Ganciclovir is also of benefit for newborns with symptomatic congenital CMV infection and may be of value in partially ameliorating the sensorineural hearing loss and developmental disabilities that are common complications of congenital CMV infection. Ganciclovir is supplied as parenteral and oral formulations. Ganciclovir ocular implants are also available for the management of CMV retinitis. The bioavailability of oral ganciclovir is poor, 75% of the dose is deposited in the oropharynx and much of it is swallowed. The actual amount distributed to the airways and lungs depends on factors such as the patient's inspiratory flow. Approximately 13% of the dose appears to be distributed to the airways and lungs, with approximately 10% of the inhaled dose distributed systemically. Local respiratory mucosal drug concentrations greatly exceed the drug concentration needed to inhibit influenza A and B viruses. Elimination is via the kidneys, and no dosage adjustment is necessary with renal insufficiency, because the amount that is systemically absorbed is low. Oseltamivir is administered as an esterified prodrug that has high oral bioavailability. It is eliminated by tubular secretion, and dosage adjustment is required for patients with renal insufficiency. Gastrointestinal adverse effects, including nausea and vomiting, are occasionally observed. The drug is indicated for both treatment and prophylaxis. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days. Treatment should be initiated within 2 days of the appearance of symptoms. Recommended treatment dosages for children vary by age and weight. The recommended dose for children younger than 1 yr of age is 3 mg/kg/dose twice a day. For children older than 1 yr of age, doses are 30 mg twice a day for children weighing ≤15 kg, 45 mg twice a day for children weighing 15-23 kg, 60 mg twice a day for those weighing 23-40 kg, and 75 mg twice a day for children weighing ≥40 kg. Dosages for chemoprophylaxis are the same for each weight group in children older than 1 yr of age, but the drug should be administered only once daily rather than twice daily. Oseltamivir is FDA approved for therapy of influenza A and B treatment in children 2 wk of age and older, whereas zanamivir is recommended for treatment of children 7 yr of age and older. Current treatment and dosage recommendations for treatment of influenza in children and for chemoprophylaxis are available at: https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm . Oseltamivir has been described to produce neuropsychiatric (narcolepsy) and

psychologic (suicidal events) side effects in some patient populations; the drug should be discontinued if behavioral or psychiatric side effects are observed. In late 2014 the FDA approved another neuraminidase inhibitor, peramivir, for treatment of influenza. It is available as a single-dose, intravenous option. The drug is currently approved for use in children >2 yr of age. The dose is 12 mg/kg dose, up to 600 mg maximum, via intravenous infusion for a minimum of 15 min in children from 2 to 12 yr of age. Children 13 and older should receive the adult dose (600 mg IV in a single, 1-time dose).

Baloxavir Oral baloxavir marboxil (Xofluza) is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in people ≥12 yr. The safety and efficacy of baloxavir for the treatment of influenza have been established in pediatric patients ≥12 yr and older weighing at least 40 kg. Safety and efficacy in patients 65 yr were not included in the initial published clinical trials. There are no available data for baloxavir treatment of hospitalized patients with influenza.

Antivirals Used for Hepatitis Seven antiviral agents have been approved by the FDA for treatment of adults with chronic hepatitis B in the United States. These agents are categorized as either interferons (IFN-α2b and peginterferon-α2a) or nucleoside or nucleotide analogs (lamivudine, adefovir, entecavir, tenofovir, telbivudine). Lamivudine is currently considered the first-line therapy in adult patients, but experience in children is limited. In 2012 tenofovir was FDA approved for children with chronic hepatitis B aged 12 yr or older weighing >35 kg. Entecavir was approved in the United States for use in children 2 yr and older with chronic HBV and evidence of active viral replication and disease activity and, with IFNα, is emerging as a first-line antiviral regimen for children with hepatitis B who are candidates for antiviral therapy. Adefovir demonstrates a favorable safety profile and is less likely to select for resistance than lamivudine, but virologic response was limited to adolescent patients and was lower than that of lamivudine. Most experts recommend

watchful waiting of children with chronic hepatitis B infection, because current therapies are only modestly effective at best and evidence of long-term benefit is scant. Young children are often believed to be immune tolerant of hepatitis B infection (i.e., they have viral DNA present in serum but normal transaminase levels and no evidence of active hepatitis). These children should have transaminases and viral load monitored but are not typically considered to be candidates for antiviral therapy. Only various combinations of interferons and ribavirin were approved by the FDA to treat adults and children with chronic hepatitis C (see Tables 272.1 and 272.2 ). The development of novel and highly effective antivirals for HCV has revolutionized the care of hepatitis C patients. These drugs are not yet licensed for pediatric use. Novel drugs include ledipasvir, sofosbuvir, daclatasvir, elbasvir, beclabuvir, grazoprevir, paritaprevir, ombitasvir, velpatasvir, and dasabuvir. Ledipasvir, ombitasvir, daclatasvir, elbasvir, and velpatasvir inhibit the virally encoded phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion, whereas sofosbuvir is metabolized to a uridine triphosphate mimic, which functions as an RNA chain terminator when incorporated into the nascent RNA by the NS5B polymerase enzyme. Dasabuvir and beclabuvir are also NS5B inhibitors. Paritaprevir and grazoprevir inhibit the nonstructural protein 3 (NS3/4) serine protease, a viral nonstructural protein that is the 70-kDa cleavage product of the hepatitis C virus polyprotein. Past efforts to treat HCV prior to the advent of these new direct therapies had yielded mixed results. Although only 10–25% of adults treated with interferon had a sustained remission of disease, treatment with a combination of interferon and ribavirin achieves remission in close to half of treated adults. Randomized controlled trials indicated that patients treated with pegylated interferons (so called because they are formulated and stabilized with polyethylene glycol), both as dual therapy with ribavirin and as monotherapy, experienced higher sustained viral response rates than did those treated with nonpegylated interferons. The advent of new, direct therapies has led to permanent remission of HCV disease in adult patients. Data on the use of these agents in infants and children are limited. In early 2017 the combination of sofosbuvir with ribavirin and the fixeddose combination of sofosbuvir/ledipasvir was approved by the FDA for treatment of children with chronic HCV infection 12 yr of age and older. The only drugs currently approved for children younger than 12 yr remain pegylated interferon and ribavirin. The use of IFN-α2b in combination with ribavirin has been approved by the FDA for chronic hepatitis C in this age group.

There are significant genotype-dependent differences in responsiveness to antiviral therapy; patients with genotype 1 had the lowest levels of sustained virologic response, and patients with genotype 2 or 3 had the highest response. The use of IFN-ααb in combination with ribavirin provides a much more favorable sustained virologic response in children with HCV genotype 2/3 than in those with HCV genotype 1. For genotype 1 hepatitis C treated with pegylated interferons combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment.

Antiviral Immune Globulins Immune globulins are useful adjuncts in the management of viral disease. However, they are most valuable when administered as prophylaxis against infection and disease in high-risk patients; their value as therapeutic agents in the setting of established infection is less clear. Varicella-zoster immune globulin (human) is valuable for prophylaxis against VZV in high-risk children, particularly newborns and immunocompromised children (see Chapter 280 ). Cytomegalovirus immune globulin is warranted for children at high risk for CMV disease, particularly SOT and HSCT patients, and can play a role in preventing injury to the infected fetus when administered to the pregnant patient (see Chapter 282 ). Palivizumab, a monoclonal antibody with anti-RSV activity, is effective for preventing severe RSV lower respiratory tract disease in high-risk premature infants and has replaced RSV immune globulin (see Chapter 287 ). Hepatitis B immune globulin is indicated in infants born to hepatitis B surface antigen-positive mothers (see Chapter 385 ).

Bibliography Defresne F, Sokal E. Chronic hepatitis B in children: therapeutic challenges and perspectives. J Gastroenterol Hepatol . 2017;32:368–371. Haidar G, Singh N. Viral infections in solid organ transplant recipients: novel updates and a review of the classics. Curr Opin Infect Dis . 2017; 10.1097/QCO.0000000000000409

[PMID] 28984642. Harris JB, Holmes AP. Neonatal herpes simplex viral infections and acyclovir: an update. J Pediatr Pharmacol Ther . 2017;22:88–93. Harrison GJ. Current controversies in diagnosis, management, and prevention of congenital cytomegalovirus: updates for the pediatric practitioner. Pediatr Ann . 2015;44(5):e115– e125. Indolfi G, Thorne C, El Sayed MH, et al. The challenge of treating children with hepatitis C virus infection. J Pediatr Gastroenterol Nutr . 2017;64:851–854. Jorquera PA, Tripp RA. Respiratory syncytial virus: prospects for new and emerging therapeutics. Expert Rev Respir Med . 2017;11:609–615. Kimberlin DW, Jester PM, Sánchez PJ, National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med . 2015;372:933–943. López-Labrador FX, Berenguer M, Navarro D. Overcoming drug resistance in HSV, CMV, HBV and HCV infection. Future Microbiol . 2015;10:1759–1766. Muller WJ. Treatment of perinatal viral infections to improve neurologic outcomes. Pediatr Res . 2017;81:162–169. Yen HL. Current and novel antiviral strategies for influenza infection. Curr Opin Virol . 2016;18:126–134.

CHAPTER 273

Measles Wilbert H. Mason, Hayley A. Gans

Measles is highly contagious, but endemic transmission has been interrupted in the United States as a result of widespread vaccination; indigenous or imported cases have occasionally resulted in epidemics in the United States in unimmunized or partially immunized American or foreign-born children (adopted children, refugees, returning tourists). In some areas of the world, measles remains a serious threat to children (Fig. 273.1 ).

FIG. 273.1 Progress toward achieving global measles milestones for measles vaccine coverage (A) , measles incidence (B) , and measles mortality (C) . A, Milestone 1: increase routine coverage with the 1st dose of measles-containing vaccine (MCV1) for children aged 1 yr to ≥90% nationally and ≥80% in every district. Progress: The number of countries with ≥90% MCV1 coverage increased from 84 (44%) in 2000 to 119 (61%) in 2015. Among countries with ≥90% MCV1 coverage nationally, the percentage with ≥80% coverage in every district was only 39% of 119 countries in 2015. B, Milestone 2: reduce global measles incidence to less than 5 cases per 1 million population. Progress: reported global annual measles incidence decreased 75% from 2000 to 2015, but only the Region of the Americas achieved the milestone of less than 5 cases per 1 million population. C, Milestone 3: reduce global measles mortality by 95% from the 2000 estimate. Progress: the number of estimated global annual measles deaths decreased 79% from 2000 to 2015. AFR, African Region; AMR, Region of the Americas; EMR, Eastern Mediterranean Region; EUR, European Region; SEAR, South-East Asia Region; WPR, Western Pacific Region. (From Moss WJ: Measles, Lancet 390:2490–2502, 2017, Fig. 2, with data from Patel MK, Gacic-Dobo M, Strebel PM, et al: Progress toward regional measles elimination—worldwide, 2000–2015. MMWR Morb Mortal Wkly Rep 65:1228–1233, 2016.)

Etiology Measles virus is a single-stranded, lipid-enveloped RNA virus in the family Paramyxoviridae and genus Morbillivirus. Other members of the genus Morbillivirus affect a variety of mammals, such as rinderpest virus in cattle and distemper virus in dogs, but humans are the only host of measles virus. Of the 6 major structural proteins of measles virus, the 2 most important in terms of induction of immunity are the hemagglutinin (H) protein and the fusion (F) protein. The neutralizing antibodies are directed against the H protein, and antibodies to the F protein limit proliferation of the virus during infection. Small variations in genetic composition have also been identified that result in no effect on protective immunity but provide molecular markers that can distinguish between viral types. Related genotypes have been grouped by clades, and the World Health Organization recognizes 8 clades, A-H, and 23 genotypes. These markers have been useful in the evaluation of endemic and epidemic spread of measles.

Epidemiology The measles vaccine has changed the epidemiology of measles dramatically. Once worldwide in distribution, endemic transmission of measles has been interrupted in many countries where there is widespread vaccine coverage. Historically, measles caused universal infection in childhood in the United States, with 90% of children acquiring the infection before 15 yr of age. Morbidity and mortality associated with measles decreased prior to the introduction of the vaccine as a result of improvements in healthcare and nutrition. However, the incidence declined dramatically following the introduction of the measles vaccine in 1963. The attack rate fell from 313 cases per 100,000 population in 1956–1960 to 1.3 cases per 100,000 in 1982–1988. A nationwide indigenous measles outbreak occurred in the United States in 1989–1991, resulting in more than 55,000 cases, 11,000 hospitalizations, and 123 deaths, demonstrating that the infection had not yet been controlled. This resurgence was attributed to vaccine failure in a small number of school-age children, low coverage of preschool-age children, and more rapid waning of maternal antibodies in infants born to mothers who had never experienced wildtype measles infection. Implementation of the 2-dose vaccine policy and more intensive immunization strategies resulted in interruption of endemic

transmission and in 2,000 measles was declared eliminated from the United States. The current rate is 90% immunity through vaccination is necessary to prevent widespread outbreaks from occurring (see Fig. 273.1 ). In 2014 the United States encountered a record number of cases since elimination in 2000, with 667 cases of measles reported to the U.S. Centers for Disease Control and Prevention (CDC). There were 23 outbreaks reported compared with a median of 4 outbreaks reported annually during 2001–2010. The majority of cases were associated with importations from other countries (returning tourists, adoptees, refugees), particularly from the Philippines, with prior year epidemics associated with epidemics in the World Health Organization European Region. Measles cases are largely restricted to unvaccinated individuals. Since 2014, cases continue to result from importations causing multistate outbreaks, but due to increased awareness and vaccination efforts, cases remain 90% 1-dose coverage at 12-15 mo and >95% 2-dose coverage in school-age children). Although measles-mumps-rubella coverage remains high (90–91.5% in children 19-35 mo for 2000–2015), pockets of lower coverage rates exist because of reluctance of parents to vaccinate their children. This variability in vaccination has contributed to outbreaks among school-age children in recent years.

Transmission The portal of entry of measles virus is through the respiratory tract or conjunctivae following contact with large droplets or small-droplet aerosols in which the virus is suspended. Patients are infectious from 3 days before to up to 4-6 days after the onset of rash. Approximately 90% of exposed susceptible individuals experience measles. Face-to-face contact is not necessary, because viable virus may be suspended in air for as long as 1 hr after the patient with the source case leaves a room. Secondary cases from spread of aerosolized virus have been reported in airplanes, physicians’ offices, and hospitals.

Pathology Measles infection causes necrosis of the respiratory tract epithelium and an accompanying lymphocytic infiltrate. Measles produces a small-vessel vasculitis on the skin and on the oral mucous membranes. Histology of the rash and exanthem reveals intracellular edema and dyskeratosis associated with formation of epidermal syncytial giant cells with up to 26 nuclei. Viral particles have been identified within these giant cells. In lymphoreticular tissue, lymphoid hyperplasia is prominent. Fusion of infected cells results in multinucleated giant cells, the Warthin-Finkeldey giant cells that are pathognomonic for measles, with up to 100 nuclei and intracytoplasmic and intranuclear inclusions.

Pathogenesis Measles infection consists of 4 phases: incubation period, prodromal illness, exanthematous phase, and recovery. During incubation, measles virus migrates to regional lymph nodes. A primary viremia ensues that disseminates the virus to the reticuloendothelial system. A secondary viremia spreads virus to body surfaces. The prodromal illness begins after the secondary viremia and is associated with epithelial necrosis and giant cell formation in body tissues. Cells are killed by cell-to-cell plasma membrane fusion associated with viral replication that occurs in many body tissues, including cells of the central nervous system. Virus shedding begins in the prodromal phase. With onset of the rash, antibody production begins, and viral replication and symptoms begin to subside. Measles virus also infects CD4+ T cells, resulting in suppression of the Th1 immune response and a multitude of other immunosuppressive effects. Measles virus attaches to specific cell receptors to infect host cells. Studies in primates show that the initial targets for measles virus are alveolar macrophages, dendritic cells, and lymphocytes. The cell receptor used appears to be the signaling lymphocyte activating molecule or more properly CD150. Subsequently, respiratory epithelial cells become infected but do not express CD150. The mechanism of infection of respiratory tissues is attachment to the PVRL4 receptor (Nectin4) that is expressed on cells in the trachea, oral mucosa, nasopharynx, and lungs. These 2 receptors, CD150 and PVRL4, account for the lymphotropic and epitheliotropic nature of natural measles virus infection and, along with the prolonged immunosuppressive effects of measles, suggest that it is more characteristic of human immunodeficiency virus infection than a

respiratory illness.

Clinical Manifestations Measles is a serious infection characterized by high fever, an enanthem, cough, coryza, conjunctivitis, and a prominent exanthem (Fig. 273.2 ). After an incubation period of 8-12 days, the prodromal phase begins with a mild fever followed by the onset of conjunctivitis with photophobia, coryza, a prominent cough, and increasing fever. Koplik spots represent the enanthem and are the pathognomonic sign of measles, appearing 1-4 days prior to the onset of the rash (Fig. 273.3 ). They first appear as discrete red lesions with bluish white spots in the center on the inner aspects of the cheeks at the level of the premolars. They may spread to involve the lips, hard palate, and gingiva. They also may occur in conjunctival folds and in the vaginal mucosa. Koplik spots have been reported in 50–70% of measles cases but probably occur in the great majority.

FIG. 273.2 Measles disease course (A) and complications (B) . ADEM, acute demyelinating encephalomyelitis; MIBE, measles inclusion body encephalitis; SSPE, subacute sclerosing panencephalitis. (Modified from Moss WJ: Measles, Lancet 390:2490–2502, 2017, Fig. 4.)

FIG. 273.3 Koplik spots on the buccal mucosa during the 3rd day of rash. (From Centers for Disease Control and Prevention (CDC): Public health image library , image #4500. Available at: http://phil.cdc.gov/phil/details.asp .)

Symptoms increase in intensity for 2-4 days until the 1st day of the rash. The rash begins on the forehead (around the hairline), behind the ears, and on the upper neck as a red maculopapular eruption. It then spreads downward to the torso and extremities, reaching the palms and soles in up to 50% of cases. The exanthem frequently becomes confluent on the face and upper trunk (Fig. 273.4 ).

FIG. 273.4 A child with measles displaying the characteristic red blotchy pattern on his face and body. (From Kremer JR, Muller CP: Measles in Europe—there is room for improvement, Lancet 373:356–358, 2009.)

With the onset of the rash, symptoms begin to subside. The rash fades over about 7 days in the same progression as it evolved, often leaving a fine desquamation of skin in its wake. Of the major symptoms of measles, the cough lasts the longest, often up to 10 days. In more severe cases, generalized lymphadenopathy may be present, with cervical and occipital lymph nodes especially prominent.

Modified Measles Infection In individuals with passively acquired antibody, such as infants and recipients of blood products, a subclinical form of measles may occur. The rash may be indistinct, brief, or, rarely, entirely absent. Likewise, some individuals who have

received a vaccine, when exposed to measles, may have a rash but few other symptoms. Persons with modified measles are not considered highly contagious.

Laboratory Findings The diagnosis of measles is almost always based on clinical and epidemiologic findings. Laboratory findings in the acute phase include reduction in the total white blood cell count, with lymphocytes decreased more than neutrophils. However, absolute neutropenia has been known to occur. In measles not complicated by bacterial infection, the erythrocyte sedimentation rate and Creactive protein level are usually normal.

Diagnosis In the absence of a recognized measles outbreak, confirmation of the clinical diagnosis is often recommended. Serologic confirmation is most conveniently made by identification of immunoglobulin (Ig) M antibody in serum. IgM antibody appears 1-2 days after the onset of the rash and remains detectable for about 1 mo. If a serum specimen is collected 23-40 kg (>51-88 60 mg twice daily lb) >40 kg (>88 lb) 75 mg twice daily Infants 0-11 mo † 3 mg/kg per dose once daily Term infants ages 0-8 3 mg/kg per dose twice mo † daily MEDICATION

Preterm infants

See details in footnote ‡ INHALED ZANAMIVIR § Adults 10 mg (two 5 mg inhalations) twice daily Children (≥7 yr old 10 mg (two 5 mg for treatment; ≥5 yr inhalations) twice daily old for chemoprophylaxis)

CHEMOPROPHYLAXIS DOSING** 75 mg once daily

30 mg once daily 45 mg once daily 60 mg once daily 75 mg once daily 3 mg/kg per dose once daily 3 mg/kg per dose once daily for infants 3-8 mo old; not recommended for infants 38°C (100.4°F) Cough Rhinitis, coryza Wheezing Tachypnea, retractions Hypoxia (O2 saturation < 94%) Chest radiograph demonstration of infiltrates or hyperinflation LESS COMMON Otitis media Pharyngitis Rales RARE Conjunctivitis Hoarseness Encephalitis Fatal respiratory failure in immunocompromised children

About half of the cases of HMPV lower respiratory tract illness in children occur in the first 6 mo of life, suggesting that young age is a major risk factor for severe disease. Both young adults and the elderly can have HMPV infection that requires medical care including hospitalization, but severe disease occurs at much lower frequencies in adults than in young children. Severe disease in pediatric and older subjects is most common in immunocompromised patients or those with complications of preterm birth, congenital heart disease, and neuromuscular disease and can be fatal. A significant number of both adult and pediatric patients with asthma exacerbations have HMPV infection; it is not clear whether the virus causes long-term wheezing. RSV and HMPV coinfections have been reported; coinfections may be more severe than infection with a single virus, resulting in pediatric intensive care unit admissions. It is difficult to define true coinfections because these viral RNA genomes can be detected by a reverse transcriptase polymerase chain reaction (PCR) in respiratory secretions for at least several weeks after illness, even when virus shedding has terminated.

Laboratory Findings The virus can be visualized only with electron microscopy. The virus grows in

primary monkey kidney cells or LLC-MK2 cell or Vero cell–line monolayer cultures in reference or research laboratories, but efficient isolation of the virus requires an experienced laboratory technician. Conventional bright-field microscopy of infected cell monolayer cultures often reveals a cytopathic effect only after multiple passages in the cell culture. The characteristics of the cytopathic effect are not sufficiently distinct to allow identification of the virus on this basis alone, even by a trained observer. The most sensitive test for identification of HMPV in clinical samples is reverse transcriptase PCR, usually performed with primers directed to conserved viral genes. Detection by this modality is also available in some multiplex PCR tests for panels of respiratory viruses. Real-time reverse transcriptase PCR tests offer enhanced sensitivity and specificity, including assays designed to detect viruses from the four known genetic lineages. Direct antigen tests for identification of HMPV antigens in nasopharyngeal secretions are available but are less efficient than nucleic acid– based detection. Some laboratories have success with the use of immunofluorescence staining with monoclonal or polyclonal antibodies to detect HMPV in nasopharyngeal secretions and shell vial cultures or in monolayer cultures in which virus has been cultivated, with reported sensitivities varying from about 65% to 90%. A four-fold rise in serum antibody titer to HMPV from the acute to convalescent time point can be used in research settings to confirm infection.

Diagnosis and Differential Diagnosis In temperate areas, the diagnosis should be suspected during the late winter in infants or young children with wheezing or pneumonia and a negative RSV diagnostic test result. The diseases caused by RSV and HMPV cannot be distinguished clinically. Many other common respiratory viruses, such as parainfluenza viruses, influenza viruses, adenoviruses, rhinoviruses, enteroviruses, and coronaviruses, can cause similar disease in young children. Some of these viruses can be identified by PCR genetic testing or conventional cell culture means. Chest radiographs are not very specific, mostly showing parahilar opacities, hyperinflation, atelectasis, and, occasionally, consolidation, but not pleural effusion or pneumothorax.

Complications

Bacterial superinfection of the lower airways is unusual but does occur. The local complication of otitis media is common, likely a result of eustachian tube dysfunction caused by the virus.

Treatment There is no specific treatment at this time for HMPV infection. Management consists of supportive care similar to that used for RSV (see Chapter 287 ). The rate of bacterial lung infection or bacteremia associated with HMPV infection is not fully defined but is suspected to be low. Antibiotics are usually not indicated in the treatment of infants hospitalized for HMPV bronchiolitis or pneumonia.

Supportive Care Treatment is supportive and includes careful attention to hydration; monitoring of respiratory status by physical examination and measurement of oxygen saturation; the use of supplemental oxygen, high-flow nasal cannula therapy, and nasal continuous positive airway pressure in an intensive care unit for increased work of breathing; and, if necessary in the case of respiratory failure, mechanical ventilation.

Prognosis Most infants and children recover from acute HMPV infection without apparent long-term consequences. Many experts believe an association exists between severe HMPV infections in infancy and the risk for recurrent wheezing or the development of asthma; however, it is not clear whether the virus causes these conditions or precipitates their first manifestations.

Prevention The only method of prevention of HMPV infection is reduction of exposure. Contact precautions are recommended for the duration of HMPV-associated illness among hospitalized infants and young children. Patients known to have HMPV infection should be housed in single rooms or with a cohort of HMPVinfected patients. When feasible, it is wise to care for patients with RSV

infection in a separate cohort from HMPV-infected patients, so as to prevent coinfection, which may be associated with more severe disease. Preventive measures include limiting exposure to contagious settings during annual epidemics (such as daycare centers) as much as possible and an emphasis on hand hygiene in all settings, including the home, especially during periods when the contacts of high-risk children have respiratory infections. However, providers should keep in mind that infection is universal in the first several years of life. Therefore, reduction of exposure makes the most sense during the first 6 mo of life, when infants are at the highest risk for severe disease.

Bibliography Arnold JC, Singh KK, Milder E, et al. Human metapneumovirus associated with central nervous system infection in children. Pediatr Infect Dis J . 2009;28:1057–1060. Bao X, Liu T, Shan Y, et al. Human meta-pneumovirus glycoprotein G inhibits innate immune responses. PLoS Pathog . 2008;4:e1000077. Crowe JE Jr. Human metapneumovirus as a major cause of human respiratory tract disease. Pediatr Infect Dis J . 2004;23(Suppl):S215–S221. Edwards KM, Zhu Y, Griffin MR, et al. Burden of human metapneumovirus infection in young children. N Engl J Med . 2013;368:633–643. Erickson JJ, Gilchuk P, Hastings AK, et al. Viral acute lower respiratory infections impair CD8+ T cells through PD-1. J Clin Invest . 2012;122:2967–2982. Foulongne V, Buyon G, Rodiere M, et al. Human metapneumovirus infection in young children hospitalized with respiratory tract disease. Pediatr Infect Dis J . 2006;25:34–39. Hilmes MA, Daniel Dunnavant F, Singh SP, et al. Chest radiographic features of human metapneumovirus infection in pediatric patients. Pediatr Radiol . 2017;47(13):1745–1750.

Klein MI, Coviello S, Bauer G, et al. The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease. J Infect Dis . 2006;193:1544–1551. Midgley CM, Baber JK, Biggs HM, et al. Severe human metapneumovirus infections—North Dakota, 2016. MMWR Morb Mortal Wkly Rep . 2017;66(18):486–488. Semple MG, Cowell A, Dove W, et al. Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis. J Infect Dis . 2005;191:382–386. Williams JV, Crowe JE Jr, Enriquez R, et al. Human metapneumovirus infection plays an etiologic role in acute asthma exacerbations requiring hospitalization in adults. J Infect Dis . 2005;192:1149–1153. Williams JV, Tollefson SJ, Heymann PW, et al. Human metapneumovirus infection in children hospitalized for wheezing. J Allergy Clin Immunol . 2005;115:1311–1312. Williams JV, Wang CK, Yang CF, et al. The role of human metapneumovirus in upper respiratory tract infections in children: a 20-year experience. J Infect Dis . 2006;193:387– 395.

CHAPTER 289

Adenoviruses Jason B. Weinberg, John V. Williams

Human adenoviruses (HAdVs) are a common cause of human disease. Conjunctivitis is a familiar illness associated with the HAdVs, but these viruses also cause upper and lower respiratory disease, pharyngitis, gastroenteritis, and hemorrhagic cystitis. HAdVs can cause severe disease in immunocompromised hosts. Outbreaks of HAdV infection occur in communities and closed populations, notably the military. No currently approved antiviral drugs are highly effective against HAdVs. Vaccines are available for HAdV types 4 and 7 but are used only for military populations.

Etiology Adenoviruses are nonenveloped viruses with an icosahedral protein capsid. The double-stranded DNA genome is contained within the particle complexed with several viral proteins. Antigenic variability in surface proteins of the virion and genomic sequencing define at least 70 serotypes grouped into seven species. Species differ in their tissue tropism and target organs, causing distinct clinical infections (Table 289.1 ). HAdVs can be shed from the gastrointestinal tract for prolonged periods and can establish persistent infection of the tonsils and adenoids. Table 289.1 Adenovirus Types With Associated Infections SPECIES TYPE A B

12, 18, 31, 61 3, 7, 11, 14, 16, 21, 34, 35, 50, 55, 66

PREFERRED SITE OF INFECTION Gastrointestinal Respiratory; renal/urinary tract

C D E F G

1, 2, 5, 6, 57 8-10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36-39, 42-49, 51, 53, 54, 56, 58-60, 63-67 4 40, 41 52

epithelium Respiratory Ocular Respiratory Gastrointestinal Gastrointestinal

Epidemiology HAdVs circulate worldwide and cause endemic infections year-round in immunocompetent hosts. Asymptomatic infections are also common. Only about one third of all known HAdV types are associated with clinically apparent disease. The most prevalent types in recent surveillance studies are HAdV types 3, 2, 1, and 5. Epidemics of conjunctivitis (often severe), pharyngitis, and respiratory disease occur, especially in schools and military settings. Outbreaks of febrile respiratory illness caused by HAdV-4 and HAdV-7 are a major source of morbidity in military barracks, with attack rates ranging from 25% to > 90%. The spread of HAdV occurs by respiratory and fecal-oral routes. An important factor in HAdV transmission, especially in epidemics, is the ability of the nonenveloped particle to survive on inanimate objects in the environment. Nosocomial outbreaks have been reported.

Pathogenesis HAdVs bind to cell surface receptors and trigger internalization by endocytosis. Acidification of the endosome induces conformational changes in the capsid, leading to eventual translocation of the genome to the cell nucleus. Viral messenger RNA transcription and genomic replication occur in the nucleus. Progeny virion particles assemble in the nucleus. Lysis of the cell releases new infectious particles and causes damage to epithelial mucosa, sloughing of cell debris, and inflammation. Host responses to HAdV infection include the recruitment of neutrophils, macrophages, and natural killer cells to the site of infection and the elaboration by those cells of a number of cytokines and chemokines. This host immune response is likely to contribute to the symptoms of HAdV infection, but specific mechanisms of pathogenesis are poorly understood. The strict species specificity of the adenoviruses has precluded the development of an animal model for HAdVs, although recent work with HAdV

in a humanized mouse model shows promise. Mouse adenovirus has also been used to study adenovirus pathogenesis using a murine model.

Clinical Manifestations HAdVs cause a variety of common clinical syndromes in both immunocompetent and immunocompromised hosts. These syndromes are difficult to distinguish reliably from similar illnesses caused by other pathogens, such as respiratory syncytial virus, human metapneumovirus, human rhinovirus, rotavirus, group A streptococcus, and other common viral and bacterial pathogens.

Acute Respiratory Disease Respiratory tract infections are common manifestations of HAdV infections in children and adults. HAdVs cause an estimated 5–10% of all childhood respiratory diseases. Primary infections in infants may manifest as bronchiolitis or pneumonia. HAdV pneumonia may present with features more typical of bacterial disease (lobar infiltrates, high fever, parapneumonic effusions). HAdV14 has emerged as a significant cause of severe acute respiratory disease in military and civilian populations, in some cases leading to hospitalization and death. Pharyngitis caused by HAdV typically includes symptoms of coryza, sore throat, and fever. The virus can be identified in 15–20% of children with isolated pharyngitis, mostly in preschool children and infants.

Ocular Infections The common follicular conjunctivitis caused by HAdV is self-limiting and requires no specific treatment. A more severe form called epidemic keratoconjunctivitis involves the cornea and conjunctiva. Pharyngoconjunctival fever is a distinct syndrome that includes a high temperature, pharyngitis, nonpurulent conjunctivitis, and preauricular and cervical lymphadenopathy.

Gastrointestinal Infections HAdV can be detected in the stools of 5–10% of children with acute diarrhea. Most cases of acute diarrhea are self-limiting, although severe disease can occur.

Enteric infection with HAdV is often asymptomatic, and shedding of virus after acute infection can be prolonged, so the causative role in these episodes is frequently uncertain. HAdV may also cause mesenteric adenitis.

Hemorrhagic Cystitis Hemorrhage cystitis consists of a sudden onset of hematuria, dysuria, frequency, and urgency with negative urine bacterial culture results. Urinalysis may show sterile pyuria in addition to red blood cells. This illness occurs more frequently in young males and typically resolves on its own in 1-2 wk.

Other Complications Less frequently, HAdVs are associated with myocarditis, hepatitis, or meningoencephalitis in immunocompetent individuals.

Adenoviruses in Immunocompromised Patients Immunocompromised persons, particularly recipients of hematopoietic stem cell transplants (HSCTs) and solid-organ transplants, are at high risk for severe and fatal disease caused by HAdV. These patients may experience primary HAdV infection. Reactivation of persistent virus in a transplant recipient and transmission of virus from a donor organ may also occur. Organ failure as a consequence of pneumonia, hepatitis, gastroenteritis, and disseminated infection occurs primarily in these patients. HAdV infection in HSCT recipients commonly manifests as pulmonary or disseminated disease and is most likely to occur in the first 100 days after transplantation. Hemorrhagic cystitis caused by HAdV can be severe in HSCT recipients. Infections caused by HAdV in solidorgan transplant recipients usually involve the transplanted organ. Immunocompromised children are at greater risk than immunocompromised adults for complicated HAdV infection, presumably because of a lack of preexisting immunity. Additional risk factors include T-cell–depleted grafts, high-level immunosuppression, and the presence of graft-versus-host disease. Some experts advocate a preemptive screening approach to detect and treat HAdV infection early in immunocompromised patients, with the intent to prevent dissemination and severe illness in this vulnerable population, though no highly effective antiviral therapy exists.

Diagnosis HAdV may be suspected as the etiology of an illness on the basis of epidemiologic or clinical features, but neither of these categories is specific enough to firmly establish the diagnosis. The frequency of asymptomatic shedding of HAdV makes assigning causality to this pathogen difficult at times. Most HAdV serotypes grow well in culture, although this method requires several days and thus is not helpful for early identification. Cells from respiratory or ocular specimens can be tested using immunofluorescent staining with antibodies to detect HAdV protein. Commercially available enzyme-linked immunoassays can be used to rapidly detect HAdV in patient specimens, usually in stool. Molecular techniques, such as polymerase chain reaction, offer a rapid, sensitive, and specific diagnosis of HAdV infections and are most useful clinically for the management of suspected HAdV infections in immunocompromised hosts. In these patients, measurement of the HAdV genome copy number using a quantitative real-time polymerase chain reaction can facilitate the diagnosis, and repeated measurements can aid in assessing a patient's response to treatment. Multiplex molecular assays capable of identifying HAdV in addition to other pathogens are increasingly available and useful for rapid diagnosis. Serology is generally useful only in epidemiologic investigations.

Complications HAdV pneumonia can lead to respiratory failure requiring mechanical ventilation, especially in immunocompromised patients. Secondary bacterial pneumonia does not appear to be as common following HAdV infection as it is after influenza infection, but data that address this issue are limited. Severe HAdV pneumonia has been linked to chronic lung disease and bronchiolitis obliterans in a minority of cases. Epidemic keratoconjunctivitis is a visionthreatening form of HAdV infection. Nearly any form of HAdV infection can be fatal in an HSCT or solid-organ transplant recipient. Refractory severe anemia requiring repeated blood transfusions can develop in HSCT recipients with hemorrhagic cystitis. Mortality rates of up to 60–80% have been reported in transplant recipients with disseminated HAdV or HAdV pneumonia.

Treatment Supportive care is the mainstay of HAdV treatment in most cases. Patients with severe HAdV conjunctivitis should be referred for ophthalmologic consultation. No specific antiviral therapy produces a definite clinical benefit against HAdV infection. The nucleoside analog cidofovir has in vitro activity against most HAdV serotypes. Cidofovir is used topically to treat epidemic keratoconjunctivitis, often in conjunction with topical steroids or other immunosuppressive agents to limit the inflammatory component. Cidofovir may be used intravenously for HAdV infections in immunocompromised patients. Cidofovir is highly nephrotoxic; however, prehydration, concomitant administration of probenecid, and weekly dosing may reduce renal toxicity. Clinical studies suggest some benefit from cidofovir, but there are no prospective, randomized controlled trials of cidofovir for HAdV infection. In addition, no formal guidelines or recommendations for treatment exist. The cidofovir derivative brincidofovir is better tolerated than cidofovir and shows promise as an approach to the prevention and treatment of HAdV disease in immunocompromised patients, but experience remains limited. There are anecdotal descriptions of benefit from intravenous immunoglobulin. Adoptive immunotherapy involving the infusion of HAdV-specific T cells may also provide some benefit for immunocompromised patients with life-threatening HAdV infections, but this intervention is not yet considered standard therapy.

Prevention Environmental and fomite transmission of HAdV occurs readily; therefore, simple measures such as handwashing and cleaning are likely to reduce spread. HAdVs are highly immunogenic and have been used as gene therapy vectors and vaccine vectors for other pathogens, including malaria and HIV, but no HAdVspecific vaccines are available for routine use. Live-attenuated HAdV-4 and HAdV-7 vaccines were used effectively in the United States military from the 1970s until 1999. Cessation of their use led to widespread outbreaks in barracks, and those vaccines were subsequently reintroduced into military use.

Bibliography

Castro-Rodriguez JA, Giebergia V, Fischer GB, et al. Postinfectious bronchiolitis obliterans in children: the South American contribution. Acta Paediatr . 2014;103:913–921. Clemmons NS, McCormic ZD, Gaydos JC, et al. Acute respiratory disease in US Army trainees 3 years after reintroduction of adenovirus vaccine. Emerg Infect Dis . 2017;23:95–98. Feucht J, Opherk K, Kayser S, et al. Adoptive T cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood . 2015;125:1986– 1994. Grimley MS, Chemaly RF, Englund JA, et al. Brincidofovir for asymptomatic adenovirus viremia in pediatric and adult hematopoietic cell transplant recipients: a randomized placebo-controlled phase II trial. Biol Blood Marrow Transplant . 2017;23:512–521. Lion T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin Microbiol Rev . 2014;27:441–462. Lynch JP, Kajon AE. Adenovirus: epidemiology, global spread of novel serotypes, and advance in treatment and prevention. Semin Respir Crit Care Med . 2016;37:586–602. McCarthy MK, Malitz DH, Procario MC, et al. Interferondependent immunoproteasome activity during mouse adenovirus type 1 infection. Virology . 2016;498:57–68. Rodriguez E, Ip WH, Kolbe V, et al. Humanized mice reproduce acute and persistent human adenovirus infection. J Infect Dis . 2017;215:70–79. Wold WSM, Ison MG. Adenoviruses. Knipe DM, Howley PM. Fields’ virology . ed 6. Lippincott Williams & Wilkins: Philadelphia; 2013:1732–1767.

CHAPTER 290

Rhinoviruses Santiago M.C. Lopez, John V. Williams

Human rhinoviruses (HRVs) are the most frequent cause of the common cold in both adults and children. Although HRVs were once thought to cause only the common cold, it is now known that they are also associated with lower respiratory infections in adults and children. Many HRVs do not grow in culture. Recent studies using molecular diagnostic tools such as the polymerase chain reaction (PCR) have revealed that HRVs are leading causes of both mild and serious respiratory illnesses in children.

Etiology HRVs are members of the Picornaviridae family (“pico” = small; “rna” = RNA genome). Traditional methods of virus typing using immune antiserum have identified approximately 100 serotypes, classified into HRVA, HRVB, and, recently, HRVC species on the basis of the genetic sequence similarity. HRVCs can be detected by reverse transcriptase PCR but have been cultured only using highly specialized methods. Virus gene sequence analysis demonstrates that HRVCs are a genetically distinct and diverse species. The increased proportions of HRV reported in recent PCR-based studies are likely the result of detection of these previously unknown HRVC viruses in addition to improved detection of known HRVA and HRVB strains.

Epidemiology Rhinoviruses are distributed worldwide. There is no consistent correlation between serotypes and epidemiologic or clinical characteristics. Several studies

suggest that HRVCs may be more strongly associated with lower respiratory infection and asthma than other HRVs, but the overall disease severity is not increased. Multiple types circulate in a community simultaneously, and particular HRV strains may be isolated during consecutive epidemic seasons, suggesting persistence in a community over an extended period. In temperate climates, the incidence of HRV infection peaks in the fall, with another peak in the spring, but HRV infections occur year-round. HRVC appears to circulate with seasonal variation, exchanging dominance with HRVA. HRVs are the major infectious trigger for asthma among young children, and numerous studies have described a sharp increase in asthmatic attacks in this age-group when school opens in the fall. The peak HRV incidence in the tropics occurs during the rainy season, from June to October. HRVs are present in high concentrations in nasal secretions and can be detected in the lower airways. HRV particles are nonenveloped and quite hardy, persisting for hours to days in secretions on hands or other surfaces such as telephones, light switches, doorknobs, and stethoscopes. Sneezing and coughing are inefficient methods of transfer. Transmission occurs when infected secretions carried on contaminated fingers are rubbed onto the nasal or conjunctival mucosa. HRVs are present in aerosols produced by talking, coughing, and sneezing. Children are the most important reservoir of these viruses.

Pathogenesis The majority of HRVs infect respiratory epithelial cells via intercellular adhesion molecule-1, but some HRV strains utilize the low-density lipoprotein receptor. The receptor for HRVC is cadherin-related family member 3 (CDHR3); however, distinct genetic alleles of this protein confer different susceptibility to HRVC infection. Infection begins in the nasopharynx and spreads to the nasal mucosa and, in some cases, to bronchial epithelial cells in the lower airway. There is no direct cellular damage from the virus, and it is thought that many of the pathogenic effects are produced by the host immune response. Infected epithelial cells release a number of cytokines and chemokines, which induce an influx of neutrophils to the upper airway. Both innate and adaptive immune mechanisms are important in HRV pathogenesis and clearance. HRV-specific nasal immunoglobulin (Ig) A can be detected on day 3 after infection, followed by the production of serum IgM and IgG after 7-8 days. Neutralizing IgG to HRVs may prevent or limit the severity of illness following reinfection.

However, cross protection by antibodies to different HRV serotypes is limited in breadth and duration, allowing recurrent infection. Both allergen exposure and elevated IgE values predispose patients with asthma to more severe respiratory symptoms in response to HRV infection. Abnormalities in the host cellular response to HRV infection that result in impaired apoptosis, and increased viral replication, may be responsible for the severe and prolonged symptoms in individuals with asthma.

Clinical Manifestations Most HRV infections produce clinical symptoms, but many are asymptomatic; however, symptomatic HRV infection induces a much more robust host immune response in the blood than asymptomatic infection. Typical symptoms of sneezing, nasal congestion, rhinorrhea, and sore throat develop following an incubation period of 1-4 days. Cough and hoarseness are present in one third of cases. Fever is less common with HRV than with other common respiratory viruses, including influenza virus, respiratory syncytial virus, and human metapneumovirus. Symptoms are frequently more severe and last longer in children, with 70% of children compared with 20% of adults still reporting symptoms by day 10. Virus can be shed for as long as 3 wk. HRVs are the most prevalent agents associated with acute wheezing, otitis media, and hospitalization for respiratory illness in children and are an important cause of severe pneumonia and exacerbation of asthma or chronic obstructive pulmonary disease in adults. HRV-associated hospitalizations are more frequent in young infants than in older children and in children with a history of wheezing or asthma. HRV infection in immunocompromised hosts may be life threatening. Certain strains or species of HRV, namely HRVC, may be more pathogenic than others.

Diagnosis Culturing HRVs is labor intensive and of relatively low yield; HRVC has only been cultivated in a polarized primary airway epithelial cell culture, a highly specialized method. Sensitive and specific diagnostic methods based on reverse transcriptase PCR are commercially available. However, because commercially available reverse transcriptase PCR tests do not identify the HRV types, it can be

difficult to distinguish prolonged shedding from newly acquired infection. An important caveat of HRV detection is the fact that HRV infection can be asymptomatic, and thus the presence of the virus does not prove causality in all cases. Serology is impractical because of the great number of HRV serotypes. A presumptive clinical diagnosis based on symptoms and seasonality is not specific, because many other viruses cause similar clinical illnesses. Rapid detection techniques for HRV might lessen the use of unnecessary antibiotics or procedures.

Complications Possible complications of HRV infection include sinusitis, otitis media, asthma exacerbation, bronchiolitis, pneumonia, and, rarely, death. HRV-associated wheezing during infancy is a significant risk factor for the development of childhood asthma. This effect appears to remain until adulthood, but the mechanisms have not been elucidated. One large study determined that genetic variants at the 17q21 locus were associated with asthma in children who had experienced HRV wheezing illnesses during infancy. A prospective study on a preterm cohort showed that a single nucleotide polymorphism on the gene coding for the vitamin D receptor was associated with development of lower respiratory infection with HRV. Further studies are required to determine the likely multiple genetic and environmental factors that contribute to HRV-related asthma.

Treatment Supportive care is the mainstay of HRV treatment. The symptoms of HRV infection are commonly treated with analgesics, decongestants, antihistamines, or antitussives. Data are limited on the effectiveness of such nonprescription cold medications for children. If bacterial superinfections are highly suspected or diagnosed, antibiotics may be appropriate. Antibiotics are not indicated for uncomplicated viral upper respiratory infection. Vaccines have not been successfully developed because of the numerous HRV serotypes and limited cross protection between serotypes.

Prevention Good handwashing remains the mainstay of the prevention of HRV infection and should be reinforced frequently, especially in young children, the predominant “vectors” for disease. A polyvalent inactivated vaccine showed promise in a nonhuman primate model, but there are no licensed vaccines or antivirals.

Bibliography Arden KE, Mackay IM. Newly identified human rhinoviruses: molecular methods heat up the cold viruses. Rev Med Virol . 2010;20:156–176. Bochkov YA, Watters K, Ashraf S, et al. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc Natl Acad Sci USA . 2015;112:5485–5490. Calışkan M, Bochkov YA, Kreiner-Møller E, et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med . 2013;368:1398–1407. Gern JE. The ABCs of rhinoviruses, wheezing, and asthma. J Virol . 2010;84:7418–7426. Heinonen S, Jartti T, Garcia C, et al. Rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis. Am J Respir Crit Care Med . 2016;193:772–782. Iwane MK, Prill MM, Lu X, et al. Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis . 2011;204:1702–1710. Jackson DJ, Lemanske RF Jr. The role of respiratory virus infections in childhood asthma inception. Immunol Allergy Clin North Am . 2010;30:513–522. Kieninger E, Fuchs O, Latzin P, et al. Rhinovirus infections in infancy and early childhood. Eur Respir J . 2013;41:443–452. Kim WK, Gern JE. Updates in the relationship between human

rhinoviruses and asthma. Allergy Asthma Immunol Res . 2012;4:116–121. Lee S, Nguyen MT, Currier MG, et al. A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques. Nat Commun . 2016;7:12838. Linder JE, Kraft DC, Mohamed Y, et al. Human rhinovirus C: age, season, and lower respiratory illness over the past 3 decades. J Allergy Clin Immunol . 2013;131:69–77. Miller EK, Edwards KM, Weinberg GA, et al. A novel group of rhinoviruses is associated with asthma hospitalizations. J Allergy Clin Immunol . 2009;123:98–104. Simmonds P, McIntyre C, Savolainen-Kopra C, et al. Proposals for the classification of human rhinovirus species C into genotypically assigned types. J Gen Virol . 2010;91:2409– 2419.

CHAPTER 291

Coronaviruses Kevin W. Graepel, Mark R. Denison

Coronaviruses are increasingly recognized as important human pathogens. They cause up to 15% of common colds and have been implicated in more serious diseases, including croup, asthma exacerbations, bronchiolitis, and pneumonia. Evidence also suggests that coronaviruses may cause enteritis or colitis in neonates and infants and may be underappreciated as agents of meningitis or encephalitis. Four coronaviruses are endemic in humans: human coronaviruses (HCoVs) 229E, OC43, NL63, and HKU1. In addition, two epidemics of previously unknown coronaviruses caused significant respiratory distress and high mortality rates among infected individuals. The discoveries of SARSassociated coronavirus (SARS-CoV) , the cause of severe acute respiratory syndrome (SARS), and of Middle East respiratory syndrome coronavirus (MERS-CoV) support the potential for coronaviruses to emerge from animal hosts such as bats and camels and become important human pathogens.

Etiology Coronaviruses are enveloped viruses of medium to large size (80-220 nm) that possess the largest known single-stranded positive-sense RNA genomes. These viruses encode the protein nsp14-ExoN, which is the first known RNA proofreading enzyme and is likely responsible for the evolution of the large and complex coronavirus genome. Coronaviruses derive their name from the characteristic surface projections of the spike protein, giving a corona or crownlike appearance on negative-stain electron microscopy. Coronaviruses are organized taxonomically by a lettering system based on genomic phylogenetic relationships. Alphacoronaviruses include HCoV-229E and HCoV-NL63. Betacoronaviruses include four human pathogens and are commonly divided

into four lineages, without formal taxonomic recognition. HCoV-OC43 and HCoV-HKU1 are in lineage A, whereas SARS-CoV falls in lineage B. Lineages C and D were exclusively comprised of bat coronaviruses until the discovery of MERS-CoV, which aligns with lineage C. Gammacoronaviruses and deltacoronaviruses presently include exclusively nonhuman pathogens. Coronaviruses received international attention during the SARS outbreak, which was responsible for more than 800 deaths in 30 countries. SARS-CoV, a novel coronavirus at the time of the epidemic, was found to be the causative agent of SARS. The detection of SARS-like coronaviruses in a live animal market in the Guangdong province in Southern China, along with serologic evidence of exposure in food handlers in the same market, suggest that these markets may have facilitated the spread of SARS-CoV to humans from an animal reservoir. Subsequent studies identified SARS-like coronaviruses in fecal specimens from asymptomatic Chinese horseshoe bats that are very closely related, but not direct precursors to, SARS-CoV and are capable of infecting human cells. Thus, although bats are a reservoir for SARS-CoV-like precursors, the precise antecedent to SARS-CoV remains to be identified. Another novel coronavirus, MERS-CoV, was isolated from a man with acute pneumonia and renal failure in Saudi Arabia. As of March 1, 2017, the WHO had recorded nearly 2000 confirmed cases of MERS, with nearly 700 deaths worldwide (~35% mortality rate). MERS-CoV differs from SARS in that it seems to be less communicable, although human-to-human transmission has been documented. MERS-CoV uses dipeptidyl peptidase 4 and carcinoembryonic antigen–like cell-adhesion molecule 5 as its cellular and coreceptor, respectively; SARS-CoV utilizes ACE-2. With this receptor specificity, MERS-CoV can infect cells from several animal lineages, including human, pig, and bat, suggesting the possibility of movement between multiple species.

Epidemiology Seroprevalence studies have demonstrated that antibodies against 229E and OC43 increase rapidly during early childhood, so that by adulthood 90–100% of persons are seropositive. Although less information is available for HKU1 and NL63, available studies demonstrate similar patterns of seroconversion to these viruses during early childhood. Although some degree of strain-specific protection may be afforded by recent infection, reinfections are common and occur despite the presence of strain-specific antibodies. Attack rates are similar

in different age-groups. Although infections occur throughout the year, there is a peak during the winter and early spring for each of these HCoVs. In the United States, outbreaks of OC43 and 229E have occurred in 2- to 3-yr alternating cycles. Independent studies of viral etiologies of upper and lower respiratory infections during the same period, but from different countries, have confirmed that all known HCoVs have a worldwide distribution. Studies using both viral culture and polymerase chain reaction (PCR) multiplex assays demonstrate that coronaviruses often appear in coinfections with other respiratory viruses, including respiratory syncytial virus, adenovirus, rhinovirus, and human metapneumovirus. Volunteer studies demonstrated that OC43 and 229E are transmitted predominantly through the respiratory route. Droplet spread appears to be most important, although aerosol transmission may also occur. There have been no identified natural or laboratory-acquired cases of SARSCoV since 2004, but the mechanisms of introduction, spread, and disease remain important for potential animal-to-human transmission and disease. The primary mode of SARS-CoV transmission occurred through direct or indirect contact of mucous membranes with infectious droplets or fomites. Aerosol transmission was less common, occurring primarily in the setting of endotracheal intubation, bronchoscopy, or treatment with aerosolized medications. Fecal-oral transmission did not appear to be an efficient mode of transmission, but may have occurred because of the profuse diarrhea observed in some patients. The seasonality of SARS-CoV remains unknown. SARS-CoV is not highly infectious, with generally only two to four secondary cases resulting from a single infected adult. During the SARS epidemic, a small number of infected individuals, “superspreaders,” transmitted infection to a much larger number of persons, but the mechanism for this high degree of spread remains unknown. In contrast, persons with mild disease, such as children younger than 12 yr of age, rarely transmitted the infection to others. Infectivity correlated with disease stage; transmission occurred almost exclusively during symptomatic disease. During the 2003 outbreak, most individuals with SARS-CoV infection were hospitalized within 3-4 days of symptom onset. Consequently, most subsequent infections occurred within hospitals and involved either healthcare workers or other hospitalized patients. As of March 1, 2017, the WHO had recorded cases of MERS-CoV in 27 countries, all of which were linked to exposures in the Arabian peninsula (~80% in Saudi Arabia). Though the route of transmission between animals and humans is not fully understood, MERS-CoV is proposed to have repeatedly entered the

human population through contact with respiratory secretions of dromedary camels and possibly with raw camel products (e.g., unpasteurized milk). Antibodies to MERS-CoV are found in dromedaries throughout the Middle East, and strains identical to human MERS-CoV isolates have been found in camels in Egypt, Oman, Qatar, and Saudi Arabia. These strains do not appear to be highly pathogenic or virulent in camels and have likely circulated within dromedaries for > 30 years. Despite well-documented zoonotic transmission, most reported cases occur through linked human-to-human transmission in healthcare settings, including outbreaks in Jordan, South Korea, and Saudi Arabia in 2015 and 2016. Risk factors for nosocomial MERS-CoV outbreaks include overcrowded emergency departments, delayed diagnosis or isolation, and poor infection control practices. Transmission most likely occurs through respiratory droplets and is thus a greater risk during aerosol-generating procedures. Outside of healthcare settings, human-to-human transmission has been infrequently documented and is primarily associated with close contact within households. No sustained human-to-human transmission has yet been reported.

Pathogenesis of SARS and MERS Severe disease in SARS and MERS likely results from both direct virologic damage and subsequent immunopathology. Studies with SARS-CoV in human airway epithelial cell cultures indicate that ciliated cells are principal targets for infection, whereas MERS-CoV preferentially infects bronchial epithelial cells, type I and II pneumocytes, and vascular endothelial cells. Substantial viral loads can be detected in the lower respiratory tract and in blood for both viruses. However, late progression to severe disease appears independent of the quantity and timing of viremia. Thus, excessive host immune responses likely play an important role in the progression to lower respiratory disease and acute respiratory distress syndrome. CoV infections are associated with massive elaboration of inflammatory cytokines and recruitment of inflammatory cells. The roles for inflammatory cells are controversial, with cytotoxic T cells and macrophages implicated variously in immune protection and immunopathology. Recapitulation of human clinical features in animal models of MERS-CoV infection remains challenging, but promising new models are in development.

Clinical Manifestations

Respiratory Infections Even though up to 50% of respiratory tract infections with OC43 and 229E are asymptomatic, coronaviruses are still responsible for up to 15% of common colds and can cause fatal disease. Cold symptoms caused by HCoVs are indistinguishable from those caused by rhinoviruses and other respiratory viruses. The average incubation period is 2-4 days, with symptoms typically lasting 4-7 days. Rhinorrhea, cough, sore throat, malaise, and headache are the most common symptoms. Fever occurs in up to 60% of cases. Coronavirus NL63 is a cause of croup in children younger than 3 yr of age. Coronavirus infections are linked to episodes of wheezing in asthmatic children, albeit at a lower frequency and severity than observed with rhinovirus and respiratory syncytial virus infections. Lower respiratory tract infections, including bronchiolitis and pneumonia, are also reported in immunocompetent and immunocompromised children and adults. As with respiratory syncytial virus or rhinovirus, coronavirus detection in upper respiratory infections is frequently associated with acute otitis media and can be isolated from middle ear fluid.

Nonrespiratory Sequelae There is some evidence to support a role for coronaviruses in human gastrointestinal disease, particularly in young children. Coronavirus-like particles have been detected by electron microscopy in the stools of infants with nonbacterial gastroenteritis. In addition, several outbreaks in neonatal intensive care units of gastrointestinal disease characterized by diarrhea, bloody stools, abdominal distention, bilious gastric aspirates, and classic necrotizing enterocolitis have also been associated with the presence of coronavirus-like particles in stools. In older children and adults, coronavirus-like viruses have been observed with similar frequency in symptomatic and asymptomatic individuals, making it difficult to discern if they are pathogenic in the gastrointestinal tract. Coronaviruses are well-known causes of neurologic disease in animals, including demyelinating encephalitis, but their role in causing human neurologic disease remains unclear. They have been detected by culture, in situ hybridization, and reverse transcriptase PCR (RT-PCR) in brain tissue from a few patients with multiple sclerosis. HCoV-OC43 has been detected by RT-PCR in the spinal fluid, nasopharynx, or brain biopsy specimens of two children with acute encephalomyelitis. However, coronavirus RNA has

also been recovered from the spinal fluid and brain tissue of adults without neurologic disease.

Severe Acute Respiratory Syndrome– Associated Coronavirus SARS-CoV infections in teenagers and adults included a viral replication phase and an immunologic phase. During the viral replication phase, there was a progressive increase in viral load that reached its peak during the second week of illness. The appearance of specific antibodies coincided with peak viral replication. The clinical deterioration that typified the second and third week of illness was characterized by a decline in the viral load and evidence of tissue injury, likely from cytokine-mediated immunity. The explanation for milder clinical disease in children younger than 12 yr of age has not been determined. Seroepidemiologic studies suggest that asymptomatic SARS-CoV infections were uncommon. The incubation period ranged from 1-14 days, with a median of 4-6 days. The clinical manifestations were nonspecific, most commonly consisting of fever, cough, malaise, coryza, chills or rigors, headache, and myalgia. Coryza was more common in children younger than 12 yr of age, whereas systemic symptoms were seen more often in teenagers. Some young children had no respiratory symptoms. Gastrointestinal symptoms, including diarrhea and nausea or vomiting, occurred in up to one third of cases. The clinical course of SARS-CoV infection varied with age. Adults were most severely affected, with initial onset of fever, cough, chills, myalgia, malaise, and headache. Following an initial improvement at the end of the first week, fever recurred and respiratory distress developed, with dyspnea, hypoxemia, and diarrhea. These symptoms progressed in 20% of patients to acute respiratory distress syndrome and respiratory failure. Acute renal failure with histologic acute tubular necrosis was present in 6.9% of patients, likely a result of hypoxic kidney damage. Of SARS patients, 28.8% had abnormal urinalysis, with viral genome detectable by quantitative RT-PCR. In contrast, children younger than 12 yr of age had a relatively mild nonspecific illness, with only a minority experiencing significant lower respiratory tract disease and illness typically lasting less than 5 days. There were no deaths or cases of acute respiratory distress syndrome in children younger than 12 yr of age from SARS-CoV infection. Adolescents manifested increasing severity in direct correlation to increasing age; respiratory distress and hypoxemia were observed in 10–20% of

patients, one third of whom required ventilator support. The case fatality rate from SARS-CoV infection during the 2003 outbreak was 10–17%. No pediatric deaths were reported. The estimated case fatality rate according to age varied from < 1% for those younger than 20 yr of age to > 50% for those older than 65 yr of age.

Middle East Respiratory Syndrome Coronavirus The incubation period of MERS-CoV is between 2-14 days. The syndrome usually presents with nonspecific clinical features typical of acute febrile respiratory illnesses, including low-grade fever, rhinorrhea, sore throat, and myalgia. In mildly symptomatic cases, radiographic findings are typically normal. Severe disease is characterized by the acute respiratory distress syndrome with multilobular airspace disease, ground-glass opacities, and occasional pleural effusions on radiography. The median time between hospitalization and ICU transfer for critical illness is 2 days. Risk factors for severe disease include age > 50 yr and comorbidities such as obesity, diabetes, COPD, end-stage renal disease, cancer, and immunosuppression. Specific host genetic risk factors have not been identified. Variation in clinical outcomes does not appear to be explained by viral strain-specific sequence variability. As with SARS, extrapulmonary manifestations are common in severe MERS disease. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea occur in one third of patients, and acute kidney injury has been documented in half of critically ill patients. Encephalitis-like neurologic manifestations have been observed in three cases. Laboratory analyses typically detect leukopenia and lymphopenia, with occasional thrombocytopenia, anemia, and aminotransferase elevations. The case fatality rate remains at 35%, though the true incidence of MERS-CoV infection is likely underestimated by existing data. Most patients have been adults, although children as young as 9 mo of age have been infected. It is not known whether children are less susceptible to MERS-CoV or present with a different clinical picture.

Diagnosis In the past, specific diagnostic tests for coronavirus infections were not available in most clinical settings. The use of conserved PCR primers for coronaviruses in multiplex RT-PCR viral diagnostic panels now allows widely available and

sensitive detection of the viruses. Virus culture of primary clinical specimens remains a challenge for HCoVs HKU1, OC43, 229E, and NL63, even though both SARS-CoV and MERS-CoV can successfully be grown in culture from respiratory samples. Serodiagnosis with complement fixation, neutralization, hemagglutination inhibition, enzyme immunoassay, and Western blots have been used in the research setting. The diagnosis of SARS-CoV infection can be confirmed by serologic testing, detection of viral RNA using RT-PCR, or isolation of the virus in cell culture. Even though the serology for SARS-CoV has a sensitivity and specificity approaching 100%, antibodies are not detectable until 10 days after the onset of symptoms, and immunoglobulin G seroconversion may be delayed for up to 4 wk. In addition, the SARS epidemic resulted in the inclusion of coronavirus-conserved primers in many diagnostic PCR multiplex assays such that coronaviruses may be more readily detected. The diagnosis of MERS-CoV should be guided by clinical features and an epidemiologic link. The mainstay for laboratory confirmation of MERS-CoV infection is real-time RT-PCR. Screening should target the region upstream of the envelope gene (upE), followed by confirmation with an assay targeting open reading frame 1a. The best diagnostic sensitivity is achieved from lower respiratory tract samples collected within the first week of infection, though MERS-CoV RNA can be detected in upper respiratory and blood samples. Alternatively, seroconversion can be documented by screening enzyme-linked immunosorbent assays followed by immunofluorescence microscopy. For all known endemic and emerging HCoVs, respiratory specimens (nasopharyngeal swabs or aspirates) are most likely to be positive, but in a setting of a possible novel coronavirus, serum or stool may be positive.

Treatment and Prevention Coronavirus infections of humans are acute and self-limited, although persistent infection and shedding occurs in multiple animal models in the setting of minimal or no symptoms. There are no available antiviral agents for clinical use against coronaviruses, although strategies targeting conserved coronavirus proteases and coronavirus polymerases have been shown to block replication of the viruses in vitro and are in the drug development pipeline. Thus, treatment of SARS-CoV and MERS-CoV infections is primarily supportive. The role of antiviral and immune-modulating agents remains inconclusive, though several clinical trials are ongoing. Ribavirin was extensively used during the 2003

SARS-CoV outbreak, but is of questionable benefit given its poor in vitro activity against SARS-CoV at clinically relevant concentrations. The identification of the proofreading nsp14-exonuclease in multiple coronaviruses suggests that this activity may be important in resistance to antiviral nucleosides and RNA mutagens such as ribavirin. Systemic corticosteroid therapy may be associated with increased mortality rates in SARS-CoV and MERS-CoV and is thus not recommended unless indicated for another clinical condition. Metaanalysis of observational studies suggests that human convalescent plasma may reduce SARS mortality rates; the use of blood products has not been wellstudied in MERS. Several monoclonal antibody preparations have shown positive results against SARS-CoV and MERS-CoV in animal studies. Challenges for the development of effective vaccines targeted against OC43, 229E, HKU1, and NL63 include the fact that infections are rarely lifethreatening and reinfection is the rule, even in the presence of natural immunity from previous infections. The durability of immunity to SARS-CoV and MERSCoV is poorly understood. Nevertheless, effective vaccines for SARS-CoV and MERS-CoV are highly desirable but not yet available. A potential vaccine target is the viral spike protein, which could be delivered as a recombinant protein or by viral or DNA vectors. This approach appears to be effective against closely related strains of SARS-CoV but not necessarily early animal or human variants. A SARS-CoV vaccine approach that recently has shown success in animal models used a live recombinant SARS-CoV mutant with inactivated ExoN, demonstrating attenuation and protection in aged, immunocompromised mice. Approaches for the rapid development of stably attenuated live viruses or broadly immunogenic and cross-protective protein immunogens continues to be a key area for future research. Although SARS-CoV demonstrated characteristics of symptomatic transmission that made it controllable by public health measures such as quarantine, these characteristics cannot be assumed for future novel HCoVs. The recent discovery of MERS-CoV serves as a reminder that coronavirus emergence is both likely and unpredictable, making it important to continue studies of the replication, emergence, and transmission of coronaviruses. Additionally, strategies for rapid recovery, testing, and development of vaccines and neutralizing human monoclonal antibodies may be essential to prevent the high morbidity and mortality rates associated with previous epidemics.

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CHAPTER 292

Rotaviruses, Caliciviruses, and Astroviruses Dorsey M. Bass

Diarrhea is a leading cause of childhood death in the world, accounting for 5-10 million deaths per year. In early childhood, the single most important cause of severe dehydrating diarrhea is rotavirus infection. Rotavirus and other gastroenteric viruses are not only major causes of pediatric deaths but also lead to significant morbidity. Children in the United States, before vaccine was available, were estimated to have a risk of hospitalization for rotavirus diarrhea of 1 : 43, corresponding to 80,000 hospitalizations annually.

Etiology Rotaviruses, astroviruses, caliciviruses such as the Norwalk agent, and enteric adenoviruses are the medically important pathogens of human viral gastroenteritis (see Chapter 366 ). Rotaviruses are in the Reoviridae family and cause disease in virtually all mammals and birds. These viruses are wheel-like, triple-shelled icosahedrons containing 11 segments of double-stranded RNA. The diameter of the particles on electron microscopy is approximately 80 nm. Rotaviruses are classified by serogroup (A, B, C, D, E, F, and G) and subgroup (I or II). Rotavirus strains are species specific and do not cause disease in heterologous hosts. Group A includes the common human pathogens as well as a variety of animal viruses. Group B rotavirus is reported as a cause of severe disease in infants and adults in China only. Occasional human outbreaks of group C rotavirus are reported. The other serogroups infect only nonhumans. Subgrouping of rotaviruses is determined by the antigenic structure of the

inner capsid protein, VP6. Serotyping of rotaviruses, described for group A only, is determined by classic cross-neutralization testing and depends on the outer capsid glycoproteins, VP7 and VP4. The VP7 serotype is referred to as the G type (for glycoprotein). There are ten G serotypes, of which four cause most illness and vary in occurrence from year to year and region to region. The VP4 serotype is referred to as the P type. There are eleven P serotypes. Although both VP4 and VP7 elicit neutralizing immunoglobulin G antibodies, the relative role of these systemic antibodies compared with that of mucosal immunoglobulin A antibodies and cellular responses in protective immunity remains unclear. Caliciviruses, which constitute the Caliciviridae family, are small, 27- to 35nm viruses that are the most common cause of gastroenteritis outbreaks in older children and adults. Caliciviruses also cause a rotavirus-like illness in young infants. They are positive-sense, single-stranded RNA viruses with a single structural protein. Human caliciviruses are divided into two genera, the noroviruses and sapoviruses. Caliciviruses have been named for locations of initial outbreaks: Norwalk, Snow Mountain, Montgomery County, Sapporo, and others. Caliciviruses and astroviruses are sometimes referred to as small, round viruses on the basis of appearance on electron microscopy. Astroviruses, which constitute the Astroviridae family, are important agents of viral gastroenteritis in young children, with a high incidence in both the developing and developed worlds. Astroviruses are positive-sense, singlestranded RNA viruses. They are small particles, approximately 30 nm in diameter, with a characteristic central five- or six-pointed star when viewed on electron microscopy. The capsid consists of three structural proteins. There are eight known human serotypes. Enteric adenoviruses are a common cause of viral gastroenteritis in infants and children. Although many adenovirus serotypes exist and are found in human stool, especially during and after typical upper respiratory tract infections (see Chapter 289 ), only serotypes 40 and 41 cause gastroenteritis. These strains are very difficult to grow in tissue culture. The virus consists of an 80-nm–diameter icosahedral particle with a relatively complex double-stranded DNA genome. Aichi virus is a picornavirus that is associated with gastroenteritis and was initially described in Asia. Several other viruses that may cause diarrheal disease in animals have been postulated but are not well established as human gastroenteritis viruses. These include coronaviruses, toroviruses, and pestiviruses. The picobirnaviruses are an unclassified group of small (30-nm), single-stranded RNA viruses that have been found in 10% of patients with HIV-

associated diarrhea.

Epidemiology Worldwide, rotavirus is estimated to cause more than 111 million cases of diarrhea annually in children younger than 5 yr of age. Of these, 18 million cases are considered at least moderately severe, with approximately 500,000 deaths per year. Rotavirus causes 3 million cases of diarrhea, 80,000 hospitalizations, and 20-40 deaths annually in the United States. Rotavirus infection is most common in winter months in temperate climates. In the United States, the annual winter peak historically spread from west to east. Unlike the spread of other winter viruses, such as influenza, this wave of increased incidence was not caused by a single prevalent strain or serotype. Since widespread adoption of vaccine, this geographic phenomenon has vanished. Typically, several serotypes predominate in a given community for one or two seasons but nearby locations may harbor unrelated strains. Disease tends to be most severe in patients 3-24 mo of age, although 25% of the cases of severe disease occur in children older than 2 yr of age, with serologic evidence of infection developing in virtually all children by 4-5 yr of age. Infants younger than 3 mo are relatively protected by transplacental antibody and possibly breastfeeding. Infections in neonates and in adults in close contact with infected children are generally asymptomatic. Some rotavirus strains have stably colonized newborn nurseries for years, infecting virtually all newborns without causing any overt illness. Rotavirus and the other gastrointestinal viruses spread efficiently via a fecaloral route, and outbreaks are common in children's hospitals and childcare centers. The virus is shed in stool at a very high concentration before and for days after the clinical illness. Very few infectious virions are needed to cause disease in a susceptible host. The epidemiology of astroviruses is not as thoroughly studied as that of rotavirus, but these viruses are a common cause of mild to moderate watery winter diarrhea in children and infants and an uncommon pathogen in adults. Hospital outbreaks are common. Enteric adenovirus gastroenteritis occurs yearround, mostly in children younger than 2 yr of age. Nosocomial outbreaks occur but are less common than with rotavirus and astrovirus. Calicivirus is best known for causing large, explosive outbreaks among older children and adults, particularly in settings such as schools, cruise ships, and hospitals. Often a single

food, such as shellfish or water used in food preparation, is identified as a source. Like astrovirus and rotavirus, caliciviruses are also commonly found in winter infantile gastroenteritis.

Pathogenesis Viruses that cause human diarrhea selectively infect and destroy villus tip cells in the small intestine. Biopsies of the small intestines show variable degrees of villus blunting and round cell infiltrate in the lamina propria. Pathologic changes may not correlate with the severity of clinical symptoms and usually resolve before the clinical resolution of diarrhea. The gastric mucosa is not affected despite the commonly used term gastroenteritis, although delayed gastric emptying has been documented during Norwalk virus infection. In the small intestine, the upper villus enterocytes are differentiated cells, which have both digestive functions, such as hydrolysis of disaccharides, and absorptive functions, such as the transport of water and electrolytes via glucose and amino acid cotransporters. Crypt enterocytes are undifferentiated cells that lack the brush-border hydrolytic enzymes and are net secretors of water and electrolytes. Selective viral infection of intestinal villus tip cells thus leads to (1) decreased absorption of salt and water and an imbalance in the ratio of intestinal fluid absorption to secretion, and (2) diminished disaccharidase activity and malabsorption of complex carbohydrates, particularly lactose. Most evidence supports altered absorption as the more important factor in the genesis of viral diarrhea. It has been proposed that a rotavirus nonstructural protein (NSP4) functions as an enterotoxin. Viremia may occur often in severe, primary infections, but symptomatic extraintestinal infection is extremely rare in immunocompetent persons— although immunocompromised patients may rarely experience central nervous system, hepatic, and renal involvement. The increased vulnerability of infants (compared with older children and adults) to severe morbidity and mortality from gastroenteritis viruses may relate to a number of factors, including decreased intestinal reserve function, lack of specific immunity, and decreased nonspecific host defense mechanisms such as gastric acid and mucus. Viral enteritis greatly enhances intestinal permeability to luminal macromolecules and has been postulated to increase the risk for food allergies.

Clinical Manifestations Rotavirus infection typically begins after an incubation period of < 48 hr (range: 1-7 days) with mild to moderate fever as well as vomiting, followed by the onset of frequent, watery stools. All three symptoms are present in about 50– 60% of cases. Vomiting and fever typically abate during the second day of illness, but diarrhea often continues for 5-7 days. The stool is without gross blood or white blood cells. Dehydration may develop and progress rapidly, particularly in infants. The most severe disease typically occurs among children 4-36 mo of age. Malnourished children and children with underlying intestinal disease, such as short-bowel syndrome, are particularly likely to acquire severe rotavirus diarrhea. Rarely, immunodeficient children experience severe and prolonged illness. Rotavirus has rarely been associated with mild encephalopathy with reversible splenium lesions; this may progress to cerebellitis. Although most newborns infected with rotavirus are asymptomatic, some outbreaks of necrotizing enterocolitis have been associated with the appearance of a new rotavirus strain in the affected nurseries. The clinical course of astrovirus infection appears to be similar to that of rotavirus gastroenteritis, with the notable exception that the disease tends to be milder, with less significant dehydration. Adenovirus enteritis tends to cause diarrhea of longer duration, often 10-14 days. The Norwalk virus has a short (12-hr) incubation period. Vomiting and nausea tend to predominate in an illness associated with the Norwalk virus, and the duration is brief, usually consisting of 1-3 days of symptoms. The clinical and epidemiologic picture of Norwalk virus often closely resembles so-called food poisoning from preformed toxins such as Staphylococcus aureus and Bacillus cereus.

Diagnosis In most cases, a satisfactory diagnosis of acute viral gastroenteritis can be made on the basis of the clinical and epidemiologic features. Many hospitals now offer multiplex PCR stool testing for multiple diarrheal pathogens, including a variety of bacterial and protozoan and all five common viral agents in one test. Enzymelinked immunosorbent assays, which offer > 90% specificity and sensitivity, are available for the detection of group A rotaviruses, caliciviruses, and enteric adenoviruses in stool samples. Latex agglutination assays are also available for group A rotavirus and are less sensitive than the enzyme-linked immunosorbent

assay. Research tools include electron microscopy of stools, RNA polymerase chain reaction analysis to identify G and P antigens, and culture. The diagnosis of viral gastroenteritis should always be questioned in patients with persistent or high fever, blood or white blood cells in the stool, or persistent severe or bilious vomiting, especially in the absence of diarrhea.

Laboratory Findings Isotonic dehydration with acidosis is the most common finding in children with severe viral enteritis. The stools are free of blood and leukocytes. Although the white blood cell count may be moderately elevated secondary to stress, the marked left shift seen with invasive bacterial enteritis is absent.

Differential Diagnosis The differential diagnosis includes other infectious causes of enteritis, such as bacteria and protozoa. Occasionally, surgical conditions such as appendicitis, bowel obstruction, and intussusception may initially mimic viral gastroenteritis.

Treatment Avoiding and treating dehydration are the main goals in the treatment of viral enteritis. A secondary goal is maintenance of the nutritional status of the patient (see Chapters 69 and 366 ). There is no routine role for antiviral drug treatment of viral gastroenteritis. Controlled studies show limited benefits for antidiarrheal drugs, and there is a significant risk for serious side effects with these types of agents. Antibiotics are similarly of no benefit. Antiemetics such as ondansetron may help alleviate vomiting in children older than 2 yr. Immunoglobulins have been administered orally to both normal and immunodeficient patients with severe rotavirus and norovirus gastroenteritis, but this treatment is currently considered experimental. Therapy with probiotic organisms such as Lactobacillus species has been shown to be helpful only in mild cases and not in dehydrating disease.

Supportive Treatment

Rehydration via the oral route can be accomplished in most patients with mild to moderate dehydration (see Chapters 69 and 366 ). Severe dehydration requires immediate intravenous therapy followed by oral rehydration. Modern oral rehydration solutions containing appropriate quantities of sodium and glucose promote the optimum absorption of fluid from the intestine. There is no evidence that a particular carbohydrate source (rice) or the addition of amino acids improves the efficacy of these solutions for children with viral enteritis. Other clear liquids, such as flat soda, fruit juice, and sports drinks, are inappropriate for the rehydration of young children with significant stool loss. Rehydration via the oral (or nasogastric) route should be done over 6-8 hr, and feedings should be initiated immediately thereafter. Providing the rehydration fluid at a slow, steady rate, typically 5 mL/min, reduces vomiting and improves the success of oral therapy. Rehydration solution should be continued as a supplement to make up for ongoing excessive stool loss. Initial intravenous fluids are required for the infant in shock or the occasional child with intractable vomiting. After rehydration has been achieved, resumption of a normal diet for age has been shown to result in a more rapid recovery from viral gastroenteritis. Prolonged (>12 hr) administration of exclusive clear liquids or dilute formula is without clinical benefit and actually prolongs the duration of diarrhea. Breastfeeding should be continued even during rehydration. Selected infants may benefit from lactose-free feedings (such as soy formula and lactose-free cow's milk) for several days, although this step is not necessary for most children. Hypocaloric diets low in protein and fat such as BRAT (b ananas, r ice, cereal, a pplesauce, and t oast) have not been shown to be superior to a regular diet.

Prognosis Most fatalities occur in infants with poor access to medical care and are attributed to dehydration. Children may be infected with rotavirus each year during the first 5 yr of life, but each subsequent infection decreases in severity. Primary infection results in a predominantly serotype-specific immune response, whereas reinfection, which is usually with a different serotype, induces a broad immune response with cross-reactive heterotypic antibody. After the initial natural infection, children have limited protection against subsequent asymptomatic infection (38%) and greater protection against mild diarrhea (73%) and moderate to severe diarrhea (87%). After the second natural infection,

protection increases against subsequent asymptomatic infection (62%) and mild diarrhea (75%) and is complete (100%) against moderate to severe diarrhea. After the third natural infection, there is even more protection against subsequent asymptomatic infection (74%) and near-complete protection against even mild diarrhea (99%).

Prevention Good hygiene reduces the transmission of viral gastroenteritis, but even in the most hygienic societies, virtually all children become infected as a result of the efficiency of infection of the gastroenteritis viruses. Good handwashing and isolation procedures can help control nosocomial outbreaks. The role of breastfeeding in prevention or amelioration of rotavirus infection may be slight, given the variable protection observed in a number of studies. Vaccines offer the best hope for control of these ubiquitous infections.

Vaccines A trivalent rotavirus vaccine was licensed in the United States in 1998 and was subsequently linked to an increased risk for intussusception, especially during the 3- to 14-day period after the first dose and the 3- to 7-day period after the second dose. The vaccine was withdrawn from the market in 1999. Subsequently, two new live, oral rotavirus vaccines have been approved in the United States after extensive safety and efficacy testing. A live, oral, pentavalent rotavirus vaccine was approved in 2006 for use in the United States. The vaccine contains five reassortant rotaviruses isolated from human and bovine hosts. Four of the reassortant rotaviruses express one serotype of the outer protein VP7 (G1, G2, G3, or G4), and the fifth expresses the protein P1A (genotype P[8]) from the human rotavirus parent strain. The pentavalent vaccine protects against rotavirus gastroenteritis when administered as a threedose series at 2, 4, and 6 mo of age. The first dose should be administered between 6 and 12 wk of age, with all three doses completed by 32 wk of age. The vaccine provides substantial protection against rotavirus gastroenteritis, with a primary efficacy of 98% against severe rotavirus gastroenteritis caused by G1G4 serotypes and 74% efficacy against rotavirus gastroenteritis of any severity through the first rotavirus season after vaccination. It provides a 96% reduction in hospitalizations for rotavirus gastroenteritis through the first 2 yr after the

third dose. In a study of more than 70,000 infants, the pentavalent vaccine did not increase the risk for intussusception, although other studies suggest a slight increased risk. Another new monovalent rotavirus vaccine was licensed in the United States and also appears to be safe and effective. It is an attenuated monovalent human rotavirus and is administered as two oral doses at 2 and 4 mo of age. The vaccine has 85% efficacy against severe gastroenteritis and was found to reduce hospital admissions for all diarrhea by 42%. Despite being monovalent, the vaccine is effective in prevention of all four common serotypes of human rotavirus. Preliminary surveillance data on the rotavirus incidence from the U.S. Centers for Disease Control and Prevention suggest that rotavirus vaccination greatly reduced the disease burden in the United States during the 2007-2008 rotavirus season and thereafter. Given the incomplete vaccine coverage during this period, the results suggest a degree of “herd immunity” from rotavirus immunization. Studies from several developed countries show greater than 90% protection against severe rotavirus disease. Studies from developing countries show 50– 60% protection from severe disease. Vaccine-associated disease has been reported in vaccine recipients who have severe combined immunodeficiency disease (a contraindication). In addition, vaccine-derived virus may undergo reassortment and become more virulent, producing diarrhea in unvaccinated siblings.

Bibliography Burke RM, Tate JE, Barin N, et al. Three rotavirus outbreaks in the postvaccine era—California, 2017. MMWR Morb Mortal Wkly Rep . 2018;67(16):470–472. Chhabra P, Gregoricus N, Weinberg G. Comparison of three commercial multiplex gastrointestinal platforms for the detection of gastroenteritis viruses. J Clin Virol . 2017;95:66– 71. Chhabra P, Payne DC, Szilagyi PG, et al. Etiology of viral gastroenteritis in children 50 yr of age. WN virus has been implicated as the cause of sporadic summertime cases of human encephalitis and meningitis in Israel, India, Pakistan, Romania, Russia, Canada, the United States, and parts of Central and South America. All American WN viruses are genetically similar and are related to a virus recovered from a goose in Israel in 1998.

FIG. 294.3 Rate (per 100,000 population) of reported cases of West Nile virus neuroinvasive disease, United States, 2016. (From Burakoff A, Lehman J, Fischer M, et al: West Nile virus and other nationally notifiable arboviral diseases, United States, 2016, MMWR 67(1):13-17, 2018.)

West Nile encephalitis (WNE) may be asymptomatic, but when clinical features appear, they include an abrupt onset of high fever, headache, myalgias, and nonspecific signs of emesis, rash, abdominal pain, or diarrhea. Most infections manifest as a flulike febrile illness, whereas a minority of patients demonstrate meningitis or encephalitis, or both. Rarely there may be cardiac dysrhythmias, myocarditis, rhabdomyolysis, optic neuritis, uveitis, retinitis, orchitis, pancreatitis, or hepatitis. WN virus disease in the United States has been accompanied by prolonged lymphopenia and an acute asymmetric polio-like paralytic illness with CSF pleocytosis involving the anterior horn cells of the spinal cord. A striking but uncommon feature has been parkinsonism and movement disorders (with tremor and myoclonus). WN virus infections have been shown to lead to chronic kidney disease in a small group of patients.

Cases of WNE and deaths due to the disease occur mainly in the elderly, although many serologic surveys show that persons of all ages are infected. In 2015, among a total of 2,175 human cases, 1,455 were neuroinvasive disease, which resulted in 146 deaths, a 10% mortality rate (see Fig. 294.2 ). Paralysis may result in permanent weakness.

Bibliography Barzon L, Pacenti M, Sinigaglia A, et al. West Nile virus infection in children. Expert Rev Anti Infect Ther . 2015;13(11):1373–1386. Burakoff A, Lehman J, Fischer M, et al. West Nile virus and other nationally notifiable arboviral diseases—United States, 2016. MMWR Morb Mortal Wkly Rep . 2018;67(1):13–17. David S, Abraham AM. Epidemiological and clinical aspects on West Nile virus, a globally emerging pathogen. Infect Dis (Lond) . 2016;48(8):571–586.

294.5

Powassan Encephalitis Scott B. Halstead

POW virus is transmitted by Ixodes cookei among small mammals in eastern Canada and the United States; it has been responsible for 39 deaths in the United States since 2008 (see Fig. 294.1 ). Other ticks may transmit the virus in a wider geographic area, and there is some concern that Ixodes scapularis (also called Ixodes dammini ), a competent vector in the laboratory, may become involved as it becomes more prominent in the United States. In a limited experience, POW encephalitis has occurred mainly in adults with

vocational or recreational exposure and has a high fatality rate. POW encephalitis has occurred mostly in adults living in enzootic areas with vocational or recreational exposure; it is associated with significant long-term morbidity and has a case-fatality rate of 10–15%.

Bibliography Piantadosi A, Rubin DB, McQuillen DP, et al. Emerging cases of Powassan virus encephalitis in New England: clinical presentation, imaging, and review of the literature. Clin Infect Dis . 2016;62(6):707–713.

294.6

La Crosse and California Encephalitis Scott B. Halstead

La Crosse viral infections are endemic in the United States, occurring annually from July to September, principally in the north-central and central states (see Fig. 294.1 ). Infections occur in peridomestic environments as the result of bites from Aedes triseriatus mosquitoes, which often breed in tree holes. The virus is maintained vertically in nature by transovarial transmission and can be spread between mosquitoes by copulation and amplified in mosquito populations by viremic infections in various vertebrate hosts. Amplifying hosts include chipmunks, squirrels, foxes, and woodchucks. A case:infection ratio of 1 : 22300 has been surmised. La Crosse encephalitis is principally a disease of children, who may account for up to 75% of cases. A mean of 100 cases has been reported annually for the past 10 yr. The clinical spectrum includes a mild febrile illness, aseptic meningitis, and

fatal encephalitis. Children typically present with a prodrome of 2-3 days of fever, headache, malaise, and vomiting. The disease evolves with clouding of the sensorium, lethargy, and, in severe cases, focal or generalized seizures. On physical examination, children are lethargic but not disoriented. Focal neurologic signs, including weakness, aphasia, and focal or generalized seizures, have been reported in 16–25% of cases. CSF shows low to moderate leukocyte counts. On autopsy, the brain shows focal areas of neuronal degeneration, inflammation, and perivascular cuffing. Recovery from California encephalitis is usually complete. The case fatality rate is approximately 1%.

294.7

Colorado Tick Fever Scott B. Halstead

Colorado tick fever virus is transmitted by the wood tick Dermacentor andersoni, which inhabits high-elevation areas of states extending from the central plains to the Pacific coast. The tick is infected with the virus at the larval stage and remains infected for life. Squirrels and chipmunks serve as primary reservoirs. Human infections typically occur in hikers and campers in indigenous areas during the spring and early summer. Colorado tick fever begins with the abrupt onset of a flulike illness, including high temperature, malaise, arthralgia and myalgia, vomiting, headache, and decreased sensorium. Rash is uncommon. The symptoms rapidly disappear after 3 days of illness. However, in approximately half of patients, a second identical episode reoccurs 24-72 hr after the first one, producing the typical saddleback temperature curve of Colorado tick fever. Complications, including encephalitis, meningoencephalitis, and a bleeding diathesis, develop in 3–7% of infected persons and may be more common in children younger than 12 yr of age. Recovery from Colorado tick fever is usually complete. Three deaths have been reported, all in persons with hemorrhagic signs.

294.8

Chikungunya Fever Scott B. Halstead

Chikungunya virus is enzootic in several species of African subhuman primates but also is endemic in urban Aedes aegypti or Aedes albopictus transmission cycles in Africa and Asia. Chikungunya exited Africa historically producing Asian pandemics in 1790, 1824, 1872, 1924, 1963, and 2005. In 1827, chikungunya reached the Western Hemisphere, predominantly the Caribbean region, probably brought by the slave trade. In 2005, another Asian pandemic proceeded east from an initial outbreak on Reunion and then traveling to Asia across the Indian Ocean. In 2013, chikungunya virus from this epidemic was introduced into Latin America. Clinical manifestations begin 3-7 days after a mosquito bite; the onset is abrupt, with high fever and often severe joint symptoms (hands, feet, ankles, wrists) that include symmetric bilateral polyarthralgia or arthritis. Most pediatric patients are relatively asymptomatic, but all ages are vulnerable to classic disease. There may be headache, myalgias, conjunctivitis, weakness, lymphopenia, and a maculopapular rash. Mortality is rare; some individuals develop prolonged joint symptoms (tenosynovitis, arthritis) lasting over a year. The acute episode lasts 7-10 days. The differential diagnosis includes dengue, West Nile, enterovirus diseases, leptospirosis, rickettsial disease, measles, parvovirus disease, rheumatologic diseases, and other alphavirus diseases (e.g., Ross River virus) in endemic areas. Fig. 294.4 lists the diagnostic criteria.

FIG. 294.4 Diagnostic criteria for chikungunya virus fever. (From Burt FJ, Rolph MS, Rulli NE, et al: Chikungunya: a re-emerging virus, Lancet 379:662-668, 2012, Fig. 6.)

The incidence of febrile convulsions is high in infants. The prognosis is generally good, although in large outbreaks in Africa and India, severe disease and deaths have been attributed to chikungunya infections, predominantly in adults.

Bibliography Weaver SC, Lecuit M. Chikungunya virus and the global spread of a mosquito-borne disease. N Engl J Med . 2015;372(13):1231–1238.

294.9

Venezuelan Equine Encephalitis Scott B. Halstead

VEE virus was isolated from an epizootic in Venezuelan horses in 1938. Human cases were first identified in 1943. Hundreds of thousands of equine and human cases have occurred over the past 70 yr. During 1971, epizootics moved through Central America and Mexico to southern Texas. After two decades of quiescence, epizootic disease emerged again in Venezuela and Colombia in 1995. Between December 1992 and January 1993, the Venezuelan state of Trujillo experienced an outbreak of this virus. Overall, 28 cases of the disease were reported, along with 12 deaths. June 1993 saw a bigger outbreak, in which 55 humans died, as well as 66 horses. A much larger outbreak in Venezuela and Colombia occurred in 1995. On May 23, 1995, equine encephalitis-like cases were reported in the northwest portion of the country. Eventually, the outbreak spread toward the north, as well as to the south. The outbreak caused about 11,390 febrile cases in humans, as well as 16 deaths. About 500 equine cases were reported with 475 deaths. The incubation period is 2-5 days, followed by the abrupt onset of fever, chills, headache, sore throat, myalgia, malaise, prostration, photophobia, nausea, vomiting, and diarrhea. In 5–10% of cases, there is a biphasic illness; the second phase is heralded by seizures, projectile vomiting, ataxia, confusion, agitation, and mild disturbances in consciousness. There is cervical lymphadenopathy and conjunctival suffusion. Cases of meningoencephalitis may demonstrate cranial nerve palsy, motor weakness, paralysis, seizures, and coma. Microscopic examination of tissues reveals inflammatory infiltrates in lymph nodes, spleen, lung, liver, and brain. Lymph nodes show cellular depletion, necrosis of germinal centers, and lymphophagocytosis. The liver shows patchy hepatocellular degeneration, the lungs demonstrate a diffuse interstitial pneumonia with intraalveolar hemorrhages, and the brain shows patchy cellular infiltrates. There is no specific treatment for VEE. The treatment is intensive supportive care (see Chapter 85 ), including control of seizures (see Chapter 611 ). In patients with VEE meningoencephalitis, the fatality rate ranges from 10% to 25%. Sequelae include nervousness, forgetfulness, recurrent headache, and easy fatigability. Several veterinary vaccines are available to protect equines. VEE virus is highly infectious in laboratory settings, and biosafety level three containment should be used. An experimental vaccine is available for use in laboratory workers. Several vaccine constructs are in the pipeline for potential use in humans.

294.10

Japanese Encephalitis Scott B. Halstead

JE is a mosquito-borne viral disease of humans, as well as horses, swine, and other domestic animals. The virus causes human infections and acute disease in a vast area of Asia, northern Japan, Korea, China, Taiwan, the Philippines, and the Indonesian archipelago and from Indochina through the Indian subcontinent. Culex tritaeniorhynchus summarosus, a night-biting mosquito that feeds preferentially on large domestic animals and birds but only infrequently on humans, is the principal vector of zoonotic and human JE in northern Asia. A more complex ecology prevails in southern Asia. From Taiwan to India, C. tritaeniorhynchus and members of the closely related Culex vishnui group are vectors. Before the introduction of JE vaccine, summer outbreaks of JE occurred regularly in Japan, Korea, China, Okinawa, and Taiwan. Over the past decade, there has been a pattern of steadily enlarging recurrent seasonal outbreaks in Vietnam, Thailand, Nepal, and India, with small outbreaks in the Philippines, Indonesia, and the northern tip of Queensland, Australia. Seasonal rains are accompanied by increases in mosquito populations and JE transmission. Pigs serve as an amplifying host. The annual incidence in endemic areas ranges from 1-10 per 10,000 population. Children younger than 15 yr of age are principally affected, with nearly universal exposure by adulthood. The case:infection ratio for JE virus has been variously estimated at 1 : 25 to 1 : 1,000. Higher ratios have been estimated for populations indigenous to enzootic areas. JE occurs in travelers visiting Asia; therefore, a travel history in the diagnosis of encephalitis is critical. After a 4- to 14-day incubation period, cases typically progress through the following four stages: prodromal illness (2-3 days), acute stage (3-4 days), subacute stage (7-10 days), and convalescence (4-7 wk). The onset may be characterized by an abrupt onset of fever, headache, respiratory symptoms, anorexia, nausea, abdominal pain, vomiting, and sensory changes, including psychotic episodes. Grand mal seizures are seen in 10–24% of children with JE;

parkinsonian-like nonintention tremor and cogwheel rigidity are seen less frequently. Particularly characteristic are rapidly changing central nervous system signs (e.g., hyperreflexia followed by hyporeflexia or plantar responses that change). The sensory status of the patient may vary from confusion through disorientation and delirium to somnolence, progressing to coma. There is usually a mild pleocytosis (100-1,000 leukocytes/µL) in the cerebrospinal fluid, initially polymorphonuclear but in a few days predominantly lymphocytic. Albuminuria is common. Fatal cases usually progress rapidly to coma, and the patient dies within 10 days. JE should be suspected in patients reporting exposure to night-biting mosquitoes in endemic areas during the transmission season. The etiologic diagnosis of JE is established by testing acute-phase serum collected early in the illness for the presence of virus-specific IgM antibodies or, alternatively, demonstrating a fourfold or greater increase in IgG antibody titers by testing paired acute and convalescent sera. The virus can also be identified by the polymerase chain reaction. There is no specific treatment for JE. The treatment is intensive supportive care (see Chapter 85 ), including control of seizures (see Chapter 611 ). Patient fatality rates for JE are 24–42% and are highest in children 5-9 yr of age and in adults older than 65 yr of age. The frequency of sequelae is 5–70% and is directly related to the age of the patient and severity of disease. Sequelae are most common in patients younger than 10 yr at the onset of disease. The more common sequelae are mental deterioration, severe emotional instability, personality changes, motor abnormalities, and speech disturbances.

Bibliography Pavli A, Maltezou HC. Travel-acquired Japanese encephalitis and vaccination considerations. J Infect Dev Ctries . 2015;9(9):917–924.

294.11

Tick-Borne Encephalitis

Scott B. Halstead

TBE refers to neurotropic tick-transmitted flaviviral infections occurring across the Eurasian land mass. In the Far East, the disease is called Russian springsummer encephalitis ; the milder, often biphasic form in Europe is simply called TBE. TBE is found in all countries of Europe except Portugal and the Benelux countries. The incidence is particularly high in Austria, Poland, Hungary, Czech Republic, Slovakia, former Yugoslavia, and Russia. The incidence tends to be very focal. Seroprevalence is as high as 50% in farm and forestry workers. The majority of cases occur in adults, but even young children may be infected while playing in the woods or on picnics or camping trips. The seasonal distribution of cases is midsummer in southern Europe, with a longer season in Scandinavia and the Russian Far East. TBE can be excreted from the milk of goats, sheep, or cows. Before World War II, when unpasteurized milk was consumed, milk-borne cases of TBE were common. Viruses are transmitted principally by hard ticks of Ixodes ricinus in Europe and Ixodes persulcatus in the Far East. Viral circulation is maintained by a combination of transmission from ticks to birds, rodents, and larger mammals and transstadial transmission from larval to nymphal and adult stages. In some parts of Europe and Russia, ticks feed actively during the spring and early fall, giving rise to the name spring-summer encephalitis. After an incubation period of 7-14 days, the European form begins as an acute nonspecific febrile illness that is followed in 5–30% of cases by meningoencephalitis. The Far Eastern variety more often results in encephalitis with higher case fatality and sequelae rates. The first phase of illness is characterized by fever, headache, myalgia, malaise, nausea, and vomiting for 2-7 days. Fever disappears but after 2-8 days may return, accompanied by vomiting, photophobia, and signs of meningeal irritation in children and more severe encephalitic signs in adults. This phase rarely lasts more than 1 wk. There is no specific treatment for TBE. The treatment is intensive supportive care (see Chapter 85 ), including control of seizures (see Chapter 611 ). The main risk for a fatal outcome is advanced age; the fatality rate in adults is approximately 1%, but sequelae in children are rare. Transient unilateral paralysis of an upper extremity is a common finding in adults. Common

sequelae include chronic fatigue, headache, sleep disorders, and emotional disturbances.

Bibliography Juckett G. Arthropod-borne diseases: the camper's uninvited guests. Microbiol Spectr . 2015;3(4). Sathiamoorthi S, Smith WM. The eye and tick-borne disease in the United States. Curr Opin Ophthalmol . 2016;27(6):530– 537. Steffen R. Epidemiology of tick-borne encephalitis (TBE) in international travellers to Western/Central Europe and conclusions on vaccination recommendations. J Travel Med . 2016;23(4).

294.12

Zika Virus Scott B. Halstead

Epidemiology Zika virus (ZIKV), a member of the Flavivirus genus, is maintained in complex African zoonotic cycles, spilling over from time to time into the Aedes aegypti/Aedes albopictus urban transmission cycles, possibly over a period of many years (Fig. 294.5 ). After the virus was discovered in Africa in 1947, human antibodies were found widely dispersed throughout tropical Asia. However, in all these locations, human ZIKV disease was mild and rare until in 2007, when there was an outbreak of a mild febrile exanthem on the Yap Islands in the western Pacific. Soon thereafter, an outbreak on Tahiti in 2013-2014 was

followed in 4 wk by a small outbreak of Guillain-Barré syndrome (GBS). In 2015, a massive epidemic in South America was accompanied by focal reports, particularly in Brazil, of ZIKV infections of pregnant women that produced infected and damaged fetuses or newborns. The epidemiology of ZIKV infections is essentially identical to that of the dengue and chikungunya viruses. Residents of urban areas, particularly those without adequate sources of piped water, are at highest risk. Aedes aegypti, the principal vector mosquito, is very abundant and widespread throughout South and Central America, Mexico, and the Caribbean region. During the American pandemic, ZIKV was found to infect the male reproductive tract, be secreted in urine and saliva, and be sexually transmitted. By 2017, the ZIKV epidemic in the American tropics appeared to wane. During 2015-2016, large numbers of imported Zika infections, some in pregnant women, were reported in the United States and other temperate-zone developed countries. Small outbreaks of endogenous human Zika infections were reported in South Florida during the summer of 2016.

FIG. 294.5 Zika virus outbreaks from 2007 to 2016. (From Baud D, Gubler DJ, Schaub B, et al: An update on Zika virus infection, Lancet 390:20992109, 2017, Fig. 2.)

From the pediatric perspective, the most important outcome of human ZIKV

infection is termed the congenital Zika syndrome (CZS), which consists of microcephaly, facial disproportion, hypertonia/spasticity, hyperreflexia, irritability, seizures, arthrogryposis, ocular abnormalities, and sensorineural hearing loss (Table 294.1 ). A comprehensive understanding of the precise antecedents to CZS is not known. It appears that the earlier during pregnancy that ZIKV infections occur, the greater the likelihood of and the more severe the CZS. Vertical transmission appears to follow viremia with ZIKV, transiting the uterus to infect the placenta and then the fetus. However, factors that affect the occurrence or severity of CZS, such as age, ethnicity, or prior immune status of the mother, are not known. In vitro studies have demonstrated that dengue antibodies can enhance ZIKV infection in vitro, in Fc-receptor–bearing cells, but, as yet, there is no evidence that a prior dengue infection alters the chance of ZIKV crossing the placenta or increases the risk of CZS. Maternal-fetal transmission of ZIKV can occur during labor and delivery. There are no reports of ZIKV infection acquired by an infant at the time of delivery leading to microcephaly. There are no data to contraindicate breastfeeding, although the virus has been identified in breast milk. Maternal and newborn laboratory testing is indicated during the first 2 wk of life if the mother had relevant epidemiologic exposure within 2 wk of delivery and had clinical manifestations of ZIKV infection (e.g., rash, conjunctivitis, arthralgia, or fever). Infants and children who acquire ZIKV infection postnatally appear to have a mild course, similar to that seen in adults. Table 294.1

Surveillance Case Classification: Children, Neonate to 2 Years of Age, Born to Mothers With Any Evidence of Zika Virus Infection During Pregnancy ZIKA-ASSOCIATED BIRTH DEFECTS Selected structural anomalies of the brain or eyes present at birth (congenital) and detected from birth to age 2 yr. Microcephaly at birth, with or without low birthweight, was included as a structural anomaly. • Selected congenital brain anomalies: intracranial calcifications; cerebral atrophy; abnormal cortical formation (e.g., polymicrogyria, lissencephaly, pachygyria, schizencephaly, gray matter heterotopia); corpus callosum abnormalities; cerebellar abnormalities; porencephaly; hydranencephaly; ventriculomegaly/hydrocephaly. • Selected congenital eye anomalies: microphthalmia or anophthalmia; coloboma; cataract; intraocular calcifications; chorioretinal anomalies involving the macula (e.g., chorioretinal atrophy and scarring, macular pallor, and gross pigmentary mottling), excluding retinopathy of prematurity; optic nerve atrophy, pallor, and other optic nerve abnormalities. • Microcephaly at birth: birth head circumference < 3rd percentile for infant sex and gestational age based on INTERGROWTH-21st online percentile calculator (http://intergrowth21.ndog.ox.ac.uk/ ).

NEURODEVELOPMENTAL ABNORMALITIES POSSIBLY ASSOCIATED WITH CONGENITAL ZIKA VIRUS INFECTION Consequences of neurologic dysfunction detected from birth (congenital) to age 2 yr. Postnatal-onset microcephaly was included as a neurodevelopmental abnormality. • Hearing abnormalities: Hearing loss or deafness documented by testing, most frequently auditory brainstem response (ABR). Includes sensorineural hearing loss, mixed hearing loss, and hearing loss not otherwise specified. Failed newborn hearing screening is not sufficient for diagnosis. • Congenital contractures: Multiple contractures (arthrogryposis) and isolated clubfoot documented at birth. Brain anomalies must be documented for isolated clubfoot but not for arthrogryposis. • Seizures: Documented by electroencephalogram or physician report. Includes epilepsy or seizures not otherwise specified; excludes febrile seizures. • Body tone abnormalities: Hypertonia or hypotonia documented at any age in conjunction with (1) a failed screen or assessment for gross motor function; (2) suspicion or diagnosis of cerebral palsy from age 1 to 2 yr; or (3) assessment by a physician or other medical professional, such as a physical therapist. • Movement abnormalities: Dyskinesia or dystonia at any age; suspicion or diagnosis of cerebral palsy from age 1 to 2 yr. • Swallowing abnormalities: Documented by instrumented or noninstrumented evaluation, presence of a gastrostomy tube, or physician report. • Possible developmental delay: Abnormal result from most recent developmental screening (i.e., failed screen for gross motor domain or failed screen for two or more developmental domains at the same time point or age); developmental evaluation; or assessment review by developmental pediatrician. Results from developmental evaluation are considered the gold standard if available. • Possible visual impairment: Includes strabismus (esotropia or exotropia), nystagmus, failure to fix and follow at age < 1 yr; diagnosis of visual impairment at age ≥ 1 yr. • Postnatal-onset microcephaly: Two most recent head circumference measurements reported from follow-up care < 3rd percentile for child's sex and age based on World Health Organization child growth standards; downward trajectory of head circumference percentiles with most recent measurement < 3rd percentile. Age at measurement was adjusted for gestational age in infants born at < 40 wk of gestational age through age 24 mo chronologic age.

From Rice ME, Galang RR, Roth NM, et al: Vital signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection: US territories and freely associated states, 2018. MMWR 67(31):858-866, 2018.

Clinical Features Congenital Zika syndrome may be defined in a fetus with diagnostic evidence of ZIKV infection, including (1) severe microcephaly (>3 SD below the mean), partially collapsed skull, overlapping cranial sutures, prominent occipital bone, redundant scalp skin, and neurologic impairment; (2) brain anomalies, including cerebral cortex thinning, abnormal gyral patterns, increased fluid spaces, subcortical calcifications, corpus callosum anomalies, reduced white matter, and cerebellar vermis hypoplasia; (3) ocular findings, such as macular scarring, focal pigmentary retinal mottling, structural anomalies (microphthalmia, coloboma, cataracts, and posterior anomalies), chorioretinal atrophy, or optic nerve hypoplasia/atrophy; (4) congenital contractures, including unilateral or bilateral clubfoot and arthrogryposis multiplex congenita; and (5) neurologic impairment,

such as pronounced early hypertonia/spasticity with extrapyramidal symptoms, motor disabilities, cognitive disabilities, hypotonia, irritability/excessive crying, tremors, swallowing dysfunction, vision impairment, hearing impairment, and epilepsy (see Table 294.1 ). Acquired Zika virus infection may present with nonspecific viral syndrome– like features. Nonetheless, patients are at increased risk of myelitis and GuillainBarré syndrome. In addition, the virus may remain present in the blood and body fluids for months after resolution of clinical symptoms.

Management For infants with confirmed Zika virus infection, close follow-up is necessary. The appropriate follow-up evaluation depends upon whether or not the infant has clinical signs and symptoms of congenital Zika syndrome. All infants should have close monitoring of growth and development, repeat ophthalmologic examinations, and auditory brainstem response testing (see Table 294.1 ).

Laboratory Diagnosis Laboratory testing for Zika virus infection in the neonate includes the following: serum and urine for Zika virus RNA via real-time reverse transcription polymerase chain reaction (rRT-PCR) and serum Zika virus immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA). If the IgM is positive, the plaque reduction neutralization test (PRNT) is used to confirm the specificity of the IgM antibodies against Zika virus and to exclude a false-positive IgM result. If CSF is available, it should be tested for Zika virus RNA (via rRT-PCR), as well as Zika virus IgM. CSF specimens need not be collected for the sole purpose of Zika virus testing but may be reasonable for the evaluation of infants with microcephaly or intracranial calcifications. A definitive diagnosis of congenital Zika virus infection is confirmed by the presence of Zika virus RNA in samples of serum, urine, or CSF collected within the first 2 days of life; IgM antibodies may be positive or negative. A negative rRT-PCR result with a positive Zika virus IgM test result indicates probable congenital Zika virus infection. Fetuses or infants born to mothers who test positive for ZIKV infection should be studied sonographically or for clinical evidence of congenital Zika syndrome,

a comprehensive evaluation (including ophthalmologic examination, laboratory tests, and specialist consultation) should be performed prior to hospital discharge.

Prognosis The prognosis of newborns with congenital Zika syndrome is unclear. Reported acute mortality rates among live-born infants range from 4% to 6%. The combination of Zika virus–related microcephaly and severe cerebral abnormalities generally has a poor prognosis, but little is known about the prognosis for congenitally infected infants with less severe or no apparent abnormalities at birth.

Differential Diagnosis The differential diagnosis for congenital Zika virus infection includes other congenital infections and other causes of microcephaly.

Prevention The prevention of the congenital Zika syndrome includes avoidance, if possible, of travel to endemic regions; if travel to endemic regions cannot be avoided, careful contraception (male and female) is essential, especially with the knowledge that Zika virus can persist in semen for months after a primary infection (Table 294.2 ). Table 294.2 CDC Recommendations for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus Among Persons With Possible Zika Virus Exposure: United States, August 2018 EXPOSURE SCENARIO Only the male partner travels to an area with risk for Zika virus transmission and couple is planning to conceive Only the female partner

RECOMMENDATIONS (UPDATE STATUS) The couple should use condoms or abstain from sex for at least 3 mo after the male partner's symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). (Updated recommendation)

The couple should use condoms or abstain from sex for at least 2 mo after the

travels to an area with risk for Zika virus transmission and couple is planning to conceive Both partners travel to an area with risk for Zika virus transmission and couple is planning to conceive One or both partners have ongoing exposure (i.e., live in or frequently travel to an area with risk for Zika virus transmission) and couple is planning to conceive Men with possible Zika virus exposure whose partner is pregnant

female partner's symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). (No change in recommendation) *

The couple should use condoms or abstain from sex for at least 3 mo from the male partner's symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). (Updated recommendation) The couple should talk with their health care provider about their plans for pregnancy, their risk for Zika virus infection, the possible health effects of Zika virus infection on a baby, and ways to protect themselves from Zika. If either partner develops symptoms of Zika virus infection or tests positive for Zika virus infection, the couple should follow the suggested timeframes listed above before trying to conceive. (No change in recommendation) * The couple should use condoms or abstain from sex for the duration of the pregnancy. (No change in recommendation) *

*

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al: Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure—United States, September 2016, MMWR Morb Mortal Wkly Rep 65:1077–1081, 2016. From Polen KD, Gilboa SM, Hills S, et al: Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for men with possible Zika virus exposure: United States, August 2018, MMWR 67(31):868–870, 2018.

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Chan JF, Choi GK, Yip CC, et al. Zika fever and congenital Zika syndrome: an unexpected emerging arboviral disease. J Infect . 2016;72(5):507–524. Falcao MB, Cimerman S, Luz KG, et al. Management of infection by the Zika virus. Ann Clin Microbiol Antimicrob . 2016;15(1):57. Hoen B, Schaub B, Funk AL, et al. Pregnancy outcomes after ZIKV infection in French territories in the Americas. N Engl J Med . 2018;378(11):985–994. Klase ZA, Khakhina S, Schneider Ade B, et al. Zika fetal neuropathogenesis: etiology of a viral syndrome. PLoS Negl Trop Dis . 2016;10(8):e0004877. Kleber de Oliveira W, de Franca GVA, Carmo EH, et al. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. Lancet . 2017;390:861–870. Landry ML, St George K. Laboratory diagnosis of Zika virus infection. Arch Pathol Lab Med . 2017;141(1):60–67. Leal MC, Muniz LF, Ferreira TSA, et al. Hearing loss in infants with microcephaly and evidence of congenital Zika virus infection—Brazil, November 2015-May 2016. MMWR Morb Mortal Wkly Rep . 2016;65(34):917–919. Likos A, Griffin I, Bingham AM, et al. Local mosquito-borne transmission of Zika virus—Miami-Dade and Broward counties, Florida, June-August 2016. MMWR Morb Mortal Wkly Rep . 2016;65(38):1032–1038. Mead PS, Duggal NK, Hook SA, et al. Zika virus shedding in semen of symptomatic infected men. N Engl J Med . 2018;378(15):1377–1384. Mecharles S, Herrmann C, Poullain P, et al. Acute myelitis due to Zika virus infection. Lancet . 2016;387:1481. Medin CL, Rothman AL. Zika virus: the agent and its biology, with relevance to pathology. Arch Pathol Lab Med .

2017;141(1):33–42. Melo ASDO, Aguiar RS, Amorim MMR, et al. Congenital Zika virus infection—beyond neonatal microcephaly. JAMA Neurol . 2016;73(12):1407–1416. Miner JJ, Diamond MS. Zika virus pathogenesis and tissue tropism. Cell Host Microbe . 2017;21(2):134–142. Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr . 2017;171(3):288–295. Musso D, Gubler DJ. Zika virus. Clin Microbiol Rev . 2016;29(3):487–524. Paz-Baily G, Rosenberg ES, Doyle K, et al. Persistence of Zika virus in body fluids—final report. N Engl J Med . 2018;379(13):1234–1242. Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med . 2016;374(16):1552–1562. Polen KD, Gilboa SM, Hills S, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for men with possible Zika virus exposure—United States, August 2018. MMWR Morb Mortal Wkly Rep . 2018;67(31):868–870. Rice ME, Galang RR, Roth NM, et al. Vital Signs: Zikaassociated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection—US territories and freely associated sataes, 2018. MMWR Morb Mortal Wkly Rep . 2018;67(31):858–866. Satterfield-Nash A, Kotzky K, Allen J, et al. Health and development at age 19-24 months of 19 children who were born with microcephaly and laboratory evidence of congenital Zika virus infection during the 2015 Zika virus outbreal—Brazil, 2017. MMWR Morb Mortal Wkly Rep . 2017;66(49):1347–1350. Ventura CV, Maia M, Dias N, et al. Zika: neurological and

ocular findings in infant without microcephaly. Lancet . 2016;387:2502. Ventura CV, Maia M, Travassos SB, et al. Risk factors associated with the ophthalmoscopic findings identified in infants with presumed Zika virus congenital infection. JAMA Ophthalmol . 2016;134(8):912–918. Weaver SC, Costa F, Garcia-Blanco MA, et al. Zika virus: history, emergence, biology, and prospects for control. Antiviral Res . 2016;130:69–80.

Bibliography Charlier C, Beaudoin MC, Couderc T, et al. Arboviruses and pregnancy: maternal, fetal, and neonatal effects. Lancet Child Adolesc Health . 2017;1:134–146. Gaensbauer JT, Lindsey NP, Messacar K, et al. Neuroinvasive arboviral disease in the United States: 2003 to 2012. Pediatrics . 2014;134(3):e642–e650. Go YY, Balasuriya UB, Lee CK. Zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses. Clin Exp Vaccine Res . 2014;3(1):58–77. Rebaza A, Lee PJ. “One more shot for the road: a review and update of vaccinations for pediatric international travelers.”. Pediatr Ann . 2015;44(4):e89–e96. Ronca SE, Dineley KT, Paessler S. Neurological sequelae resulting from encephalitic alphavirus infection. Front Microbiol . 2016;7:959. Wilson AL, Dhiman RC, Kitron U, et al. Benefit of insecticidetreated nets, curtains and screening on vector borne diseases, excluding malaria: a systematic review and meta-analysis. PLoS Negl Trop Dis . 2014;8(10):e3228.

CHAPTER 295

Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue Scott B. Halstead

Dengue fever is a benign syndrome caused by several arthropod-borne viruses and is characterized by biphasic fever, myalgia or arthralgia, rash, leukopenia, and lymphadenopathy. Dengue hemorrhagic fever (Philippine, Thai, or Singapore hemorrhagic fever; hemorrhagic dengue; acute infectious thrombocytopenic purpura) is a severe, often fatal, febrile disease caused by one of four dengue viruses. It is characterized by capillary permeability, abnormalities of hemostasis, and, in severe cases, a protein-losing shock syndrome (dengue shock syndrome), which is thought to have an immunopathologic basis. A revised case definition adopted by the World Health Organization (WHO) in 2009 includes as severe dengue those cases accompanied by fluid loss leading to shock, fluid loss with respiratory distress, liver damage evidenced by elevations of ALT or AST to > 1000 U/L, severe bleeding, and altered consciousness or significant heart abnormalities.

Etiology There are at least four distinct antigenic types of dengue virus (dengue 1, 2, 3, and 4), members of the family Flaviviridae. In addition, three other arthropodborne viruses (arboviruses) cause similar dengue fever syndromes with rash (Table 295.1 ; see also Chapter 294 ). Table 295.1

Vectors and Geographic Distribution of Dengue-Like

Diseases GEOGRAPHIC GENUS AND DISEASE Togavirus Chikungunya VIRUS

Togavirus O'nyong-nyong Flavivirus West Nile fever

VECTOR

DISTRIBUTION

Aedes aegypti Aedes africanus Aedes albopictus Anopheles funestus Culex molestus Culex univittatus

Africa, India, Southeast Asia, Latin America, United States

East Africa Europe, Africa, Middle East, India

Epidemiology Dengue viruses are transmitted by mosquitoes of the Stegomyia family. Aedes aegypti, a daytime biting mosquito, is the principal vector, and all four virus types have been recovered from it. Transmission occurs from viremic humans by bite of the vector mosquito where virus multiplies during an extrinsic incubation period and then by bite is passed on to a susceptible human in what is called the urban transmission cycle. In most tropical areas, A. aegypti is highly urbanized, breeding in water stored for drinking or bathing and in rainwater collected in any container. Dengue viruses have also been recovered from Aedes albopictus, as in the 2001 and 2015 Hawaiian epidemics, whereas outbreaks in the Pacific area have been attributed to several other Aedes species. These species breed in water trapped in vegetation. In Southeast Asia and West Africa, dengue virus may be maintained in a cycle involving canopy-feeding jungle monkeys and Aedes species, which feed on monkeys. In the 19th and 20th centuries, epidemics were common in temperate areas of the Americas, Europe, Australia, and Asia. Dengue fever and dengue-like disease are now endemic in tropical Asia, the South Pacific Islands, northern Australia, tropical Africa, the Arabian Peninsula, the Caribbean, and Central and South America (Fig. 295.1 ). Dengue fever occurs frequently among travelers to these areas. Locally acquired disease has been reported in Florida, Arizona, and Texas, and imported cases in the United States occur in travelers to endemic areas. More than 390 million dengue infections occur annually; approximately 96 million have clinical disease.

FIG. 295.1 Global dengue burden, 2014. (From Guzman MG, Harris E: Dengue, Lancet 385:453-462, 2015, Fig. 1.)

Dengue outbreaks in urban areas infested with A. aegypti may be explosive; in virgin soil epidemics, up to 70–80% of the population may be involved. Most overt disease occurs in older children and adults. Because A. aegypti has a limited flight range, spread of an epidemic occurs mainly through viremic human beings and follows the main lines of transportation. Sentinel cases may infect household mosquitoes; a large number of nearly simultaneous secondary infections give the appearance of a contagious disease. Where dengue is highly endemic, children and susceptible foreigners may be the only persons to acquire overt disease, because adults have become immune.

Dengue-Like Diseases Dengue-like diseases may occur in epidemics. Epidemiologic features depend on the vectors and their geographic distribution (see Chapter 294 ). Chikungunya virus is enzootic in subhuman primates throughout much of West, Central, and South Africa. Periodic introductions of virus into the urban transmission cycle have led to pandemics, resulting in widespread endemicity in the most populous areas of Asia. In Asia, A. aegypti is the principal vector; in Africa, other Stegomyia species may be important vectors. In Southeast Asia, dengue and chikungunya outbreaks occur concurrently in the urban cycle. Outbreaks of o'nyong-nyong fever usually involve villages or small towns, in contrast to the urban outbreaks of dengue and chikungunya. West Nile virus is enzootic in Africa. Chikungunya is now endemic in urban cycles in tropical countries throughout the world. Intense transmission in Caribbean and Central and South

American countries beginning in 2013 results in the emergence of limited chikungunya transmission in the United States.

Dengue Hemorrhagic Fever Dengue hemorrhagic fever occurs where multiple types of dengue virus are simultaneously or sequentially transmitted. It is endemic in tropical America, Asia, the Pacific Islands, and parts of Africa, where warm temperatures and the practices of water storage in homes plus outdoor breeding sites result in large, permanent populations of A. aegypti. Under these conditions, infections with dengue viruses of all types are common. A first infection, referred to as a primary infection, may be followed by infection with a different dengue virus, referred to as a secondary infection. In areas of high endemicity, secondary infections are frequent. Secondary dengue infections are relatively mild in the majority of instances, ranging from an inapparent infection through an undifferentiated upper respiratory tract or dengue-like disease, but may also progress to dengue hemorrhagic fever. Nonimmune foreigners, both adults and children, who are exposed to dengue virus during outbreaks of hemorrhagic fever have classic dengue fever or even milder disease. The differences in clinical manifestations of dengue infections between natives and foreigners in Southeast Asia are related to immunologic status. Dengue hemorrhagic fever can occur during primary dengue infections, most frequently in infants whose mothers are immune to dengue. Dengue hemorrhagic fever or severe dengue occurs rarely in individuals of African ancestry because of an as yet incompletely described resistance gene that is consistent with the low incidence of severe dengue throughout much of Africa and among African populations in the American tropics despite high rates of dengue infection.

Pathogenesis The pathogenesis of dengue hemorrhagic fever is incompletely understood, but epidemiologic studies usually associate this syndrome with second heterotypic infections with dengue types 1-4 or in infants born to mothers who have had two or more lifetime dengue infections. Retrospective studies of sera from human mothers whose infants acquired dengue hemorrhagic fever and prospective studies in children acquiring sequential dengue infections have shown that the

circulation of infection-enhancing antibodies at the time of infection is the strongest risk factor for development of severe disease. The absence of crossreactive neutralizing antibodies and presence of enhancing antibodies from passive transfer or active production are the best correlates of risk for dengue hemorrhagic fever. Monkeys that are infected sequentially or are receiving small quantities of enhancing antibodies have enhanced viremias. In humans studied early during the course of secondary dengue infections, viremia levels directly predicted disease severity. When dengue virus immune complexes attach to monocyte/macrophage Fc receptors, a signal is sent that suppresses innate immunity, resulting in enhanced viral production. In the Americas, dengue hemorrhagic fever and dengue shock syndrome have been associated with dengue types 1-4 strains of recent Southeast Asian origin. Outbreaks of dengue hemorrhagic fever in all areas of the world are correlated with secondary dengue infections while recent outbreaks in India, Pakistan, and Bangladesh are related to imported dengue strains. Early in the acute stage of secondary dengue infections, there is rapid activation of the complement system. Shortly before or during shock, blood levels of soluble tumor necrosis factor receptor, interferon-γ, and interleukin-2 are elevated. C1q, C3, C4, C5-C8, and C3 proactivators are depressed, and C3 catabolic rates are elevated. Circulating viral nonstructural protein 1 (NS1) is a viral toxin that activates myeloid cells to release cytokines by attaching to toll receptor 4. It also contributes to increased vascular permeability by activating complement, interacting with and damaging endothelial cells, and interacting with blood clotting factors and platelets. The mechanism of bleeding in dengue hemorrhagic fever is not known, but a mild degree of disseminated intravascular coagulopathy, liver damage, and thrombocytopenia may operate synergistically. Capillary damage allows fluid, electrolytes, small proteins, and, in some instances, red blood cells to leak into extravascular spaces. This internal redistribution of fluid, together with deficits caused by fasting, thirsting, and vomiting, results in hemoconcentration, hypovolemia, increased cardiac work, tissue hypoxia, metabolic acidosis, and hyponatremia. Usually no pathologic lesions are found to account for death. In rare instances, death may be a result of gastrointestinal or intracranial hemorrhages. Minimal to moderate hemorrhages are seen in the upper gastrointestinal tract, and petechial hemorrhages are common in the interventricular septum of the heart, on the pericardium, and on the subserosal surfaces of major viscera. Focal hemorrhages are occasionally seen in the lungs, liver, adrenals, and subarachnoid space. The

liver is usually enlarged, often with fatty changes. Yellow, watery, and at times blood-tinged effusions are present in serous cavities in approximately 75% of patients at autopsy. Dengue virus is frequently absent in tissues at the time of death; viral antigens or RNA have been localized to hepatocytes and macrophages in the liver, spleen, lung, and lymphatic tissues.

Clinical Manifestations Dengue Fever The incubation period is 1-7 days. The clinical manifestations are variable and are influenced by the age of the patient. In infants and young children, the disease may be undifferentiated or characterized by fever for 1-5 days, pharyngeal inflammation, rhinitis, and mild cough. A majority of infected older children and adults experience sudden onset of fever, with temperature rapidly increasing to 39.4-41.1°C (103-106°F), usually accompanied by frontal or retroorbital pain, particularly when pressure is applied to the eyes. Occasionally, severe back pain precedes the fever (back-break fever). A transient, macular, generalized rash that blanches under pressure may be seen during the first 24-48 hr of fever. The pulse rate may be slow relative to the degree of fever. Myalgia and arthralgia occur soon after the onset of fevers and increase in severity over time. From the second to sixth day of fever, nausea and vomiting are apt to occur, and generalized lymphadenopathy, cutaneous hyperesthesia or hyperalgesia, taste aberrations, and pronounced anorexia may develop. Approximately 1-2 days after defervescence, a generalized, morbilliform, maculopapular rash appears that spares the palms and soles. It disappears in 1-5 days; desquamation may occur. Rarely there is edema of the palms and soles. About the time this second rash appears, the body temperature, which has previously decreased to normal, may become slightly elevated and demonstrate the characteristic biphasic temperature pattern.

Dengue Hemorrhagic Fever and Dengue Shock Syndrome (DHF/DSS) The differentiation between dengue fever and dengue hemorrhagic fever is difficult early in the course of illness. A relatively mild first phase with abrupt

onset of fever, malaise, vomiting, headache, anorexia, and cough may be followed after 2-5 days by rapid clinical deterioration and collapse. In this second phase, the patient usually has cold, clammy extremities, a warm trunk, flushed face, diaphoresis, restlessness, irritability, midepigastric pain, and decreased urinary output. Frequently, there are scattered petechiae on the forehead and extremities; spontaneous ecchymoses may appear, and easy bruising and bleeding at sites of venipuncture are common. A macular or maculopapular rash may appear, and there may be circumoral and peripheral cyanosis. Respirations are rapid and often labored. The pulse is weak, rapid, and thready, and the heart sounds are faint. The liver may enlarge to 4-6 cm below the costal margin and is usually firm and somewhat tender. Approximately 20– 30% of cases of dengue hemorrhagic fever are complicated by shock (dengue shock syndrome). Dengue shock can be subtle, arising in patients who are fully alert, and is accompanied by increased peripheral vascular resistance and raised diastolic blood pressure. Shock is not from congestive heart failure but from venous pooling. With increasing cardiovascular compromise, the diastolic pressure rises toward the systolic level and the pulse pressure narrows. Fewer than 10% of patients have gross ecchymosis or gastrointestinal bleeding, usually after a period of uncorrected shock. After a 24- to 36-hr period of crisis, convalescence is fairly rapid in the children who recover. The temperature may return to normal before or during the stage of shock. Bradycardia and ventricular extrasystoles are common during convalescence.

Dengue With Warning Signs and Severe Dengue In hyperendemic areas, among Asian children, the DHF/DSS continues to be the dominant life-threatening event, always challenging to an identifying physician using classical WHO diagnostic criteria. When the four dengue viruses spread to the American hemisphere and to South Asia, there were millions of primary and secondary dengue infections, many of them adults of all ages. Dengue disease in these areas presented a wider clinical spectrum resulting in a new diagnostic algorithm and case definitions (see below).

Diagnosis A clinical diagnosis of dengue fever derives from a high index of suspicion and knowledge of the geographic distribution and environmental cycles of causal

viruses (for nondengue causes see Chapter 294 ). Because clinical findings vary and there are many possible causative agents, the term dengue-like disease should be used until a specific diagnosis is established. A case is confirmed by isolation of the virus, viral antigen, or genome by polymerase chain reaction analysis, the detection of IgM dengue antibodies as well as demonstration of a four-fold or greater increase in antibody titers. A probable case is a typical acute febrile illness with supportive serology and occurrence at a location where there are confirmed cases. The WHO criteria for dengue hemorrhagic fever are fever (2-7 days in duration or biphasic), minor or major hemorrhagic manifestations including a positive tourniquet test, thrombocytopenia (≤100,000/µL), and objective evidence of increased capillary permeability (hematocrit increased by ≥ 20%), pleural effusion or ascites (by chest radiography or ultrasonography), or hypoalbuminemia. Dengue shock syndrome criteria include those for dengue hemorrhagic fever as well as hypotension, tachycardia, narrow pulse pressure (≤20 mm Hg), and signs of poor perfusion (cold extremities). In 2009, the WHO promulgated guidelines for the diagnosis of probable dengue, dengue with warning signs, and a category called severe dengue (Fig. 295.2 ). The presence of warning signs in an individual with probable dengue alerts the physician to the possible need for hospitalization. Severe dengue is a mixture of syndromes associated with dengue infection, including classical DHF/DSS, but also rare instances of encephalitis or encephalopathy, liver damage, or myocardial damage. Severe dengue also includes respiratory distress, a harbinger of pulmonary edema caused by overhydration, an all too common outcome of inexpert treatment (see Treatment and Complications sections).

FIG. 295.2 Suggested dengue case classification and levels of severity. (From World Health Organization (WHO) and Special Programme for Research and Training in Tropical Diseases (TDR): 2009 Dengue: guidelines for diagnosis, treatment, prevention and control, Fig. 1.4, http://apps.who.int/iris/bitstream/handle/10665/44188/9789241547871_eng.pdf? sequence=1 .)

Virologic diagnosis can be established by serologic tests, by detection of viral proteins or viral RNA, or by the isolation of the virus from blood leukocytes or acute-phase serum. Following primary and secondary dengue infections, there is an appearance of antidengue (immunoglobulin [Ig] M) antibodies. These disappear after 6-12 wk, a feature that can be used to date a dengue infection. In secondary dengue infections, most dengue antibody is of the IgG class. Serologic diagnosis depends on a four-fold or greater increase in IgG antibody titer in paired sera by hemagglutination inhibition, complement fixation, enzyme immunoassay, or neutralization test. Carefully standardized IgM and IgG capture enzyme commercial immunoassays are now widely used to identify acute-phase antibodies from patients with primary or secondary dengue infections in singleserum samples. Usually such samples should be collected not earlier than 5 days and not later than 6 wk after onset. It may not be possible to distinguish the infecting virus by serologic methods alone, particularly when there has been prior infection with another member of the same arbovirus group. Virus can be recovered from acute-phase serum after inoculating tissue culture or living mosquitoes. Viral RNA can be detected in blood or tissues by specific complementary RNA probes or amplified first by polymerase chain reaction or

by real-time polymerase chain reaction. A viral nonstructural protein, NS1, is released by infected cells into the circulation and can be detected in acute-stage blood samples using monoclonal or polyclonal antibodies. The detection of NS1 is the basis of commercial tests, including rapid lateral flow tests. These tests offer a reliable point-of-care diagnosis of acute dengue infection.

Differential Diagnosis The differential diagnosis of dengue fever includes dengue-like diseases, viral respiratory and influenza-like diseases, the early stages of malaria, mild yellow fever, scrub typhus, viral hepatitis, and leptospirosis. Four arboviral diseases have dengue-like courses but without rash: Colorado tick fever, sandfly fever, Rift Valley fever, and Ross River fever (see Chapter 294 ). Colorado tick fever occurs sporadically among campers and hunters in the western United States; sandfly fever in the Mediterranean region, the Middle East, southern Russia, and parts of the Indian subcontinent; and Rift Valley fever in North, East, Central, and South Africa. Ross River fever is endemic in much of eastern Australia, with epidemic extension to Fiji. In adults, Ross River fever often produces protracted and crippling arthralgia involving weight-bearing joints. Because meningococcemia, yellow fever (see Chapter 296 ), other viral hemorrhagic fevers (see Chapter 297 ), many rickettsial diseases, and other severe illnesses caused by a variety of agents may produce a clinical picture similar to dengue hemorrhagic fever, the etiologic diagnosis should be made only when epidemiologic or serologic evidence suggests the possibility of a dengue infection.

Laboratory Findings In dengue fever, pancytopenia may develop after the 3-4 days of illness. Neutropenia may persist or reappear during the latter stage of the disease and may continue into convalescence, with white blood cell counts < 2,000/µL. Platelet counts rarely fall below 100,000/µL. Venous clotting, bleeding and prothrombin times, and plasma fibrinogen values are within normal ranges. The tourniquet test result may be positive. Mild acidosis, hemoconcentration, increased transaminase values, and hypoproteinemia may occur during some

primary dengue virus infections. The electrocardiogram may show sinus bradycardia, ectopic ventricular foci, flattened T waves, and prolongation of the P-R interval. The most common hematologic abnormalities during dengue hemorrhagic fever and dengue shock syndrome are hemoconcentration with an increase of > 20% in the hematocrit, thrombocytopenia, a prolonged bleeding time, and a moderately decreased prothrombin level that is seldom < 40% of control. Fibrinogen levels may be subnormal, and fibrin split-product values are elevated. Other abnormalities include moderate elevations of serum transaminase levels, consumption of complement, mild metabolic acidosis with hyponatremia, occasionally hypochloremia, slight elevation of serum urea nitrogen, and hypoalbuminemia. Roentgenograms of the chest reveal pleural effusions (right > left) in nearly all patients with dengue shock syndrome. Ultrasonography can be used to detect serosal effusions of the thorax or abdomen. Thickening of the gallbladder wall and the presence of perivesicular fluid are characteristic signs of increased vascular permeability.

Treatment Treatment of uncomplicated dengue fever is supportive. Bed rest is advised during the febrile period. Antipyretics should be used to keep the body temperature < 40°C (104°F). Analgesics or mild sedation may be required to control pain. Aspirin is contraindicated and should not be used because of its effects on hemostasis. Fluid and electrolyte replacement is required for deficits caused by sweating, fasting, thirsting, vomiting, and diarrhea.

Dengue Hemorrhagic Fever and Dengue Shock Syndrome Dengue shock syndrome is a medical emergency that may occur in any child who lives in or has a recent travel history to a tropical destination. Management begins with diagnostic suspicion and the understanding that shock often accompanies defervescence. Detailed instructions for case management are available at the Geneva or New Delhi WHO websites: http://www.who.int/csr/don/archive/disease/dengue_fever/dengue.pdf . Management of dengue hemorrhagic fever and dengue shock syndrome includes

immediate evaluation of vital signs and degrees of hemoconcentration, dehydration, and electrolyte imbalance. Close monitoring is essential for at least 48 hr because shock may occur or recur precipitously, usually several days after the onset of fever. Patients who are cyanotic or have labored breathing should be given oxygen. Rapid intravenous replacement of fluids and electrolytes can frequently sustain patients until spontaneous recovery occurs. Normal saline is more effective than the more expensive Ringer lactated saline in treating shock. When the pulse pressure is ≤10 mm Hg or when elevation of the hematocrit persists after the replacement of fluids, plasma or colloid preparations are indicated. Oral rehydration of children who are being monitored is useful. Prophylactic platelet transfusions have not been shown to reduce the risk of hemorrhaging or improve low platelet counts and may be associated with adverse effects. Care must be taken to avoid overhydration, which may contribute to cardiac failure. Transfusions of fresh blood may be required to control bleeding but should not be given during hemoconcentration but only after evaluation of hemoglobin or hematocrit values. Salicylates are contraindicated because of their effect on blood clotting. Sedation may be required for children who are markedly agitated. Use of vasopressors has not resulted in a significant reduction of mortality rates over that observed with simple supportive therapy. Disseminated intravascular coagulation may require treatment (see Chapter 510 ). Corticosteroids do not shorten the duration of disease or improve the prognosis in children receiving careful supportive therapy.

Complications Hypervolemia during the fluid reabsorptive phase may be life-threatening and is heralded by a decrease in hematocrit with wide pulse pressure. Diuretics and digitalization may be necessary. Primary infections with dengue fever and dengue-like diseases are usually self-limited and benign. Fluid and electrolyte losses, hyperpyrexia, and febrile convulsions are the most frequent complications in infants and young children. Epistaxis, petechiae, and purpuric lesions are uncommon but may occur at any stage. Blood from epistaxis that is swallowed, vomited, or passed by rectum may be erroneously interpreted as gastrointestinal bleeding. In adults and possibly in children, underlying conditions may lead to clinically significant bleeding.

Convulsions may occur during a high temperature. Infrequently, after the febrile stage, prolonged asthenia, mental depression, bradycardia, and ventricular extrasystoles may occur in children. In endemic areas, dengue hemorrhagic fever should be suspected in children with a febrile illness suggestive of dengue fever who experience hemoconcentration and thrombocytopenia.

Prognosis Dengue Fever The prognosis for dengue fever is good. Care should be taken to avoid the use of drugs that suppress platelet activity.

Dengue Hemorrhagic Fever The prognosis of dengue hemorrhagic fever is adversely affected by a late diagnosis and delayed or improper treatment. Death has occurred in 40–50% of patients with shock, but with adequate intensive care, deaths should occur in < 1% of cases. Infrequently, there is residual brain damage as a consequence of prolonged shock or occasionally of intracranial hemorrhage. Many fatalities are caused by overhydration.

Prevention Dengue vaccines have been under development continuously since the 1970s. One such vaccine, Dengvaxia, developed by Sanofi Pasteur, is a mixture of four chimeras, DENV structural genes coupled with nonstructural genes of yellow fever 17D. In 2015, Dengvaxia completed phase III per protocol analyses on 32,568 children, vaccinated and controls, ages 2-16 yr. These studies revealed poor protection of seronegatives and good protection of seropositives with a reduction of hospitalization and severe disease in vaccinated children 9 yr old versus controls. Based on these data, this vaccine was endorsed by the WHO for targeted use in individuals 9 yr of age and older, living in countries that are highly endemic for dengue; it now is licensed for use in 14 countries. Other dengue type 1-4 vaccines are under development by the U.S. National Institutes of Health and Instituto Butantan in Sao Paulo, Brazil, and Takeda, Inc.

Dengvaxia seronegative recipients who were incompletely protected were apparently sensitized to experience the enhanced disease of hospitalized dengue. Prophylaxis in the absence of vaccine consists of avoiding daytime householdbased mosquito bites through the use of insecticides, repellents, body covering with clothing, screening of houses, and destruction of A. aegypti breeding sites. If water storage is mandatory, a tight-fitting lid or a thin layer of oil may prevent egg laying or hatching. A larvicide, such as Abate (O,O′-[thiodi-p -phenylene] O,O,O,O′-tetramethyl phosphorothioate), available as a 1% sand-granule formation and effective at a concentration of 1 ppm, may be added safely to drinking water. Ultra-low-volume spray equipment effectively dispenses the adulticide malathion from trucks or airplanes for rapid intervention during an epidemic. Mosquito repellants and other personal antimosquito measures are effective in preventing mosquito bites in the field, forest, or jungle.

Bibliography Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature . 2013;496(7446):504–507. Brady OJ, Gething PW, Bhatt S, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis . 2012;6(8):e1760. Furuya-Kanamori L, Liang S, Milinovich G, et al. Codistribution and co-infection of chikungunya and dengue viruses. BMC Infect Dis . 2016;16:84. Glasner DR, Puerta-Guardo H, Beatty PR, et al. The good, the bad, and the shocking: the multiple roles of dengue virus nonstructural protein 1 in protection and pathogenesis. Annu Rev Virol . 2018;5(1):227–253. Guzman MG, Gubler DJ, Izquierdo A, et al. Dengue infection. Nat Rev Dis Primers . 2016;2:16055. Halstead SB. Pathogenesis of dengue: dawn of a new era. F1000Res . 2015;4(F1000FacultyRev):1315. Halstead SB. Dengue. Lancet . 2007;370(9599):1644–1652. Halstead SB. Safety issues from a Phase 3 clinical trial of a live-

attenuated chimeric yellow fever tetravalent dengue vaccine. Hum Vaccin Immunother . 2018;14(9):2158–2162. Halstead SB. Which dengue vaccine approach is the most promising, and should we be concerned about enhanced disease after vaccination? there is only one true winner. Cold Spring Harb Perspect Biol . 2018;10(6). Johnstom D, Viray M, Ushiroda J, et al. Outbreak of locally acquired cases of dengue fever—Hawaii, 2015. MMWR Morb Mortal Wkly Rep . 2016;65(2):34. Jones JM, Lopez B, Adams L, et al. Binational dengue outbreak along the United States-Mexico border—Yuma county, Arizona, and Sonora, Mexico, 2014. MMWR Morb Mortal Wkly Rep . 2016;65(19):495–499. Katzelnick LC, Coloma J, Harris E. Dengue: knowledge gaps, unmet needs, and research priorities. Lancet Infect Dis . 2017;17(3):ee100. Lee TH, Lee LK, Lye DC, et al. Current management of severe dengue infection. Expert Rev Anti Infect Ther . 2017;15(1):67–78. Lye DC, Archuleta S, Syed-Omar SF, et al. Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a mulricentre, open-label, randomised, superiority trial. Lancet . 2017;389:1611–1618. Martina BE, Barzon L, Pijlman GP, et al. Human to human transmission of arthropod-borne pathogens. Curr Opin Virol . 2017;22:13–21. Medeiros DN, Ferranti JF, Delgado AF, et al. Colloids for the Initial Management of Severe Sepsis and Septic Shock in Pediatric Patients: a Systematic Review. Pediatr Emerg Care . 2015;31:e11. Sharp TM, Tomashek KM, Read JS, et al. A new look at an old disease: recent insights into the global epidemiology of

Dengue. Curr Epidemiol Rep . 2017;4(1):11–21. Simmons CP, McPherson K, Van Vinh Chau N, et al. Recent advances in dengue pathogenesis and clinical management. Vaccine . 2015;33(50):7061–7068. Sierra B, Triska P, Soares P, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against Dengue haemorrhagic fever in admixed Cubans. PLoS Pathog . 2017;13(2):e1006220. Stanaway JD, Shepard DS, Undurraga EA, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis . 2016;16(6):71223. Wakimoto MD, Camacho LA, Guaraldo L, et al. Dengue in children: a systematic review of clinical and laboratory factors associated with severity. Expert Rev Anti Infect Ther . 2015;13(12):1441–1456. World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control . WHO.: Geneva, Switzerland; 2009 http://apps.who.int/iris/bitstream/handle/10665/44188/9789241547871_e sequence=1 .

CHAPTER 296

Yellow Fever Scott B. Halstead

Yellow fever is an acute infection characterized in its most severe form by fever, jaundice, proteinuria, and hemorrhage. The virus is mosquito-borne and occurs in epidemic or endemic form in South America and Africa. Seasonal epidemics occurred in cities located in temperate areas of Europe and the Americas until 1900, and epidemics continue in West, Central, and East Africa.

Etiology Yellow fever is the prototype of the Flavivirus genus of the family Flaviviridae, which are enveloped single-stranded RNA viruses 35-50 nm in diameter. Yellow fever circulates zoonotically as five genotypes: type IA in West Central Africa, type IB in South America, type II in West Africa, type III in East Central Africa, and type IV in East Africa. Types IA and IB virus are capable of urban transmission between human beings by Aedes aegypti. Sometime in the 1600s, yellow fever virus was brought to the American tropics through the African slave trade. Subsequently, yellow fever caused enormous coastal and riverine epidemics in the Atlantic and Caribbean basins until the 20th century, when the virus and its urban and sylvan mosquito cycles were identified, mosquito control methods were perfected, and a vaccine was developed. The East and East/Central African genotypes have not fully entered the urban cycle and have not spread to the East Coast of Africa or to the countries of Asia.

Epidemiology Human and nonhuman primate hosts acquire the yellow fever infection by the

bite of infected mosquitoes. After an incubation period of 3-6 days, virus appears in the blood and may serve as a source of infection for other mosquitoes. The virus must replicate in the gut of the mosquito and pass to the salivary gland before the mosquito can transmit the virus. Yellow fever virus is transmitted in an urban cycle—human to A. aegypti to human—and a jungle cycle—monkey to jungle mosquitoes to monkey. Classic yellow fever epidemics in the United States, South America, the Caribbean, and parts of Europe were of the urban variety. Since 2000, West Africa has experienced five urban epidemics, including in the capital cities of Abidjan (Cote d'Ivoire), Conakry (Guinea), and Dakar (Senegal). In 2012-2013, large outbreaks of East and East/Central yellow fever occurred across a large, predominantly rural area of war-ravaged Darfur in southwestern Sudan and in adjacent areas of northern Uganda. Beginning in 2015 and continuing to mid-2016, there were sharp outbreaks of yellow fever in and around Rwanda, Angola, and the bordering Democratic Republic of Congo, where there were 7,000 reported cases and 500 deaths. Eleven cases were imported into China by workers in Angola. In South America, all of the approximately 200 cases reported each year are jungle yellow fever. In late 2016 and continuing through 2018, a widespread zoonosis resulted in an estimated 2,000 yellow fever cases in Brazil. In colonial times, urban yellow fever attack rates in white adults were very high, suggesting that subclinical infections are uncommon in this age-group. Yellow fever may be less severe in children, with subclinical infection:clinical case ratios ≥ 2:1. In areas where outbreaks of urban yellow fever are common, most cases involve children because many adults are immune. Transmission in West Africa is highest during the rainy season, from July to November. In tropical forests, yellow fever virus is maintained in a transmission cycle involving monkeys and tree hole–breeding mosquitoes (Haemagogus in Central and South America; the Aedes africanus complex in Africa). In the Americas, most cases involve tourists, campers, those who work in forested areas, and vacationers exposed to infected mosquitoes. In Africa, enzootic virus is prevalent in moist savanna and savanna transition areas, where other tree hole– breeding Aedes vectors transmit the virus between monkeys and humans and between humans.

Pathogenesis Pathologic changes seen in the liver include (1) coagulative necrosis of

hepatocytes in the midzone of the liver lobule, with sparing of cells around the portal areas and central veins; (2) eosinophilic degeneration of hepatocytes (Councilman bodies); (3) microvacuolar fatty change; and (4) minimal inflammation. The kidneys show acute tubular necrosis. In the heart, myocardial fiber degeneration and fatty infiltration are seen. The brain may show edema and petechial hemorrhages. Direct viral injury to the liver results in impaired ability to perform functions of biosynthesis and detoxification; this is the central pathogenic event of yellow fever. Hemorrhage is postulated to result from decreased synthesis of vitamin K–dependent clotting factors and, in some cases, disseminated intravascular clotting. However, because the pathogenesis of shock in patients with yellow fever appears similar to that described for dengue shock syndrome and the other viral hemorrhagic fevers, viral damage to platelets and endothelial cells resulting in the release of prohemorrhagic factors may be the central mechanism of hemorrhage in yellow fever. Death and severe disease rates are lower in susceptible subSaharan African blacks than in other racial groups, suggesting existence of a resistance gene. Renal dysfunction has been attributed to hemodynamic factors (prerenal failure progressing to acute tubular necrosis).

Clinical Manifestations In Africa, inapparent, abortive, or clinically mild infections are frequent; some studies suggest that children experience a milder disease than do adults. Abortive infections, characterized by fever and headache, may be unrecognized except during epidemics. In its classic form, yellow fever begins with a sudden onset of fever, headache, myalgia, lumbosacral pain, anorexia, nausea, and vomiting. Physical findings during the early phase of illness, when virus is present in the blood, include prostration, conjunctival injection, flushing of the face and neck, reddening of the tongue at the tip and edges, and relative bradycardia. After 2-3 days, there may be a brief period of remission, followed in 6-24 hr by the reappearance of fever with vomiting, epigastric pain, jaundice, dehydration, gastrointestinal and other hemorrhages, albuminuria, hypotension, renal failure, delirium, convulsions, and coma. Death may occur after 7-10 days, with the fatality rate in severe cases approaching 50%. Some patients who survive the acute phase of illness later succumb to renal failure or myocardial damage. Laboratory abnormalities include leukopenia; prolonged clotting, prothrombin, and partial

thromboplastin times; thrombocytopenia; hyperbilirubinemia; elevated serum transaminase values; albuminuria; and azotemia. Hypoglycemia may be present in severe cases. Electrocardiogram abnormalities such as bradycardia and ST-T changes are described.

Diagnosis Yellow fever should be suspected when fever, headache, vomiting, myalgia, and jaundice appear in residents of enzootic areas or in unimmunized visitors who have recently traveled (within 2 wk Before the onset of symptoms) to endemic areas. There are clinical similarities between yellow fever and dengue hemorrhagic fever. In contrast to the gradual onset of acute viral hepatitis resulting from hepatitis A, B, C, D, or E virus, jaundice in yellow fever appears after 3-5 days of high temperature and is often accompanied by severe prostration. Mild yellow fever is dengue-like and cannot be distinguished from a wide variety of other infections. Jaundice and fever may occur in any of several other tropical diseases, including malaria, viral hepatitis, louse-borne relapsing fever, leptospirosis, typhoid fever, rickettsial infections, certain systemic bacterial infections, sickle cell crisis, Rift Valley fever, Crimean-Congo hemorrhagic fever, and other viral hemorrhagic fevers. Outbreaks of yellow fever always include cases with severe gastrointestinal hemorrhage. The specific diagnosis depends on the detection of the virus or viral antigen in acute-phase blood samples or antibody assays. The immunoglobulin M enzyme immunoassay is particularly useful. Sera obtained during the first 10 days after the onset of symptoms should be kept in an ultra-low-temperature freezer (−70°C [−94°F]) and shipped on dry ice for virus testing. Convalescent-phase samples for antibody tests are managed by conventional means. In handling acute-phase blood specimens, medical personnel must take care to avoid contaminating themselves or others on the evacuation trail (laboratory personnel and others). The postmortem diagnosis is based on virus isolation from liver or blood, identification of Councilman bodies in liver tissue, or detection of antigen or viral genome in liver tissue.

Treatment It is customary to keep patients with yellow fever in a mosquito-free area, with

use of mosquito nets if necessary. Patients are viremic during the febrile phase of the illness. Although there is no specific treatment for yellow fever, medical care is directed at maintaining the physiologic status with the following measures: (1) sponging and acetaminophen to reduce a high temperature, (2) vigorous fluid replacement of losses resulting from fasting, thirsting, vomiting, or plasma leakage, (3) correcting an acid-base imbalance, (4) maintaining nutritional intake to lessen the severity of hypoglycemia, and (5) avoiding drugs that are either metabolized by the liver or toxic to the liver, kidney, or central nervous system.

Complications Complications of acute yellow fever include severe hemorrhage, liver failure, and acute renal failure. Bleeding should be managed by transfusion of fresh whole blood or fresh plasma with platelet concentrates if necessary. Renal failure may require peritoneal dialysis or hemodialysis.

Prevention Yellow fever 17D is a live-attenuated vaccine with a long record of safety and efficacy. It is administered as a single 0.5-mL subcutaneous injection at least 10 days before arrival in a yellow fever–endemic area. YF-VAX, manufactured by Sanofi Pasteur, is licensed for use in the United States. With the exceptions noted later, individuals traveling to endemic areas in South America and Africa should be considered for vaccination, but the length of stay, exact locations to be visited, and environmental or occupational exposure may determine the specific risk and individual need for vaccination. Persons traveling from yellow fever– endemic to yellow fever–receptive countries may be required by national authorities to obtain a yellow fever vaccine (e.g., from South America or Africa to India). Usually, countries that require travelers to obtain a yellow fever immunization do not issue a visa without a valid immunization certificate. Vaccination is valid for 10 yr for international travel certification, although immunity lasts at least 40 yr and probably for life. Immunoglobulin M antibodies circulate for years after administration of yellow fever vaccine. Since 1996, there have been a number of reports of yellow fever vaccine– associated viscerotropic disease with a higher risk in elderly vaccine recipients and a few cases in persons with previous thymectomies. Yellow fever vaccine

should not be administered to persons who have symptomatic immunodeficiency diseases, are taking immunosuppressant drugs, have HIV, or have a history of thymectomy. A recent study has shown that individuals taking maintenance corticosteroids may be successfully vaccinated. Although the vaccine is not known to harm fetuses, its administration during pregnancy is not advised. The vaccine virus may be rarely transmitted through breastfeeding. In very young children, there is a small risk of encephalitis and death after yellow fever 17D vaccination. The 17D vaccine should not be administered to infants younger than 6 mo. Residence in or travel to areas of known or anticipated yellow fever activity (e.g., forested areas in the Amazon basin), which puts an individual at high risk, warrants immunization of infants 6-8 mo of age. Immunization of children 9 mo of age and older is routinely recommended before entry into endemic areas. Immunization of persons older than 60 yr of age should be weighed against their risk for sylvatic yellow fever in the American tropics and for urban or sylvatic yellow fever in Africa. Vaccination should be avoided in persons with a history of egg allergy. Alternatively, a skin test can be performed to determine whether a serious allergy exists that would preclude vaccination.

Bibliography https://wwwnc.cdc.gov/travel/yellowbook/2016/infectiousdiseases-related-to-travel/yellow-fever . Barrett AD. Yellow fever in Angola and Beyond—The problem of vaccine supply and demand. N Engl J Med . 2016;375:301–303. Boyd AT, Dombaxe D, Moreira R, et al. Investigation of patients testing positive for yellow fever viral RNA after vaccination during a mass yellow fever vaccination campaign —Angola, 2016. MMWR Morb Mortal Wkly Rep . 2017;66(10):282–283. Calisher CH, Woodall JP. Yellow fever-more a policy and planning problem than a biological one. Emerg Infect Dis . 2016;22:1859–1860. Collins ND, Barrett AD. Live attenuated yellow fever 17D vaccine: a legacy vaccine still controlling outbreaks in

modern day. Curr Infect Dis Rep . 2017;19:14. Grobbelaar AA, Weyer J, Moolla N, et al. Resurgence of yellow fever in Angola, 2015-2016. Emerg Infect Dis . 2016;22:1854–1855. Hamer DH, Angelo K, Caumes E, et al. Fatal yellow fever in travelers to Brazil, 2018. MMWR Morb Mortal Wkly Rep . 2018;67(11):340–341. Lindsey NP, Rabe IB, Miller ER, et al. Adverse event reports following yellow fever vaccination, 2007-13. J Travel Med . 2016;23(5). Monath TP, Vasconcelos PF. Yellow fever. J Clin Virol . 2015;64:160–173. Otshudiema JO, Ndakala NG, Mawanda EK, et al. Yellow fever outbreak—Kongo Central Province, Democratic Republic. MMWR Morb Mortal Wkly Rep . 2017;66(12):335–338. Paules CI, Fauci AS. Yellow fever—once again on the radar screen in the Americas. N Engl J Med . 2017;376(15):1397– 1400. Seligman SJ. Risk groups for yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Vaccine . 2014;32:5769– 5775. Thomas RE. Yellow fever vaccine-associated viscerotropic disease: current perspectives. Drug Des Devel Ther . 2016;10:3345–3353. Wieten RW, Jonker EF, van Leeuwen EM, et al. A single 17D yellow fever vaccination provides lifelong immunity; characterization of yellow-fever-specific neutralizing antibody and T-cell responses after vaccination. PLoS ONE . 2016;11:e0149871.

CHAPTER 297

Ebola and Other Viral Hemorrhagic Fevers Scott B. Halstead

Viral hemorrhagic fevers are a loosely defined group of clinical syndromes in which hemorrhagic manifestations are either common or especially notable in severe illness. Both the etiologic agents and clinical features of the syndromes differ, but coagulopathy may be a common pathogenetic feature.

Etiology Six of the viral hemorrhagic fevers are caused by arthropod-borne viruses (arboviruses) (Table 297.1 ). Four are caused by togaviruses of the family Flaviviridae: Kyasanur Forest disease, Omsk hemorrhagic fever, dengue (see Chapter 295 ), and yellow fever (see Chapter 296 ) viruses. Three are caused by viruses of the family Bunyaviridae: Congo fever, Hantaan fever, and Rift Valley fever (RVF) viruses. Four are caused by viruses of the family Arenaviridae: Junin fever, Machupo fever, Guanarito fever, and Lassa fever. Two are caused by viruses in the family Filoviridae : Ebola virus and Marburg virus, enveloped, filamentous RNA viruses that are sometimes branched, unlike any other known virus. Table 297.1

Viral Hemorrhagic Fevers MODE OF TRANSMISSION Tick-borne

DISEASE Crimean-Congo hemorrhagic fever (HF)* Kyasanur Forest disease Omsk HF

VIRUS Congo Kyasanur Forest disease Omsk

Mosquito-borne † Infected animals or materials to humans

Dengue HF Rift Valley fever Yellow fever Argentine HF Bolivian HF Lassa fever* Marburg disease* Ebola HF* HF with renal syndrome

Dengue (4 types) Rift Valley fever Yellow fever Junin Machupo Lassa Marburg Ebola Hantaan

* Patients may be contagious; nosocomial infections are common. † Chikungunya virus is associated infrequently with petechiae and epistaxis. Severe hemorrhagic

manifestations have been reported in some cases.

Epidemiology With some exceptions, the viruses causing viral hemorrhagic fevers are transmitted to humans via a nonhuman entity. The specific ecosystem required for viral survival determines the geographic distribution of disease. Although it is commonly thought that all viral hemorrhagic fevers are arthropod borne, seven may be contracted from environmental contamination caused by animals or animal cells or from infected humans (see Table 297.1 ). Laboratory and hospital infections have occurred with many of these agents. Lassa fever and Argentine and Bolivian hemorrhagic fevers are reportedly milder in children than in adults.

Crimean-Congo Hemorrhagic Fever Sporadic human infection with Crimean-Congo hemorrhagic fever in Africa provided the original virus isolation. Natural foci are recognized in Bulgaria, western Crimea, and the Rostov-on-Don and Astrakhan regions; disease occurs in Central Asia from Kazakhstan to Pakistan. Index cases were followed by nosocomial transmission in Pakistan and Afghanistan in 1976, in the Arabian Peninsula in 1983, and in South Africa in 1984. In the Russian Federation, the vectors are ticks of the species Hyalomma marginatum and Hyalomma anatolicum, which, along with hares and birds, may serve as viral reservoirs. Disease occurs from June to September, largely among farmers and dairy workers.

Kyasanur Forest Disease

Human cases of Kyasanur Forest disease occur chiefly in adults in an area of Mysore State, India. The main vectors are two Ixodidae ticks, Haemaphysalis turturis and Haemaphysalis spinigera. Monkeys and forest rodents may be amplifying hosts. Laboratory infections are common.

Omsk Hemorrhagic Fever Omsk hemorrhagic fever occurs throughout south-central Russia and northern Romania. Vectors may include Dermacentor pictus and Dermacentor marginatus, but direct transmission from moles and muskrats to humans seems well established. Human disease occurs in a spring–summer–autumn pattern, paralleling the activity of vectors. This infection occurs most frequently in persons with outdoor occupational exposure. Laboratory infections are common.

Rift Valley Fever The virus causing RVF is responsible for epizootics involving sheep, cattle, buffalo, certain antelopes, and rodents in North, Central, East, and South Africa. The virus is transmitted to domestic animals by Culex theileri and several Aedes species. Mosquitoes may serve as reservoirs by transovarial transmission. An epizootic in Egypt in 1977-1978 was accompanied by thousands of human infections, principally among veterinarians, farmers, and farm laborers. Smaller outbreaks occurred in Senegal in 1987, Madagascar in 1990, and Saudi Arabia and Yemen in 2000-2001. Humans are most often infected during the slaughter or skinning of sick or dead animals. Laboratory infection is common.

Argentine Hemorrhagic Fever Before the introduction of vaccine, hundreds to thousands of cases of Argentine hemorrhagic fever occurred annually from April through July in the maizeproducing area northwest of Buenos Aires that reaches to the eastern margin of the Province of Cordoba. Junin virus has been isolated from the rodents Mus musculus, Akodon arenicola, and Calomys laucha. It infects migrant laborers who harvest the maize and who inhabit rodent-contaminated shelters.

Bolivian Hemorrhagic Fever The recognized endemic area of Bolivian hemorrhagic fever consists of the

sparsely populated province of Beni in Amazonian Bolivia. Sporadic cases occur in farm families who raise maize, rice, yucca, and beans. In the town of San Joaquin, a disturbance in the domestic rodent ecosystem may have led to an outbreak of household infection caused by Machupo virus transmitted by chronically infected Calomys callosus, ordinarily a field rodent. Mortality rates are high in young children.

Venezuelan Hemorrhagic Fever In 1989, an outbreak of hemorrhagic illness occurred in the farming community of Guanarito, Venezuela, 200 miles south of Caracas. Subsequently, in 19901991, there were 104 cases reported with 26 deaths caused by Guanarito virus. Cotton rats (Sigmodon alstoni) and cane rats (Zygodontomys brevicauda) have been implicated as likely reservoirs of Venezuelan hemorrhagic fever.

Lassa Fever Lassa virus has an unusual potential for human-to-human spread, which has resulted in many small epidemics in Nigeria, Sierra Leone, and Liberia. In 2012, an outbreak of more than 1,000 cases of Lassa fever occurred in east-central Nigeria. Medical workers in Africa and the United States have also contracted the disease. Patients with acute Lassa fever have been transported by international aircraft, necessitating extensive surveillance among passengers and crews. The virus is probably maintained in nature in a species of African peridomestic rodent, Mastomys natalensis. Rodent-to-rodent transmission and infection of humans probably operate via mechanisms established for other arenaviruses.

Marburg Disease Previously, the world experience of human infections caused by Marburgvirus had been limited to 26 primary and 5 secondary cases in Germany and Yugoslavia in 1967 and to small outbreaks in Zimbabwe in 1975, Kenya in 1980 and 1988, and South Africa in 1983. However, in 1999 a large outbreak occurred in the Republic of Congo, and in 2005 a still larger outbreak occurred in Uige Province, Angola, with 252 cases and 227 deaths. In laboratory and clinical settings, transmission occurs by direct contact with tissues of the African green

monkey or with infected human blood or semen. A reservoir in bats has been demonstrated. It appears that the virus is transmitted by close contact between fructivorous bats and from bats by aerosol to humans.

Ebola Hemorrhagic Fever Ebola virus was isolated in 1976 from a devastating epidemic involving small villages in northern Zaire and southern Sudan; smaller outbreaks have occurred subsequently. Outbreaks have initially been nosocomial. Attack rates have been highest in children from birth to 1 yr of age and persons from 15 to 50 yr of age. The virus is in the Filovirus family and closely related to viruses of the genus Marburg virus. An Ebola virus epidemic occurred in Kikwit, Zaire, in 1995, followed by scattered outbreaks in Uganda and Central and West Africa. The virus has been recovered from chimpanzees, and antibodies have been found in other subhuman primates, which apparently acquire infection from a zoonotic reservoir in bats. The natural reservoir of Ebola is believed to be fruit bats. Reston virus, related to Ebola virus, has been recovered from Philippine monkeys and pigs and has caused subclinical infections in humans working in monkey colonies in the United States. In 2014, West Africa experienced the largest outbreak of Ebola virus disease (EVD) in history and the first transmission in a large urban area (Fig. 297.1 ). Countries primarily affected were Liberia, Sierra Leone, and Guinea, with imported cases reported in Nigeria, Mali, and Senegal, as well as Europe and the United States. The outbreak was caused by the Zaire Ebola virus (species of Ebola virus include the Zaire, Sudan, Bundibugyo, Reston, and Tai Forest species), which has a mortality rate of approximately 55–65%. As of 8 May 2016, the World Health Organization (WHO) and respective governments reported a total of 28,616 suspected cases and 11,310 deaths (39.5%), though the WHO believes that this substantially understates the magnitude of the outbreak. The outbreak had largely subsided by the end of 2015. In 2018, an outbreak occurred in the Democratic Republic of the Congo, affecting more than 500 people (aged 8-80 yr), with a case fatality of approximately 50% (Fig. 297.2 ).

FIG. 297.1 Cumulative number of Ebola virus disease cases reported— three countries, West Africa, April 13, 2016. Reported from Sierra Leone (14,124 cases) and Liberia (10,678), followed by Guinea (3,814). (Data from the number of cases and deaths in Guinea, Liberia, and Sierra Leone during the 2014-2016 West Africa Ebola Outbreak. Accessed at https://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html .)

FIG. 297.2 Map of Ebola-affected health zones in the Democratic Republic of the Congo (DRC), 2018. (Courtesy of the Centers for Disease Control and Prevention, 2018. Accessed at https://www.cdc.gov/vhf/ebola/outbreaks/drc/drc-map.html .)

EVD may occur following exposure to fruit bats or bushmeat but most often occurs through exposure to body fluids of infected individuals (blood, sweat, saliva, vomitus, diarrhea, and less often human milk or semen) (Table 297.2 ). Persistent infection after recovery from acute EVD has been well documented, with virus particles present in body fluids such as semen for many months in apparently healthy survivors. Patients are infectious once they are symptomatic;

the incubation period is 2-21 days (mean: 11 days). The age range in the West African epidemic was broad, but most patients were between 15 and 44 yr old. Table 297.2 Clinical Recommendations for Ebola Virus Infection RECOMMENDATION POPULATION 1 Oral rehydration 2

Parenteral administration of fluids

3

4

Systematic monitoring and charting of vital signs and volume status Serum biochemistry

5

Staffing ratio

6 7

Communication with family and friends Analgesic therapy

8

Antibiotics

INTERVENTION Patients with suspected, probable, or confirmed Ebola virus disease Patients with suspected, probable, or confirmed Ebola virus disease who are unable to drink or who have inadequate oral intake Patients with suspected, probable, or confirmed Ebola virus disease Patients with suspected, probable, or confirmed Ebola virus disease Patients with suspected, probable, or confirmed Ebola virus disease Patients with suspected, probable, or confirmed Ebola virus disease Patients with suspected, probable, or confirmed Ebola virus disease who are in pain Patients with suspected, probable, or confirmed Ebola virus disease with high severity of illness

*Confidence is based on the quality of the evidence for the main outcome. Modified from Lamontagne F, Fowler RA, Adhikari NK, et al: Evidence-based guidelines for supportive care of patients with Ebola virus disease, Lancet 391:700-708, 2018,Table 2.

Hemorrhagic Fever With Renal Syndrome The endemic area of hemorrhagic fever with renal syndrome (HFRS), also known as epidemic hemorrhagic fever and Korean hemorrhagic fever, includes Japan, Korea, far eastern Siberia, north and central China, European and Asian Russia, Scandinavia, Czechoslovakia, Romania, Bulgaria, Yugoslavia, and Greece. Although the incidence and severity of hemorrhagic manifestations and the mortality rates are lower in Europe than in northeastern Asia, the renal lesions are the same. Disease in Scandinavia, nephropathia epidemica, is caused by a different although antigenically related virus, Puumala virus, associated with the bank vole, Clethrionomys glareolus. Cases occur predominantly in the spring and summer. There appears to be no age factor in susceptibility, but because of occupational hazards, young adult men are most

frequently attacked. Rodent plagues and evidence of rodent infestation have accompanied endemic and epidemic occurrences. Hantaan virus has been detected in the lung tissue and excreta of Apodemus agrarius coreae. Antigenically related agents have been detected in laboratory rats and in urban rat populations around the world, including Prospect Hill virus in the wild rodent Microtus pennsylvanicus in North America and sin nombre virus in the deer mouse in the southern and southwestern United States; these viruses are causes of hantavirus pulmonary syndrome (see Chapter 299 ). Rodent-to-rodent and rodent-to-human transmission presumably occurs via the respiratory route.

Clinical Manifestations Dengue hemorrhagic fever (see Chapter 295 ) and yellow fever (see Chapter 296 ) cause similar syndromes in children in endemic areas.

Crimean-Congo Hemorrhagic Fever The incubation period of 3-12 days is followed by a febrile period of 5-12 days and a prolonged convalescence. Illness begins suddenly with fever, severe headache, myalgia, abdominal pain, anorexia, nausea, and vomiting. After 1-2 days, the fever may subside until the patient experiences an erythematous facial or truncal flush and injected conjunctivae. A second febrile period of 2-6 days then develops, with a hemorrhagic enanthem on the soft palate and a fine petechial rash on the chest and abdomen. Less frequently, there are large areas of purpura and bleeding from the gums, nose, intestines, lungs, or uterus. Hematuria and proteinuria are relatively rare. During the hemorrhagic stage, there is usually tachycardia with diminished heart sounds and occasionally hypotension. The liver is usually enlarged, but there is no icterus. In protracted cases, central nervous system signs include delirium, somnolence, and progressive clouding of the consciousness. Early in the disease, leukopenia with relative lymphocytosis, progressively worsening thrombocytopenia, and gradually increasing anemia occur. In convalescence there may be hearing and memory loss. The mortality rate is 2–50%.

Kyasanur Forest Disease and Omsk Hemorrhagic Fever

After an incubation period of 3-8 days, both Kyasanur Forest disease and Omsk hemorrhagic fever begin with the sudden onset of fever and headache. Kyasanur Forest disease is characterized by severe myalgia, prostration, and bronchiolar involvement; it often manifests without hemorrhage but occasionally with severe gastrointestinal bleeding. In Omsk hemorrhagic fever, there is moderate epistaxis, hematemesis, and a hemorrhagic enanthem but no profuse hemorrhage; bronchopneumonia is common. In both diseases, severe leukopenia and thrombocytopenia, vascular dilation, increased vascular permeability, gastrointestinal hemorrhages, and subserosal and interstitial petechial hemorrhages occur. Kyasanur Forest disease may be complicated by acute degeneration of the renal tubules and focal liver damage. In many patients, recurrent febrile illness may follow an afebrile period of 7-15 days. This second phase takes the form of a meningoencephalitis.

Rift Valley Fever Most RVF infections have occurred in adults with signs and symptoms resembling those of dengue fever (see Chapter 295 ). The onset is acute, with fever, headache, prostration, myalgia, anorexia, nausea, vomiting, conjunctivitis, and lymphadenopathy. The fever lasts 3-6 days and is often biphasic. The convalescence is often prolonged. In the 1977-1978 outbreak, many patients died after showing signs that included purpura, epistaxis, hematemesis, and melena. RVF affects the uvea and posterior chorioretina; macular scarring, vascular occlusion, and optic atrophy occur, resulting in permanent visual loss in a high proportion of patients with mild to severe RVF. At autopsy, extensive eosinophilic degeneration of the parenchymal cells of the liver has been observed.

Argentine, Venezuelan, and Bolivian Hemorrhagic Fevers and Lassa Fever The incubation period in Argentine, Venezuelan, and Bolivian hemorrhagic fevers and Lassa fever is commonly 7-14 days; the acute illness lasts for 2-4 wk. Clinical illnesses range from undifferentiated fever to the characteristic severe illness. Lassa fever is most often clinically severe in white persons. The onset is usually gradual, with increasing fever, headache, diffuse myalgia, and anorexia (Table 297.3 ). During the first wk., signs frequently include a sore throat,

dysphagia, cough, oropharyngeal ulcers, nausea, vomiting, diarrhea, and pains in the chest and abdomen. Pleuritic chest pain may persist for 2-3 wk. In Argentine and Bolivian hemorrhagic fevers and less frequently in Lassa fever, a petechial enanthem appears on the soft palate 3-5 days after onset and at about the same time on the trunk. The tourniquet test may be positive. The clinical course of Venezuelan hemorrhagic fever has not been well described. Table 297.3 Clinical Stages of Lassa Fever STAGE 1 (days 1-3) 2 (days 4-7) 3 (after 7 days) 4 (after 14 days)

SYMPTOMS General weakness and malaise. High fever > 39°C (102.2°F), constant with peaks of 40-41°C (104105.8°F) Sore throat (with white exudative patches) very common; headache; back, chest, side, or abdominal pain; conjunctivitis; nausea and vomiting; diarrhea; productive cough; proteinuria; low blood pressure (systolic < 100 mm Hg); anemia Facial edema; convulsions; mucosal bleeding (mouth, nose, eyes); internal bleeding; confusion or disorientation Coma and death

From Richmond JK, Baglole DJ: Lassa fever: epidemiology, clinical features, and social consequences, BMJ 327:1271-1275, 2003.

In 35–50% of patients, these diseases may become severe, with persistent high temperature, increasing toxicity, swelling of the face or neck, microscopic hematuria, and frank hemorrhages from the stomach, intestines, nose, gums, and uterus. A syndrome of hypovolemic shock is accompanied by pleural effusion and renal failure. Respiratory distress resulting from airway obstruction, pleural effusion, or congestive heart failure may occur. A total of 10–20% of patients experience late neurologic involvement, characterized by intention tremor of the tongue and associated speech abnormalities. In severe cases, there may be intention tremors of the extremities, seizures, and delirium. The cerebrospinal fluid is normal. In Lassa fever, nerve deafness occurs in early convalescence in 25% of cases. Prolonged convalescence is accompanied by alopecia and, in Argentine and Bolivian hemorrhagic fevers, by signs of autonomic nervous system lability, such as postural hypotension, spontaneous flushing or blanching of the skin, and intermittent diaphoresis. Laboratory studies reveal marked leukopenia, mild to moderate thrombocytopenia, proteinuria, and, in Argentine hemorrhagic fever, moderate abnormalities in blood clotting, decreased fibrinogen, increased fibrinogen split

products, and elevated serum transaminases. There is focal, often extensive eosinophilic necrosis of the liver parenchyma, focal interstitial pneumonitis, focal necrosis of the distal and collecting tubules, and partial replacement of splenic follicles by amorphous eosinophilic material. Usually bleeding occurs by diapedesis with little inflammatory reaction. The mortality rate is 10–40%.

Marburg Disease and Ebola Hemorrhagic Fever After an incubation period of 4-7 days, the illness begins abruptly, with severe frontal headache, malaise, drowsiness, lumbar myalgia, vomiting, nausea, and diarrhea. A maculopapular eruption begins 5-7 days later on the trunk and upper arms. It becomes generalized and often hemorrhagic and exfoliates during convalescence. The exanthem is accompanied by a dark red enanthem on the hard palate, conjunctivitis, and scrotal or labial edema. Gastrointestinal hemorrhage occurs as the severity of illness increases. Late in the illness, the patient may become tearfully depressed, with marked hyperalgesia to tactile stimuli. In fatal cases, patients become hypotensive, restless, and confused and lapse into coma. Convalescent patients may experience alopecia and may have paresthesias of the back and trunk. There is a marked leukopenia with necrosis of granulocytes. Dysfunction in bleeding and clotting and thrombocytopenia are universal and correlated with the severity of disease; there are moderate abnormalities in concentrations of clotting proteins and elevations of serum transaminases and amylase. Pregnant women and young children are at high risk of severe disease with a fatal outcome. The mortality rate of Marburg disease is 25–85%, and the mortality rate of Ebola hemorrhagic fever 50–90%. High viral loads in acute-phase blood samples convey a poor prognosis. Viral RNA persists in tissues long after symptoms subside, and the virus has been excreted in semen more than 1 yr after recovery. Manifestations of EVD may come in stages, but most EVD begins with the sudden onset of fever accompanied by fatigue, weakness, myalgias, headache, and sore throat. This is followed by gastrointestinal involvement, including anorexia, nausea, abdominal pain, vomiting, and diarrhea. Hemorrhage (defined by any evidence of bleeding) is seen in more than 50% and is a serious later phase, often accompanied by vascular leakage, multiorgan failure, and death. Those who survive improve on approximately days 6-11 of EVD. One late relapse, producing meningoencephalitis, has been reported.

Hemorrhagic Fever With Renal Syndrome In most cases, HFRS is characterized by fever, petechiae, mild hemorrhagic phenomena, and mild proteinuria, followed by a relatively uneventful recovery. In 20% of recognized cases, the disease may progress through four distinct phases. The febrile phase is ushered in with fever, malaise, and facial and truncal flushing. It lasts 3-8 days and ends with thrombocytopenia, petechiae, and proteinuria. The hypotensive phase, of 1-3 days, follows defervescence. Loss of fluid from the intravascular compartment may result in marked hemoconcentration. Proteinuria and ecchymoses increase. The oliguric phase, usually 3-5 days in duration, is characterized by a low output of protein-rich urine, increasing nitrogen retention, nausea, vomiting, and dehydration. Confusion, extreme restlessness, and hypertension are common. The diuretic phase, which may last for days or weeks, usually initiates clinical improvement. The kidneys show little concentrating ability, and rapid loss of fluid may result in severe dehydration and shock. Potassium and sodium depletion may be severe. Fatal cases manifest as abundant protein-rich retroperitoneal edema and marked hemorrhagic necrosis of the renal medulla. The mortality rate is 5–10%.

Diagnosis The diagnosis of these viral hemorrhagic fevers depends on a high index of suspicion in endemic areas. In nonendemic areas, histories of recent travel, recent laboratory exposure, or exposure to an earlier case should evoke suspicion of a viral hemorrhagic fever. In all viral hemorrhagic fevers, the viral agent circulates in the blood at least transiently during the early febrile stage. Togaviruses and bunyaviruses can be recovered from acute-phase serum samples by inoculation into a tissue culture or living mosquitoes. Argentine, Bolivian, and Venezuelan hemorrhagic fever viruses can be isolated from acute-phase blood or throat washings by intracerebral inoculation into guinea pigs, infant hamsters, or infant mice. Lassa virus may be isolated from acute-phase blood or throat washings by inoculation into tissue cultures. For Marburg disease and Ebola hemorrhagic fever, acutephase throat washings, blood, and urine may be inoculated into a tissue culture, guinea pigs, or monkeys. The viruses are readily identified on electron microscopy, with a filamentous structure differentiating them from all other known agents. Specific complement-fixing and immunofluorescent antibodies

appear during convalescence. The virus of HFRS is recovered from acute-phase serum or urine by inoculation into a tissue culture. A variety of antibody tests using viral subunits is becoming available. The serologic diagnosis depends on the demonstration of seroconversion or a four-fold or greater increase in immunoglobulin G antibody titer in acute and convalescent serum specimens collected 3-4 wk apart. Viral RNA may also be detected in blood or tissues with the use of reverse transcriptase polymerase chain reaction analysis. The diagnosis of EVD is confirmed by enzyme-linked immunosorbent assay immunoglobulin M and polymerase chain reaction (which may need to be repeated if initially negative) testing. Criteria to aid in the diagnosis of EVD include temperature > 38.6°C (101.5°F) plus symptoms; contact with an affected patient, the patient's body fluids, or the funeral; residence in or travel to an endemic region; or a history of handling bats, rodents, or primates from an endemic area. Handling blood and other biologic specimens is hazardous and must be performed by specially trained personnel. Blood and autopsy specimens should be placed in tightly sealed metal containers, wrapped in absorbent material inside a sealed plastic bag, and shipped on dry ice to laboratories with biocontainment safety level 4 facilities. Even routine hematologic and biochemical tests should be done with extreme caution.

Differential Diagnosis Mild cases of hemorrhagic fever may be confused with almost any self-limited systemic bacterial or viral infection. More severe cases may suggest typhoid fever; epidemic, murine, or scrub typhus; leptospirosis; or a rickettsial spotted fever, for which effective chemotherapeutic agents are available. Many of these disorders may be acquired in geographic or ecologic locations endemic for a viral hemorrhagic fever. The differential diagnosis of EVD includes malaria, typhoid, Lassa fever, influenza infection, and meningococcemia.

Treatment Ribavirin administered intravenously is effective in reducing mortality rates in Lassa fever and HFRS. Further information and advice about the management, control measures, diagnosis, and collection of biohazardous specimens can be

obtained from the Centers for Disease Control and Prevention, National Center for Infectious Diseases, Viral Special Pathogens Branch, Atlanta, Georgia 30333 (470-312-0094). The therapeutic principle involved in all of these diseases, especially HFRS, is the reversal of dehydration, hemoconcentration, renal failure, and protein, electrolyte, or blood losses (see Table 297.2 ). The contribution of disseminated intravascular coagulopathy to the hemorrhagic manifestations is unknown, and the management of hemorrhage should be individualized. Transfusions of fresh blood and platelets are frequently given. Good results have been reported in a few patients after the administration of clotting factor concentrates. The efficacy of corticosteroids, ε-aminocaproic acid, pressor amines, and α-adrenergic blocking agents has not been established. Sedatives should be selected with regard to the possibility of kidney or liver damage. The successful management of HFRS may require renal dialysis. Whole-blood transfusions from Ebola virus–immune donors and administration of Ebola monoclonal antibodies have been shown to be effective in lowering case fatality rates. Patients suspected of having Lassa fever, Ebola fever, Marburg fever, or Congo-Crimean hemorrhagic fever should be placed in a private room on standard contact and droplet precautions. Caretakers should use barrier precautions to prevent skin or mucous membrane exposure. All persons entering the patient's room should wear gloves and gowns and face shields. Before exiting the patient's room, caretakers should safely remove and dispose of all protective gear and should clean and disinfect shoes. Protocols require twoperson clinical care teams, one observer and one caregiver (see CDC website: www.cdc.gov/vhf/ebola ). Treatment of EVD often requires an intensive care unit and management of multiorgan system dysfunction, including correction of hypovolemia, hyponatremia, hypokalemia, hypoalbuminemia, hypocalcemia, and hypoxia, often with renal replacement therapy as well as ventilation support (Table 297.2 ). Convalescent serum and monoclonal antibodies have been employed on an experimental basis. Strict isolation and appropriate barrier protection of healthcare workers is mandatory. Several vaccines have been shown to be immunogenic, and one used late in the epidemic was protective. Epidemic control measures, isolation, and quarantine have been used to attempt to decrease the spread of the West African epidemic.

Prevention A live-attenuated vaccine (Candid-I) for Argentine hemorrhagic fever (Junin virus) is highly efficacious. A form of inactivated mouse brain vaccine is reported to be effective in preventing Omsk hemorrhagic fever. Inactivated RVF vaccines are widely used to protect domestic animals and laboratory workers. HFRS inactivated vaccine is licensed in Korea, and killed and live-attenuated vaccines are widely used in China. A vaccinia-vector glycoprotein vaccine provides protection against Lassa fever in monkeys. Single doses of recombinant vesicular stomatitis virus or adenovirus type 3 vaccines containing surface glycoproteins from Ebola and Marburg viruses have been shown to protect monkeys against Ebola virus and Marburg virus disease. The vesicular stomatitis-vectored Ebola vaccine was shown to be effective in preventing Ebola cases in a ring vaccination trial in Guinea and has been used widely in the 2018 Congo outbreak. Prevention of mosquito-borne and tick-borne infections includes use of repellents, wearing of tight-fitting clothing that fully covers the extremities, and careful examination of the skin after exposure, with removal of any vectors found. Diseases transmitted from a rodent-infected environment can be prevented through methods of rodent control; elimination of refuse and breeding sites is particularly successful in urban and suburban areas. Patients should be isolated until they are virus-free or for 3 wk after illness. Patient urine, sputum, blood, clothing, and bedding should be disinfected. Disposable syringes and needles should be used. Prompt and strict enforcement of barrier nursing may be lifesaving. The mortality rate among medical workers contracting these diseases is 50%. A few entirely asymptomatic Ebola infections result in strong antibody production.

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CHAPTER 298

Lymphocytic Choriomeningitis Virus Daniel J. Bonthius

Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen and an important cause of meningitis in children and adults. Capable of crossing the placenta and infecting the fetus, LCMV is also an important cause of neurologic birth defects and encephalopathy in the newborn.

Etiology LCMV is a member of the family Arenaviridae, which are enveloped, negativesense single-stranded RNA viruses. The name of the arenaviruses is derived from arenosus, the Latin word for “sandy,” because of the fine granularities observed within the virion on ultrathin electron microscopic sections.

Epidemiology Like all arenaviruses, LCMV utilizes rodents as its reservoir. The common house mouse, Mus musculus, is both the natural host and primary reservoir for the virus, which is transferred vertically from one generation of mice to the next via intrauterine infection. Hamsters and guinea pigs are also potential reservoirs. Although heavily infected with LCMV, rodents that acquire the virus transplacentally often remain asymptomatic because congenital infection provides rodents with immunologic tolerance for the virus. Infected rodents shed the virus in large quantities in nasal secretions, urine, feces, saliva, and milk throughout their lives. Humans typically acquire LCMV by contacting fomites contaminated with infectious virus or by inhaling aerosolized virus. Most human infections occur

during the fall and early winter, when mice move into human habitations. Humans can also acquire the virus via organ transplantation. Congenital LCMV infection occurs when a woman acquires a primary LCMV infection during pregnancy. The virus passes through the placenta to the fetus during maternal viremia. The fetus may also acquire the virus during passage through the birth canal from exposure to infected vaginal secretions. Outside of organ transplantation and vertical transmission during pregnancy, there have been no cases of human-to-human transmission of LCMV. LCMV is prevalent in the environment, has a great geographic range, and infects large numbers of humans. The virus is found throughout the world's temperate regions and probably occurs wherever the genus Mus has been introduced (which is every continent but Antarctica). An epidemiologic study found that 9% of house mice are infected and that substantial clustering occurs, where the prevalence is higher. Serologic studies demonstrate that approximately 5% of adult humans possess antibodies to LCMV, indicating prior exposure and infection.

Pathogenesis LCMV is not a cytolytic virus. Thus, unlike many other nervous system pathogens that directly damage the brain by killing host brain cells, LCMV pathogenesis involves other underlying mechanisms. Furthermore, the pathogenic mechanisms are different in postnatal (acquired) infection than in prenatal (congenital) infection. A critical difference in the pathogenesis of postnatal versus prenatal infection is that the virus infects brain parenchyma in the case of prenatal infection, but is restricted to the meninges and choroid plexus in postnatal cases. In postnatal infections, LCMV replicates to high titers in the choroid plexus and meninges. Viral antigen within these tissues becomes the target of an acute mononuclear cell infiltration driven by CD8+ T lymphocytes. The presence of lymphocytes in large numbers within the meninges and cerebrospinal fluid leads to the symptoms of meningitis that mark acquired LCMV infection. As the lymphocytes clear the virus from the meninges and cerebrospinal fluid, the density of lymphocytes declines, and the symptoms of meningitis resolve. Thus, symptoms of acquired (postnatal) LCMV infection are immune mediated and are a result of the presence of large numbers of lymphocytes. Prenatal infection likewise inflames the tissues surrounding the brain

parenchyma, and this inflammation leads to some of the signs of congenital LCMV. In particular, within the ventricular system, congenital LCMV infection often leads to ependymal inflammation, which may block the egress of cerebrospinal fluid (CSF) at the cerebral aqueduct and lead to hydrocephalus. However, unlike postnatal cases, prenatal infection with LCMV includes infection of the substance of the brain rather than just the meninges or ependyma. This infection of brain parenchyma leads to the substantial neuropathologic changes typically accompanying congenital LCMV infection. In particular, LCMV infects the mitotically active neuroblasts, located at periventricular sites. Through an unknown mechanism, the presence of the virus kills these periventricular cells, leading to periventricular calcifications, a radiographic hallmark of this disorder. Within the fetal brain, LCMV infection of neurons and glial cells also disrupts neuronal migration, leading to abnormal gyral patterns, and interferes with neuronal mitosis, leading to microcephaly and cerebellar hypoplasia.

Clinical Manifestations The clinical manifestations of LCMV infection depend on whether the infection occurs prenatally or postnatally. Congenital infection with LCMV is unique, as it involves both the postnatal infection of a pregnant woman and the prenatal infection of a fetus.

Acquired (Postnatal) Lymphocytic Choriomeningitis Virus Infection LCMV infection during postnatal life (during childhood or adulthood) typically consists of a brief febrile illness, from which the patient fully recovers. The illness classically consists of two clinical phases. In the first phase, the symptoms are those of a nonspecific viral syndrome and include fever, myalgia, malaise, nausea, anorexia, and vomiting. These symptoms usually resolve after several days but are followed by a second phase, consisting of central nervous system disease. The symptoms of this second phase are those of aseptic meningitis, including headache, fever, nuchal rigidity, photophobia, and vomiting. The entire course of the biphasic disease is typically 1-3 wk. The clinical spectrum of LCMV infection is broad. One third of postnatal

infections are asymptomatic. Other patients develop extraneural disease that extends beyond the usual symptoms and may include orchitis, pneumonitis, myocarditis, parotitis, dermatitis, alopecia, and pharyngitis. In others, the neurologic disease may be considerably more severe than usual and may include transverse myelitis, Guillain-Barré syndrome, hydrocephalus, and encephalitis. Recovery from acquired LCMV infection is usually complete, but fatalities occasionally occur. LCMV infections acquired via solid-organ transplantation always induce severe disease. Several weeks following the transplantation, recipients of infected organs develop fever, leukopenia, and lethargy. Following these nonspecific symptoms, the course of the disease rapidly progresses to multiorgan system failure and shock. These cases are almost always fatal.

Congenital Lymphocytic Choriomeningitis Virus Infection LCMV infection during pregnancy can kill the fetus and induce spontaneous abortion. Among surviving fetuses, the two clinical hallmarks of congenital LCMV infection are vision impairment and brain dysfunction. The vision impairment in congenital LCMV infection is a result of chorioretinitis and the formation of chorioretinal scars. The scarring is usually bilateral and most commonly located in the periphery of the fundus, but involvement of the macula also occurs. Although the retinal injuries from congenital LCMV infection are often severe, it is the brain effects that cause the greatest disability. Prenatal infection with LCMV commonly induces either macrocephaly or microcephaly. Macrocephaly following LCMV infection is almost invariably caused by noncommunicating hydrocephalus, stemming from inflammation within the ventricular system. Microcephaly is a result of the virus-induced failure of brain growth. In addition to disturbances of head size, periventricular calcifications are also cardinal features of congenital LCMV infection. Although hydrocephalus, microencephaly, and periventricular calcifications are by far the most commonly observed abnormalities of the brain in congenital LCMV, other forms of neuropathology, alone or in combination, can also occur. These include periventricular cysts, porencephalic cysts, encephalomalacia, intraparenchymal calcifications, cerebellar hypoplasia, and neuronal migration disturbances.

Infants with congenital LCMV infection typically present during the newborn period with evidence of brain dysfunction. The most common signs are lethargy, seizures, irritability, and jitteriness. Within the fetus, LCMV has a specific tropism for the brain. Thus, unlike many other congenital infections, LCMV usually does not induce systemic manifestations. Birthweight is typically appropriate for gestational age. Skin rashes and thrombocytopenia, which are common in several other prominent congenital infections, are unusual in congenital LCMV infection. Hepatosplenomegaly is only rarely observed, and serum liver enzyme levels are usually normal. Auditory deficits are unusual.

Laboratory Findings In acquired (postnatal) LCMV infection, the hallmark laboratory abnormality occurs during the second (central nervous system) phase of the disease and is CSF pleocytosis. The CSF typically contains hundreds to thousands of white blood cells, almost all of which are lymphocytes. However, CSF eosinophilia may also occur. Mild elevations of CSF protein and hypoglycorrhachia are common. In congenital LCMV infection, laboratory findings in the newborn depend on whether the infant is still infected or not. If the infant still harbors the infection, then examination of the CSF may reveal a lymphocytic pleocytosis. Unlike many other congenital infections, LCMV does not typically induce elevations in liver enzymes, thrombocytopenia, or anemia. In many cases, the most reliably abnormal test is the head CT scan, which typically reveals a combination of microencephaly, hydrocephalus, and periventricular calcifications (Fig. 298.1 ).

FIG. 298.1 Head CT scan from a 2 mo old microcephalic baby with congenital lymphocytic choriomeningitis virus infection. The scan reveals enlargement of the lateral ventricles (LV) and periventricular calcifications (arrows).

Diagnosis and Differential Diagnosis Acute LCMV infections can be diagnosed by isolating the virus from CSF. Polymerase chain reaction has also been used to detect LCMV RNA in patients with active infections. However, by the time of birth, a baby prenatally infected with LCMV may no longer harbor the virus. Thus, congenital LCMV infection is more commonly diagnosed by serologic testing. The immunofluorescent antibody test detects both immunoglobulin (Ig) M and IgG and has greater sensitivity than the more widely available complement fixation method. The immunofluorescent antibody test is commercially available, and its specificity and sensitivity make it an acceptable diagnostic tool. A more sensitive test for detecting congenital LCMV infection is the enzyme-linked immunosorbent assay, which measures titers of LCMV IgG and IgM and is performed at the Centers for Disease Control and Prevention. For acquired (postnatal) LCMV infection, the principal items in the differential diagnosis are the other infectious agents that can induce meningitis. These include bacteria, fungi, viruses, and some other forms of pathogens. The

most common viral causes of meningitis are the enteroviruses, including coxsackieviruses and echoviruses, and the arboviruses, including La Crosse encephalitis virus and equine encephalitis virus. Unlike LCMV, which is most common in winter, the enteroviruses and arboviruses are most commonly acquired in summer and early fall. The principal items in the differential diagnosis of congenital LCMV infection are the other infectious pathogens that can cross the placenta and damage the developing fetus. These infectious agents are linked by the acronym TORCHS and include Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, and syphilis. Toxoplasmosis, Zika virus infection, and cytomegalovirus infection are particularly difficult to differentiate from LCMV, because all of these infectious agents can produce microcephaly, intracerebral calcifications, and chorioretinitis. Although clinical clues may aid in distinguishing one congenital infection from another, definitive identification of the causative infectious agent usually requires laboratory data, including cultures and serologic studies.

Complications Complications in children with congenital LCMV infection are nonspecific and include the medical problems that commonly arise in scenarios, involving ventriculoperitoneal shunts, severe seizure disorders, and static encephalopathy. These complications include shunt failure or infection, aspiration pneumonia, injuries from falls, and joint contractures.

Treatment There is no specific treatment for acquired or congenital LCMV infection. An effective antiviral therapy for LCMV infection has not yet been developed. Ribavirin is active against LCMV and other arenaviruses in vitro, but its utility in vivo is unproven. Immunosuppressive therapy, if present, should be reduced.

Supportive Care Children with hydrocephalus from congenital LCMV infection often require placement of a ventriculoperitoneal shunt during infancy for treatment of

hydrocephalus. Seizures often begin during early postnatal life, are often difficult to control, and require administration of multiple antiepileptic medications. The mental retardation induced by congenital LCMV infection is often profound. In most cases, affected children should be referred for educational intervention during early life. The spasticity accompanying congenital LCMV infection is often severe. Although physical therapy can help to maintain the range of motion and minimize painful spasms and contractures, implantation of a baclofen pump is often helpful.

Prognosis The great majority of patients with postnatally acquired LCMV infection have a full recovery with no permanent sequelae. Rarely, postnatal infections induce hydrocephalus and require shunting. Rarer yet, postnatal LCMV infection is fatal. In contrast to the usual benign outcome of postnatal infections, prenatal infections typically lead to severe and permanent disability. In children with congenital LCMV infection, brain function is nearly always impaired and chorioretinitis is invariably present. Mental retardation, cerebral palsy, ataxia, epilepsy, and blindness are common neurologic sequelae. However, children with congenital LCMV infection have diverse outcomes. All children with the combination of microencephaly and periventricular calcifications are profoundly neurologically impaired. Blindness, medically refractory epilepsy, spastic quadriparesis, and mental retardation are typical of this group. However, other children with congenital LCMV infection who do not have the combination of microencephaly and periventricular calcifications often have a more favorable outcome, with less severe motor, mental, and vision impairments. Children with isolated cerebellar hypoplasia may be ataxic but have only mild or moderate mental retardation and vision loss.

Prevention No vaccine exists to prevent LCMV infection. However, measures can be taken to reduce the risk of infection. Because rodents, especially house mice, are the principal reservoir of LCMV, people can reduce their risk of contracting LCMV by minimizing their exposure to the secretions and excretions of mice. This can

be accomplished most effectively by eliminating cohabitation with mice. Congenital LCMV infection will not occur unless a woman contracts a primary infection with LCMV during pregnancy. Thus, women should be especially careful to avoid contact or cohabitation with mice during pregnancy. Pregnant women should also avoid contact with pet rodents, especially mice and hamsters. These facts should be stressed during prenatal visits. Acquisition of LCMV from solid-organ transplantation represents a substantial risk to organ recipients. Prospective donors with LCMV meningitis or encephalitis pose a clear risk for transmitting a fatal infection to recipients. Healthcare providers, transplantation centers, and organ procurement organizations should be aware of the risks posed by LCMV and should consider LCMV in any potential donor with signs of aseptic meningitis but no identified infectious agent. The risks and benefits of offering and receiving organs from donors with possible LCMV infection should be carefully considered.

Bibliography Bonthius DJ. Lymphocytic choriomeningitis virus: an underrecognised cause of neurologic disease in the fetus, child, and adult. Semin Pediatr Neurol . 2012;19:89–95. Bonthius DJ, Nichols B, Harb H, et al. Lymphocytic choriomeningitis virus infection in brain: critical role of host age. Ann Neurol . 2007;62:356–374. Bonthius DJ, Perlman S. Congenital viral infections of the brain: lessons learned from lymphocytic choriomeningitis virus in the neonatal rat. PLoS Pathog . 2007;3(11):e149. Bonthius DJ, Wright R, Tseng B, et al. Congenital lymphocytic choriomeningitis virus infection: spectrum of disease. Ann Neurol . 2007;62:347–355. Centers for Disease Control and Prevention (CDC). Update: interim guidance for minimizing risk for human lymphocytic choriomeningitis virus infection associated with pet rodents. MMWR Morb Mortal Wkly Rep . 2005;54:799–801. Childs J, Glass G, Korch G, et al. Lymphocytic

choriomeningitis virus infection and house mouse (Mus musculus) distribution in urban baltimore. Am J Trop Med Hyg . 1992;47:27–34. Farmer M, Sebire G. Genetic mimics of congenital lymphocytic choriomeningitis virus encephalitis. Ann Neurol . 2008;64:353–355. Fischer SA, Graham MB, Kuehnert MJ, et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med . 2006;34:2235–2249. Macneil A, Stroher U, Farnon E, et al. Solid organ transplantassociated lymphocytic choriomeningitis, United States, 2011. Emerg Infect Dis . 2012;18:1256–1262. Mathur G, Yadav K, Ford B, et al. High clinical suspicion of donor-derived disease leads to timely recognition and early intervention to treat solid organ transplant-transmitted lymphocytic choriomeningitis virus. Transpl Infect Dis . 2017;19(4); 10.1111/tid.12707 . Wright R, Johnson D, Neumann M, et al. Congenital lymphocytic choriomeningitis virus syndrome. A disease that mimics congenital toxoplasmosis or cytomegalovirus infection. Pediatrics . 1997;100:E9.

CHAPTER 299

Hantavirus Pulmonary Syndrome Scott B. Halstead

The hantavirus pulmonary syndrome (HPS) is caused by multiple closely related hantaviruses that have been identified from the western United States, with sporadic cases reported from the eastern United States (Fig. 299.1 ) and Canada and important foci of disease in several countries in South America. HPS is characterized by a febrile prodrome followed by the rapid onset of noncardiogenic pulmonary edema and hypotension or shock. Sporadic cases in the United States caused by related viruses may manifest with renal involvement. Cases in Argentina and Chile sometimes include severe gastrointestinal hemorrhaging; nosocomial transmission has been documented in this geographic region only.

FIG. 299.1 Total number of confirmed cases of Hantavirus pulmonary

syndrome, by state reporting, United States, 1993-2016. N = 728 as of January 2017. (From Viral Special Pathogens Branch, Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/hantavirus/surveillance/reporting-state.html ).

Etiology Hantaviruses are a genus in the family Bunyaviridae, which are lipid-enveloped viruses with a negative-sense RNA genome composed of three unique segments. Several pathogenic viruses that have been recognized within the genus include Hantaan virus, which causes the most severe form of hemorrhagic fever with renal syndrome (HFRS) seen primarily in mainland Asia (see Chapter 297 ); Dobrava virus, which causes the most severe form of HFRS seen primarily in the Balkans; Puumala virus, which causes a milder form of HFRS with a high proportion of subclinical infections and is prevalent in northern Europe; and Seoul virus, which results in moderate HFRS and is transmitted predominantly in Asia by urban rats or worldwide by laboratory rats. Prospect Hill virus, a hantavirus that is widely disseminated in meadow voles in the United States, is not known to cause human disease. There are an increasing number of case reports of European hantaviruses causing HPS. HPS is associated with sin nombre virus, isolated from deer mice, Peromyscus maniculatus, in New Mexico. Multiple HPS-like agents in the American hemisphere isolated to date belong to a single genetic group of hantaviruses and are associated with rodents of the family Muridae, subfamily Sigmodontinae. These rodent species are restricted to the Americas, suggesting that HPS may be a Western hemisphere disease.

Epidemiology Persons acquiring HPS generally have a history of recent outdoor exposure or live in an area with large populations of deer mice. Clusters of cases have occurred among individuals who have cleaned houses that were rodent infested. P. maniculatus is one of the most common North American mammals and, where found, is frequently the dominant member of the rodent community. About half of the average of 30+ cases seen annually occurs between the months of May and July. Patients are almost exclusively 12-70 yr of age; 60% of patients

are 20-39 yr of age. Rare cases are reported in children younger than 12 yr of age. Two thirds of patients are male, probably reflecting their greater outdoor activities. It is not known whether almost complete absence of disease in young children is a reflection of innate resistance or simply lack of exposure. Evidence of human-to-human transmission has been reported in Argentine outbreaks. Hantaviruses do not cause apparent illness in their reservoir hosts, which remain asymptomatically infected for life. Infected rodents shed virus in saliva, urine, and feces for many weeks, but the duration of shedding and the period of maximum infectivity are unknown. The presence of infectious virus in saliva, the sensitivity of these animals to parenteral inoculation with hantaviruses, and field observations of infected rodents indicate that biting is important for rodentto-rodent transmission. Aerosols from infective saliva or excreta of rodents are implicated in the transmission of hantaviruses to humans. Persons visiting animal care areas housing infected rodents have been infected after exposure for as little as 5 min. It is possible that hantaviruses are spread through contaminated food and breaks in skin or mucous membranes; transmission to humans has occurred by rodent bites. Person-to-person transmission is distinctly uncommon but has been documented in Argentina.

Pathogenesis HPS is characterized by sudden and catastrophic pulmonary edema, resulting in anoxia and acute heart failure. The virus is detected in pulmonary capillaries, suggesting that pulmonary edema is the consequence of a T-cell attack on virusinfected capillaries. The disease severity is predicted by the level of acute-phase viremia titer. A useful hamster model of HPS is available.

Clinical Manifestations HPS is characterized by a prodrome and a cardiopulmonary phase. The mean duration after the onset of prodromal symptoms to hospitalization is 5.4 days. The mean duration of symptoms to death is 8 days (median: 7 days; range: 2-16 days). The most common prodromal symptoms are fever and myalgia (100%); cough or dyspnea (76%); gastrointestinal symptoms, including vomiting, diarrhea, and midabdominal pain (76%); and headache (71%). The cardiopulmonary phase is heralded by progressive cough and shortness of

breath. The most common initial physical findings are tachypnea (100%), tachycardia (94%), and hypotension (50%). Rapidly progressive acute pulmonary edema, hypoxia, and shock develop in most severely ill patients. Pulmonary vascular permeability is complicated by cardiogenic shock associated with increased vascular resistance. The clinical course of the illness in patients who die is characterized by pulmonary edema accompanied by severe hypotension, frequently terminating in sinus bradycardia, electromechanical dissociation, ventricular tachycardia, or fibrillation. Hypotension may be progressive even with adequate oxygenation. HPS virus is excreted in the urine during the acute illness phase, and survivors may demonstrate evidence of chronic renal damage.

Diagnosis The diagnosis of HPS should be considered in a previously healthy patient presenting with a febrile prodrome, acute respiratory distress, and thrombocytopenia who has had outdoor exposure in the spring and summer months. A specific diagnosis of HPS is made by serologic tests that detect hantavirus immunoglobulin M antibodies. The early appearance of immunoglobulin G antibodies signals probable recovery. Hantavirus antigen can be detected in tissue by immunohistochemistry and amplification of hantavirus nucleotide sequences detected by reverse transcriptase polymerase chain reaction. The state health department or the Centers for Disease Control and Prevention should be consulted to assist in the diagnosis, epidemiologic investigations, and outbreak control.

Laboratory Findings Laboratory findings include leukocytosis (median: 26,000 cells/µL), an elevated hematocrit resulting from hemoconcentration, thrombocytopenia (median: 64,000 cells/µL), prolonged prothrombin and partial thromboplastin times, elevated serum lactate dehydrogenase concentration, decreased serum protein concentrations, proteinuria, and microscopic hematuria. Patients who die often experience disseminated intravascular coagulopathy including frank hemorrhage and exceptionally high leukocyte counts.

Differential Diagnosis The differential diagnosis includes adult respiratory distress syndrome, pneumonic plague, psittacosis, severe mycoplasmal pneumonia, influenza, leptospirosis, inhalation anthrax, rickettsial infections, pulmonary tularemia, atypical bacterial and viral pneumonial diseases, legionellosis, meningococcemia, and other sepsis syndromes. The key determinant in the diagnosis of HPS is thrombocytopenia.

Treatment Management of patients with hantavirus infection requires maintenance of adequate oxygenation and careful monitoring and support of cardiovascular function. The pathophysiology of HPS somewhat resembles that of dengue shock syndrome (see Chapter 295 ). Pressor or inotropic agents, such as dobutamine, should be administered in combination with judicious volume replacement to treat symptomatic hypotension or shock while avoiding exacerbation of the pulmonary edema. Intravenous ribavirin, which is lifesaving if given early in the course of HFRS and is effective in preventing death in the hamster model, has not yet been demonstrated to be of value in HPS. Further information and advice about management, control measures, diagnosis, and collection of biohazardous specimens can be obtained from the Centers for Disease Control and Prevention, National Center for Infectious Diseases, Viral Special Pathogens Branch, Atlanta, Georgia 30333 (470-3120094).

Prognosis In some geographic areas, fatality rates for HPS have been 50%. Severe abnormalities in hematocrit, white blood cell count, lactate dehydrogenase value, and partial thromboplastin time, and a high viral load predict death with high specificity and sensitivity. The early appearance of immunoglobulin G antibodies may signal a hopeful prognosis.

Prevention

Avoiding contact with rodents is the only preventive strategy against HPS. Rodent control in and around the home is important. Barrier nursing is advised, and biosafety level 3 facilities and practices are recommended for laboratory handling of blood, body fluids, and tissues from suspect patients or rodents, because the virus may be aerosolized.

Bibliography Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome (HPS) . http://www.cdc.gov/hantavirus/hps/ . Diaz JH. Rodent-borne infectious disease outbreaks after flooding disasters: epidemiology, management, and prevention. J Emerg Manag . 2015;13:459. Figueiredo LT, Souza WM, Ferres M, et al. Hantaviruses and cardiopulmonary syndrome in South America. Virus Res . 2014;187:43. Hartline J, Mierek C, Knutson T, et al. Hantavirus infection North America: a clinical review. Am J Emerg Med . 2013;31:978–982. MacNeil A, Ksiazek TG, Rollin PE. Hantavirus pulmonary syndrome, United States, 1993-2009. Emerg Infect Dis . 2011;17(7):1195–1201. Mattar S, Guzman C, Figueiredo LT. Diagnosis of hantavirus infection in humans. Expert Rev Anti Infect Ther . 2015;13:939. Rhee DK, Clark RP, Blair RJ, et al. Clinical problem-solving. Breathtaking journey. N Engl J Med . 2012;367(5):452–457. Sargianou M, Watson DC, Chra P, et al. Hantavirus infections for the clinician: from case presentation to diagnosis and treatment. Crit Rev Microbiol . 2012;38(4):317–329. Schmaljohn CS. Vaccines for hantaviruses: progress and issues. Expert Rev Vaccines . 2012;11(5):511–513.

Srikiatkhachorn A, Spiropoulou CF. Vascular events in viral hemorrhagic fevers: a comparative study of dengue and hantaviruses. Cell Tissue Res . 2014;355:621–633. Watson DC, Sargianou M, Papa A, et al. Epidemiology of Hantavirus infections in humans: a comprehensive, global overview. Crit Rev Microbiol . 2014;40:261.

CHAPTER 300

Rabies Rodney E. Willoughby Jr.

Rabies virus is a bullet-shaped, negative-sense, single-stranded, enveloped RNA virus from the family Rhabdoviridae, genus Lyssavirus. There currently are 14 species of Lyssavirus. The classic rabies virus (genotype 1) is distributed worldwide and naturally infects a large variety of animals. The other genotypes are more geographically confined, with none found in the Americas. Seven Lyssavirus genotypes are associated with rabies in humans, although genotype 1 accounts for the great majority of cases. Within genotype 1, a number of genetic variants have been defined. Each variant is specific to a particular animal reservoir, although cross-species transmission can occur.

Epidemiology Rabies is present on all continents except Antarctica. Rabies predominantly afflicts underaged, poor, and geographically isolated populations. Approximately 59,000 cases of human rabies occur in Africa and Asia annually. Theoretically, rabies virus can infect any mammal (which then can transmit disease to humans), but true animal reservoirs that maintain the presence of rabies virus in the population are limited to terrestrial carnivores and bats. Worldwide, transmission from dogs accounts for > 90% of human cases. In Africa and Asia, other animals serve as prominent reservoirs, such as jackals, mongooses, and raccoon dogs. In industrialized nations, canine rabies has been largely controlled through the routine immunization of pets. In the United States, raccoons are the most commonly infected wild animal along the eastern seaboard. Three phylogenies of skunk rabies are endemic in the Midwest (north and south) and California, gray foxes harbor rabies in Arizona and Texas, red foxes and arctic foxes harbor rabies in Alaska, and mongooses carry rabies in Puerto Rico.

Rabies occurs infrequently in livestock. Among American domestic pets, infected cats outnumber infected dogs, probably because cats frequently prowl unsupervised and are not uniformly subject to vaccine laws. Rabies is rare in small mammals, including mice, squirrels, and rabbits; to date, no animal-tohuman transmission from these animals has been documented. The epidemiology of human rabies in the United States is dominated by cryptogenic bat rabies. Bats are migratory in the spring and fall; rabid bats are identified in every state of the union except Hawaii. In one study, the largest proportion of cases of human rabies were infected with a bat variant, and in almost all cases of bat-associated human rabies there was no history of a bat bite. Among inhabitants of the Peruvian Amazon region who have exposure to rabiesinfected vampire bats, there are some who have rabies virus–neutralizing antibodies and have survived. Antibody-positive patients remember bat bites but do not recall symptoms of rabies. In the United States, 30,000 episodes of rabies postexposure prophylaxis (PEP) occur annually. Between one and three endemic human cases are diagnosed annually, half postmortem. There have been five outbreaks of rabies associated with solid-organ and corneal transplantations.

Transmission Rabies virus is found in large quantities in the saliva of infected animals, and transmission occurs almost exclusively through inoculation of the infected saliva through a bite or scratch from a rabid mammal. Approximately 35–50% of people who are bitten by a known rabies-infected animal and receive no PEP actually contract rabies. The transmission rate is increased if the victim has suffered multiple bites and if the inoculation occurs in highly innervated parts of the body such as the face and the hands. Infection does not occur after exposure of intact skin to infected secretions, but virus may enter the body through intact mucous membranes. Claims that spelunkers may experience rabies after inhaling bat excreta have come under doubt, although inhalational exposure can occur during laboratory accidents. No case of nosocomial transmission to a healthcare worker has been documented to date, but caregivers of a patient with rabies are advised to use full barrier precautions. The virus is rapidly inactivated in the environment, and contamination of fomites is not a mechanism of spread.

Pathogenesis After inoculation, rabies virus replicates slowly and at low levels in muscle or skin. This slow initial step likely accounts for the disease's long incubation period. Virus then enters the peripheral motor nerve, utilizing the nicotinic acetylcholine receptor and possibly several other receptors for entry. Once in the nerve, the virus travels by fast axonal transport, crossing synapses roughly every 12 hr. Rapid dissemination occurs throughout the brain and spinal cord before symptoms appear. Infection of the dorsal root ganglia is apparently futile but causes characteristic radiculitis. Infection concentrates in the brainstem, accounting for autonomic dysfunction and relative sparing of cognition. Despite severe neurologic dysfunction with rabies, histopathology reveals limited damage, inflammation, or apoptosis. The pathologic hallmark of rabies, the Negri body, is composed of clumped viral nucleocapsids that create cytoplasmic inclusions on routine histology. Negri bodies can be absent in documented rabies virus infection. Rabies may be a metabolic disorder of neurotransmission; tetrahydrobiopterin deficiency in human rabies causes severe deficiencies in dopamine, norepinephrine, and serotonin metabolism. After infection of the central nervous system, the virus travels anterograde through the peripheral nervous system to virtually all innervated organs, further exacerbating dysautonomia. It is through this route that the virus infects the salivary glands. Many victims of rabies die from uncontrolled cardiac dysrhythmia. Deficiency of tetrahydrobiopterin, an essential cofactor for neuronal nitric oxide synthase, is predicted to lead to spasm of the basilar arteries. Onset of vasospasm has been confirmed in a few patients within 5-8 days of the first hospitalization, at about the time coma supervenes in the natural history. Increased intracranial pressure is regularly measured early in rabies in association with elevated N -acetylaspartate in cerebrospinal fluid (CSF), but is rarely radiologically apparent. Metabolites in CSF consistent with ketogenesis are associated with demise.

Clinical Manifestations The incubation period for rabies is 1-3 mo. In severe wounds to the head, symptoms may occur within 5 days after exposure, and occasionally the incubation period can extend to 8 yr. Rabies has two principal clinical forms.

Encephalitic or furious rabies begins with nonspecific symptoms, including fever, sore throat, malaise, headache, nausea and vomiting, and weakness. These symptoms are often accompanied by paresthesia and pruritus at or near the site of the bite that then extend along the affected limb. Soon thereafter the patient begins to demonstrate symptoms of encephalitis, with agitation, sleep disturbance, or depressed mentation. Characteristically, patients with rabies encephalitis initially have periods of lucidity alternating with periods of profound encephalopathy. Hydrophobia and aerophobia are the cardinal signs of rabies; they are unique to humans and are not universal or specific. Phobic spasms are manifested by agitation and fear created by being offered a drink or fanning of air in the face, which in turn produce choking and aspiration through spasms of the pharynx, neck, and diaphragm. Seizures are rare and should point to an alternative diagnosis; orofacial dyskinesias and myoclonia may be confused with seizures. The illness is relentlessly progressive. There is a dissociation of electrophysiologic or encephalographic activity with findings of brainstem coma caused by anterograde denervation. Death almost always occurs within 1-2 days of hospitalization in developing countries and by 18 days of hospitalization with intensive care. A second form of rabies known as paralytic or dumb rabies is seen much less frequently and is characterized principally by fevers and ascending motor weakness affecting both the limbs and the cranial nerves. Most patients with paralytic rabies also have some element of encephalopathy as the disease progresses subacutely. Case reports suggest that milder forms of rabies encephalitis may exist, and 28 rabies survivors are known. Rabies should be considered earlier and more frequently than current practice to improve outcomes.

Differential Diagnosis The differential diagnosis of rabies encephalitis includes all forms of severe cerebral infections, tetanus, and some intoxications and envenomations. Rabies can be confused with autoimmune (anti–N -methyl-D -aspartate receptor, NMDAR) encephalitis, other infectious forms of encephalitis, psychiatric illness, drug abuse, and conversion disorders. Paralytic rabies is frequently confused with Guillain-Barré syndrome. The diagnosis of rabies is frequently delayed in Western countries because of the unfamiliarity of the medical staff with the infection. These considerations highlight the need to pursue a history of contact

with an animal belonging to one of the known reservoirs for rabies or to establish a travel history to a rabies-endemic region.

Diagnosis The Centers for Disease Control and Prevention (CDC) require a number of tests to confirm a clinically suspected case of rabies. Reverse transcription polymerase chain reaction is the most sensitive available assay for the diagnosis of rabies when done iteratively. Rabies virus RNA has been detected in saliva, skin, and brain by the reverse transcription polymerase chain reaction. The virus can be grown both in cell culture and after animal injection, but identification of rabies by these methods is slow. Rabies antigen is detected through immunofluorescence of saliva or biopsies of hairy skin or brain. Corneal impressions are not recommended. Rabies-specific antibody can be detected in serum or CSF samples, but most patients die while seronegative. Antirabies antibodies are present in the sera of patients who have received an incomplete course of the rabies vaccine, precluding a meaningful interpretation in this setting. Recent treatment with intravenous immunoglobulin may result in a falsepositive antibody test. Antibody in CSF is rarely detected after vaccination and is considered diagnostic of rabies regardless of immunization status. CSF abnormalities in cell count, glucose, and protein content are minimal and are not diagnostic. MRI findings in the brain are late.

Treatment and Prognosis Rabies is generally fatal. Conventional critical care yielded 6 survivors from 79 attempts since 1990. Seventeen of 80 patients survived with use of the Milwaukee Protocol (MP) (http://www.mcw.edu/rabies ); neurologic outcomes are poor in half of patients. Neither rabies immunoglobulin (RIG) nor rabies vaccine provides benefit once symptoms have appeared. Among 10 survivors of rabies after use of biologics, 7 had poor neurologic outcomes. Among 7 vaccinenaïve survivors, 2 had poor outcomes. Antiviral treatments have not been effective; favipiravir has been administered to 4 patients as compassionate use. Ribavirin and RIG delay the immune response and should be avoided. In contrast, appearance of the normal antibody response by 7 days is associated with clearance of salivary viral load and survival.

Prevention Primary prevention of rabies infection includes vaccination of domestic animals and education to avoid wild animals, stray animals, and animals with unusual behavior.

Immunization and Fertility Control of Animal Reservoirs The introduction of routine rabies immunization for domestic pets in the United States and Europe during the middle of the 20th century virtually eliminated infection in dogs. In the 1990s, control efforts in Europe and North America shifted to immunization of wildlife reservoirs of rabies, where rabies was newly emerging. These programs employed bait laced with either an attenuated rabies vaccine or a recombinant rabies surface glycoprotein inserted into vaccinia, distributed by air or hand into areas inhabited by rabid animals. Human contact with vaccine-laden bait has been infrequent. Adverse events after such contact have been rare, but the vaccinia vector poses a threat to the same population at risk for vaccinia itself, namely, pregnant women, immunocompromised patients, and people with atopic dermatitis. Mass culling of endemic reservoirs has never worked; vaccination and fertility control stop outbreaks. Bats are ubiquitous and very important for insect control. Less than 1% of free-flying bats but > 8% of downed bats and bats found in dwellings are rabid.

Postexposure Prophylaxis The relevance of rabies for most pediatricians centers on evaluating whether an animal exposure warrants PEP (Table 300.1 ). No case of rabies has been documented in a person receiving the recommended schedule of PEP since introduction of modern cellular vaccines in the 1970s. Table 300.1

Rabies Postexposure Prophylaxis Guide ANIMAL TYPE Dogs, cats, and ferrets

EVALUATION AND DISPOSITION OF ANIMAL Healthy and available for 10 days of observation

POSTEXPOSURE PROPHYLAXIS RECOMMENDATIONS Prophylaxis only if animal shows signs of rabies*

Rabid or suspected of being rabid † Immediate immunization and RIG Unknown (escaped) Consult public health officials for advice Regarded as rabid unless Immediate immunization and RIG geographic area is known to be free of rabies or until animal proven negative by laboratory tests †

Bats, skunks, raccoons, foxes, and most other carnivores; woodchucks Livestock, rodents, Consider individually and lagomorphs (rabbits, hares, and pikas)

Consult public health officials. Bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice and other rodents, rabbits, hares, and pikas almost never require antirabies treatment

* During the 10-day observation period, at the first sign of rabies in the biting dog, cat, or ferret,

treatment of the exposed person with RIG (human) and vaccine should be initiated. The animal should be euthanized immediately and tested. † The animal should be euthanized and tested as soon as possible. Holding for observation is not

recommended. Immunization is discontinued if the immunofluorescent test result for the animal is negative. RIG, rabies immunoglobulin.

Given the incubation period for rabies, PEP is a medical urgency, not emergency. Algorithms have been devised to aid practitioners in deciding when to initiate rabies PEP (Fig. 300.1 ). The decision to proceed ultimately depends on the local epidemiology of animal rabies as determined by active surveillance programs, information that can be obtained from local and state health departments. In general, bats, raccoons, skunks, coyotes, and foxes should be considered rabid unless proven otherwise through euthanasia and testing of brain tissue, whereas bites from small herbivorous animals (squirrels, hamsters, gerbils, chipmunks, rats, mice, and rabbits) can be discounted. The response to bites from a pet, particularly a dog, cat, or ferret, depends on local surveillance statistics and on whether the animal is vaccinated and available for observation.

FIG. 300.1 Algorithm for evaluating a child for rabies postexposure prophylaxis. This and any other algorithm should be used in concert with local epidemiologic information regarding the incidence of animal rabies in any given location.

The approach to nonbite bat exposures is controversial. In response to the observation that most cases of rabies in the United States have been caused by bat variants and that the majority of affected patients had no recollection of a bat bite, the CDC has recommended that rabies PEP be considered after any physical contact with bats and when a bat is found in the same room as persons who may not be able to accurately report a bite, assuming that the animal is unavailable for testing. Such people include young children, the mentally disabled, and intoxicated individuals. Other nonbite contacts (e.g., handling a carcass, exposure to an animal playing with a carcass, or coming into contact with blood or excreta from a potentially rabid animal) usually do not require PEP. In all instances of a legitimate exposure, effort should be made to recover the animal for quarantine and observation or brain examination after euthanasia. Testing obviates the need for PEP more than half the time. In most instances, PEP can be deferred until the results of observation or brain histology are known. In dogs, cats, and ferrets, symptoms of rabies always occur within several days of viral shedding; therefore, in these animals a 10-day observation period is sufficient to eliminate the possibility of rabies.

No duration of time between exposure and onset of symptoms should preclude rabies prophylaxis. Rabies PEP is most effective when applied expeditiously. Nevertheless, the series should be initiated in the asymptomatic person as soon as possible, regardless of the length of time since the bite. The vaccine and RIG are contraindicated once symptoms develop. The first step in rabies PEP is to cleanse the wound thoroughly. Soapy water is sufficient to inactivate an enveloped virus, and its effectiveness is supported by broad experience. Other commonly used disinfectants, such as iodinecontaining preparations, are virucidal and should be used in addition to soap when available. Probably the most important aspect of this component is that the wound is cleansed with copious volumes of disinfectant. Primary closure is avoided; wounds may be bacterially infected as well, so cosmetic repair should follow. Antibiotics and tetanus prophylaxis (see Chapter 238 ) should be applied with the use of usual wound care criteria. The second component of rabies PEP consists of passive immunization with RIG. Most failures of PEP are attributed to not using RIG. Human RIG, the formulation used in industrialized countries, is administered at a dose of 20 IU/kg. As much of the dose is infused around the wound as possible, and the remainder is injected intramuscularly in a limb distant from the one injected with the killed vaccine. Like other immunoglobulin preparations, RIG interferes with the take of live viral vaccines for at least 4 mo after administration of the RIG dose. Human RIG is not available in many parts of the developing world. Equine RIG serves as a substitute for the human immunoglobulin preparation in some areas. Modern preparations of equine RIG are associated with fewer side effects than prior products composed of crude horse serum. Regrettably, for a large segment of the world's population, no passive immunization product is available at all. Monoclonal antibody products are in clinical trials and may alleviate this deficiency. The third component of rabies PEP is immunization with inactivated vaccine. In most of the world, cell-based vaccines have replaced previous preparations. Two formulations currently are available in the United States, namely, RabAvert (Chiron Behring Vaccines, Maharashtra, India), a purified chick-embryo cell cultivated vaccine, and Imovax Rabies (Aventis Pasteur, Bridgewater, NJ), cultivated in human diploid cell cultures. In both children and adults, both vaccines are administered intramuscularly in a 1-mL volume in the deltoid or anterolateral thigh on days 0, 3, 7, and 14 after presentation. Injection into the gluteal area is associated with a blunted antibody response, so this area should

not be used. The rabies vaccines can be safely administered during pregnancy. In most persons the vaccine is well tolerated; most adverse effects are related to booster doses. Pain and erythema at the injection site occur commonly, and local adenopathy, headache, and myalgias occur in 10–20% of patients. Approximately 5% of patients who receive the human diploid cell vaccine experience an immune complex–mediated allergic reaction, including rash, edema, and arthralgias, several days after a booster dose. The World Health Organization has approved schedules using smaller amounts of vaccine, administered intradermally, that are immunogenic and protective (http://www.who.int/rabies/human/post_exp_prophylaxis/en/ ), but none is approved for use in the United States. Other cell culture–derived rabies virus vaccines are available in the developing world. A few countries still produce nerve tissue–derived vaccines; these preparations are poorly immunogenic, and cross reactivity with human nervous tissue may occur with their use, producing severe neurologic symptoms even in the absence of rabies infection.

Preexposure Prophylaxis The killed rabies vaccine can be given to prevent rabies in persons at high risk for exposure to wild-type virus, including laboratory personnel working with rabies virus, veterinarians, and others likely to be exposed to rabid animals as part of their occupation. Preexposure prophylaxis should be considered for persons traveling to a rabies-endemic region where there is a credible risk for a bite or scratch from a rabies-infected animal, particularly if there is likely to be a shortage of RIG or cell culture–based vaccine (see Chapter 200 ). Rabies vaccine as part of the routine vaccine series is under investigation in some countries. The schedule for preexposure prophylaxis consists of three intramuscular injections on days 0, 7, and 21 or 28. PEP in the patient who has received preexposure prophylaxis or a prior full schedule of PEP consists of two doses of vaccine (one each on days 0 and 3) and does not require RIG. Immunity from preexposure prophylaxis wanes after several years and requires boosting if the potential for exposure to rabid animals recurs.

Bibliography Caicedo Y, Paez A, Kuzmin I, et al. Virology, immunology and pathology of human rabies during treatment. Pediatr Infect

Dis J . 2015;34:520–528. Christiansen AH, Rodriguez AB, Nielsen J, Cowan SA. Should travellers to rabies-endemic countries be pre-exposure vaccinated? An assessment of post-exposure prophylaxis and pre-exposure prophylaxis given to Danes travelling to rabiesendemic countries 2000-12. J Travel Med . 2016;23(4); 10.1093/jtm/taw022 . Cote A, Guagliardo AJ, Tran CH, et al. Assessing rabies risk after a mass bat exposure at a research facility in a national park, Wyoming, 2017. MMWR Morb Mortal Wkly Rep . 2018;67(10):313–314. Dato VM, Campagnolo ER, Long J, Rupprecht CE. A systematic review of human bat rabies virus variant cases: evaluating unprotected physical contact with claws and teeth in support of accurate risk assessments. PLoS ONE . 2016;11(7):e0159443. Fitzpatrick JL, Dyer JL, Blanton JD, et al. Rabies in rodents and lagomorphs in the United States, 1995-2010. J Am Vet Med Assoc . 2014;245(3):333–337. Hampson K, Coudeville L, Lembo T, et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis . 2015;9(4):e0003709. Hemachudha T, Ugolini G, Wacharapluesadee S, et al. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol . 2013;12:498–513. Mani RS. Human rabies survivors in India: an emerging paradox? PLoS Negl Trop Dis . 2016;10:e0004774. Schroeder B, Boland A, Pieracci EG, et al. Assessment of rabies exposure risk among residents of a university sorority house —Indiana, February 2017. MMWR Morb Mortal Wkly Rep . 2018;67(5):166. Styczynski A, Tran C, Dirlikov E, et al. Human rabies—Puerto Rico, 2015. MMWR Morb Mortal Wkly Rep .

2017;65(52):1474–1476. Vashishtha VM, Choudhury P, Kalra A, et al. Indian Academy of Pediatrics (IAP) recommended immunization schedule for children aged 0 through 18 years–India, 2014 and updates on immunization. Indian Pediatr . 2014;51:785–800. Vora NM, Orciari LA, Bertumen JB, et al. Potential confounding of diagnosis of rabies in patients with recent receipt of intravenous immune globulin. MMWR Morb Mortal Wkly Rep . 2018;67(5):161–164. Wallace RM, Gilbert A, Slate D, et al. Right place, wrong species: a 20-year review of rabies virus cross species transmission among terrestrial mammals in the United States. PLoS ONE . 2014;9(10):e107539. 2013. World Health Organ Tech Rep Ser . 2013;(982):1–139 [back cover].

CHAPTER 301

Polyomaviruses Gregory A. Storch

The polyomaviruses are small (45 nm), nonenveloped, circular, double-stranded DNA viruses with genomes of approximately 5,000 bp. Because of the association of animal polyomaviruses with tumors in the animals they infect, there has been concern for a relationship to neoplasia in humans; however, there is strong evidence for an etiologic role in neoplasia only for Merkel cell polyomavirus (see below). Among the other polyomaviruses, the traditional human pathogens are JC virus and BK virus. The number of human polyomaviruses has expanded dramatically, with discovery of up to 12 additional viruses. Two polyomaviruses, designated KI virus and WU virus, can be detected in respiratory samples from children; however, a pathogenic role for these viruses has not been proven to date. Merkel cell polyomavirus is associated with Merkel cell carcinoma, an unusual neuroectodermal tumor of the skin that occurs primarily in elderly and immunocompromised individuals. Clonal integration of Merkel cell polyomavirus DNA is present in Merkel cell carcinoma cells, supporting an etiologic role for the virus in the development of the tumor. Another human polyomavirus has been isolated from patients with the dermatologic condition trichodysplasia spinulosa and has been named trichodysplasia spinulosa–associated polyomavirus. Trichodysplasia spinulosa is a condition of the skin that occurs in immunocompromised individuals and involves the development of follicular papules and keratin spines, usually involving the face. Two other viruses, designated human polyomaviruses 6 and 7, have also been found in human skin samples. They have been implicated in pruritic skin rashes in immunocompromised individuals. Human polyomavirus 9 was detected in serum from a renal transplant recipient. Other recently discovered viruses, named Malawi virus and St. Louis virus, were first detected in stool samples, but a role in gastrointestinal or other disease has not been

established at this time. JC and BK viruses are tropic for renal epithelium; JC virus also infects brain oligodendrocytes and is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a rare and often fatal demyelinating disease of immunocompromised persons, especially those with AIDS. PML is known to occur in individuals receiving the immunomodulatory agents natalizumab (Tysabri), used to treat multiple sclerosis and Crohn disease, efalizumab (Raptiva), used to treat psoriasis, the anti-CD20 monoclonal antibody rituximab (Rituxan), and the anti-CD52 monoclonal antibody alemtuzumab (Campath), as well as multiple other immunomodulatory agents. BK virus is the cause of transplant nephropathy in renal transplant recipients and of hemorrhagic cystitis in hematopoietic stem cell and bone marrow transplant recipients. Several million persons in the United States were exposed to simian virus 40 (SV40), an oncogenic polyomavirus of Asian macaques, from contaminated poliovirus vaccines administered during the years 1955 to 1963. There were no recognized sequelae and no demonstrable increased risk for cancer. Seroepidemiologic studies have shown that infection with all of the human polyomaviruses appears to be widespread, often occurring during childhood. Primary infection with these viruses is not recognized clinically. Approximately half of children in the United States are infected with BK virus by 3-4 yr of age and with JC virus by 10-14 yr of age, and approximately 60–80% of adults are seropositive for one or both viruses. Infection with polyomaviruses is thought to persist throughout life, with JC and BK viruses remaining latent in renal epithelium, oligodendrocytes, and peripheral blood mononuclear cells. The site of latency of the other human polyomaviruses is not currently known. Approximately 30–50% of healthy persons have detectable BK or JC virus in renal tissue at autopsy. Reactivation and viruria occur with increased frequency with advancing age and are more common in immunocompromised persons. On the basis of polymerase chain reaction results, BK and JC viruria occurs in 2.6% and 13.2%, respectively, of persons younger than 30 yr of age and in approximately 9% and 50%, respectively, of persons older than 60 yr of age. Reactivation of BK and JC viruses with asymptomatic viruria occurs in 10– 50% of hematopoietic stem cell and bone marrow transplant recipients and in 30% of renal transplant recipients. Of those renal transplant recipients who demonstrate BK viruria, approximately one third also have plasma viremia. Recipients with plasma viremia are at risk for development of nephropathy, which can clinically mimic allograft rejection and can result in failure of the

allograft. Reduction of immunosuppression has been effective in preventing progression from viremia to nephropathy, and thus posttransplantation monitoring of either urine or plasma by polymerase chain reaction is important. It is particularly important to distinguish BK nephropathy from rejection because the treatments are different—increase in immunosuppression for rejection but decrease in immunosuppression for BK nephropathy. Polymerase chain reaction is the preferred means for detecting the BK and JC viruses. The high seroprevalence in the general population and lack of clear relationship to clinical illness limit the usefulness of serologic testing, although recent studies suggest that high levels of anti-BK antibodies in renal transplant donors are associated with an increased risk of BK disease in the recipient. There are no proven antiviral treatments for BK or JC virus infection, although cidofovir may be effective in some cases of BK-related transplant nephropathy. Effective treatment of AIDS with antiretroviral therapy can prevent the progression of progressive multifocal leukoencephalopathy. Allogeneic BK virus–specific T cells are a potentially beneficial therapy for PML.

Bibliography Allander T, Andreasson K, Gupta S, et al. Identification of a third human polyomavirus. J Virol . 2007;81:4130–4136. Dalianis T, Hirsch HH. Human polyomaviruses in disease and cancer. Virology . 2013;437:63–72. DeCaprio JA, Garcea RL. A cornucopia of human polyomaviruses. Nat Rev Microbiol . 2013;11:264–276. Egli A, Infanti L, Dumoulin A, et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis . 2009;199:837–846. Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science . 2008;319:1096–1100. Gaynor AM, Nissen MD, Whiley DM, et al. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog . 2007;3:e64. Hirsch HH, Knowles S, Dickenmann M, et al. Prospective study

of polyomavirus type BK replication and nephropathy in renal–transplant recipients. N Engl J Med . 2002;347:488– 496. Lam WY, Leung BW, Chu IM, et al. Survey for the presence of BK, JC, KI, WU and Merkel cell polyomaviruses in human brain tissues. J Clin Virol . 2010;48:11–14. Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med . 2010;61:35–47. Muftuoglu M, Olson A, Marin D, et al. Allogenic BK virusspecific T cells for progressive multifocal leukoencephalopathy. N Engl J Med . 2018;379(15):1443– 1450. Nguyen KD, Lee EE, Yue Y, et al. Human polyomaviruses 6 and 7 are associated with pruritic and dyskeratotic dermatoses. J Am Acad Dermatol . 2017;76(5):932–940. van der Meijda E, Janssens RWA, Lauber C, et al. Discovery of a new human polyomavirus associated with Trichodysplasia spinulosa in an immunocompromised patient. PLoS Pathog . 2010;6:e1001024. Wunderink HF, van der Meijden E, ban der Blij-de Brouwer CS, et al. Pretransplantation donor-recipient pair seroreactivity against BK polyomavirus predicts viremia and nephropathy after renal transplantation. Am J Transplant . 2017;17:161– 172.

CHAPTER 302

Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Ericka V. Hayes

Advances in research and major improvements in the treatment and management of HIV infection have brought about a substantial decrease in the incidence of new HIV infections and AIDS in children. Globally, from 2000 to 2015, there has been an estimated 70% decline in new infections in children aged 0-14 yr, largely the result of antiretroviral treatment (ART) of HIV-infected pregnant women for the prevention of mother-to-child transmission. Seventy percent of adults and children with HIV infection live in sub-Saharan Africa, where the disease continues to have a devastating impact (Fig. 302.1 ). Children experience more rapid disease progression than adults, with up to half of untreated children dying within the first 2 yr of life. This rapid progression is correlated with a higher viral burden and faster depletion of infected CD4 lymphocytes in infants and children than in adults. Accurate diagnostic tests and the early initiation of potent drugs to inhibit HIV replication have dramatically increased the ability to prevent and control this disease.

FIG. 302.1 Estimated number of people living with HIV in 2016 by WHO region. Data from WHO 2017 report. (Courtesy World Health Organization, 2017. Global Health Observatory (GHO) data. http://www.who.int/gho/hiv/epidemic_status/cases_all/en/ .)

Etiology HIV-1 and HIV-2 are members of the Retroviridae family and belong to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species. The HIV-1 genome contains two copies of singlestranded RNA that is 9.2 kb in size. At both ends of the genome there are identical regions, called long terminal repeats, which contain the regulation and expression genes of HIV. The remainder of the genome includes three major sections: the GAG region, which encodes the viral core proteins (p24 [capsid protein: CA], p17 [matrix protein: MA], p9, and p6, which are derived from the precursor p55); the POL region, which encodes the viral enzymes (i.e., reverse transcriptase [p51], protease [p10], and integrase [p32]); and the ENV region, which encodes the viral envelope proteins (gp120 and gp41, which are derived from the precursor gp160). Other regulatory proteins, such as transactivator of transcription (tat: p14), regulator of virion (rev: p19), negative regulatory factor

(nef: p27), viral protein r (vpr: p15), viral infectivity factor (vif: p23), viral protein u (vpu in HIV-1: P16), and viral protein x (vpx in HIV-2: P15), are involved in transactivation, viral messenger RNA expression, viral replication, induction of cell cycle arrest, promotion of nuclear import of viral reverse transcription complexes, downregulation of the CD4 receptors and class I major histocompatibility complex, proviral DNA synthesis, and virus release and infectivity (Fig. 302.2 ).

FIG. 302.2 The human immunodeficiency virus and associated proteins and their functions.

The HIV tropism to the target cell is determined by its envelope glycoprotein (Env). Env consists of two components, namely, the surface, heavily glycosylated subunit, gp120 protein and the associated transmembrane subunit glycoprotein gp41. Both gp120 and gp41 are produced from the precursor protein gp160. The glycoprotein gp41 is very immunogenic and is used to detect HIV-1 antibodies in diagnostic assays; gp120 is a complex molecule that includes the highly variable V3 loop. This region is immunodominant for neutralizing antibodies. The heterogeneity of gp120 presents major obstacles in establishing an effective HIV vaccine. The gp120 glycoprotein also carries the binding site for the CD4 molecule, the most common host cell surface receptor of T lymphocytes. This tropism for CD4+ T cells is beneficial to the virus because of the resulting reduction in the effectiveness of the host immune system. Other CD4-bearing cells include macrophages and microglial cells. The observations that CD4− cells are also infected by HIV and that some CD4+ T cells are resistant to such infections suggests that other cellular attachment sites are needed for the interaction between HIV and human cells. Several chemokines serve as coreceptors for the envelope glycoproteins, permitting

membrane fusion and entry into the cell. Most HIV strains have a specific tropism for one of the chemokines, including the fusion-inducing molecule CXCR-4, which acts as a coreceptor for HIV attachment to lymphocytes, and CCR-5, a β chemokine receptor that facilitates HIV entry into macrophages. Several other chemokine receptors (CCR-3) have also been shown in vitro to serve as virus coreceptors. Other mechanisms of attachment of HIV to cells use nonneutralizing antiviral antibodies and complement receptors. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (macrophages, fibroblasts), thus facilitating virus transfer into the cell. Other cell-surface receptors, such as the mannose-binding protein on macrophages or the DC-specific, C-type lectin (DC-SIGN) on dendritic cells, also bind to the HIV-1 envelope glycoprotein and increase the efficiency of viral infectivity. Cell-to-cell transfer of HIV without formation of fully formed particles is a more rapid mechanism of spreading the infection to new cells than is direct infection by the virus. Following viral attachment, gp120 and the CD4 molecule undergo conformational changes, and gp41 interacts with the fusion receptor on the cell surface (Fig. 302.3 ). Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. This process involves accessory viral proteins (nef, vif) and binding of cyclophilin A (a host cellular protein) to the capsid protein (p24). The p24 protein is involved in virus uncoating, recognition by restriction factors, and nuclear importation and integration of the newly created viral DNA. Viral DNA copies are then transcribed from the virion RNA through viral reverse transcriptase enzyme activity, which builds the first DNA strand from the viral RNA and then destroys the viral RNA and builds a second DNA strand to produce double-stranded circular DNA. The HIV-1 reverse transcriptase is error prone and lacks error-correcting mechanisms. Thus, many mutations arise, creating a wide genetic variation in HIV-1 isolates even within an individual patient. Many of the drugs used to fight HIV infection were designed to block the reverse transcriptase action. The circular DNA is transported into the cell nucleus, using viral accessory proteins such as vpr, where it is integrated (with the help of the virus integrase) into the host chromosomal DNA and referred to as the provirus. The provirus has the advantage of latency, because it can remain dormant for extended periods, making it extremely difficult to eradicate. The infected CD4+ T cells that survive long enough to revert to resting memory state become the HIV latent reservoir where the virus persists indefinitely even in patients who respond favorably to potent antiretroviral therapy. The molecular

mechanisms of this latency are complex and involve unique biologic properties of the latent provirus (e.g., absence of tat, epigenetic changes inhibiting HIV gene expression) and the nature of the cellular host (e.g., absence of transcription factors such as nuclear factor κB). Integration usually occurs near active genes, which allow a high level of viral production in response to various external factors such as an increase in inflammatory cytokines (by infection with other pathogens) and cellular activation. Anti-HIV drugs that block the integrase enzyme activity have been developed. Depending on the relative expression of the viral regulatory genes (tat, rev, nef), the proviral DNA may encode production of the viral RNA genome, which, in turn, leads to production of viral proteins necessary for viral assembly.

FIG. 302.3 HIV life cycle showing the sites of action and different classes of antiretroviral drugs. (Adapted from Walker BN, Colledge NR, Ralston SH, Penman I, editors: Davidson's principles and practice of medicine, ed 22, London, 2014, Churchill Livingstone.)

HIV-1 transcription is followed by translation. A capsid polyprotein is cleaved to produce the virus-specific protease (p10), among other products. This enzyme

is critical for HIV-1 assembly because it cleaves the long polyproteins into the proper functional pieces. Several HIV-1 antiprotease drugs have been developed, targeting the increased sensitivity of the viral protease, which differs from the cellular proteases. The regulatory protein vif is active in virus assembly and Gag processing. The RNA genome is then incorporated into the newly formed viral capsid that requires zinc finger domains (p7) and the matrix protein (MA: p17). The matrix protein forms a coat on the inner surface of the viral membrane, which is essential for the budding of the new virus from the host cell's surface. As new virus is formed, it buds through specialized membrane areas, known as lipid rafts, and is released. The virus release is facilitated by the viroporin vpu, which induces rapid degradation of newly synthesized CD4 molecules that impede viral budding. In addition, vpu counteracts host innate immunity (e.g., hampering natural killer T-cell activity). Full-length sequencing of the HIV-1 genome demonstrated three different groups (M [main], O [outlier], and N [non-M, non-O]), probably occurring from multiple zoonotic infections from primates in different geographic regions. The same technique identified eight groups of HIV-2 isolates. Group M diversified to nine subtypes (or clades A to D, F to H, J, and K). In each region of the world, certain clades predominate, for example, clade A in Central Africa, clade B in the United States and South America, clade C in South Africa, clade E in Thailand, and clade F in Brazil. Although some subtypes were identified within group O, none was found in any of the HIV-2 groups. Clades are mixed in some patients as a result of HIV recombination, and some crossing between groups (i.e., M and O) has been reported. HIV-2 has a similar life cycle to HIV-1 and is known to cause infection in several monkey species. Subtypes A and B are the major causes of infection in humans, but rarely cause infection in children. HIV-2 differs from HIV-1 in its accessory genes (e.g., it has no vpu gene but contains the vpx gene, which is not found in HIV-1). It is most prevalent in western Africa, but increasing numbers of cases are reported from Europe and southern Asia. The diagnosis of HIV-2 infection is more difficult because of major differences in the genetic sequences between HIV-1 and HIV-2. Thus, several of the standard confirmatory assays (immunoblot), which are HIV-1 specific, may give indeterminate results with HIV-2 infection. If HIV-2 infection is suspected, a combination screening test that detects antibody to HIV-1 and HIV-2 peptides should be used. In addition, the rapid HIV detection tests have been less reliable in patients suspected to be dually infected with HIV-1 and HIV-2, because of lower antibody concentrations

against HIV-2. HIV-2 viral loads also have limited availability. Notably, HIV-2 infection demonstrates a longer asymptomatic stage of infection and slower declines of CD4+ T-cell counts than HIV-1, as well as is less efficiently transmitted from mother to child, likely related to lower levels of viremia with HIV-2.

Epidemiology In 2015, the World Health Organization (WHO) estimated that 1.8 million children younger than 15 yr of age worldwide were living with HIV-1 infection; the 150,000 new infections annually in children was a 70% reduction since 2000. Approximately 80% of new infections in this age-group occur in sub-Saharan Africa. These trends reflect the slow but steady expansion of services to prevent perinatal transmission of HIV to infants. Notably, there are still 110,000 deaths worldwide of children < 15 yr of age with HIV. Unfortunately, through 2016, an estimated 16.5 million children have been orphaned by AIDS, defined as having one or both parents die from AIDS. Globally, the vast majority of HIV infections in childhood are the result of vertical transmission from an HIV-infected mother. In the United States, approximately 11,700 children, adolescents, or young adults were reported to be living with perinatally acquired HIV infection in 2014. The number of U.S. children with AIDS diagnosed each year increased from 1984 to 1992 but then declined by more than 95% to < 100 cases annually by 2003, largely from the success of prenatal screening and perinatal antiretroviral treatment of HIVinfected mothers and infants. From 2009 to 2013, there were 497 infants born with perinatally acquired HIV in the United States and Puerto Rico. Children of racial and ethnic minority groups are disproportionately overrepresented, particularly non-Hispanic African-Americans and Hispanics. Race and ethnicity are not risk factors for HIV infection but more likely reflect other social factors that may be predictive of an increased risk for HIV infection, such as lack of educational and economic opportunities. As of 2014, New York, Florida, Texas, Georgia, Illinois, and California are the states with the highest numbers of perinatally acquired cases of HIV in the United States. Adolescents (13-24 yr of age) constitute an important growing population of newly infected individuals; in 2015, 22% of all new HIV infections occurred in this age-group, with 81% of youth cases occurring in young males who have sex with males (MSM); 8% of cases of AIDS also occurred in this age-group.

Targeted efforts have decreased new cases by 18% among youth MSM from 2008 to 2014. It is estimated than 50% of HIV-positive youth are unaware of their diagnosis, the highest of any age-group. Considering the long latency period between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data significantly underrepresents the impact of the disease in adolescents. Based on a median incubation period of 8-12 yr, it is estimated that 15–20% of all AIDS cases were acquired between 13 and 19 yr of age. Risk factors for HIV infection vary by gender in adolescents. For example, 91–93% of males between the ages of 13 and 24 yr with HIV acquire infection through sex with males. In contrast, 91–93% of adolescent females with HIV are infected through heterosexual contact. Adolescent racial and ethnic minority populations are overrepresented, especially among females.

Transmission Transmission of HIV-1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from mother to child via exposure to vaginal secretions during birth or via breast milk. The primary route of infection in the pediatric population ( 500 cells/µL for ages 15 yr), but these vaccines should not be given to severely immunocompromised children (i.e., CD4 cell percentage < 15%, absolute CD4 count < 500 cells/µL for age 1-5 yr). Of note, prior immunizations do not always provide protection, as evidenced by outbreaks of measles and pertussis in immunized HIV-infected children. The durability of vaccine-induced titers is often short, especially if vaccines are administered when the child's CD4 cell count is low, and reimmunization when the CD4 count has increased may be indicated. It is recommended that children with HIV receive quadrivalent meningococcal conjugate vaccine at a younger age than the routine schedule. Adolescent vaccines are also important, including the Tdap booster and HPV vaccine. The current recommended annotated vaccine schedule for HIV-infected children is found here: https://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html .

FIG. 302.5 Routine childhood immunization schedule for HIV-infected children.

Prophylactic regimens are integral for the care of HIV-infected children. All infants between 4-6 wk and 1 yr of age who are proven to be HIV-infected should receive prophylaxis to prevent P. jiroveci pneumonia regardless of the CD4 count or percentage (Tables 302.5 and 302.6 ). Infants exposed to HIVinfected mothers should receive the same prophylaxis until they are proven to be noninfected; however, prophylaxis does not have to be initiated if there is strong presumptive evidence of noninfection (i.e., non–breastfed infant with two negative HIV PCR tests at older than 14 days and 4 wk of age, respectively). When the HIV-infected child is older than 1 yr of age, prophylaxis should be given according to the CD4 lymphocyte count (see Table 302.5 ). The best prophylactic regimen is 150 mg/m2 /day of TMP and 750 mg/m2 /day of SMX (maximum: 320/1,600 mg) given as 1-2 daily doses 3 days (consecutively or every other day) per wk. For severe adverse reactions to TMP-SMX, alternative therapies include dapsone, atovaquone, and aerosolized pentamidine.

Table 302.5 Recommendations for PJP Prophylaxis and CD4 Monitoring for HIV-Exposed Infants and HIV-Infected Children, by Age and HIV Infection Status AGE/HIV INFECTION STATUS Birth to 4-6 wk, HIV-exposed HIV infection reasonably excluded* 6 yr, HIV-infected

PJP PROPHYLAXIS

CD4 MONITORING

No prophylaxis No prophylaxis

None None

Prophylaxis regardless of CD4 count or percentage Prophylaxis if CD4 < 500 cells/µL or < 15% † Prophylaxis if CD4 < 200 cells/µL or < 15% † ‡

According to local practice for initiation or follow-up of cART According to local practice for initiation or follow-up of cART According to local practice for initiation or follow-up of cART

* See text. † More frequent monitoring (e.g., monthly) is recommended for children whose CD4 counts or

percentages are approaching the threshold at which prophylaxis is recommended. ‡ Prophylaxis should be considered on a case-by-case basis for children who might otherwise be

at risk for PJP, such as children with rapidly declining CD4 counts or percentages or children with category C conditions. Children who have had PJP should receive PJP prophylaxis until their CD4 count is ≥200 cells/mm3 for patients aged ≥6 yr, CD4 percentage is ≥15% or CD4 count is ≥500 cells/mm3 for patients aged 1 to 3 consecutive mo after receiving cART for ≥6 mo. The National Perinatal HIV Hotline (1-888-448-8765) provides consultation on all aspects of perinatal HIV care. cART, combined antiretroviral therapy; PJP, Pneumocystis jiroveci pneumonia.

Table 302.6

Prophylaxis to Prevent First Episode of Opportunistic Infections Among HIV-Exposed and HIV-Infected Infants and Children, United States* PREVENTIVE REGIMEN INDICATION FIRST CHOICE STRONGLY RECOMMENDED AS STANDARD OF CARE Pneumocystis HIV-infected or HIV-indeterminate TMP-SMX , 150/750 pneumonia † infants aged 1-12 mo; HIV-infected mg/m2 body surface area children aged 1-5 yr with CD4 count per day or 5-10 mg/kg/day of < 500 cells/µL or CD4 percentage (TMP)/25-50 mg/kg/day of < 15%; HIV-infected children (SMX) (max: 320/1,600 aged 6-12 yr with CD4 count of < mg) orally qd or bid 3 times 200 cells/µL or CD4 percentage of < weekly on consecutive days 15%; >13 yr with CD4 count 40 kg: 1 adult tablet (250 mg/100 mg)

Doxycycline, 2.2 mg/kg body weight (maximum 100 mg) orally qd for children >8 yr Chloroquine, 5 mg/kg base (equal 7.5 mg/kg chloroquine phosphate) orally up to 300 mg weekly (only for regions where the parasite is sensitive)

Isoniazid, 10-15 mg/kg body weight (max: 300 mg) qd for 9 mo or 20-30 mg/kg body weight (max: 900 mg) orally 2 times weekly for 9 mo; DOT highly recommended

Rifampin, 10-20 mg/kg body weight (max: 600 mg) orally daily for 4-6 mo

TST reaction ≥ 5 mm or Prior positive TST result without treatment or Close contact with any person who has contagious TB. TB disease must be excluded before start of treatment Same as previous pathogen; increased probability of exposure to isoniazid-resistant TB Same as previous pathogen; increased probability of exposure to multidrug-resistant TB

Rifampin, 10-20 mg/kg body weight (max: 600 mg) orally daily for 4-6 mo Choice of drugs requires consultation with public health authorities and depends on susceptibility of isolate from

Consult TB expert

Mycobacterium For children age ≥ 6 yr with CD4 avium complex ‡ count of < 50 cells/µL; age 2-5 yr with CD4 count of < 75 cells/µL; age 1-2 yr with CD4 count of < 500 cells/ µL; age < 1 yr with CD4 count of < 750 cells/µL

Varicella-zoster virus §

Exposure to varicella or shingles with no history of varicella or Zoster or seronegative status for VZV or Lack of evidence for ageappropriate vaccination

source patient Clarithromycin, 7.5 mg/kg (max: 500 mg) orally bid or Azithromycin, 20 mg/kg (max: 1,200 mg) orally once a week

Varicella-zoster immunoglobulin (VariZIG), 125 IU/10 kg (max: 625 IU) IM, administered ideally within 96 hr after exposure; potential benefit up to 10 days after exposure

VaccineStandard recommendations for HIV- Routine vaccinations (see Fig. preventable exposed and HIV-infected children 302.5 ) pathogens USUALLY RECOMMENDED Toxoplasma Seropositive IgG to Toxoplasma and TMP-SMX, 150/750 mg/m2 gondii ¶ severe immunosuppression: age < 6 orally qd or divided bid yr with CD4 percentage < 15%; age or ≥ 6 yr with CD4 count < 100 cells/µL Same dosage qd 3 times weekly on consecutive days or bid 3 times weekly on alternate days

Invasive Hypogammaglobulinemia (i.e., IgG < IVIG 400 mg/kg body weight bacterial 400 mg/dL) every 2-4 wk infections Cytomegalovirus CMV antibody positivity and Valganciclovir, 900 mg orally severe immunosuppression (CD4 qd with food for older children count < 50 cells/µL for >6 yr; who can receive adult dosing CD4 percentage 6 yr of age) (see Table 302.6 ). The drugs of choice are azithromycin (20 mg/kg [maximum: 1,200 mg] once a week orally or 5 mg/kg [maximum: 250 mg] once daily orally) or clarithromycin (7.5 mg/kg bid orally). In rare situations, rifabutin 300 mg qd can be an alternative for children older than 6 yr of age though efficacy data in children is very limited. Based on adult data, primary prophylaxis against most opportunistic infections may be discontinued if patients have experienced sustained (>6 mo duration) immune reconstitution with cART, even if they had previous opportunistic infections such as Pneumocystis pneumonia or disseminated MAC. HIV-infected children are at higher risk for TB and thus should have tuberculin skin testing (5 tuberculin units purified protein derivation) or interferon gamma release assay

(IGRA) testing for TB at least once per year; an induration of 5 mm or more should be considered positive for the PPD. If the child is living in close contact with a person with TB, the child should be tested more frequently. Of note, the sensitivity of purified protein derivation and IGRA is reduced in severely immunocompromised patients. The Guidelines for Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children (http://aidsinfo.nih.gov ) should be consulted for these and other opportunistic infections that may occur in these populations. To reduce the incidence of opportunistic infections, parents should be counseled about (1) the importance of good hand washing, (2) avoiding raw or undercooked food (Salmonella) , (3) avoiding drinking or swimming in lake or river water or being in contact with young farm animals (Cryptosporidium) , and (4) the risk of playing with pets (Toxoplasma and Bartonella from cats, Salmonella from reptiles).

Prognosis The improved understanding of the pathogenesis of HIV infection in children and the availability of more effective antiretroviral drugs has changed the prognosis considerably for children with HIV infection. The earlier cART is started, the better the prognosis. In settings with ready access to early diagnosis and antiretroviral therapy, progression of the disease to AIDS has significantly diminished. Since the advent of cART in the mid-1990s, mortality rates in perinatally infected children have declined more than 90% and many children survive to adolescence and adulthood. Even with only partial reduction of the viral load, children may have both significant immunologic and clinical benefits. In general, the best prognostic indicators are the sustained suppression of the plasma viral load and the restoration of a normal CD4+ lymphocyte count. If determinations of the viral load and CD4 lymphocytes are available, the results can be used to evaluate the prognosis. It is unusual to see rapid progression in an infant with a viral load < 100,000 copies/mL. In contrast, a high viral load (>100,000 copies/mL) over time is associated with a greater risk for disease progression and death. CD4 count is also another prognostic indicator with mortality rate significantly higher in profoundly immunosuppressed individuals. To define the prognosis more accurately, the use of changes in both markers (CD4 lymphocyte percentage and plasma viral load) is recommended. Even in resource-limited countries where cART and molecular diagnostic tests are less available, the use of cART has had a substantial benefit on the survival

of HIV-infected children and has reduced the likelihood of mortality by > 75%. Children with opportunistic infections (e.g., Pneumocystis pneumonia, MAC), encephalopathy and regressing developmental milestones, or wasting syndrome, which are all AIDS defining conditions, have the worst prognosis, with 75% dying before 3 yr of age. A higher risk of death was documented in children who did not receive TMP-SMX preventive therapy. Persistent fever and/or oral thrush, serious bacterial infections (meningitis, pneumonia, sepsis), hepatitis, persistent anemia ( 10% of adults are seropositive), areas of the Caribbean, including Jamaica and Trinidad (≤6%), and in parts of sub-Saharan Africa (≤5%). Lower seroprevalence rates are found in South America (≤2%) and Taiwan (0.1–1%). There is microclustering with marked variability within geographic regions. The seroprevalence of HTLV-1 and HTLV-2 in the United States in the general population is 0.01–0.03% for each virus, with higher rates with increasing age. The prevalence of HTLV-1 infection is highest in babies born in endemic areas or in persons who have had sexual contact with persons from endemic areas. The prevalence of HTLV-2 infection is highest in intravenous drug users, with a seroprevalence of 8.8–17.6% in this population. HTLV-1 and -2 are transmitted as cell-associated viruses from mother to child and transmission through genital secretions, contaminated blood products, and intravenous drug use. Mother-to-child transmission during the intrauterine period or peripartum period is estimated to occur in less than 5% of cases but increases to approximately 20% with breastfeeding. A higher maternal HTLV-1 proviral load and prolonged breastfeeding are associated with a greater risk of mother-to-child transmission. In Japan, approximately 20–25% of children born to HTLV-1–infected mothers became infected prior to recommendations that seropositive mothers should avoid breastfeeding, with a marked reduction to 2.5% transmission following restriction of breastfeeding. HTLV-2 may also be transmitted via breastfeeding, but it has a slightly lower reported transmission rate via breast milk of approximately 14%.

Diagnosis HTLV-1 and HTLV-2 infections are diagnosed by screening using a secondgeneration enzyme immunoassay, with confirmation by immunoblot, indirect immunofluorescence, or line immunoassays. The polymerase chain reaction can also be used to distinguish HTLV-1 from HTLV-2 infection.

Clinical Manifestations The lifetime risk of disease associated with HTLV-1 infection is estimated at 5– 10% and is highest following vertical transmission. HTLV-1 is associated with ATL and several nonmalignant conditions, including the neurodegenerative disorder HTLV-1–associated myelopathy (HAM), also known as tropical spastic paraparesis and sometimes termed HAM/tropical spastic paraparesis. The geographic epidemiologic characteristics of ATL and HAM are similar. HTLV1–associated arthropathy mimics rheumatoid arthritis, including a positive rheumatoid factor. Treatment is with antiinflammatory agents. HTLV-1– associated uveitis may be unilateral or bilateral, is more common among females, and resolves spontaneously, although it often recurs within 1-3 yr. Topical corticosteroids hasten recovery. HTLV-1–associated infective dermatitis is a chronic and recurrent eczematous disease occurring during childhood and adolescence, which predisposes to staphylococcal infection. HTLV-1 infection predisposes to disseminated and recurrent Strongyloides stercoralis infection, an increased risk of developing tuberculosis disease following latent infection, and severe scabies.

Adult T-Cell Leukemia/Lymphoma The age distribution of ATL peaks at approximately 50 yr, underscoring the long latent period of HTLV-1 infection. HTLV-1–infected persons remain at risk for ATL even if they move to an area of low HTLV-1 prevalence, with a lifetime risk for ATL of 2–4%. Most cases of ATL are associated with monoclonal integration of the HTLV-1 provirus into the cellular genome of CD4+ T lymphocytes, resulting in unchecked proliferation of CD4 T cells. There is a spectrum of disease that is categorized into different forms: acute, lymphomatous, chronic, primary cutaneous smoldering, and primary cutaneous tumoral. The acute form of ATL comprises 55–75% of all cases. Smoldering, subclinical lymphoproliferation may spontaneously resolve (the outcome in approximately half of cases) or progress to chronic leukemia or lymphomatous or even acute ATL. Chronic, low-grade, HTLV-1–associated lymphoproliferation (preATL) may persist for years with abnormal lymphocytes with or without peripheral lymphadenopathy before progressing to the acute form. Acute ATL is characterized by hypercalcemia, lytic bone lesions, lymphadenopathy that spares the mediastinum, hepatomegaly, splenomegaly, cutaneous lymphomas, and

opportunistic infections. Leukemia may develop with circulating polylobulated malignant lymphocytes, called flower cells, possessing mature T-cell markers. Antiviral therapy with zidovudine and interferon-α is the standard therapy for leukemic-type ATL in the United States and Europe. In lymphoma-type ATL, response rates may be improved using the anti-CCR4 monoclonal antibody mogamulizumab with chemotherapy. Allogeneic hematopoietic stem cell transplantation is sometimes employed.

Human T-Cell Lymphotropic Virus-1– Associated Myelopathy HAM is more common in females than in males and has a relatively short incubation period of 1-4 yr after HTLV-1 infection, compared with 40-60 yr for ATL. HAM occurs in up to 4% of persons with HTLV-1 infection, usually developing during middle age. It is characterized by infiltration of mononuclear cells into the gray and white matter of the thoracic spinal cord, leading to severe white matter degeneration and fibrosis. HTLV-1 is found near but not directly within the lesions, suggesting that reactive inflammation is a major mechanism of disease. The cerebrospinal fluid typically shows a mildly elevated protein and a modest monocytic pleocytosis, along with anti–HTLV-1 antibodies. Neuroimaging studies are normal or show periventricular lesions in the white matter. Clinical manifestations include a gradual onset of slowly progressive, symmetric neurologic degeneration of the corticospinal tracts and, to a lesser extent, the sensory system that leads to lower-extremity spasticity or weakness, lower back pain, and hyperreflexia of the lower extremities with an extensor plantar response. The bladder and intestines may become dysfunctional, and men may become impotent. Some patients develop dysesthesias of the lower extremities with diminished sensation to vibration and pain. Upper-extremity function and sensation, cranial nerves, and cognitive function are usually preserved. Treatment regimens have been attempted with corticosteroids, danazol, interferon, plasmapheresis, high-dose vitamin C, and antivirals, all with minimal effects.

Human T-Cell Lymphotropic Virus-2 HTLV-2 was originally identified in patients with hairy cell leukemia, although

most patients with hairy cell leukemia are seronegative for HTLV-2 infection. HTLV-2 has been rarely isolated from patients with leukemias or with myelopathies resembling HAM, and there is limited evidence of disease specifically associated with HTLV-2 infection.

Prevention Routine antibody testing of all blood products for HTLV-1 and -2 is performed in many developed countries and is effective in preventing blood transfusion– associated infections. Unfortunately, this routine testing is not always available in low and middle-income countries with higher endemicity. Prenatal screening and avoidance of breastfeeding by HTLV-1–infected mothers is an effective means of reducing mother-to-child transmission of HTLV-1. Safe sexual practices to avoid sexually transmitted infections, such as condom use and avoiding multiple sexual partners, may reduce transmission of both HTLV-I and HTLV-2. No vaccine is available.

Bibliography Bangham CR, Araujo A, Yamano Y, Taylor GP. HTLV-1associated myelopathy/tropical spastic paraparesis. Nat Rev Dis Primers . 2015;1:15012. Bangham CR, Ratner L. How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)? Curr Opin Virol . 2015;14:93– 100. Cook LB, Elemans M, Rowan AG, Asquith B. HTLV-1: persistence and pathogenesis. Virology . 2013;435(1):131– 140. de Oliveira Mde F, Fatal PL, Primo JR, et al. Infective dermatitis associated with human T-cell lymphotropic virus type 1: evaluation of 42 cases observed in Bahia, Brazil. Clin Infect Dis . 2012;54(12):1714–1719. Fuzii HT, da Silva Dias GA, de Barros RJ, et al. Immunopathogenesis of HTLV-1-assoaciated

myelopathy/tropical spastic paraparesis (HAM/TSP). Life Sci . 2014;104(1–2):9–14. Hlela C, Bittencourt A. Infective dermatitis associated with HTLV-1 mimics common eczemas in children and may be a prelude to severe systemic diseases. Dermatol Clin . 2014;32(2):237–248. Martin JL, Maldonado JO, Mueller JD, et al. Molecular studies of HTLV-1 replication: an update. Viruses . 2016;8(2). Matsuoka M, Yasunaga J. Human T-cell leukemia virus type 1: replication, proliferation and propagation by Tax and HTLV-1 bZIP factor. Curr Opin Virol . 2013;3(6):684–691. Murphy EL. Infection with human T-lymphotropic virus types-1 and -2 (HTLV-1 and -2): implications for blood transfusion safety. Transfus Clin Biol . 2016;23(1):13–19. Percher F, Jeannin P, Martin-Latil S, et al. Mother-to-Child transmission of HTLV-1 epidemiological aspects, mechanisms and determinants of Mother-to-Child transmission. Viruses . 2016;8(2).

CHAPTER 304

Transmissible Spongiform Encephalopathies David M. Asher

The transmissible spongiform encephalopathies (TSEs, prion diseases) are slow infections of the human nervous system, consisting of at least four diseases of humans (Table 304.1 ): kuru; Creutzfeldt-Jakob disease (CJD) with its variants— sporadic CJD (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), and newvariant or variant CJD (vCJD); Gerstmann-Sträussler-Scheinker syndrome (GSS); and fatal familial insomnia (FFI), or the even more rare sporadic fatal insomnia syndrome. TSEs also affect animals; the most common and bestknown TSEs of animals are scrapie in sheep, bovine spongiform encephalopathy (BSE or mad cow disease) in cattle, and a chronic wasting disease (CWD) of deer, elk, and moose found in parts of the United States, Canada, Norway, and Finland. All TSEs have similar clinical and histopathologic manifestations, and all are slow infections with very long asymptomatic incubation periods (often years), durations of several months or more, and overt disease affecting only the nervous system. TSEs are relentlessly progressive after illness begins and are invariably fatal. The most striking neuropathologic change that occurs in each TSE, to a greater or lesser extent, is spongy degeneration of the cerebral cortical gray matter. Table 304.1

Clinical and Epidemiologic Features of Human Transmissible Spongiform Encephalopathies (Prion Diseases) CLINICAL

SOURCE OF

GEOGRAPHIC

USEFUL

DURATION

DISEASE FEATURES

INFECTION

sCJD

Dementia, myoclonus, ataxia

Unknown

OF ILLNESS 1-24 mo (mean: 4-6 mo)

fCJD

Dementia, myoclonus, ataxia

ANCILLARY TESTS EEG— PSWCs; CSF 14-3-3; MRI/DWI Gene testing; EEG—PSWC rare; MRI/DWI (?)

iCJD

≈1% of CJD cases in toto (cadaver dural grafts), > 100 cases (human pituitary hormones), > 100 cases; corneal transplantation, 3 cases; neurosurgical instruments, 6 cases, including 2 from cortical depth electrodes; RBC transfusions, 4 cases of vCJD infection, 3 clinical, 1 preclinical (United Kingdom); human plasma–derived factor VIII, 1 preclinical case of vCJD (United Kingdom) Mood and Linked to BSE >230 clinical cases (see iatrogenic Tonsil biopsy behavioral in cattle, vCJD, above): none living, May may show abnormalities, transfusion 2017 PrPTSE paresthesias, plasma MRI/FLAIR dementia products Incoordination, Linked to Fore people of Papua New Guinea EEG—no ataxia, tremors, cannibalism (≈2,600 known cases) PSWCs; CSF dementia (late) 14-3-3 often negative; MRI (?) Incoordination, 90% genetic Worldwide; >50 families; ≈1PRNP gene chronic (PRNP 10/100 million/yr sequencing progressive mutations) ataxia, corticospinal tract signs, dementia (late), myoclonus (rare) Disrupted sleep, PRNP ≈27 families in Europe, United EEG— intractable gene Kingdom, United States, Finland, PSWCs only insomnia; mutation Australia, China, Japan rarely autonomic (D 178L); positive; MRI hyperactivation; very rare —no DWI myoclonus, sporadic abnormalities; ataxia; cases CSF 14-3-3 corticospinal positive in ≈ tract signs; 50% dementia

1 mo-10 yr

vCJD

Kuru

GSS

FFI

Genetic association (PRNP mutations) ?? Possible exogenous source of infection Incoordination, Cadaver dural dementia (late) grafts, human pituitary hormones, corneal transplantation, neurosurgical instruments, EEG depth electrodes

DISTRIBUTION AND PREVALENCE Worldwide; ≈1/1 million/yr; 85– 95% of all CJD cases in United States Worldwide—geographic clusters; >100 known families; 5–15% of CJD cases

Mean ≈15 mo

8-36 mo (mean 14 mo)

3-24 mo

2-12 yr (mean ≈ 57 mo)

8 mo to 6 yr (mean: PRNP 129 MM 12 ± 4 mo 129 MV 21 ± 15 mo)

BSE, bovine spongiform encephalopathy; CSF, cerebrospinal fluid; CJD, Creutzfeldt-Jakob disease; DWI, diffusion-weighted image; EEG, electroencephalography; fCJD, familial CreutzfeldtJakob disease; FFI, fatal familial insomnia; FLAIR, fluid attenuation inversion recovery MRI; GSS, Gerstmann-Sträussler-Scheinker syndrome; iCJD, iatrogenic Creutzfeldt-Jakob disease; PRNP , prion protein encoding gene; PrPTSE , abnormal prion protein; PSWCs, periodic sharp wave complexes; RBC, red blood cell; sCJD, sporadic Creutzfeldt-Jakob disease; vCJD, variant Creutzfeldt-Jakob disease. NOTE: PRNP 129 MM, homozygous, encoding the amino acid methionine at both codons 129 of the prion-protein-encoding (PRNP) gene on chromosome 20; 129 MV, heterozygous at PRNP codon 129, encoding methionine on one chromosome 20 and valine on the other. Modified from Mandell GL, Bennett JE, Dolin R (eds): Principles and practice of infectious diseases, 6e, Philadelphia, 2005, Elsevier, p. 2222; and Love S, Louis DN, Ellison DW (eds): Greenfield's neuropathology, 8e, London, 2008, Hodder Arnold, p. 1239.

Etiology The TSEs are transmissible to susceptible animals by inoculation of tissues from affected subjects. Although the infectious agents replicate in some cell cultures, they do not achieve the high titers of infectivity found in brain tissues or cause recognizable cytopathic effects in cultures. Most previous studies of TSE agents have used in vivo assays, relying on the transmission of typical neurologic disease to animals as evidence that the agent was present and intact. Inoculation of susceptible recipient animals with small amounts of the infectious TSE agent results, months later, in the accumulation in tissues of large amounts of the agent with the same physical and biologic properties as the original agent. The TSE agents display a spectrum of extreme resistance to inactivation by a variety of chemical and physical treatments that is unknown among conventional pathogens. This characteristic, as well as their partial sensitivity to proteindisrupting treatments and their consistent association with abnormal isoforms of a normal host-encoded protein (prion protein or PrP), stimulated the hypothesis that the TSE agents are probably subviral in size, composed of protein, and devoid of nucleic acid. The term prion (for proteinaceous infectious agent), coined by S.B. Prusiner, is now widely used for such agents. The prion hypothesis proposes that the molecular mechanism by which the pathogen-specific information of TSE agents is propagated involves a self-replicating change in the folding host-encoded PrP associated with a transition from an α-helix–rich structure in the native proteasesensitive conformation (cellular PrP or PrPC ) to a β-sheet–rich structure in the protease-resistant conformation associated with infectivity. The existence of a

second host-encoded protein—termed protein X—that participates in the transformation was also postulated to explain certain otherwise puzzling findings but has never been identified. The prion hypothesis is still not universally accepted; it relies on the postulated existence of a genome-like coding mechanism based on differences in protein folding that have not been satisfactorily explained at a molecular level. In addition, it has yet to account convincingly for the many biologic strains of TSE agent that have been observed, although strain-specific differences in the abnormal forms of the PrP have been found and proposed as providing a plausible molecular basis for the coding. It fails to explain why pure PrP uncontaminated with nucleic acid from an infected host has not transmitted a convincingly typical spongiform encephalopathy consistently associated with a serially self-propagating agent. A finding that was also troubling, in several experimental models and human illnesses, was that abnormal PrP and infectivity were not consistently associated. Particularly problematic is the finding that some illnesses associated with mutations in the PRNP gene and accompanied by abnormal PrP failed to transmit infection to animals. If the TSE agents ultimately prove to consist of protein and only protein, without any obligatory nucleic acid component, then the term prion will indeed be appropriate and the early proponents of the prion hypothesis will prove to have been prescient. If the agents are ultimately found to contain small nucleic acid genomes, then they might better be considered atypical viruses, for which the term virino has been suggested. Until the actual molecular structure of the infectious TSE pathogens and the presence or absence of a nucleic acid genome are rigorously established, it seems less contentious to continue calling them TSE agents, although most authorities have accepted the term prion (sometimes referring to the agent of a TSE and sometimes to the abnormal protein, even when nontransmissible). The earliest evidence that abnormal proteins are associated with the TSE was morphologic: Scrapie-associated fibrils were found in extracts of tissues from patients and animals with spongiform encephalopathies but not in normal tissues. Scrapie-associated fibrils resemble but are distinguishable from the amyloid fibrils that accumulate in the brains of patients with Alzheimer disease. A group of antigenically related protease-resistant proteins (PrPs) proved to be components of scrapie-associated fibrils and to be present in the amyloid plaques found in the brains of patients and animals with TSEs. The abnormal forms of PrP are variously designated PrPSc (scrapie-type PrP), PrP-res (protease-resistant PrP), PrPTSE (TSE-associated PrP), or PrPD (disease-associated PrP) by different

authorities. It remains unclear whether abnormal PrP constitutes the complete infectious particle of spongiform encephalopathies, is a component of those particles, or is a pathologic host protein not usually separated from the actual infectious entity by currently used techniques. The demonstration that PrP is encoded by a normal host gene seemed to favor the last possibility. Several studies suggest that agentspecific pathogenic information can be transmitted and replicated by different conformations of a protein with the same primary amino acid sequence in the absence of agent-specific nucleic acids. Properties of two fungal proteins were found to be heritable without encoding in nucleic acid, although those properties have not been naturally transmitted to recipient fungi as infectious elements. Whatever its relationship to the actual infectious TSE particles, PrP clearly plays a central role in the susceptibility to infection, because the normal PrP must be expressed in mice and cattle if they are to acquire a TSE or to sustain replication of the infectious agents. Furthermore, inherited normal variations in the PrP phenotype are associated with increased susceptibility to vCJD and (to a lesser extent) to sCJD and with occurrence of familial TSEs (fCJD and GSS). PrPs are glycoproteins; protease-resistant PrPs, when aggregated, have the physical properties of amyloid proteins. The PrPs of different species of animals are very similar in their amino acid sequences and antigenicity but are not identical in structure. The primary structure of PrP is encoded by the host and is not altered by the source of the infectious agent provoking its formation. The function of the ubiquitous protease-sensitive PrP precursor (designated PrPC , for cellular PrP, or PrP-sen, for protease-sensitive PrP) in normal cells is unknown; it binds copper and may play some role in normal synaptic transmission, but it is not required for life or for relatively normal cerebral function in mice and cattle. As noted, animals must express PrP to develop scrapie disease and to support replication of the TSE agents. The degree of homology between amino acid sequences of PrPs in different animal species may correlate with the species barrier that affects the susceptibility of animals of one species to infection with a TSE agent adapted to grow in another species, although the degree of sequence homology does not always predict susceptibility to the same TSE agent. Attempts to find particles resembling those of viruses or virus-like agents in brain tissues of humans or animals with spongiform encephalopathies have been unsuccessful. Peculiar tubulovesicular structures reminiscent of some viruses have been seen repeatedly in thin sections of TSE-infected brain tissues and cultured cells but not in normal cells. It has never been established that those

structures are associated with infectivity.

Epidemiology Kuru once affected many children of both sexes ≥ 4 yr of age, adolescents, and young adults (mainly females) living in one limited area of Papua New Guinea. The complete disappearance of kuru among people born after 1957 suggests that the practice of ritual cannibalism (thought to have ended that year) was probably the only mechanism by which the infection spread in Papua New Guinea. CJD, the most common human spongiform encephalopathy, was formerly thought to occur only in older adults; however, iCJD and, much more rarely, sCJD (to date, seven reports in adolescents, one a 14 yr old female) have affected young people. A single case of sporadic fatal insomnia was recognized in a U.S. adolescent. GSS has not been diagnosed in children or adolescents. vCJD has a peculiar predilection for younger people. Of 174 cases of vCJD reported through 2010 in the United Kingdom, all except 23 were in people younger than 40 yr of age and 22 were in people younger than 20 yr of age; the youngest age at onset was 12 yr. sCJD has been recognized worldwide, at yearly rates of 0.25-2 cases/million population (not age-adjusted), with CJD foci of considerably higher incidence among Libyan Jews in Israel, in isolated villages of Slovakia, and in other limited areas. Sporadic CJD has not been convincingly linked to any common exposure, and the source of infection remains unknown. Proponents of the prion hypothesis are convinced that PrP can spontaneously misfold, becoming self-replicating and causing sCJD; skeptics favor infection with some ubiquitous TSE agent, which, fortunately, has a very low attack rate except in persons with certain mutations in the PRNP gene. Neither of those possible etiologies has been proven. Person-to-person spread has been confirmed only for iatrogenic cases. Spouses and household contacts of patients are not at risk of acquiring CJD, although two instances of conjugal CJD have been reported. However, medical personnel exposed to brains of patients with CJD may be at some increased risk; at least 20 healthcare workers have been recognized with the disease. The striking resemblance of CJD to scrapie prompted a concern that infected sheep tissues might be a source of spongiform encephalopathy in humans. No reliable epidemiologic evidence suggests that exposure to potentially scrapiecontaminated animals, meat, meat products, or experimental preparations of the scrapie agent have transmitted a TSE to humans. The potential of the CWD

agent to infect human beings has also not been demonstrated but remains under investigation; deer, elk, and moose in 15 U.S. states and 2 Canadian provinces have been naturally infected; cases of CWD were recently detected in wild reindeer and moose (European elk) in Norway and Finland. Consumption of contaminated meat, including venison from animals infected with the CWD agent, has not been implicated as a risk factor for human TSE by epidemiologic studies; however, a recent unpublished study requiring several years yielded evidence that CWD was experimentally transmitted to monkeys fed venison from overtly healthy infected deer, prompting a health advisory from Canadian authorities. The outbreak of BSE among cattle (possibly infected by eating scrapie-agent–contaminated meat-and-bone meal added to feed) was first recognized in the United Kingdom in 1986 and later reported in cattle of 27 other countries, including Canada and the United States. More than 190,000 cases of BSE have been reported to the World Organization for Animal Health (OIE), almost 97% of those from the United Kingdom. Cases in the United Kingdom progressively declined after 1992 and later in other countries; in 2016 only 2 cases worldwide were reported to OIE (from France and Spain) and none from the United Kingdom. The finding of a new TSE in ungulate and feline animals in British zoos and later in domestic cats raised a fear that the BSE agent had acquired a range of susceptible hosts broader than that of scrapie, posing a potential danger for humans. That remains the most plausible explanation for the occurrence of vCJD, first described in adolescents in Britain in 1996 and, as of May 2017, eventually affecting at least 178 people in the United Kingdom. (not counting a disturbing number of people with evidence of possible asymptomatic or “preclinical” vCJD infection) and more than 50 in 11 other countries (total 231 cases worldwide): 27 in France, 5 in Spain, 4 in Ireland, 3 in the Netherlands, 2 each in Italy and Portugal, and single cases in Japan and Saudi Arabia. Variant CJD has also occurred in former U.K. residents (>6 mo) living in Ireland (two cases), France (one case), Canada (one case), Taiwan (one case), and the United States (two cases). Two cases of vCJD—one in the United States and one in Canada—have been reported in former long-time residents of Saudi Arabia, a country that has not recognized BSE but might have imported contaminated meat products from the United Kingdom. A third case of vCJD was previously confirmed in a Saudi citizen residing in Saudi Arabia. The most recent case of vCJD diagnosed in the United States occurred in an immigrant deemed by the CDC to have most likely been infected during early years spent in Kuwait.

No case of vCJD has been confirmed in anyone born in the United Kingdom after 1989. However, examination of resected appendixes in the United Kingdom for evidence of subclinical infection with prions suggested that about 1 in 2,000 people tested had a detectable accumulation of PrPTSE in lymphoid follicles. It remains controversial whether those accumulations resulted from subclinical vCJD or another TSE; none of the subjects to date has presented to medical attention with overt TSE. Iatrogenic transmissions of CJD have been recognized for more than 30 yr (Table 304.2 ). Such accidental transmissions of CJD have been attributed to use of contaminated neurosurgical instruments (no case reported since 1980) or operating facilities, use of cortical electrodes contaminated during epilepsy surgery, injections of human cadaveric pituitary growth hormone and gonadotropin (no longer marketed in the United States), and transplantation of contaminated corneas and allografts of human dura mater, still in limited use in the United States as a surgical patching material. Pharmaceuticals and tissue grafts derived from or contaminated with human neural tissues, particularly if obtained from unselected donors and large pools of donors, pose special risks. Table 304.2

Iatrogenic Transmission of Creutzfeldt-Jakob Disease by Products of Human Origin PRODUCT

NO. OF PATIENTS

Cornea Dura mater allograft Pituitary extract Growth hormone Gonadotropin Red blood cells Plasma-derived coagulation factor VIII

3 >100

INCUBATION TIME Mean Range 17 mo 16-18 mo 7.4 yr 1.3-16 yr

>100* 4 4 1

12 yr 13 yr ? 6 yr ? > 11 yr ‡

5-38.5 yr 12-16 yr 6.3-8.5 yr †

* There have been 28 cases reported among approximately 8,000 recipients of human cadaveric

growth hormone in the United States; the remaining cases have been reported in other countries. † The second transfusion-transmitted case of vCJD (Peden AH, Head MW, Ritchie DL, et al:

Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient, Lancet 364:527-529, 2004) died of unrelated causes about 5 yr after transfusion but was found to have accumulations of abnormal PrP in the spleen and cervical lymph node—a finding unique to vCJD and interpreted as probable preclinical infection. ‡ The diagnosis of vCJD infection attributed to treatment with human plasma–derived coagulation

factor VIII (UK Health Protection Agency: vCJD abnormal prion protein found in a patient with haemophilia at post mortem, Press release 17 February 2009, http://webarchive.nationalarchives.gov.uk/20140714084352/http://www.hpa.org.uk/webw/HPAweb&HPAwebStand p=1231252394302 ) was also supported by immunohistochemical testing for abnormal PrP in the spleen of a person who died of other causes. Both patients with “preclinical” infections are thought to have died during the asymptomatic incubation period of vCJD.

Studies of animals experimentally infected with TSE agents first suggested that blood and blood components from humans with preclinical CJD infections might pose a risk of transmitting disease to recipients, and since the 1980s such blood components have been withdrawn as a precaution in the United States when a donor was later found to have CJD and blood products were still in-date. A surveillance program in the United Kingdom reported vCJD in three recipients of nonleukoreduced red blood cells from donors later diagnosed with vCJD; there was autopsy evidence of a preclinical vCJD infection in a fourth red cell recipient who died of another disease. (vCJD has not occurred in any recipient of leukoreduced red blood cells from a donor who later developed vCJD.) A study conducted over more than 20 yr by the American Red Cross and CDC found no recipient of blood components obtained from donors later diagnosed with sporadic CJD (and from one donor with familial CJD) developed a TSE. Evidence of a preclinical vCJD infection was found at autopsy in a U.K. patient with hemophilia A treated with a human plasma–derived coagulation factor VIII to which at least one vCJD-infected donor contributed; the coagulation factor involved was never licensed in the United States. U.K. authorities have described two recipients of plasma-derived coagulation factors (both having a history of a transfusion with blood components, as well) who later developed sporadic CJD, concluding that the finding, while of concern, might be coincidental.

Pathogenesis and Pathology The probable portal of entry for the TSE agent in kuru is thought to have been either through the gastrointestinal tract or lesions in the mouth or integument incidentally exposed to the agent during cannibalism. Patients with vCJD (and animals with BSE and BSE-related TSEs) are thought to have been similarly infected with the BSE agent by consuming contaminated beef products. Except after direct introduction into the nervous system, the first site of replication of TSE agents appears to be in tissues of the reticuloendothelial system. TSE agents have been detected in low titers in the blood of experimentally infected animals

(mice, monkeys, hamsters, and sheep and in the blood of persons with vCJD and perhaps sCJD); infectivity was mainly associated with nucleated cells, although the plasma contained a substantial portion of total infectivity in blood. Circulating lymphoid cells seem to be required to infect mice by peripheral routes. Limited evidence suggests that TSE agents also spread to the central nervous system by ascending peripheral nerves. Several research groups claimed to detect the CJD agent in human blood, although other attempts failed. In human kuru, it seems probable that the only portal of exit of the agent from the body, at least in quantities sufficient to infect others, was through infected tissues exposed during cannibalism. In iatrogenically transmitted CJD, the brains and eyes of patients with CJD have been the probable sources of contamination. Experimental transmission of the agent to animals from the kidney, liver, lung, lymph node, and spleen showed that those tissues as well as the cerebrospinal fluid (CSF) sometimes contain the CJD agent; none of those sources has been implicated in accidental transmission of CJD to humans. At no time during the course of any TSE have antibodies or cell-mediated immunity to the infectious agents been convincingly demonstrated in either patients or animals. However, mice must be immunologically competent to be infected with the scrapie agent by peripheral routes of inoculation. Typical changes in TSE include vacuolation and loss of neurons with hypertrophy and proliferation of glial cells, most pronounced in the cerebral cortex in patients with CJD and in the cerebellum in those with kuru. The central nervous system lesions are usually most severe in or even confined to gray matter, at least early in the disease. Loss of myelin appears to be secondary to the degeneration of neurons. There generally is no inflammation, but a marked increase in the number and size of astrocytes is usual. Spongiform changes are not a striking autopsy finding in patients with FFI, and neuronal degeneration and gliosis are largely restricted to thalamic nuclei. Amyloid plaques are found in the brains of all patients with GSS and in at least 70% of those with kuru. These plaques are less common in patients with CJD. Amyloid plaques are most common in the cerebellum but occur elsewhere in the brain, as well. In brains of patients with vCJD, plaques surrounded by halos of vacuoles (described as flower-like or florid plaques) have been a consistent finding. TSE amyloid plaques react with antiserum prepared against PrP. Even in the absence of plaques, extracellular PrP can be detected in the brain parenchyma by immunostaining.

Clinical Manifestations Kuru, no longer seen, is a progressive degenerative disease of the cerebellum and brainstem with less obvious involvement of the cerebral cortex. The first sign of kuru was usually cerebellar ataxia followed by progressive incoordination. Coarse, shivering tremors were characteristic. Variable abnormalities in cranial nerve function appeared, frequently with impairment in conjugate gaze and swallowing. Patients died of inanition and pneumonia or of burns from cooking fires, usually within 1 yr after onset. Although changes in mentation were common, there was no frank dementia or progression to coma, as in CJD. There were no signs of acute encephalitis, such as fever, headaches, and convulsions. CJD occurs throughout the world. Patients initially have either sensory disturbances (most often visual) or confusion and inappropriate behavior, progressing over weeks or months to frank dementia, akinetic mutism, and, ultimately, coma. Some patients have cerebellar ataxia early in the disease, and most patients experience myoclonic jerking movements. The mean survival time of patients with sCJD has been < 1 yr from the earliest signs of illness, although approximately 10% live for 2 yr. Variant CJD (Table 304.3 ) differs from the more common sCJD; patients with vCJD are much younger at onset (as young as 12 yr) and more often present with complaints of dysesthesia and subtle behavioral changes, often mistaken for psychiatric illness. Severe mental deterioration occurs later in the course of vCJD. Patients with vCJD have survived substantially longer than those with sCJD. Attempts have been made to subclassify cases of CJD based on the electrophoretic differences in PrPTSE and variation in its sensitivity to digestion with the proteolytic enzyme proteinase (PK); the different variants are said to have somewhat different clinical features, including the duration of illness, though all are ultimately fatal. Table 304.3 Clinical and Histopathologic Features of Patients With Variant and Typical Sporadic Creutzfeldt-Jakob Disease FEATURE

VARIANT CJD (FIRST 10 PATIENTS)

Years of age at death* (range) Duration of illness, mo

29 (19-74)

SPORADIC CJD (185 PATIENTS) 65

12 (8-23)

4

(range) Presenting signs Later signs Periodic complexes on EEG PRNP 129 Met/Met

Abnormal behavior, dysesthesia

Dementia

Dementia, ataxia, myoclonus Rare

Ataxia, myoclonus Most

All tested (except one transfusion-transmitted case, one plasmaderivative transmitted case; one possible clinical case in United Kingdom where no tissue was available to confirm) Histopathologic Vacuolation, neuronal loss, astrocytosis, plaques (100%) changes Florid PrP plaques † PrPTSE glycosylation pattern

83%

100%

Vacuolation, neuronal loss, astrocytosis, plaques (≤15%) 0

BSE-like ‡

Not BSE-like

* Median age and duration for variant CJD; averages for typical sporadic CJD. † Dense plaques with a pale periphery of surrounding vacuolated cells. ‡ Characterized by an excess of high-molecular-mass band (diglycosylated) and 19-kDa

nonglycosylated band glycoform of PrP-res (Collinge J, Sidle KC, Meads J, et al: Molecular analysis of prion strain variation and the aetiology of “new variant” CJD, Nature 383:685-690, 1996). BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease; EEG, electroencephalogram; Met, codon 129 of one PRNP gene encoding for methionine; PRNP , prion protein–encoding gene; PrP, prion protein. Modified from Will RG, Ironside JW, Zeidler M, et al: A new variant of Creutzfeldt-Jakob disease in the UK, Lancet 347:921-925, 1996.

GSS is a familial disease resembling CJD but with more prominent cerebellar ataxia and amyloid plaques. Dementia may appear only late in the course, and the average duration of illness is longer than typical sCJD. Progressively severe insomnia and dysautonomia, as well as ataxia, myoclonus, and other signs resembling those of CJD and GSS, characterize FFI and sporadic fatal insomnia. A case of sporadic fatal insomnia has been described in a young adolescent. GSS has not been diagnosed in children or adolescents. A novel prion disease has been reported that is expressed in several generations with an autosomal dominant pattern associated with a unique mutation in the PRNP gene. The affected persons were middle-aged with a history of chronic diarrhea for years plus autonomic neuropathy and modest mental impairment but without full-blown dementia; PK-resistant PrP deposits with amyloid properties occurred in the brain, lymphoid tissues, kidney, spleen, and intestinal tract. The disease was not successfully transmitted to three lines of

mice susceptible to several TSEs. It is not clear that such a syndrome—not a spongiform encephalopathy and apparently not associated with an infectious agent—should be lumped together with TSEs. It might well result from the abnormal PRNP gene product itself; if so, it would not pose the same potential threat to public health as do the TSEs.

Diagnosis The diagnosis of spongiform encephalopathies is most often determined on clinical grounds after excluding other diseases. The presence of 14-3-3 protein (see Laboratory Findings ) in CSF may aid in distinguishing between CJD and Alzheimer disease—not a consideration in children. Elevations of 14-3-3 protein levels in the CSF are not specific to TSEs and are common in viral encephalitis and other conditions causing rapid necrosis of brain tissue. Brain biopsy may be diagnostic of CJD, but it can be recommended only if a potentially treatable disease remains to be excluded or if there is some other compelling reason to make an antemortem diagnosis. The definitive diagnosis usually requires the microscopic examination of brain tissue obtained at autopsy. The demonstration of protease-resistant PrP in brain extracts augments the histopathologic diagnosis. Accumulation of the abnormal PrP in lymphoid tissues, even before the onset of neurologic signs, is typical of vCJD. Tonsil biopsy may avoid the need for brain biopsy when antemortem diagnosis of vCJD is indicated. To date, no blood-based test has been validated for antemortem testing of either humans or animals. Transmission of disease to susceptible animals by inoculation of brain suspension, while sensitive, specific, and reliable, must be reserved for cases of special research interest.

Laboratory Findings Virtually all patients with typical sporadic, iatrogenic, and familial forms of CJD have abnormal electroencephalograms (EEGs) as the disease progresses; the background becomes slow and irregular with diminished amplitude. A variety of paroxysmal discharges such as slow waves, sharp waves, and spike-and-wave complexes may also appear, and these may be unilateral or focal or bilaterally synchronous. Paroxysmal discharges may be precipitated by a loud noise. Many patients have typical periodic suppression-burst complexes of high-voltage slow

activity on EEG at some time during the illness. Patients with vCJD have had only generalized slowing, without periodic bursts of high-voltage discharges on EEG. The CT or MRI may show cortical atrophy and large ventricles late in the course of CJD. Many patients with vCJD have an increase in density of the pulvinar on MRI. Reliable interpretation of the images is best left to experienced radiologists. There may be a modest elevation of CSF protein content in patients with TSE. Unusual protein spots were observed in CSF specimens after two-dimensional separation in gels and silver staining; the spots were identified as 14-3-3 proteins, normal proteins (not related to PrP) abundant in neurons but not ordinarily detected in CSF. However, 14-3-3 protein has also been detected in CSF specimens from some patients with acute viral encephalitides and recent cerebral infarctions and is not specific to CJD. Finding the 14-3-3 protein in CSF is neither sensitive nor specific but has been of some help in confirming the diagnosis of vCJD, especially when accompanied by increases in other cellular proteins. The diagnosis usually rests on recognizing the typical constellation of clinical findings, clinical course, and testing (CSF examination, CT or MRI, EEG), confirmed by histopathology and detection of PrPTSE in brain tissues at autopsy (or, less often, by tonsil or brain biopsy). Research techniques that amplify PrPTSE in CSF, nasal brushings, and blood may eventually improve antemortem diagnosis but remain inadequately validated for routine use.

Treatment No treatment has proven effective. Studies of cell cultures and rodents experimentally infected with TSE agents suggested that treatment with chlorpromazine, quinacrine, and tetracyclines might be of benefit, especially during the incubation period. Results of clinical trials based on those studies have been discouraging, and it seems unlikely that the severe brain damage found in late disease can be reversed by treatment. Infusions with pentosan polysulfate directly into the cerebral ventricles appear to have delayed the progression of vCJD in a least one patient but did not reverse earlier brain damage. Appropriate supportive care should be provided to all CJD patients as for other progressive fatal neurologic diseases. On the basis of experimental studies in animals, several prophylactic postexposure treatment regimens have been suggested, but none has been widely accepted.

Genetic Counseling TSEs sometimes occur in families in a pattern consistent with an autosomal dominant mode of inheritance. In patients with a family history of CJD, the clinical and histopathologic findings are similar to those seen in sporadic cases. In the United States, only approximately 10% of cases of CJD are familial. GSS and FFI are always familial. In some affected families, approximately 50% of siblings and children of a patient with a familial TSE eventually acquire the disease; in other families, the penetrance of illness may be less. The gene coding for PrP is closely linked if not identical to that controlling the incubation periods of scrapie in sheep and both scrapie and CJD in mice. The gene encoding PrP in humans is designated the PRNP gene and is located on the short arm of chromosome 20. It has an open reading frame of 759 nucleotides (253 codons), in which more than 20 different point mutations and a variety of inserted sequences encoding extra tandem-repeated octapeptides are linked to the occurrence of spongiform encephalopathy in families with a pattern consistent with autosomal dominance of variable penetrance. The same nucleotide substitution at codon 178 of the PRNP gene associated with CJD in some families has been found in all patients with FFI. Homozygosity for valine (V) and especially for methionine (M) at codon 129 seems to increase the susceptibility to iCJD and sCJD. Almost all patients with vCJD to be genotyped have been homozygous for methionine at codon 129 of the PRNP gene. A few probable preclinical vCJD infections and two clinically typical cases of vCJD (one confirmed and another not completely evaluated) occurred in persons with the 129 MV heterozygous genotype. It is of interest that when the PRNP genes from appendices containing accumulations of what appears to be PrPTSE in the UK were sequenced, a surprising number were homozygous for V—the genotype of only approximately 10% of U.K. subjects and never found in a case of vCJD. The significance of this finding is not clear. U.K. authorities have adopted the precautionary assumption that some persons with PrPTSE in lymphoid tissues may have latent infections. Whether the blood of such persons is infectious remains unknown. Although the interpretation of these findings in regard to the prion hypothesis is in dispute, persons from families with CJD or GSS who have the associated mutations in the PRNP gene clearly have a high probability of eventually acquiring spongiform encephalopathy. Bearers of TSE-associated mutations have employed a preimplantation genetic diagnosis and in vitro selection of

embryos to avoid passing the mutant gene to offspring. The significance of mutations in the PRNP genes of individuals from families with no history of spongiform encephalopathy is not known. It seems wise to avoid alarming those from unaffected families who have miscellaneous mutations in the PRNP gene, because the implications are not yet clear. In the United States, persons are deferred from donating blood if a blood relative has been diagnosed with a TSE unless the donor does not have a TSE-related mutation.

Prognosis The prognosis of all spongiform encephalopathies is uniformly poor. Approximately 10% of patients may survive for longer than 1 yr, but the quality of life is poor.

Family Support The CJD Foundation (http://www.cjdfoundation.org ), organized and maintained by family members and friends of patients with CJD and related disorders, working closely with the Centers for Disease Control and Prevention (www.cdc.gov/prions/index.html ) and with the National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland (http://www.cjdsurveillance.com ), is a support and educational group and a useful source of information regarding available resources for those dealing with the diseases.

Prevention Exposure to the BSE agent in meat products clearly poses a special danger— now greatly reduced. Authorities in Canada, the United States, and other countries responded by implementing progressively more stringent agricultural and public health measures during the past 20 yr, with elimination of most bovine-derived materials from animal feeds probably the most effective measure. Three cases of BSE in native cattle were recognized in the United States from 2004 through 2012; a case was also found in a Canadian cow imported into the United States in 2003. Canada found 20 native cattle with BSE between 2003 and 2015 (and imported a case from the United Kingdom in

1993). In spite of encouraging epidemiologic studies that failed to implicate exposure to scrapie or CWD agents in human TSEs, it seems prudent to avoid exposing children to meat and other products likely to be contaminated with any TSE agent. The safety of human blood, blood components, and plasma derivatives in the United States and Canada is protected by deferring those donors with histories suggesting an increased risk of TSEs: persons treated with cadaveric pituitary hormones (no longer used) or dura mater allografts, patients with a family history of CJD (unless sequencing shows that the TSE-affected blood relative or the donor has revealed no TSE-related mutation in either PRNP gene), and persons who spent substantial periods of time in specified countries during years when BSE was prevalent. Persons transfused with blood in the United Kingdom and France after 1980 should be deferred from donating blood (similar deferral policies are in place for donors of human cells and tissues). U.K. authorities have warned persons treated with U.K.-sourced pooled coagulation factor concentrates or antithrombin between 1989 and 2001 that they may be “at risk of vCJD for public health purposes” and that “special infection control precautions” apply to them. In principle, it would be better to identify the few blood and tissue donors actually infected with a TSE rather than deferring all those at increased risk of exposure, because most of them are unlikely to have been infected. Antemortem screening tests that might eventually identify donors with preclinical TSE infections are currently under development though not clinically validated. It is unlikely that any test will be adopted to screen blood donors without simultaneously implementing a highly specific validated confirmatory test to avoid the serious adverse implications of inevitable false-positive screening results. Standard precautions should be used to handle all human tissues, blood, and body fluids. Materials and surfaces contaminated with tissues or fluids from patients suspected of having CJD must be treated with great care. Whenever possible, discard contaminated instruments by careful packaging and incineration. Contaminated tissues and biologic products probably cannot be completely freed of infectivity without destroying their structural integrity and biologic activity; therefore, the medical and family histories of individual tissue donors should be carefully reviewed to exclude a diagnosis of TSE. Histopathologic examination of brain tissues of cadaveric donors and testing for abnormal PrP might be performed where feasible to provide an additional

assurance of safety. Although no method of sterilization can be relied on to remove all infectivity from contaminated surfaces, exposures to moist heat, sodium hydroxide, chlorine bleach, concentrated formic acid, acidified detergent, and guanidine salts markedly reduced infectivity in experimental studies.

Bibliography Asher DM. Medical devices utilizing animal tissues and their derivatives—Part 4: Principles for elimination and/or inactivation of transmissible spongiform encephalopathy (TSE) agents and validation assays for those processes (ISO Technical Information Report/American National Standards Institute Technical Report) . [with; AAMI TSE Elimination Working Group (AAMI Tissue Product Safety Committee); In ANSI/AAMI ISO (Association for the Advancement of Medical Instrumentation), Arlington, VA, pp 1-10, and i-xi, introduction] 2011. Belay ED, Schonberger LB, Brown P, et al. Disinfection and sterilization of prion-contaminated medical instruments. Infect Control Hosp Epidemiol . 2010;31:1304–1306 [and author reply, 31:1306-1308, 2010]. Blase J, Cracco L, Schonberger L, et al. Sporadic fatal insomnia in an adolescent. Pediatrics . 2014;133(3):e766–e770. Botsios S, Manuelidis L. CJD and scrapie require agentassociated nucleic acids for infection. J Cell Biochem . 2016;117(8):1947–1958. Coulthart MB, Geschwind MD, Qureshi S, et al. A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia. Brain . 2016;139:2609–2616. Crowder LA, Schonberger LB, Dodd RY, Steele WR. Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk. Transfusion .

2017;57(8):1875–1878. Czub S, et al. Prion . 2017 [Edinburgh, Conference Abstracts]. Douet JY, Zafar S, Perret-Liaudet A, et al. Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease. Emerg Infect Dis . 2014;20:114– 117. http://www.cjdfoundation.org . http://www.cjdsurveillance.com . https://app.box.com/s/hhhhg857fjpu2bnxhv6e/1/2936396377/91796156506 . https://www.gov.uk/government/uploads/system/uploads/attachment_data/fi pndxIII.pdf . https://www.thetyee.ca/Documents/2017/06/24/Risk-AdvisoryOpinion-CWD-2017.pdf . Maheshwari A, Fischer M, Gambetti P, et al. Recent US case of variant Creutzfeldt-Jakob disease-global implications. Emerg Infect Dis . 2015;21:750–759. Occupational Safety and Health Administration, US Department of Labor. Occupational exposure to bloodborne pathogens; final rule: bloodborne pathogens (29 CFR Part 1910.1030). Fed Regist . 1991;56:64175–64182. Prusiner SB. Madness and memory. The discovery of prions: a new biological principle of disease . Yale University Press: New Haven and London; 2014. Urwin P, Thanigaikumar K, Ironside JW, et al. Sporadic Creutzfeldt-Jakob disease in 2 plasma product recipients, United Kingdom. Emerg Infect Dis . 2017;23:893–897. www.cdc.gov/prions/index.html .

SECTION 14

Antiparasitic Therapy OUTLINE Chapter 305 Principles of Antiparasitic Therapy

CHAPTER 305

Principles of Antiparasitic Therapy Beth K. Thielen, Mark R. Schleiss

Parasites are divided into three main groups taxonomically: protozoans, which are unicellular, and helminths and ectoparasites, which are multicellular. Chemotherapeutic agents appropriate for one group may not be appropriate for the others, and not all drugs are readily available (Table 305.1 ). Some drugs are not available in the United States, and some are available only from the manufacturer, specialized compounding pharmacies, or the Centers for Disease Control and Prevention (CDC). Information on the availability of drugs and expert guidance in management can be obtained by contacting the CDC Parasitic Diseases Branch (1-404-718-4745; e-mail [email protected] (M-F, 8 AM -4 PM , Eastern time). For assistance in the management of malaria, healthcare providers should call the CDC Malaria Hotline: 1-770-488-7788 or 1-855-856-4713 tollfree (M-F, 9 AM -5 PM , Eastern time). For all emergency consultations after hours, clinicians can contact the CDC Emergency Operations Center at 1-770488-7100 and request to speak with a CDC Malaria Branch clinician or on-call parasitic diseases physician. Some antiparasitic drugs are not licensed for use in the United States but can be obtained as investigational new drugs (INDs) from the CDC; providers should call the CDC Drug Service, Division of Scientific Resources and Division of Global Migration and Quarantine, at 1-404-639-3670. Table 305.1

Drugs for Parasitic Infections Parasitic infections are found throughout the world. With increasing travel, immigration, use of immunosuppressive drugs, and the spread of HIV, physicians anywhere may see infections caused by previously unfamiliar parasites. The table below lists first-choice and alternative drugs for most parasitic infections. INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE Acanthamoeba keratitis Drug of choice: See footnote 1

Amebiasis (Entamoeba histolytica) Asymptomatic infection Drug of choice: Iodoquinol (Yodoxin) 2 or

Paromomycin

Alternative:

Diloxanide furoate 3

Mild to moderate intestinal disease Drug of choice: Metronidazole or

Tinidazole 4

Either followed by: Iodoquinol 2 or

Paromomycin

Alternative:

Nitazoxanide 5

Severe intestinal and extraintestinal disease Drug of choice: Metronidazole

650 mg PO tid × 20 days

30-40 mg/kg/day (max 1950 mg) in 3 doses PO × 20 days 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3 7 days doses × 7 days 500 mg tid PO × 10 days 20 mg/kg/day PO in 3 doses × 10 days 500-750 mg tid PO × 7-10 days

35-50 mg/kg/day PO in 3 doses × 7-10 days 2 g PO once daily × 3 days 50 mg/kg/day PO (max 2 g) in 1 dose × 3 days 650 mg PO tid × 20 days 30-40 mg/kg/day PO in 3 doses × 20 days (max 2 g) 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3 7 days doses × 7 days 500 mg bid × 3 days 1-3 yr: 100 mg bid × 3 days 4-11 yr: 100 mg bid × 3 days 12+ yr: use adult dosing 750 mg PO tid × 7-10 days

35-50 mg/kg/day PO in 3 doses × 7-10 days 4 or Tinidazole 2 g PO once daily × 5 days 50 mg/kg/day PO (max 2 g) × 5 days Either followed by: Iodoquinol 2 650 mg PO tid × 20 days 30-40 mg/kg/day PO in 3 doses × 20 days (max 2 g) or Paromomycin 25-35 mg/kg/day PO in 3 doses × 25-35 mg/kg/day PO in 3 7 days doses × 7 days Amebic meningoencephalitis, primary and granulomatous Naegleria fowleri Drug of choice: Amphotericin B 1.5 mg/kg/day IV in 2 divided 1.5 mg/kg/day IV in 2 deoxycholate 6 , 7 doses × 3 days, then 1 mg/kg divided doses × 3 days, daily IV × 11 days then 1 mg/kg daily IV × 11 days plus Amphotericin B 1.5 mg/kg intrathecally daily × 2 1.5 mg/kg intrathecally deoxycholate 6 , 7 days, then 1 mg/kg intrathecally daily × 2 days, then 1 every other day × 8 days mg/kg intrathecally every other day × 8 days 10 mg/kg (max 600 mg) IV or PO 10 mg/kg (max 600 mg) IV plus Rifampin 7 daily × 28 days or PO daily × 28 days 10 mg/kg (max 600 mg) IV or PO 10 mg/kg (max 600 mg) IV plus Fluconazole 7 daily × 28 days or PO daily × 28 days 500 mg IV or PO daily × 28 days 10 mg/kg (max 500 mg) IV plus Azithromycin 7 or PO daily × 28 days 50 mg PO tid × 28 days 21 wk gestation Congenital infection in infant POSTNATAL Acute, symptomatic Acute, selflimited symptoms Chronic, asymptomatic Acute, severely symptomatic

TOXOPLASMA -SPECIFIC DIAGNOSTIC TESTS TREATMENT SAMPLE SOURCE G M A E Av AC/HS PCR Subinoculation Sp PSL* Mother

+ +

+ + L

Acute

AF (17-18 wk)

NS

Mother

+ +

+ + L

Acute

AF (may not be necessary)

NS

Mother

+ +

+ + L

Acute

AF

NS

Infant

+ +

+ + L

Acute

Placenta/buffy Placenta/buffy coat coat

+

Child

+ +

+ + L

Acute

NS

NS

+

Child

+ −

− − H

Chronic NS

NS

Child

+ +

+ + L

Acute

Immune compromised ¶

Child

+/ +/ +/ +/ +/ +/− − − − − −

§

Laboratory accident

Child

+/ +/ +/ +/ +/ +/− − − − − −

NS

Body fluids/buffy coat Body fluids/buffy coat NS

Child

+ +/ − + +/ − + +/ −

NS

NS

NS

NS

+

NS

NS

+

||

Eye Disease Quiescent scar** Active chorioretinitis** Active CNVM**

Child Child

+/ − +/ − +/ −

+/ − +/ − +/ −

+/ +/− − +/ +/− − +/ +/− −

§

+

+ † No P 1st trimester + † No P 1st trimester +

+

+

* Pyrimethamine and leucovorin should be adjusted for granulocytopenia; complete blood counts,

including platelets, should be monitored each Monday and Thursday. If there is sulfonamide allergy, alternative medicines include clindamycin, azithromycin, or clarithromycin in place of sulfadiazine. †

Do not use pyrimethamine in the 1st 14 wk of gestation.

‡ Occasionally, corticosteroids (prednisone) have been used when CSF protein is ≥1 g/dL or when

active chorioretinitis threatens vision and should be continued until signs of inflammation or active chorioretinitis that threatens vision have subsided; then dosage can be tapered and the steroids discontinued. § Utility of PCR depends on clinical setting. For example, the following may be useful to establish

the diagnosis: PCR of body fluids such as amniotic fluid or CSF; cells from bronchoalveolar lavage from a patient with pneumonia; or tissue such as placenta where presence of parasites or parasite DNA would support a diagnosis of infection. ¶ In some cases, in immunocompromised persons, there is no detectable serologic response to T.

gondii . However, if clinical presentation is indicative of infection in the absence of positive serologic results, CSF, buffy coat of peripheral blood, histopathology of tissue samples, or body fluids tested with PCR or subinoculation may be useful. If PCR demonstrates the presence of T. gondii DNA in the sample, it is useful for diagnosis. However, the sensitivity of PCR has been variable in this setting. In some circumstances, presumptive treatment may be warranted. || Whether a person should be treated for a laboratory accident depends on the nature of the

accident, the serology of the person before the accident, and other factors. When there is risk of infection, treatment is given. ** Serologic results depend on whether infection is acute (recently acquired) or chronic. When

testing serum from persons with ocular toxoplasmosis, T. gondii –specific IgG may be demonstrable only in an undiluted serum sample. †† Corticosteroids (prednisone) are used if inflammation or edema caused by infection threatens

vision and should be continued until signs of inflammation or active chorioretinitis that threatens vision have subsided; then dosage can be tapered and the steroids discontinued. +, Positive; −, negative; +/−, equivocal; A, T. gondii– specific IgA; AC/HS, direct agglutination; AF, amniotic fluid; Av, T. gondii– specific IgG avidity; CNVM, choroidal neovascular membrane; Co, corticosteroids (prednisone); CSF, cerebrospinal fluid; E, T. gondii– specific IgE; G, T. gondii– specific IgG; IG, immunoglobulin; Lu, Lucentis (antibody to vascular endothelial growth factor); M, T. gondii– specific IgM; NS, not standard to obtain; PCR, polymerase chain reaction; PSL, pyrimethamine, sulfadiazine, leucovorin (folinic acid); Sp, spiramycin. Adapted from Remington JS, McLeod R, et al: Toxoplasmosis. In Remington JS, Klein JO, editors: Infectious diseases of the fetus and newborn infant , ed 6, Philadelphia, 2006, Saunders.

Isolation Organisms can be isolated by inoculation of body fluids, leukocytes, or tissue specimens into mice or tissue cultures. Body fluids should be processed and inoculated immediately, but T. gondii has been isolated from tissues and blood

that have been stored overnight or even for 4-5 days at 4°C (39.2°F). Freezing or treatment of specimens with formalin kills T. gondii. From 6-10 days after inoculation into mice, or earlier if mice die, peritoneal fluids should be examined for tachyzoites. If inoculated mice survive for 6 wk and seroconvert, definitive diagnosis is made by visualization of Toxoplasma cysts in mouse brain. If cysts are not seen, subinoculation of mouse tissue into other mice are performed. Treatment of mice that receive subinoculated tissues with corticosteroid appears to enhance ability to isolate the parasite. Microscopic examination of tissue culture inoculated with T. gondii shows necrotic, heavily infected cells with numerous extracellular tachyzoites. Isolation of T. gondii from blood or body fluids reflects acute infection. Except in the fetus or neonate, it is usually not possible to distinguish acute from past infection by isolation of T. gondii from tissues (e.g., skeletal muscle, lung, brain, eye) obtained by biopsy or at autopsy. Diagnosis of acute infection can be established by visualization of tachyzoites in biopsy tissue sections, bone marrow aspirate, or body fluids (e.g., CSF, amniotic fluid). Immunofluorescent antibody and immunoperoxidase staining techniques may be necessary, because it is often difficult to distinguish the tachyzoite using ordinary stains. Tissue cysts are diagnostic of infection but do not differentiate between acute and chronic infection, although the presence of many cysts suggests recent acute infection. Cysts in the placenta or tissues of the newborn infant establish the diagnosis of congenital infection. Characteristic histologic features strongly suggest the diagnosis of toxoplasmic lymphadenitis.

Serologic Testing Serologic tests are useful in establishing the diagnosis of congenital or acutely acquired Toxoplasma infection. Each laboratory that reports serologic test results must have established values for their tests that diagnose infection in specific clinical settings, provide interpretation of their results, and ensure appropriate quality control before therapy is based on serologic test results. Serologic test results used as the basis for therapy should ideally be confirmed in a reference laboratory. The Sabin-Feldman dye test is sensitive and specific. It measures primarily IgG antibodies. Results should be expressed in international units (IU/mL), based on international standard reference sera available from the World Health Organization (WHO).

The IgG indirect fluorescent antibody (IgG-IFA) test measures the same antibodies as the dye test, and the titers tend to be parallel. These antibodies usually appear 1-2 wk after infection, reach high titers (≥1 : 1,000) after 6-8 wk, and then decline over months to years. Low titers (1 : 4 to 1 : 64) usually persist for life. Antibody titer does not correlate with severity of illness. An agglutination test (Bio-Mérieux, Lyon, France) available commercially in Europe uses formalin-preserved whole parasites to detect IgG antibodies. This test is accurate, simple to perform, and inexpensive. The IgM-IFA test is useful for the diagnosis of acute acquired infection with T. gondii in the older child because IgM antibodies appear earlier, often by 5 days after infection, and diminish more quickly than IgG antibodies. In most instances, IgM antibodies rise rapidly (1 : 50 to 2 (a value of one reference laboratory; each laboratory must establish its own value for positive results) indicates that Toxoplasma infection most likely has been acquired recently. The IgM-ELISA identifies approximately 50–75% of infants with congenital infection. IgM-ELISA avoids both the false-positive results from rheumatoid factor (RF) and the false-negative results from high levels of passively transferred maternal IgG antibody in fetal serum, as may occur in the IgM-IFA test. Results obtained with commercial kits must be interpreted with caution, because false-positive reactions can occur. Care must also be taken to determine whether kits have been standardized for diagnosis of infection in specific clinical settings, such as in the newborn infant. The IgA-ELISA also is a sensitive test for detection of maternal and congenital infection, and results may be positive when those of the IgM-ELISA are not. The immunosorbent agglutination assay (ISAGA) combines trapping of a patient's IgM to a solid surface and use of formalin-fixed organisms or antigencoated latex particles. It is read as an agglutination test. There are no false-

positive results from RF or antinuclear antibodies (ANAs). IgM-ISAGA is more sensitive than and may detect specific IgM antibodies before and for longer periods than IgM-ELISA. At present, IgM-ISAGA and IgA-ELISA are the most useful tests for diagnosis of congenital infection in the newborn but are not positive in all infected infants. The IgE-ELISA and IgE-ISAGA are also sometimes useful in establishing the diagnosis of congenital toxoplasmosis or acute acquired T. gondii infection. The presence of IgM antibodies in the older child or adult can never be used alone to diagnose acute acquired infection. The differential agglutination test (HS/AC) compares antibody titers obtained with formalin-fixed tachyzoites (HS antigen ) with titers obtained using acetone-fixed tachyzoites (AC antigen ) to differentiate recent and remote infections in adults and older children. This method may be particularly useful in differentiating remote infection in pregnant women, because levels of IgM and IgA antibodies detectable by ELISA or ISAGA may remain elevated for months to years in adults and older children. The avidity test can be helpful to establish time of acquisition of infection. A high-avidity test result indicates that infection began >12-16 wk earlier, which is especially useful in determining time of acquisition of infection in the 1st or final 16 wk of gestation. A low-avidity test result may be present for many months or even years and does not definitively identify recent acquisition of infection. A relatively higher level of Toxoplasma antibody in the aqueous humor or in CSF demonstrates local production of antibody during active ocular or CNS toxoplasmosis. This comparison is performed, and a coefficient [C] is calculated as follows:

Significant coefficients [C] are >8 for ocular infection, >4 for CNS for congenital infection, and >1 for CNS infection in patients with AIDS. If the serum dye test titer is >300 IU/mL, it is not possible to demonstrate significant local antibody production using this formula with either the dye test or the IgMIFA test titer. IgM antibody may be detectable in CSF. Comparative Western immunoblot tests of sera from a mother and infant

may detect congenital infection. Infection is suspected when the mother's serum and her infant's serum contain antibodies that react with different Toxoplasma antigens. The enzyme-linked immunofiltration assay using micropore membranes permits simultaneous study of antibody specificity by immunoprecipitation and characterization of antibody isotypes by immunofiltration with enzyme-labeled antibodies. This method able to detect 85% of cases of congenital infection in the 1st few days of life. Serologic tests in development include multiplex antibody tests for IgG, IgM, and IgA-specific antibodies, as well as point-of-care tests designed to provide accurate and rapid identification of recent infection or seroconversion in pregnant women. PCR is used to amplify the DNA of T. gondii, which then can be detected by using a DNA probe. Detection of repetitive T. gondii genes, the B1 or 529 bp, 300 copy gene, in amniotic fluid is the PCR target of choice for establishing the diagnosis of congenital Toxoplasma infection in the fetus. Sensitivity and specificity of this test in amniotic fluid obtained to diagnose infections acquired between 17 and 21 wk of gestation are approximately 95%. Before and after that time, PCR with the 529 bp, 300 copy repeat gene as the template is 92% sensitive and 100% specific for detection of congenital infection. PCR of vitreous or aqueous fluids also has been used to diagnose ocular toxoplasmosis. PCR of peripheral white blood cells, CSF, and urine has been reported to detect congenital infection. Point-of-care tests such as the Toxoplasma ICT IgG-IgM test or a nanogold test will lower the cost of and increase the ease of rapid testing. Lymphocyte blastogenesis to Toxoplasma antigens has been used to diagnose congenital toxoplasmosis when the diagnosis is uncertain and other test results are negative. However, a negative result does not exclude the diagnosis because peripheral blood lymphocytes of infected newborns may not respond to T. gondii antigens because of immune tolerance testing in specific circumstances.

Acquired Toxoplasmosis Recent infection is diagnosed by seroconversion from a negative to a positive IgG antibody titer (in the absence of transfusion); a 2-tube increase in Toxoplasma -specific IgG titer when serial sera are obtained 3 wk apart and tested in parallel; or the detection of Toxoplasma -specific IgM antibody in

conjunction with other tests, but never alone.

Ocular Toxoplasmosis IgG antibody titers of 1 : 4 to 1 : 64 are usual in older children with active Toxoplasma chorioretinitis. Even the presence of antibodies measurable only when serum is tested undiluted is helpful in establishing the diagnosis. The diagnosis is likely with characteristic retinal lesions and positive serologic tests. PCR of aqueous or vitreous fluid has been used to diagnose ocular toxoplasmosis but is infrequently performed because of the risks associated with obtaining intraocular fluid.

Immunocompromised Persons IgG antibody titers may be low, and Toxoplasma -specific IgM is often absent in immunocompromised stem cell transplant recipients, but not in kidney or heart transplant recipients with toxoplasmosis. Demonstration of Toxoplasma DNA by PCR in serum, blood, and CSF may identify disseminated Toxoplasma infection in immunocompromised persons. Resolution of CNS lesions during a therapeutic trial of pyrimethamine and sulfadiazine has been useful to diagnose toxoplasmic encephalitis in patients with AIDS. Brain biopsy has been used to establish the diagnosis if there is no response to a therapeutic trial and to exclude other possible diagnoses such as CNS lymphoma.

Congenital Toxoplasmosis Fetal ultrasound examination, performed every 2 wk during gestation, beginning at diagnosis of acute acquired infection in a pregnant woman, and PCR analysis of amniotic fluid are used for prenatal diagnosis. T. gondii may also be isolated from the placenta at delivery. Serologic tests are also useful in establishing a diagnosis of congenital toxoplasmosis. Either persistent or rising titers in the dye test or IFA test, or a positive IgM-ELISA or IgM-ISAGA result, is diagnostic of congenital toxoplasmosis. The half-life of IgM is approximately 2 days, so if there is a placental leak, the level of IgM antibodies in the infant's serum decreases significantly, usually within 1 wk. Passively transferred maternal IgG antibodies may require many months to a year to disappear from the infant's serum,

depending on the magnitude of the original titer. The half-life of passively transferred maternal IgG is approximately 30 days, so the titer diminishes by half each 30 days. Synthesis of Toxoplasma antibody is usually demonstrable by the 3rd mo of life if the infant is untreated, although the rate of IgG synthesis varies considerably in infants 10% eosinophils in more than half of patients, with mildly elevated protein, a normal glucose level, and an elevated opening pressure. Head CT or MRI is usually unremarkable. The diagnosis is established clinically with supporting travel and diet history. A sensitive and specific enzyme-linked immunosorbent assay (ELISA) is available on a limited basis from the Centers for Disease Control and Prevention (CDC) for testing CSF or serum. Treatment is primarily supportive because the majority of infections are mild, and most patients recover within 2 mo without neurologic sequelae. Analgesics should be given for headache. Careful, repeated lumbar punctures should be performed to relieve hydrocephalus. Anthelmintic drugs have not been shown to influence the outcome and may exacerbate neurologic symptoms. The use of corticosteroids may shorten the duration of persistent and severe headaches.

There is a higher incidence of permanent neurologic sequelae and mortality among children than among adults. Infection can be avoided by not eating raw or undercooked crabs, prawns, or snails.

Angiostrongylus Costaricensis Angiostrongylus costaricensis is a nematode that infects several species of rodents and causes abdominal angiostrongyliasis , which has been described predominantly in Latin America and the Caribbean. The mode of transmission to humans, who are accidental hosts, is unknown. It is speculated that infectious larvae from a molluscan intermediate host, such as the slug Vaginulus plebeius, contaminate water or vegetation that is inadvertently consumed (chopped up in salads or on vegetation contaminated with the slug's mucus secretions). Although this slug is not indigenous to the continental United States, it has been found on imported flowers and produce. The incubation period for abdominal angiostrongyliasis is unknown, but limited data suggest that it ranges from 2 wk to several months after ingestion of larvae. Third-stage larvae migrate from the gastrointestinal tract to the mesenteric arteries, where they mature into adults. These eggs degenerate and elicit an eosinophilic granulomatous reaction. The clinical findings of abdominal angiostrongyliasis mimic appendicitis, although the former are typically more indolent. Children can have fever, right lower quadrant pain, a tumor-like mass, abdominal rigidity, and a painful rectal examination. Most patients have leukocytosis with eosinophilia. Radiologic examination may show bowel wall edema, spasticity, or filling defects in the ileocecal region and the ascending colon. Examination of stool for ova and parasites is not useful for A. costaricensis but is useful for evaluating the presence of other intestinal parasites. An ELISA is available for diagnosis on a limited basis from the CDC, but the test has a low specificity and is known to cross react with Toxocara, Strongyloides, and Paragonimus. Many patients undergo laparotomy for suspected appendicitis and are found to have a mass in the terminal ileum to the ascending colon. No specific treatment is known for abdominal angiostrongyliasis. Even though the use of anthelmintic therapy has not been studied systematically, thiabendazole or diethylcarbamazine has been suggested. The prognosis is generally good. Most cases are self-limited, although surgery may be required in some patients. Cornerstones of prevention include avoidance of slugs and not ingesting raw food and water that may be contaminated with imperceptible slugs or slime from slugs. Rat control is also

important in preventing the spread of infection.

Dracunculiasis (Dracunculus Medinensis) Dracunculiasis is caused by the guinea worm, Dracunculus medinensis. WHO has targeted dracunculiasis for eradication. As of 2016, the transmission of the infection was confined to Chad, Ethiopia, Mali, and South Sudan. Humans become infected by drinking contaminated stagnant water that contains immature forms of the parasite in the gut of tiny crustaceans (copepods or water fleas). Larvae are released in the stomach, penetrate the mucosa, mature, and mate. Approximately 1 yr later, the adult female worm (1-2 mm in diameter and up to 1 m long) migrates and partially emerges through the human host skin, usually of the legs. Thousands of immature larvae are released when the affected body part is immersed in the water. The cycle is completed when larval forms are ingested by the crustaceans. Infected humans have no symptoms until the worm reaches the subcutaneous tissue, causing a stinging papule that may be accompanied by urticaria, nausea, vomiting, diarrhea, and dyspnea. The lesion vesiculates, ruptures, and forms a painful ulcer in which a portion of the worm is visible. Diagnosis is established clinically. Larvae can be identified by microscopic examination of the discharge fluid. Metronidazole (25 mg/kg/day orally divided into 3 doses for 10 days; maximum dose: 750 mg) decreases local inflammation. Although the drug does not kill the worm, it facilitates its removal. The worm must be physically removed by rolling the slowly emerging 1 m–long parasite onto a thin stick over a week. Topical corticosteroids shorten the time to complete healing while topical antibiotics decrease the risk of secondary bacterial infection. Dracunculiasis can be prevented by boiling or chlorinating drinking water or passing the water through a cloth sieve before consumption. Eradication is dependent on behavior modification and education.

Gnathostoma Spinigerum Gnathostoma spinigerum is a dog and cat nematode endemic to Southeast Asia, Japan, China, Bangladesh, and India, but has been identified in Mexico and parts of South America. Infection is acquired by ingesting intermediate hosts

containing larvae of the parasite, such as raw or undercooked freshwater fish, chickens, pigs, snails, or frogs. Penetration of the skin by larval forms and prenatal transmission has also been described. Nonspecific signs and symptoms such as generalized malaise, fever, urticaria, anorexia, nausea, vomiting, diarrhea, and epigastric pain develop 24-48 hr after ingestion of G. spinigerum. Ingested larvae penetrate the gastric wall and migrate through soft tissue for up to 10 yr. Moderate to severe eosinophilia can develop. Cutaneous gnathostomiasis manifests as intermittent episodes of localized, migratory nonpitting edema associated with pain, pruritus, or erythema. Central nervous system involvement in gnathostomiasis is suggested by focal neurologic findings, initially neuralgia followed within a few days by paralysis or changes in mental status. Multiple cranial nerves may be involved, and CSF may be xanthochromic but typically shows an eosinophilic pleocytosis. Diagnosis of gnathostomiasis is based on clinical presentation and epidemiologic background. Brain and spinal cord lesions may be seen on CT or MRI. Serologic testing varies in sensitivity and specificity and is available through the CDC. There is no well-documented effective chemotherapy, although albendazole (400 mg orally twice daily for 21 days) as first-line therapy or ivermectin (200 µg/kg for 2 days) as an alternative is recommended without or with surgical removal. Multiple courses may be needed. Corticosteroids have been used to relieve focal neurologic deficits. Surgical resection of the Gnathostoma is the major mode of therapy and the treatment of choice. Blind surgical resection of subcutaneous areas of diffuse swelling is not recommended because the worm can rarely be located. Prevention through the avoidance of ingestion of poorly cooked or raw fish, poultry, or pork should be emphasized for individuals living in or visiting endemic areas.

Bibliography Onchocerciasis (Onchocerca volvulus) Botto C, Basañez MG, Escalona M, et al. Evidence of suppression of onchocerciasis transmission in the Venezuelan Amazonian focus. Parasit Vectors . 2016;9:40. Boussinesq M. Anew powerful drug to combat river blindness. Lancet . 2018;392:1170–1172.

Johnson TP, Tyagi R, Lee PR, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus . Sci Transl Med . 2017;9(377) [pii: eaaf6953]. Richards F Jr, Rizzo N, Diaz Espinoza CE, et al. One hundred years after its discovery in Guatemala by Rodolfo Robles, Onchocerca volvulus transmission has been eliminated from the Central Endemic Zone. Am J Trop Med Hyg . 2015;93:1295–1304. World Health Organization. Guidelines for stopping mass drug administration and verifying elimination of human onchocerciasis: criteria and procedures . WHO: Geneva; 2016.

Loiasis (Loa loa) Chesnais CB, Takougang I, Paguélé M, et al. Excess mortality associated with loiasis: a retrospective population-based cohort study. Lancet Infect Dis . 2017;17:108–116. Geary TG. A step toward eradication of human filariases in areas where Loa is endemic. MBio . 2016;7:e00456-16. Kamgno J, Nguipdop-Djomo P, Gounoue R, et al. Effect of two or six doses 800 mg of albendazole every two months on Loa loa microfilaraemia: a double blind, randomized, placebocontrolled trial. PLoS Negl Trop Dis . 2016;10:e0004492.

Infection With Animal Filariae Dantas-Torres F, Otranto D. Dirofilariosis in the Americas: a more virulent Dirofilaria immitis ? Parasit Vectors . 2013;6:288.

Angiostrongylus cantonensis Liu EW, Schwartz BS, Hysmith ND, et al. Rat lungworm

infection associated with central nervous system disease— eight US states, January 2011–January 2017. MMWR Morb Mortal Wkly Rep . 2018;67(30):825–828. Martins YC, Tanowitz HB, Kazacos KR. Central nervous system manifestations of Angiostrongylus cantonensis infection. Acta Trop . 2015;141(Pt A):46–53.

Angiostrongylus costaricensis and Gnathostoma spinigerum Ramirez-Avila L, Slome S, Schuster FL, et al. Eosinophilic meningitis due to Angiostrongylus and Gnathostoma species. Clin Infect Dis . 2009;48(3):322–327.

Dracunculiasis (Dracunculus medinensis) 2016. Dracunculiasis eradication: global surveillance summary, 2015. Wkly Epidemiol Rec . 2016;91:219–236.

CHAPTER 324

Toxocariasis (Visceral and Ocular Larva Migrans) Arlene E. Dent, James W. Kazura

Etiology Most cases of human toxocariasis are caused by the dog roundworm , Toxocara canis. Adult female T. canis worms live in the intestinal tracts of young puppies and their lactating mothers. Large numbers of eggs are passed in the feces of dogs and embryonate under optimal soil conditions. Toxocara eggs can survive relatively harsh environmental conditions and are resistant to freezing and extremes of moisture and pH. Humans ingest embryonated eggs contaminating soil, hands, or fomites. The larvae hatch and penetrate the intestinal wall and travel via the circulation to the liver, lung, and other tissues. Humans do not excrete T. canis eggs because the larvae are unable to complete their maturation to adult worms in the intestine. The cat roundworm , Toxocara cati, is responsible for far fewer cases of visceral larva migrans (VLM) than T. canis. Ingestion of infective larvae of the raccoon ascarid Baylisascaris procyonis rarely leads to VLM but can cause neural larva migrans , resulting in fatal eosinophilic meningitis. Ingestion of larvae from the opossum ascarid Lagochilascaris minor leads to VLM rarely.

Epidemiology Human T. canis infections have been reported in almost all parts of the world, primarily in temperate and tropical areas where dogs are popular household pets. Young children are at highest risk because of their unsanitary play habits and tendency to place fingers in the mouth. Other behavioral risk factors include

pica , contact with puppy litters, and institutionalization. In North America, the highest prevalences of infection are in the southeastern United States and Puerto Rico, particularly among socially disadvantaged African American and Hispanic children. In the United States, serosurveys show that 4.6–7.3% of children are infected. Assuming an unrestrained and untreated dog population, toxocariasis is prevalent in settings where other geohelminth infections , such as ascariasis, trichuriasis, and hookworm infections, are common.

Pathogenesis T. canis larvae secrete large amounts of immunogenic glycosylated proteins. These antigens induce immune responses that lead to eosinophilia and polyclonal and antigen-specific immunoglobulin E production. The characteristic histopathologic lesions are granulomas containing eosinophils, multinucleated giant cells (histiocytes), and collagen. Granulomas are typically found in the liver but may also occur in the lungs, central nervous system (CNS), and ocular tissues. Clinical manifestations reflect the intensity and chronicity of infection, anatomic localization of larvae, and host granulomatous responses.

Clinical Manifestations Three major clinical syndromes are associated with human toxocariasis: VLM, ocular larva migrans (OLM) , and covert toxocariasis (Table 324.1 ). The classic presentation of VLM includes eosinophilia, fever, and hepatomegaly and occurs most often in toddlers with a history of pica and exposure to puppies. The findings include fever, cough, wheezing, bronchopneumonia, anemia, hepatomegaly, leukocytosis, eosinophilia, and positive Toxocara serology. Cutaneous manifestations such as pruritus, eczema, and urticaria can be present. OLM tends to occur in older children without signs or symptoms of VLM. Presenting symptoms include unilateral visual loss, eye pain, white pupil, or strabismus that develops over weeks. Granulomas occur on the posterior pole of the retina and may be mistaken for retinoblastoma. Serologic testing for Toxocara has allowed the identification of individuals with less obvious or covert symptoms of infection. These children may have nonspecific complaints that do not constitute a recognizable syndrome. Common findings include hepatomegaly, abdominal pain, cough, sleep disturbance, failure to thrive, and

headache with elevated Toxocara antibody titers. Eosinophilia may be present in 50–75% of cases. The prevalence of positive Toxocara serology in the general population supports that most children with T. canis infection are asymptomatic and will not develop overt clinical sequelae over time. A correlation between positive Toxocara serology and allergic asthma has also been described. Table 324.1

Clinical Syndromes of Human Toxocariasis CLINICAL FINDINGS Visceral larva Fevers, migrans hepatomegaly, asthma Ocular larva Visual migrans disturbances, retinal granulomas, endophthalmitis, peripheral granulomas Covert Abdominal pain, toxocariasis gastrointestinal symptoms, weakness, hepatomegaly, pruritus, rash SYNDROME

AVERAGE INFECTIOUS INCUBATION AGE DOSE PERIOD 5 yr Moderate to Weeks to high months 12 yr

Low

Months to years

School-age to adult

Low to moderate

Weeks to years

LABORATORY FINDINGS Eosinophilia, leukocytosis, elevated IgE Usually none

± Eosinophilia ± Elevated IgE

ELISA High (≥1 : 16) Low

Low to moderate

ELISA, Enzyme-linked immunosorbent assay; IgE, immunoglobulin E; ±, with or without. Adapted from Liu LX: Toxocariasis and larva migrans syndrome. In Guerrant RL, Walker DH, Weller PF, editors: Tropical infectious diseases: principles, pathogens & practice, Philadelphia, 206, Churchill-Livingstone, p 1209.

Diagnosis A presumptive diagnosis of toxocariasis can be established in a young child with eosinophilia (>20%), leukocytosis, hepatomegaly, fevers, wheezing, and a history of geophagia and exposure to puppies or unrestrained dogs. Supportive laboratory findings include hypergammaglobulinemia and elevated isohemagglutinin titers to A and B blood group antigens. Most patients with VLM have an absolute eosinophil count >500/µL. Eosinophilia is less common in patients with OLM. Biopsy confirms the diagnosis. When biopsies cannot be obtained, an enzyme-linked immunosorbent assay using excretory-secretory

proteins harvested from T. canis larvae maintained in vitro is the standard serologic test used to confirm toxocariasis. A titer of 1 : 32 is associated with a sensitivity of approximately 78% and a specificity of approximately 92%. The sensitivity for OLM is significantly less. The diagnosis of OLM can be established in patients with typical clinical findings of a retinal or peripheral pole granuloma or endophthalmitis with elevated antibody titers. Vitreous and aqueous humor fluid anti-Toxocara titers are usually greater than serum titers. The diagnosis of covert toxocariasis should be considered in individuals with chronic weakness, abdominal pain, or allergic signs with eosinophilia and increased IgE. In temperate regions of the world, nonparasitic causes of eosinophilia that should be considered in the differential diagnosis include allergies, drug hypersensitivity, lymphoma, vasculitis, and idiopathic hypereosinophilic syndrome (see Chapter 155 ).

Treatment Most patients do not require treatment because signs and symptoms are mild and subside over weeks to months. Several anthelmintic drugs have been used for symptomatic cases, often with adjunctive corticosteroids to limit inflammatory responses that presumably result from release of Toxocara antigens by dying parasites. Albendazole (400 mg orally twice daily for 5 days for all ages) has demonstrated efficacy in both children and adults. Mebendazole (100-200 mg PO twice daily for 5 days for all ages) is also useful. Anthelmintic treatment of CNS and ocular disease should be extended (3-4 wk). Even with no clinical trials on OLM therapy, a course of oral corticosteroids such as prednisone (1 mg/kg/day PO for 2-4 wk) has been recommended to suppress local inflammation while treatment with anthelmintic agents is initiated.

Prevention Transmission can be minimized by public health measures that prevent dog feces from contaminating the environment. These include keeping dogs on leashes and excluding pets from playgrounds and sandboxes that toddlers use. Children should be discouraged from putting dirty fingers in their mouth and eating dirt. Vinyl covering of sandboxes reduces the viability of T. canis eggs. Widespread veterinary use of broad-spectrum anthelmintics effective against Toxocara may

lead to a decline in parasite transmission to humans.

Bibliography Ahn SJ, Ryoo NK, Woo SJ. Ocular toxocariasis: clinical features, diagnosis, treatment, and prevention. Asia Pac Allergy . 2014;4(3):134–141. Lee RM, Moore LB, Bottazzi ME, Hotez PJ. Toxocariasis in north America: a systematic review. PLoS Negl Trop Dis . 2014;8:e3116. Macpherson CN. The epidemiology and public health importance of toxocariasis: a zoonosis of global importance. Int J Parasitol . 2013;43(12/13):999–1008. Padhi TR, Das S, Sharma S, et al. Ocular parasitoses: a comprehensive review. Surv Ophthalmol . 2017;62(2):161– 189. Sircar AD, Abanyie F, Blumberg D, et al. Raccoon roundworm infection associated with central nervous system disease and ocular disease—six states, 2013–2015. MMWR . 2016;65(35):930–933. Woodhall DM, Eberhard ML, Parise ME. Neglected parasitic infections in the United States: toxocariasis. Am J Trop Med Hyg . 2014;90(5):810–813.

CHAPTER 325

Trichinellosis (Trichinella spiralis) Arlene E. Dent, James W. Kazura

Etiology Human trichinellosis (also called trichinosis ) is caused by consumption of meat containing encysted larvae of Trichinella spiralis, a tissue-dwelling nematode with a worldwide distribution. After ingestion of raw or inadequately cooked meat from pigs (or other commercial meat sources such as horses) containing viable Trichinella larvae, the organisms are released from the cyst by acid-pepsin digestion of the cyst walls in the stomach and then pass into the small intestine. The larvae invade the small intestine columnar epithelium at the villi base and develop into adult worms. The adult female worm produces about 500 larvae over 2 wk and is then expelled in the feces. The larvae enter the bloodstream and seed striated muscle by burrowing into individual muscle fibers. Over a period of 3 wk, they coil as they increase about 10 times in length and become capable of infecting a new host if ingested. The larvae eventually become encysted and can remain viable for years. Sylvatic Trichinella spp. (T. brivoti, T. nativa, T. pseudospiralis, and T. murrelli ) present in traditional native foods such as walrus meat, and game meat may also cause disease similar to that caused by T. spiralis .

Epidemiology Despite public health efforts to control trichinellosis by eliminating the practice of feeding garbage to domestic swine, epidemics and isolated cases of Trichinella spp. infection continue to be a health problem in many areas of the world. It is most common in Asia, Latin America, and Central Europe. Swine fed with garbage may become infected when given uncooked trichinous scraps,

usually pig meat, or when the carcasses of infected wild animals such as rats are eaten. Prevalence rates of T. spiralis in domestic swine range from 0.001% in the United States to ≥25% in China. The resurgence of this disease can be attributed to translocations of animal populations, human travel, and export of food as well as ingestion of sylvatic Trichinella through game meat. In the United States from 1997 to 2001, wild game meat (especially bear or walrus meat) was the most common source of infection. Most outbreaks occur from the consumption of T. spiralis –infected pork (or horse meat in areas of the world where horse is eaten) obtained from a single source.

Pathogenesis During the 1st 2-3 wk after infection, pathologic reactions to infection are limited to the gastrointestinal (GI) tract and include a mild, partial villous atrophy with an inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and macrophages in the mucosa and submucosa. Larvae are released by female worms and disseminate over the next several weeks. Skeletal muscle fibers show the most striking changes with edema and basophilic degeneration. The muscle fiber may contain the typical coiled worm, the cyst wall derived from the host cell, and the surrounding lymphocytic and eosinophilic infiltrate.

Clinical Manifestations The development of symptoms depends on the number of viable larvae ingested. Most infections are asymptomatic or mild, and children often show milder symptoms than adults who consumed the same amount of infected meat. Watery diarrhea is the most common symptom corresponding to maturation of the adult worms in the GI tract, which occurs during the 1st 1-2 wk after ingestion. Patients may also complain of abdominal discomfort and vomiting. Fulminant enteritis may develop in individuals with extremely high worm burdens. The classic symptoms of facial and periorbital edema, fever, weakness, malaise, and myalgia peak approximately 2-3 wk after the infected meat is ingested, as the larvae migrate and then encyst in the muscle. Headache, cough, dyspnea, dysphagia, subconjunctival and splinter hemorrhages, and a macular or petechial rash may occur. Patients with high-intensity infection may die from myocarditis, encephalitis, or pneumonia. In symptomatic patients, eosinophilia is common

and may be dramatic.

Diagnosis The Centers for Disease Control and Prevention (CDC) diagnostic criteria for trichinellosis require positive serology or muscle biopsy for Trichinella with 1 or more compatible clinical symptoms (eosinophilia, fever, myalgia, facial or periorbital edema). To declare a discrete outbreak, at least 1 person must have positive serology or muscle biopsy. Antibodies to Trichinella are detectable approximately 3 wk after infection. Severe muscle involvement results in elevated serum creatine phosphokinase and lactic dehydrogenase levels. Muscle biopsy is not usually necessary, but if needed, a sample should be obtained from a tender swollen muscle. A history of eating undercooked meat supports the diagnosis. The cysts may calcify and may be visible on radiograph.

Treatment Recommended treatment of trichinellosis diagnosed at the GI phase is albendazole (400 mg orally twice daily for 8-10 days for all ages) to eradicate the adult worms if a patient has ingested contaminated meat within the previous 1 wk. An alternative regimen is mebendazole (200-400 mg PO 3 times daily for 3 days followed by 400-500 mg three times daily for 10 days). There is no consensus for treatment of muscle-stage trichinellosis. Corticosteroids may be used, although evidence for efficacy is anecdotal.

Prevention Trichinella larvae can be killed by cooking meat (≥55°C [131°F]) until there is no trace of pink fluid or flesh, or by storage in a freezer (−15°C [5°F]) for ≥3 wk. Freezing to kill larvae should only be applied to pork meat, because larvae in horse, wild boar, or game meat can remain viable even after 4 wk of freezing. Smoking, salting, and drying meat are unreliable methods of killing Trichinella. Strict adherence to public health measures, including garbage feeding regulations, stringent rodent control, prevention of exposure of pigs and other livestock to animal carcasses, constructing barriers between livestock, wild animals, and domestic pets, and proper handling of wild animal carcasses by

hunters, can reduce infection with Trichinella. Current meat inspection for trichinellosis is by direct digestion and visualization of encysted larvae in meat samples. Serologic testing does not have a role in meat inspection.

Bibliography Faber M, Schink S, Mayer-Scholl A, et al. Outbreak of trichinellosis due to wild boar meat and evaluation of the effectiveness of post exposure prophylaxis, Germany, 2013. Clin Infect Dis . 2015;60(12):e98–e104. Greene YG, Padovani T, Rudroff JA, et al. Trichinellosis caused by consumption of wild boar meat—Illinois, 2013. MMWR Morb Mortal Wkly Rep . 2014;63(20):451. Heaton D, Huang S, Shiau R, et al. Trichinellosis outbreak linked to consumption of privately raised raw boar meat— California, 2017. MMWR Morb Mortal Wkly Rep . 2018;67(8):247–249. Messiaen P, Forier A, Vanderschueren S, et al. Outbreak of trichinellosis related to eating imported wild boar meat, Belgium, 2014. Euro Surveill . 2016;21(37). Murrell KD. The dynamics of Trichinella spiralis epidemiology: out to pasture? Vet Parasitol . 2016;231:92– 96. Pozio E, Zarlenga DS. New pieces of the Trichinella puzzle. Int J Parasitol . 2013;43(12/13):983–997. Shimoni Z, Froom P. Uncertainties in diagnosis, treatment and prevention of trichinellosis. Expert Rev Anti Infect Ther . 2015;13(10):1279–1288. Springer YP, Casillas S, Helfrich K, et al. Two outbreaks of trichinellosis linked to consumption of walrus meat—Alaska, 2016–2017. MMWR Morb Mortal Wkly Rep . 2017;66(26):692–696. Wilson NO, Hall RL, Montgomery SP, Jones JL. Trichinellosis

surveillance—United States, 2008–2012. MMWR Surveill Summ . 2015;64(1):1–8.

CHAPTER 326

Schistosomiasis (Schistosoma) Charles H. King, Amaya L. Bustinduy

The term schistosomiasis (bilharzia) encompasses the acute and chronic inflammatory disorders caused by human infection with Schistosoma spp. parasites. Disease is related to both the systemic and the focal effects of schistosome infection and its consequent host immune responses triggered by parasite eggs deposited in the tissues. For the affected individuals, this frequently manifests as disabling chronic morbidity.

Etiology Schistosoma organisms are the trematodes, or flukes , that parasitize the bloodstream. Five schistosome species infect humans: Schistosoma haematobium, S. mansoni, S. japonicum, S. intercalatum, and S. mekongi . Humans are infected through contact with water contaminated with cercariae , the free-living infective stage of the parasite. These motile, forked-tail organisms emerge from infected snails and are capable of penetrating intact human skin. As they reach maturity, adult worms migrate to specific anatomic sites characteristic of each schistosome species: S. haematobium adults are found in the perivesical and periureteral venous plexus, S. mansoni in the inferior mesenteric veins, and S. japonicum in the superior mesenteric veins. S. intercalatum and S. mekongi are usually found in the mesenteric vessels. Adult schistosome worms (1-2 cm long) are clearly adapted for an intravascular existence. The female accompanies the male in a groove formed by the lateral edges of its body. On fertilization, female worms begin oviposition in the small venous tributaries. The eggs of the 3 main schistosome species have characteristic morphologic features: S. haematobium has a terminal spine, S. mansoni has a lateral spine, and S.

japonicum has a smaller size with a short, curved spine (Fig. 326.1 ). Parasite eggs provoke a significant granulomatous inflammatory response that allows them to ulcerate through host tissues to reach the lumen of the urinary tract or the intestines. They are carried to the outside environment in urine or feces (depending on the species), where they will hatch if deposited in freshwater. Motile miracidia emerge, infect specific freshwater snail intermediate hosts, and divide asexually. After 4-12 wk, the infective cercariae are released by the snails into the contaminated water.

FIG. 326.1 Eggs of common human trematodes. Clockwise from upper left: Schistosoma mansoni, S. japonicum, S. haematobium, Clonorchis sinensis, Paragonimus westermani , and Fasciola hepatica (note the partially open operculum). (From Centers for Disease Control and Prevention: DPDx: laboratory identification of parasites of public health concern. http://www.cdc.gov/dpdx/az.html .)

Epidemiology Schistosomiasis infects more than 300 million people worldwide and puts more than 700 million people at risk, primarily children and young adults. There are 3.3 million disability-adjusted life-years (DALYs) attributed to schistosomiasis, making it the 2nd most disabling parasitic disease after malaria. Prevalence is increasing in many areas as population density increases and new irrigation projects provide broader habitats for vector snails . Humans are the main definitive hosts for the 5 clinically important species of schistosomes, although

S. japonicum is also a zoonosis, infecting animals such as dogs, rats, pigs, and cattle. S. haematobium is prevalent in Africa and the Middle East; S. mansoni is prevalent in Africa, the Middle East, the Caribbean, and South America; and S. japonicum is prevalent in China, the Philippines, and Indonesia, with some sporadic foci in parts of Southeast Asia. The other 2 species are less prevalent. S. intercalatum is found in West and Central Africa, and S. mekongi is found only along the upper Mekong River in the Far East. Transmission depends on water contamination by human excreta, the presence of specific intermediate snail hosts, and the patterns of water contact and social habits of the population (Fig. 326.2 ). The distribution of infection in endemic areas shows that prevalence increases with age, to a peak at 10-20 yr old. Exposure to infected water starts early in life for children living in endemic areas. Passive water contact by infants (accompanying mothers in their daily household activities) evolves to more active water contact as preschool and school-age children pursue recreational activities such as swimming and wading.

FIG. 326.2 Life cycle of Schistosoma mansoni, S. haematobium, and S. japonicum . A, Paired adult worms (larger male enfolding slender female). B, Eggs (left to right, S. haematobium, S. mansoni, S. japonicum) . C, Ciliated miracidium. D, Intermediate host snails (left to right, Oncomelania, Biomphalaria, Bulinus) . E, Cercariae. (From Colley DG, Bustinduy AL, Secor WE, King CH: Human schistosomiasis, Lancet 383:2253–2264, 2014, Fig 1.)

Measuring intensity of infection (by quantitative egg count in urine or feces) demonstrates that the heaviest worm loads are found in school-age and adolescent children. Even though schistosomiasis is most prevalent and most severe in older children and young adults, who are at maximal risk for suffering from its acute and chronic sequelae, preschool children can also exhibit significant disease manifestations.

Pathogenesis

Both early and late manifestations of schistosomiasis are immunologically mediated. Acute schistosomiasis, known as snail fever or Katayama syndrome , is a febrile illness that represents an immune complex disease associated with early infection and oviposition. The major pathology of infection occurs later, with chronic schistosomiasis, in which retention of eggs in the host tissues is associated with chronic granulomatous injury. Eggs may be trapped at sites of deposition (urinary bladder, ureters, intestine) or may be carried by the bloodstream to other organs, most frequently the liver and less often the lungs and central nervous system (CNS). The host response to these eggs involves local as well as systemic manifestations. The cell-mediated immune response leads to granulomas composed of lymphocytes, macrophages, and eosinophils that surround the trapped eggs and add significantly to the degree of tissue destruction. Granuloma formation in the bladder wall and at the ureterovesical junction results in the major disease manifestations of schistosomiasis haematobia: hematuria, dysuria, and obstructive uropathy. Intestinal as well as hepatic granulomas underlie the pathologic sequelae of the other schistosome infections: ulcerations and fibrosis of intestinal wall, hepatosplenomegaly, and portal hypertension caused by presinusoidal obstruction of blood flow. In terms of systemic disease, antischistosome inflammation increases circulating levels of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6, associated with elevated levels of C-reactive protein. These responses are associated with hepcidin-mediated inhibition of iron uptake and use, leading to anemia of chronic inflammation. Schistosomiasis-related undernutrition may be the result of similar pathways of chronic inflammation. Acquired partial protective immunity against schistosomiasis has been demonstrated in some animal species and may occur in humans.

Clinical Manifestations Two main chronic clinical syndromes arise from Schistosoma spp. infection: urogenital schistosomiasis caused by S. haematobium and intestinal schistosomiasis caused by S. mansoni or S. japonicum. Most chronically infected individuals experience mild symptoms and may not seek medical attention; the more severe symptoms of schistosomiasis occur mainly in those who are heavily infected or who have been infected over longer periods. In addition to organ-specific morbidities, infected patients frequently demonstrate anemia, chronic pain, diarrhea, exercise intolerance, and chronic undernutrition

manifesting as growth stunting. Cercarial penetration of human skin may result in a papular pruritic rash known as schistosomal dermatitis or swimmer's itch . It is more pronounced in previously exposed individuals and is characterized by edema and intense cellular infiltrates in the dermis and epidermis. Acute schistosomiasis (Katayama syndrome) may occur, particularly in heavily infected individuals, 4-8 wk after exposure; this is a serum sickness–like syndrome manifested by the acute onset of fever, cough, chills, sweating, abdominal pain, lymphadenopathy, hepatosplenomegaly, and eosinophilia. Acute schistosomiasis typically presents in first-time visitors to endemic areas who experience primary infection at an older age. Symptomatic children with chronic urogenital schistosomiasis usually complain of frequency, dysuria, and hematuria. Urine examination shows erythrocytes, parasite eggs, and occasional eosinophiluria. In endemic areas, moderate to severe pathologic lesions have been demonstrated in the urinary tract of >20% of infected children. The extent of disease correlates with the intensity of infection, but significant morbidity can occur even in lightly infected children. The advanced stages of urogenital schistosomiasis are associated with chronic renal failure, secondary infections, and squamous carcinoma of the bladder. An important complication of S. haematobium infection is female genital schistosomiasis . Eggs migrate from the vesical plexus to lodge in the female genital tract where they induce a granulomatous inflammatory response that can manifest as contact bleeding, pain, and eventual infertility. Symptoms start as early as 10 yr of age, with an apparent 3-4–fold greater risk of HIV transmission. Pathognomonic lesions can be visualized in the cervix by photocolposcopy. Male genital schistosomiasis can also present with hematospermia, pain, and lumpy semen. Children with chronic schistosomiasis mansoni, japonica, intercalatum, or mekongi may have intestinal symptoms; colicky abdominal pain and bloody diarrhea are the most common. However, the intestinal phase may remain subclinical, and the late syndrome of hepatosplenomegaly, portal hypertension, ascites, and hematemesis may then be the first clinical presentation. Liver disease is caused by granuloma formation and subsequent periportal fibrosis ; no appreciable liver cell injury occurs, and hepatic function may be preserved for a long time. Schistosome eggs may escape into the lungs, causing pulmonary hypertension and cor pulmonale. S. japonicum worms may migrate to the brain vasculature and produce localized lesions that cause seizures.

Transverse myelitis , spinal compression, and other CNS involvement (meningoencephalitis) are rare but well-known complications in children or young adults with either acute or chronic S. haematobium or S. mansoni infection. Although end-organ scarring is pathognomonic, affected children may also have persistent long-term systemic effects of infection, including poor growth, anemia, decreased aerobic capacity, and cognitive impairment.

Diagnosis Schistosome eggs are found in the excreta of infected individuals; quantitative methods should be used to provide an indication of the burden of infection. For diagnosis of S. haematobium infection, a volume of 10 mL of urine should be collected around midday, the time of maximal egg excretion, and filtered for microscopic examination. Stool examination by the Kato-Katz thick smear procedure and detection of parasite antigen in patient serum or urine are the methods of choice for diagnosis and quantification of other schistosome infections (S. mansoni and S. japonicum ). The unique schistosome antigens circulating anodic antigen (CAA) and circulating cathodic antigen (CCA) may also be detected in the urine or plasma.

Treatment Treatment of children with schistosomiasis should be based on an appreciation of the intensity of infection and the extent of disease. The recommended treatment for schistosomiasis is praziquantel (40 mg/kg/day orally [PO] divided twice daily [bid] for 1 day for schistosomiasis haematobia, mansoni, and intercalatum; 60 mg/kg/day PO divided 3 times daily [tid] for 1 day for schistosomiasis japonica and mekongi). Children 30 yr), localized obstruction of a bile duct results from repeated local trauma and inflammation. In these patients, cholangitis and cholangiohepatitis may lead to liver enlargement and jaundice. In Hong Kong,

Korea, and other parts of Asia, cholangiocarcinoma is associated with chronic C. sinensis infection. Clonorchiasis is diagnosed by examination of feces or duodenal aspirates for the parasite eggs. The recommended treatment of clonorchiasis is praziquantel (75 mg/kg/day PO divided 3 times daily [tid] for 2 days). An alternative, used in adults, is albendazole (10 mg/kg once daily PO for 7 days). Tribendimidine (400 mg PO for 3 days) has been recently used in China with good cure rates.

Opisthorchiasis (Opisthorchis spp.) Infections with species of Opisthorchis are clinically similar to those caused by C. sinensis. Opisthorchis felineus and Opisthorchis viverrini are liver flukes of cats and dogs that infect humans through ingestion of metacercariae in freshwater fish. Infection with O. felineus is endemic in Eastern Europe and Southeast Asia, and O. viverrini is found mainly in Thailand, affecting an estimated 10 million people. Most individuals are minimally symptomatic; liver enlargement, relapsing cholangitis, and jaundice may occur in heavily infected individuals. Diagnosis is based on recovering eggs from stools or duodenal aspirates. The recommended treatment of opisthorchiasis is praziquantel (75 mg/kg/day PO tid for 2 days).

Lung Flukes Paragonimiasis (Paragonimus spp.) Human infection by the lung fluke Paragonimus westermani, and less frequently other species of Paragonimus, occurs throughout the Far East, in localized areas of West Africa, and in several parts of Central and South America, affecting approximately 20 million people. The highest incidence of paragonimiasis occurs in older children and adolescents 11-15 yr of age. Although P. westermani is found in many carnivores, human cases are relatively rare and seem to be associated with specific dietary habits, such as eating raw freshwater crayfish or crabs. These crustaceans contain the infective metacercariae in their tissues. After ingestion, the metacercariae excyst in the duodenum, penetrate the intestinal wall, and migrate to their final habitat in the lungs. Adult worms (5-10 mm) encapsulate within the lung parenchyma and deposit brown operculated eggs (60-100 µm) that pass into the bronchioles and are expectorated by

coughing (see Fig. 327.1 ). Ova can be detected in the sputum of infected individuals or in their feces. If eggs reach freshwater, they hatch and undergo asexual multiplication in specific snails. The cercariae encyst in the muscles and viscera of crayfish and freshwater crabs. Most individuals infected with P. westermani harbor low or moderate worm loads and are minimally symptomatic. The clinical manifestations include cough, production of rust-colored sputum, and hemoptysis (mimicking tuberculosis), which is the principal manifestation and occurs in 98% of symptomatic children. There are no characteristic physical findings, but laboratory examination usually demonstrates marked eosinophilia. Chest radiographs often reveal small, patchy infiltrates or radiolucencies in the middle lung fields; however, radiographs may appear normal in one fifth of infected individuals. In rare circumstances, lung abscess, pleural or pericardial effusion, or bronchiectasis may develop. Extrapulmonary localization of P. westermani in the brain, peritoneum, intestines, or pericardium may rarely occur. Cerebral paragonimiasis occurs primarily in heavily infected individuals living in highly endemic areas of the Far East. The clinical presentation resembles jacksonian epilepsy or the symptoms of cerebral tumors. Definitive diagnosis of paragonimiasis is established by identification of eggs in fecal or sputum smears. The recommended treatment of paragonimiasis is praziquantel (75 mg/kg/day PO tid for 2 days). Triclabendazole can also be used (10 mg/kg PO daily for 1-2 days).

Intestinal Flukes Several wild and domestic animal intestinal flukes, including Fasciolopsis buski, Nanophyetus salmincola, and Heterophyes heterophyes, may accidentally infect humans who eat uncooked or undercooked fish or water plants. For example, F. buski is endemic in the Far East, where humans who ingest metacercariae encysted on aquatic plants become infected. These develop into large flukes (1-5 cm) that inhabit the duodenum and jejunum. Mature worms produce operculated eggs that pass with feces; the organism completes its life cycle through specific snail intermediate hosts. Individuals with F. buski infection are usually asymptomatic; heavily infected patients complain of abdominal pain and diarrhea and show signs of malabsorption. Diagnosis of fasciolopsiasis and other intestinal fluke infections is established by fecal examination and identification of the eggs (see Fig. 327.1 ). As for other fluke infections, praziquantel (75

mg/kg/day PO tid for 2 days) is the drug of choice.

Bibliography Andrews RH, Sithithaworn P, Petney TN. Opisthorchis viverrini : an underestimated parasite in world health. Trends Parasitol . 2008;24:497–501. Keiser J, Utzinger J. Food-borne trematodiases. Clin Microbiol Rev . 2009;22:466–483. Lun ZR, Gasser RB, Lai DH, et al. Clonorchiasis: a key foodborne zoonosis in China. Lancet Infect Dis . 2005;5:31– 41. Mahanty S, MacLean JD, Cross JH. Liver, lung and intestinal fluke infections. Guerrant RL, Walker DH, Weller PF. Tropical infectious diseases: principles, pathogens & practice . ed 3. Saunders Elsevier: Edinburgh; 2011:854–867. Mas-Coma S, Valero MA, Bargues MD. Chapter 2. Fasciola , lymnaeids and human fascioliasis, with a global overview on disease transmission, epidemiology, evolutionary genetics, molecular epidemiology and control. Adv Parasitol . 2009;69:41–146. The Medical Letter. Drugs for parasitic infections. Med Lett Drugs Ther . 2013;11(Suppl):e1–e31. Millan JC, Mull R, Freise S, et al. The efficacy and tolerability of triclabendazole in Cuban patients with latent and chronic Fasciola hepatica infection. Am J Trop Med Hyg . 2000;63:264–269. Qian MB, Utzinger J, Keiser J, Zhou XN. Clonorchiasis. Lancet . 2016;387:800–810. Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma. PLoS Med . 2007;4:e201. Zarrin-Khameh N, Citron DR, Stager CE, et al. Pulmonary paragonimiasis diagnosed by fine-needle aspiration biopsy. J

Clin Microbiol . 2008;46:2137–2140.

CHAPTER 328

Adult Tapeworm Infections Philip R. Fischer, A. Clinton White Jr

Tapeworms are adult forms of cestodes , multicellular helminth parasites, that live in human intestines and cause non–life-threatening illness. Invasive larval forms of cestodes are associated with cysts that lead to severe human disease such as neurocysticercosis (Taenia solium ; see Chapter 329 ) and echinococcosis (mostly Echinococcus granulosa and E. multilocularis ; Chapter 330 ). The adult worms themselves are flat and multisegmented, varying in length from 8 mm to 10 meters (m). Table 328.1 summarizes the key features of tapeworms that affect children. Table 328.1

Key Features of Common Tapeworms in Children PARASITE SPECIES Taenia saginata

GEOGRAPHY SOURCE

SYMPTOMS

TREATMENT

Asia, Africa, Latin America

Cysts in beef

Abdominal discomfort, motile proglottid migration, passing segments

Taenia solium

Asia, Africa, Latin America

Cysticerci in pork

Minimal, proglottids in stool

Taenia asiatica

Asia

Pigs

Minimal

Plerocercoid cysts in freshwater fish Infected humans,

Usually minimal; with prolonged or heavy infection with D. latum , vitamin B12 deficiency

Praziquantel or niclosamide, possibly nitazoxanide Praziquantel or niclosamide, possibly nitazoxanide Praziquantel or niclosamide, possibly nitazoxanide Praziquantel or niclosamide

Diphyllobothrium Worldwide, spp. often northern areas Hymenolepis

Worldwide, often northern

Mild abdominal discomfort

Praziquantel, niclosamide, or

Dipylidium caninum

areas Worldwide

rodents Domestic dogs and cats

Proglottids in stool, anal pruritus confused with pinworm

nitazoxanide Praziquantel or niclosamide

Etiology The beef tapeworm (Taenia saginata) , the pork tapeworm (T. solium), and the Asian tapeworm (Taenia asiatica) are long worms (4-10 m) named for their intermediate hosts (T. saginata , T. solium ) or geographic distribution (T. asiatica ; larval host is the pig). The adult worms are found only in the human intestine. As with the adult stage of all tapeworms, their body is a series of 100s or 1000s of flattened segments (proglottids ) with an anterior attachment organ (scolex) that anchors the parasite to the bowel wall. New segments arise from the distal aspect of the scolex with progressively more mature segments attached distally. The gravid terminal segments contain 50,000-100,000 eggs, and the eggs or even detached intact proglottids pass out of the child through the anus (with or separate from defecation). These tapeworms differ most significantly in that the intermediate stage of the pork tapeworm (cysticercus ) can also infect humans and cause significant morbidity (see Chapter 329 ), whereas the larval stage of T. saginata does not cause human disease. T. asiatica is similar to and often confused with the beef tapeworm.

Epidemiology The pork and beef tapeworms are distributed worldwide, with the highest risk for infection in Latin America, Africa, India, Southeast Asia, and China, where the relevant intermediate host is raised domestically. The prevalence in adults may not reflect the prevalence in young children, because cultural practices may dictate how well meat is cooked and how much is served to children.

Pathogenesis When children ingest raw or undercooked meat containing larval cysts, gastric acid and bile facilitate release of immature scolices that attach to the lumen of the small intestine. The parasite grows, adding new segments at the base of the scolex. The terminal segments mature and after 2-3 mo produce eggs that are

released in stool. The surface of proglottids serves as an absorptive organ to “steal” nutritional elements from the child's small bowel for use by the parasite. There is sometimes a transient eosinophilia before the parasite matures enough to release eggs.

Clinical Manifestations Nonspecific abdominal symptoms have been reported with beef and pork tapeworm infections, but the most bothersome symptom is the psychologic distress caused by seeing proglottids in the stool or undergarments. The released segments of the worms are motile (especially those of T. saginata ) and sometimes lead to anal pruritus. The adult beef and pork tapeworms are only rarely associated with other symptoms.

Diagnosis Identification of the infecting tapeworm species facilitates understanding of risk for invasive disease. Carriers of adult pork tapeworms are at increased risk for transmitting eggs with the pathogenic intermediate stage (cysticercus) to themselves or others, whereas children infected with the beef tapeworm or T. asiatica are a risk only to livestock. Because proglottids are generally passed intact, visual examination for gravid proglottids in the stool is a sensitive test; these segments may be used to identify species. Eggs, by contrast, are often absent from stool and cannot distinguish between T. saginata and T. solium (Fig. 328.1 ). If the parasite is completely expelled, the scolex of each species is diagnostic. The scolex of T. saginata has only a set of 4 anteriorly oriented suckers, whereas T. solium is armed with a double row of hooks in addition to suckers. The proglottids of T. saginata have >20 branches from a central uterine structure, and the proglottids of T. solium have ≤10 branches. Expelled proglottid segments are usually approximately 0.5 × 1-2 × 0.1 cm in size. Molecular methods can distinguish T. saginata from T. asiatica . Antigen detection tests are increasingly available.

FIG. 328.1 Eggs of Taenia saginata recovered from feces (original magnification ×400). A and B, The eggs are generally bile-stained, dark, and prismatic. There is occasionally some surrounding cellular material from the proglottid in which the egg develops, which is more evident in B than in A. The larva within the egg shows 3 pairs of hooklets (A ), which may occasionally be observed in motion.

Differential Diagnosis Anal pruritus may mimic symptoms of pinworm (Enterobius vermicularis) infection. Diphyllobothrium latum and Ascaris lumbricoides (a long round worm) may be mistaken for T. saginata or T. solium in stools.

Treatment Infections with all adult tapeworms respond to praziquantel (25 mg/kg orally [PO] once). When available, an alternative treatment for taeniasis is niclosamide (50 mg/kg PO once for children; 2 g PO once for adults). Nitazoxanide is sometimes effective as well. The parasite is usually expelled on the day of administration. Treatment with electrolyte–polyethylene glycol bowel preparations can increase the yield of passage of scolices.

Prevention Prolonged freezing or thorough cooking of beef and pork kills the larval cystic forms of the parasite. Appropriate human sanitation can interrupt transmission by preventing infection in livestock.

Diphyllobothriasis (Diphyllobothrium

Spp.) Etiology The fish tapeworms of the genus Diphyllobothrium are the longest human tapeworms, reaching >10 m in length, and have an anatomic organization similar to that of other adult cestodes. An elongated scolex, equipped with slits (bothria ) along each side but no suckers or hooks, is followed by 1000s of segments looped in the small bowel. Gravid terminal proglottids detach periodically but tend to disintegrate before expulsion, thus releasing eggs rather than intact worm segments in the feces. In contrast to taeniids, the life cycle of Diphyllobothrium spp. requires 2 intermediate hosts. Small, freshwater crustaceans (copepods) take up the larvae that hatch from parasite eggs. The parasite passes up the food chain as small fish eat the copepods and are in turn eaten by larger fish. In this way, the juvenile parasite becomes concentrated in pike, walleye, perch, burbot, and perhaps salmon associated with aquaculture. Consumption of raw or undercooked fish leads to human infection with adult fish tapeworms.

Epidemiology The fish tapeworm is most prevalent in the temperate climates of Europe, North America, and Asia but may be found along the Pacific coast of South America and in Africa. In North America the prevalence is highest in Alaska, Canada, and northern areas of continental United States. The tapeworm is found in fish from those areas that are then taken to market. Persons who prepare raw fish for home or commercial use or who sample fish before cooking are particularly at risk for infection.

Pathogenesis The adult worm of Diphyllobothrium latum (found in northern Europe) has highaffinity receptors and efficiently scavenges vitamin B12 for its own use in the constant production of large numbers of segments and as many as 1 million eggs per day. As a result, diphyllobothriasis causes megaloblastic anemia in 2–9% of infections. Interestingly, other Diphyllobothrium spp. do not out-compete the host for vitamin B12 . Children with other causes of vitamin B12 or folate deficiency, such as chronic infectious diarrhea, celiac disease, or congenital

malabsorption, are more likely to develop symptomatic infection.

Clinical Manifestations Infection is largely asymptomatic. Segments may be noted in stool. Those who develop vitamin B12 or folate deficiency present with megaloblastic anemia with leukopenia, thrombocytopenia, glossitis, and/or signs of spinal cord posterior column dysfunction (loss of vibratory sense, proprioception, and coordination).

Diagnosis Parasitological examination of the stool is useful because eggs are abundant in the feces and have morphology distinct from that of all other tapeworms. The eggs are ovoid and have an operculum , which is a cap structure at one end that opens to release the embryo (Fig. 328.2 ). The worm itself has a distinct scolex and proglottid morphology; however, these are not likely to be passed spontaneously.

FIG. 328.2 Eggs of Diphyllobothrium latum as seen in feces (original magnification ×400). A and B, The caplike operculum is at the upper end of the eggs here.

Differential Diagnosis A segment or a whole section of the worm might be confused with Taenia or Ascaris after it is passed. Pernicious anemia, bone marrow toxins, and dietary restriction may contribute to or mimic the nutritional deficiencies associated with diphyllobothriasis.

Treatment As with all adult tapeworms, D. latum infections respond to praziquantel (5-10 mg/kg PO once). Niclosamide (50 mg/kg PO in a single dose) is also effective.

Prevention The intermediate stage is easily killed by brief cooking or prolonged freezing of fish before ingestion. Because humans are the major reservoir for adult worms, health education is one of the most important tools for preventing transmission, together with improved human sanitation.

Hymenolepiasis (Hymenolepis) Infection with Hymenolepis nana, the dwarf tapeworm, is very common in developing countries. Most cases are asymptomatic. However, heavy infection has been associated with diarrhea, weight loss, fever, and eosinophilia. The intermediate stage of Hymenolepis diminuta develops in various hosts (e.g., rodents, ticks, fleas), but the entire life cycle of H. nana is completed in humans. Therefore, hyperinfection with 1000s of small adult worms in a single child may occur. A similar infection may occur less often with H. diminuta. Eggs but not segments may be found in the stool. H. nana infection responds to praziquantel (25 mg/kg PO once). Nitazoxanide is effective in about three fourths of children (100 mg PO twice daily [bid] for 3 days for children 1-3 yr old, 200 mg bid for 3 days for children 4-11 yr old, and 500 mg bid for 3 days for older children).

Dipylidiasis (Dipylidium Caninum) Dipylidium caninum is a common tapeworm of domestic dogs and cats. Human infection is relatively rare. Direct transmission between pets and humans does

not occur; human infection requires ingestion of the parasite's intermediate host, the dog or cat flea. Infants and small children are particularly susceptible because of their level of hygiene, generally more intimate contact with pets, and activities in areas where fleas can be encountered. Thus, children are most at risk of inadvertent ingestion of fleas infected with the larvae. The most common symptom is passage of proglottids in stool. The proglottids are similar in size and shape to white rice grains. Anal pruritus, vague abdominal pain, and diarrhea have at times been associated with dipylidiasis, which is thus sometimes confused with pinworm (E. vermicularis). Dipylidiasis responds to treatment with praziquantel (5-10 mg/kg PO once) and niclosamide (50 mg/kg PO as a single dose). Deworming of pets and flea control are the best preventive measures.

Bibliography Anantaphruti MT, Yamasaki H, Nakao M, et al. Sympatric occurrence of Taenia solium, T. saginata , and T. asiatica , Thailand. Emerg Infect Dis . 2007;13:1413–1416. Cabada MM, Morales ML, Lopez M, et al. Hymenolepis nana impact among children in the highlands of Cusco-Peru: an emerging neglected parasite infection. Am J Trop Med Hyg . 2016;95:1031–1036. Craig P, Ito A. Intestinal cestodes. Curr Opin Infect Dis . 2007;20:524–532. Samkari A, Kiska DL, Riddell SW, et al. Dipylidium caninum mimicking recurrent Enterobius vermicularis (pinworm) infection. Clin Pediatr (Phila) . 2008;47:397–399. Scholz T, Garcia HH, Kuchta R, et al. Update on the human broad tapeworm (genus Diphyllobothrium ), including clinical relevance. Clin Microbiol Rev . 2009;22:146–160.

CHAPTER 329

Cysticercosis A. Clinton White Jr., Philip R. Fischer

Etiology Taenia solium, also known as the pork tapeworm , causes 2 different infections in children. In its normal life cycle, children can acquire the tapeworm form by ingestion of undercooked pork containing the larval cysts (see Chapter 328 ). In the intestines, the cyst converts into the tapeworm form. Children are also susceptible to infection by the eggs shed by tapeworm carriers. After the eggs are ingested, the larvae are released from the eggs, invade through the intestines, and migrate through the bloodstream to the muscles (and other organs), where they form tissue cysts (0.2-2.0 cm fluid-filled bladders containing a single invaginated scolex ). Infection with the cystic form is termed cysticercosis , and involvement of the central nervous system (CNS) is termed neurocysticercosis. The tapeworm form only develops after ingestion of undercooked pork. Ingestion of pork is not necessary to develop cysticercosis, but individuals harboring an adult worm may infect themselves with the eggs by the fecal-oral route.

Epidemiology The pork tapeworm is widely distributed wherever pigs are raised and have contact with human fecal material. Intense transmission occurs in Central and South America, southern and Southeast Asia, and much of sub-Saharan Africa. In these areas, approximately 30% of cases of seizures may be a result of cysticercosis. Most cases of cysticercosis in the United States are imported; however, local transmission has been documented.

Pathogenesis Living, intact cystic stages usually suppress the host immune and inflammatory responses. Intact cysts can be associated with disease when they obstruct the flow of cerebrospinal fluid. Most cysts remain asymptomatic for a few years. Symptoms typically develop as the cysticerci begin to degenerate, associated with a host inflammatory response. The natural history of cysts is eventually to resolve by complete resorption or calcification, but this process may take years. Cysticerci can also present as subcutaneous nodules, ocular infection, or spinal lesions with myelopathy or radiculopathy.

Clinical Manifestations Seizures are the presenting finding in the vast majority of children with neurocysticercosis. Less common manifestations include hydrocephalus, diffuse cerebral edema, or focal neurologic findings. It is important to classify neurocysticercosis as parenchymal, intraventricular, subarachnoid, spinal, or ocular on the basis of anatomic location, clinical presentation, and radiologic appearance, since the prognosis and management vary with location. Parenchymal neurocysticercosis typically presents with seizures. The seizures are usually focal, but often generalize. Children may present with a single seizure or recurrent epilepsy. Mild neurocognitive defects have been documented from cysticerci alone but are more commonly associated with poorly controlled seizures. A fulminant encephalitis-like presentation may rarely occur after a massive initial infection associated with cerebral edema. Intraventricular neurocysticercosis (up to 20% of cases) is associated with obstructive hydrocephalus and acute, subacute, or intermittent signs of increased intracranial pressure, usually without localizing signs. Subarachnoid neurocysticercosis is rare in children. It can be associated with basilar arachnoiditis that can present with signs of meningeal irritation, communicating hydrocephalus, cerebral infarction, or spinal disease with radiculitis or transverse myelitis. Cysticerci in the tissues may present with focal findings from mass effect. Ocular neurocysticercosis causes decreased visual acuity because of cysticerci in the retina or vitreous, retinal detachment, or iridocyclitis.

Diagnosis

Neurocysticercosis should be suspected in a child with onset of seizures or hydrocephalus and who also has a history of residence in an endemic area and/or a care provider from an endemic area. The most useful diagnostic study for parenchymal disease is MRI of the head. MRI provides the most information about cyst location, cyst viability, and associated inflammation. The protoscolex is sometimes visible within the cyst, which provides a pathognomonic sign for cysticercosis (Fig. 329.1A ). The MRI also better detects basilar arachnoiditis (Fig. 329.1B ), intraventricular cysts (Fig. 329.1C ), and cysts in the spinal cord. CT is best for identifying calcifications. A solitary parenchymal cyst, with or without contrast enhancement, or CNS calcifications are the most common findings in children (Fig. 329.2 ). Plain films may reveal calcifications in muscle or brain consistent with cysticercosis. In children from endemic regions, the presentation with a single enhancing lesion that is round and 20) liver cysts. (From Ben-Shimol S, Zelcer I: Liver hydatid cysts, J Pediatr 163:1792, 2013.)

Serologic studies are used to confirm the diagnosis of cystic echinococcosis.

However, most of the antibody detection tests available use crude hydatid fluid antigens, which include epitopes that cross-react with other helminths. Crossreaction has been reported with other noninfectious illness as well. In addition, some children with active cystic echinococcosis may not have circulating levels of specific antibody. Thus the sensitivity and specificity of the enzyme-linked immunosorbent assay to diagnose cystic echinococcosis may vary from 50– 100% and 40–100%, respectively, depending on the antigen used and cyst stage, location, number, and viability. The sensitivity is higher for hepatic or bone disease, but the false-negative rate may be >50% with pulmonary or central nervous system (CNS) infection.

Differential Diagnosis Benign hepatic cysts are common but can be distinguished from cystic hydatid disease by the absence of a distinct 3-layer wall, internal membranes, and hydatid sand. The density of bacterial hepatic abscesses is distinct from the watery cystic fluid characteristic of E. granulosus infection, but hydatid cysts may also be complicated by secondary bacterial infection. Alveolar echinococcosis is often confused with hepatoma or metastatic tumor.

Treatment Management of cystic hydatid disease should be individualized and guided by disease stage and location. Approaches range from surgical resection for disease that tends to respond poorly to drugs and complicated cysts to watchful waiting for cysts that have already degenerated. For cystic echinococcosis (CE ) types 1 or 3a (see Fig. 330.2 ) that are bacterial > protozoal) Food poisoning Systemic infection Antibiotic associated

Gastroenteritis (viral > bacterial > protozoal) Food poisoning Antibiotic associated

Toxic ingestion Hemolytic uremic syndrome Intussusception

Hyperthyroidism Appendicitis

Postinfectious secondary lactase deficiency Irritable bowel syndrome Celiac disease Cystic fibrosis Lactose intolerance Excessive fruit juice (sorbitol) ingestion Giardiasis Inflammatory bowel disease AIDS enteropathy

Irritable bowel syndrome Inflammatory bowel disease Lactose intolerance Giardiasis Laxative abuse (anorexia nervosa) Constipation with encopresis

Primary immune defects Autoimmune enteropathy IPEX and IPEX-like syndromes Glucose-galactose malabsorption Microvillus inclusion disease (microvillus atrophy) Congenital transport defects (chloride, sodium) Primary bile acid malabsorption Factitious syndrome by proxy Hirschsprung disease Shwachman syndrome Secretory tumors Acrodermatitis enteropathica Lymphangiectasia Abetalipoproteinemia Eosinophilic gastroenteritis Short bowel syndrome

Primary and acquired immune defects Secretory tumors Pseudoobstruction Sucrase-isomaltase deficiency Eosinophilic gastroenteritis Secretory tumors

Secretory tumor Primary bowel tumor Parasitic infections and venereal diseases Appendiceal abscess Addison disease

IPEX, Immunodysregulation polyendocrinopathy enteropathy X-linked. From Kliegman RM, Greenbaum LA, Lye PS, editors: Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, Elsevier, p 272.

Constipation Any definition of constipation is relative and depends on stool consistency, stool frequency, and difficulty in passing the stool. A normal child might have a soft stool only every second or third day without difficulty; this is not constipation. A hard stool passed with difficulty every third day should be treated as constipation. Constipation can arise from defects either in filling or emptying the rectum (Table 332.12 ). Table 332.12

Causes of Constipation NONORGANIC (FUNCTIONAL)—RETENTIVE Anatomic Anal stenosis, atresia with fistula Imperforate anus Anteriorly displaced anus Intestinal stricture (postnecrotizing enterocolitis) Anal stricture Abnormal Musculature Prune-belly syndrome Gastroschisis Down syndrome Muscular dystrophy

Intestinal Nerve or Muscle Abnormalities Hirschsprung disease Pseudoobstruction (visceral myopathy or neuropathy) Intestinal neuronal dysplasia Spinal cord lesions Tethered cord Autonomic neuropathy Spinal cord trauma Spina bifida Chagas disease Drugs Anticholinergics Narcotics Methylphenidate Phenytoin Antidepressants Chemotherapeutic agents (vincristine) Pancreatic enzymes (fibrosing colonopathy) Lead, arsenic, mercury Vitamin D intoxication Calcium channel blocking agents Metabolic Disorders Hypokalemia Hypercalcemia Hypothyroidism Diabetes mellitus, diabetes insipidus Porphyria Intestinal Disorders Celiac disease Cow's milk protein intolerance Cystic fibrosis (meconium ileus equivalent) Inflammatory bowel disease (stricture) Tumor Connective tissue disorders Systemic lupus erythematosus Scleroderma Psychiatric Diagnosis Anorexia nervosa

A nursing infant might have very infrequent stools of normal consistency; this is usually a normal pattern. True constipation in the neonatal period is most likely secondary to Hirschsprung disease, intestinal pseudoobstruction, or hypothyroidism. Defective rectal filling occurs when colonic peristalsis is ineffective (in cases of hypothyroidism or opiate use and when bowel obstruction is caused either by a structural anomaly or by Hirschsprung disease). The resultant colonic stasis leads to excessive drying of stool and a failure to initiate reflexes from the rectum that normally trigger evacuation. Emptying the rectum by spontaneous evacuation depends on a defecation reflex initiated by pressure receptors in the rectal muscle. Therefore stool retention can also result from lesions involving

these rectal muscles, the sacral spinal cord afferent and efferent fibers, or the muscles of the abdomen and pelvic floor. Disorders of anal sphincter relaxation can also contribute to fecal retention. Constipation tends to be self-perpetuating, whatever its cause. Hard, large stools in the rectum become difficult and even painful to evacuate; thus more retention occurs and a vicious circle ensues. Distention of the rectum and colon lessens the sensitivity of the defecation reflex and the effectiveness of peristalsis. Fecal impaction is common and leads to other problems. Eventually, watery content from the proximal colon might percolate around hard retained stool and pass per rectum unperceived by the child. This involuntary encopresis may be mistaken for diarrhea. Constipation itself does not have deleterious systemic organic effects, but urinary tract stasis with increased risk of urinary tract infections can accompany severe long-standing cases and constipation can generate anxiety, having a marked emotional impact on the patient and family.

Abdominal Pain There is considerable variation among children in their perception and tolerance for abdominal pain. This is one reason the evaluation of chronic abdominal pain is difficult. A child with functional abdominal pain (no identifiable organic cause) may be as uncomfortable as one with an organic cause. It is very important to distinguish between organic and nonorganic (functional) abdominal pain because the approach for the management is based on this. Normal growth and physical examination (including a rectal examination) and the absence of anemia or hematochezia are reassuring in a child who is suspected of having functional pain. A specific cause may be difficult to find, but the nature and location of a painprovoking lesion can usually be determined from the clinical description. Two types of nerve fibers transmit painful stimuli in the abdomen. In skin and muscle, A fibers mediate sharp localized pain; C fibers from viscera, peritoneum, and muscle transmit poorly localized, dull pain. These afferent fibers have cell bodies in the dorsal root ganglia, and some axons cross the midline and ascend to the medulla, midbrain, and thalamus. Pain is perceived in the cortex of the postcentral gyrus, which can receive impulses arising from both sides of the body. In the gut, the usual stimulus provoking pain is tension or stretching. Inflammatory lesions can lower the pain threshold, but the mechanisms producing pain or inflammation are not clear. Tissue metabolites released near

nerve endings probably account for the pain caused by ischemia. Perception of these painful stimuli can be modulated by input from both cerebral and peripheral sources. Psychologic factors are particularly important. Tables 332.13 and 332.14 list features of abdominal pain. Pain that suggests a potentially serious organic etiology is associated with age younger than 5 yr; fever; weight loss; bile- or blood-stained emesis; jaundice; hepatosplenomegaly; back or flank pain or pain in a location other than the umbilicus; awakening from sleep in pain; referred pain to shoulder, groin or back; elevated erythrocyte sedimentation rate, white blood cell count, or C-reactive protein; anemia; edema; hematochezia; or a strong family history of inflammatory bowel disease or celiac disease. Table 332.13

Chronic Abdominal Pain in Children DISORDER NONORGANIC Functional abdominal pain Irritable bowel syndrome Nonulcer dyspepsia

CHARACTERISTICS

KEY EVALUATIONS

Nonspecific pain, often periumbilical

Hx and PE; tests as indicated

Intermittent cramps, diarrhea, and constipation Peptic ulcer–like symptoms without abnormalities on evaluation of the upper GI tract GASTROINTESTINAL TRACT Chronic constipation Hx of stool retention, evidence of constipation on examination Lactose intolerance Symptoms may be associated with lactose ingestion; bloating, gas, cramps, and diarrhea Parasite infection Bloating, gas, cramps, and diarrhea (especially Giardia ) Excess fructose or Nonspecific abdominal pain, bloating, sorbitol ingestion gas, and diarrhea Crohn disease See Chapter 362 Peptic ulcer Burning or gnawing epigastric pain; worse on awakening or before meals; relieved with antacids Esophagitis Epigastric pain with substernal burning Meckel diverticulum Periumbilical or lower abdominal pain; may have blood in stool (usually painless) Recurrent Paroxysmal severe cramping abdominal intussusception pain; blood may be present in stool with episode Internal, inguinal, or Dull abdomen or abdominal wall pain abdominal wall hernia

Hx and PE Hx; esophagogastroduodenoscopy

Hx and PE; plain x-ray of abdomen Trial of lactose-free diet; lactose breath hydrogen test Stool evaluation for O&P; specific immunoassays for Giardia Large intake of apples, fruit juice, or candy or chewing gum sweetened with sorbitol Esophagogastroduodenoscopy, upper GI contrast x-rays, or MRI enteroscopy Esophagogastroduodenoscopy Meckel scan or enteroclysis Identify intussusception during episode or lead point in intestine between episodes with contrast studies of GI tract PE, CT of abdominal wall

Chronic appendicitis Recurrent RLQ pain; often incorrectly or appendiceal diagnosed, may be rare cause of mucocele abdominal pain GALLBLADDER AND PANCREAS Cholelithiasis RUQ pain, might worsen with meals Choledochal cyst RUQ pain, mass ± elevated bilirubin Recurrent pancreatitis Persistent boring pain, might radiate to back, vomiting GENITOURINARY TRACT Urinary tract infection Dull suprapubic pain, flank pain Hydronephrosis Unilateral abdominal or flank pain Urolithiasis Progressive, severe pain; flank to inguinal region to testicle Other genitourinary Suprapubic or lower abdominal pain; disorders genitourinary symptoms MISCELLANEOUS CAUSES Abdominal migraine See text; nausea, family Hx migraine Abdominal epilepsy Might have seizure prodrome Gilbert syndrome

Familial Mediterranean fever Sickle cell crisis Lead poisoning Henoch-Schönlein purpura Angioneurotic edema Acute intermittent porphyria Anterior cutaneous nerve entrapment syndrome (ACNES)

Mild abdominal pain (causal or coincidental?); slightly elevated unconjugated bilirubin Paroxysmal episodes of fever, severe abdominal pain, and tenderness with other evidence of polyserositis Anemia Vague abdominal pain ± constipation Recurrent, severe crampy abdominal pain, occult blood in stool, characteristic rash, arthritis Swelling of face or airway, crampy pain

Barium enema, CT

Ultrasound of gallbladder Ultrasound or CT of RUQ Serum amylase and lipase ± serum trypsinogen; ultrasound, CT, or MRI-ERCP of pancreas Urinalysis and urine culture; renal scan Ultrasound of kidneys Urinalysis, ultrasound, IVP, CT Ultrasound of kidneys and pelvis; gynecologic evaluation Hx EEG (can require >1 study, including sleepdeprived EEG) Serum bilirubin

Hx and PE during an episode, DNA diagnosis

Hematologic evaluation Serum lead level Hx, PE, urinalysis

Hx, PE, upper GI contrast x-rays, serum C1 esterase inhibitor Severe pain precipitated by drugs, fasting, Spot urine for porphyrins or infections Exquisite localized (~2 × 2 cm) Pain relief within 15 min of abdominal wall tenderness that is replicable, most often injection of local anesthetic; may need right lower quadrant surgery

ERCP, Endoscopic retrograde cholangiopancreatography.EEG , Electroencephalogram; GI , gastrointestinal; Hx , history; IVP , intravenous pyelography; O&P , ova and parasites; PE , physical exam; RLQ , right lower quadrant; RUQ , right upper quadrant.

Table 332.14

Distinguishing Features of Acute Abdominal Pain in Children DISEASE Pancreatitis

ONSET LOCATION Acute Epigastric, left upper quadrant

REFERRAL QUALITY COMMENTS Back Constant, sharp, Nausea, emesis, boring tenderness

Intestinal obstruction

Acute or Periumbilical-lower abdomen Back gradual

Appendicitis

Acute (1-3 days)

Periumbilical, then localized to lower right quadrant; generalized with peritonitis

Back or pelvis if retrocecal

Intussusception Acute

Periumbilical-lower abdomen None

Urolithiasis

Acute, sudden

Back (unilateral)

Groin

Urinary tract infection

Acute

Back

Bladder

Pelvic inflammatory disease Small bowel obstruction Ruptured ectopic pregnancy

Acute

Pelvis, lower quadrant

Upper thigh

Acute to Periumbilical subacute Acute Pelvis, lower quadrant sudden

None None

Alternating cramping (colic) and painless periods Sharp, steady

Distention, obstipation, emesis, increased bowel sounds Anorexia, nausea, emesis, local tenderness, fever with peritonitis Cramping, with Hematochezia, knees painless periods in pulled-up position Sharp, Hematuria intermittent, cramping Dull to sharp Fever, costovertebral angle tenderness, dysuria, urinary frequency Aching, Vaginal discharge, peritoneal signs fever Cramping diffuse Sharp, intense, localized

Emesis and obstipation Vaginal bleeding, shock

Visceral pain tends to be dull and aching and is experienced in the dermatome from which the affected organ receives innervations. So, most often, the pain and tenderness are not felt over the site of the disease process. Painful stimuli originating in the liver, pancreas, biliary tree, stomach, or upper bowel are felt in the epigastrium; pain from the distal small bowel, cecum, appendix, or proximal colon is felt at the umbilicus; and pain from the distal large bowel, urinary tract, or pelvic organs is usually suprapubic. The pain from the cecum, ascending colon, and descending colon sometimes is felt at the site of the lesion because of the short mesocecum and corresponding mesocolon. The pain caused by appendicitis is initially felt in the periumbilical region, and pain from the transverse colon is usually felt in the supra pubic region. The shifting (localization) of pain is a pointer toward diagnosis; for example, periumbilical pain of a few hours localizing to the right lower quadrant suggests appendicitis. Radiation of pain can be helpful in diagnosis; for example, in biliary colic the radiation of pain is toward the inferior angle of the right scapula, pancreatic pain radiated to the back, and the renal colic pain is radiated to the inguinal region on the same side. Somatic pain is intense and usually well localized. When the inflamed viscus comes in contact with a somatic organ such as the parietal peritoneum or the abdominal wall, pain is localized to that site. Peritonitis gives rise to generalized

abdominal pain with rigidity, involuntary guarding, rebound tenderness, and cutaneous hyperesthesia on physical examination. Referred pain from extraintestinal locations, from shared central projections with the sensory pathway from the abdominal wall, can give rise to abdominal pain, as in pneumonia when the parietal pleural pain is referred to the abdomen.

Gastrointestinal Hemorrhage Bleeding can occur anywhere along the GI tract, and identification of the site may be challenging (Table 332.15 ). Bleeding that originates in the esophagus, stomach, or duodenum can cause hematemesis. When exposed to gastric or intestinal juices, blood quickly darkens to resemble coffee grounds; massive bleeding is likely to be red. Red or maroon blood in stools, hematochezia, signifies either a distal bleeding site or massive hemorrhage above the distal ileum. Moderate to mild bleeding from sites above the distal ileum tends to cause blackened stools of tarry consistency (melena); major hemorrhages in the duodenum or above can also cause melena. Table 332.15

Differential Diagnosis of Gastrointestinal Bleeding in Childhood INFANT COMMON Bacterial enteritis Milk protein allergy intolerance Intussusception Swallowed maternal blood Anal fissure Lymphonodular hyperplasia

RARE Volvulus Necrotizing enterocolitis Meckel diverticulum Stress ulcer, gastritis Coagulation disorder (hemorrhagic disease of newborn) Esophagitis

CHILD Bacterial enteritis Anal fissure Colonic polyps Intussusception Peptic ulcer/gastritis Swallowed epistaxis Prolapse (traumatic) gastropathy secondary to emesis Mallory-Weiss syndrome Esophageal varices Esophagitis Meckel diverticulum Lymphonodular hyperplasia Henoch-Schönlein purpura Foreign body Hemangioma, arteriovenous malformation

ADOLESCENT Bacterial enteritis Inflammatory bowel disease Peptic ulcer/gastritis Prolapse (traumatic) gastropathy secondary to emesis Mallory-Weiss syndrome Colonic polyps Anal fissure

Hemorrhoids Esophageal varices Esophagitis Pill ulcer Telangiectasia-angiodysplasia Graft versus host disease Duplication cyst • Angiodysplasia

Sexual abuse Hemolytic-uremic syndrome Inflammatory bowel disease Coagulopathy Duplication cyst • Angiodysplasia • Angiodysplasia with von Willebrand disease • Blue rubber bleb nevus syndrome

• Angiodysplasia with von Willebrand disease • Blue rubber bleb nevus syndrome

Erosive damage to the mucosa of the GI tract is the most common cause of bleeding, although variceal bleeding secondary to portal hypertension occurs often enough to require consideration. Prolapse gastropathy producing subepithelial hemorrhage and Mallory-Weiss lesions secondary to mucosal tears associated with emesis are causes of upper intestinal bleeds. Vascular malformations are a rare cause in children; they are difficult to identify (Figs. 332.1 and 332.2 ). Upper intestinal bleeding is evaluated with esophagogastroduodenoscopy. Evaluation of the small intestine is facilitated by capsule endoscopy. The capsule-sized imaging device is swallowed in older children or placed endoscopically in younger children. Lower GI bleeding is investigated with a colonoscopy. In brisk intestinal bleeding of unknown location, a tagged red blood cell scan is helpful in locating the site of the bleeding, although CT angiography is usually diagnostic. Occult blood in stool is usually detected by using commercially available fecal occult blood testing cards, which are based on a chemical reaction between the chemical guaiac and oxidizing action of a substrate (hemoglobin), giving a blue color. The guaiac test is very sensitive, but random testing can miss chronic blood loss, which can lead to iron-deficiency anemia. GI hemorrhage can produce hypotension and tachycardia but rarely causes GI symptoms; brisk duodenal or gastric bleeding can lead to nausea, vomiting, or diarrhea. The breakdown products of intraluminal blood might tip patients into hepatic coma if liver function is already compromised and can lead to elevation of serum bilirubin.

FIG. 332.1 A 7 yr old boy had tarry stool for days. Panendoscopy showed multiple cherry red flat spots in the gastric mucosa, compatible with the findings of angiodysplasia in computed tomographic angiography. (From Chuang F, Lin JS, Yeung C, et al: Intestinal angiodysplasia: an uncommon cause of gastrointestinal bleeding in children. Pediatr Neonatol 52:214– 218, 2011. Fig. 2.)

FIG. 332.2 Operative features of blue rubber bleb nevus syndrome: these lesions are similar to cutaneous lesions. (From Hasosah MY, Abdul-Wahab AA, Bin-Yahab SA, et al: Blue rubber bled nevus syndrome: extensive small bowel vascular lesions responsible for gastrointestinal bleeding. J Pediatr Child Health 46:63–65, 2010. Fig 3.)

Abdominal Distention and Abdominal Masses Enlargement of the abdomen can result from diminished tone of the wall musculature or from increased content: fluid, gas, or solid. Ascites, the accumulation of fluid in the peritoneal cavity, distends the abdomen both in the flanks and anteriorly when it is large in volume. This fluid shifts with movement of the patient and conducts a percussion wave. Ascitic fluid is usually a transudate with a low protein concentration resulting from reduced plasma colloid osmotic pressure of hypoalbuminemia and/or from raised portal venous pressure. In cases of portal hypertension, the fluid leak probably occurs from lymphatics on the liver surface and from visceral peritoneal capillaries, but ascites does not usually develop until the serum albumin level falls. Sodium excretion in the urine decreases greatly as the ascitic fluid accumulates, and thus additional dietary sodium goes directly to the peritoneal space, taking with it more water. When ascitic fluid contains a high protein concentration, it is usually an exudate caused by an inflammatory or neoplastic lesion. When fluid distends the gut, either obstruction or imbalance between absorption and secretion should be suspected. The factors causing fluid accumulation in the bowel lumen often cause gas to accumulate too. The result may be audible gurgling noises. The source of gas is usually swallowed air, but endogenous flora can increase considerably in malabsorptive states and produce excessive gas when substrate reaches the lower intestine. Gas in the peritoneal cavity (pneumoperitoneum) is usually caused by a perforated viscus and can cause abdominal distention depending on the amount of gas leak. A tympanitic percussion note, even over solid organs such as the liver, indicates a large collection of gas in the peritoneum. An abdominal organ can enlarge diffusely or be affected by a discrete mass. In the digestive tract, such discrete masses can occur in the lumen, wall, omentum, or mesentery. In a constipated child, mobile, nontender fecal masses are often found. Congenital anomalies, cysts, or inflammatory processes can affect the wall of the gut. Gut wall neoplasms are extremely rare in children. The pathologic enlargement of liver, spleen, bladder, and kidneys can give rise to abdominal distention.

Bibliography American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain. Chronic abdominal pain in children. Pediatrics . 2003;115:812–815. American Academy of Pediatrics Subcommittee and NASPGHAN Committee on Chronic Abdominal Pain. Chronic abdominal pain in children: a technical report of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr . 2005;40:249–261. American Academy of Pediatrics Subcommittee and NASPGHAN Committee on Chronic Abdominal Pain. Chronic abdominal pain in children: a clinical report of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr . 2005;40:245–248. Auth MKH, Vora R, Farrelly P, et al. Childhood constipation. BMJ . 2012;345:38–43. Bairdain S, Dinakar P, Mooney DP. Anterior cutaneous nerve entrapment syndrome in children. J Pediatr Surg . 2015;50:1177–1179. Burgers R, Levin AD, Di Lorenzo C, et al. Functional defecation disorders in children: comparing the Rome II with the Rome III criteria. J Pediatr . 2012;161:615–620. Carty HM. Paediatric emergencies: non-traumatic abdominal emergencies. Eur Radiol . 2002;12:2835–2848. Carvalho RS, Michail SK, Ashai-Khan F, Mezoff AG. An update in pediatric gastroenterology and nutrition: a review of some recent advances. Curr Probl Pediatr Adolesc Health Care . 2008;38:197–234. Chelimsky TC, Chelimsky GG. Autonomic abnormalities in cyclic vomiting. J Pediatr Gastroenterol Nutr . 2007;44:326–

330. Chuang F, Lin JS, Yeung C, et al. Intestinal angiodysplasia: an uncommon cause of gastrointestinal bleeding in children. Pediatr Neonatol . 2011;52:214–218. El-Chammas K, Majeskie A, Simpson P, et al. Red flags in children with chronic abdominal pain and Crohn's disease—a single center experience. J Pediatr . 2013;162:783–787. Fitzpatrick E, Bourke B, Drumm B, et al. Outcome for children with cyclical vomiting syndrome. Arch Dis Child . 2007;92:1001–1004. Franchini M, Mannucci PM. Gastrointestinal angiodysplasia and bleeding in von Willebrand disease. Thromb Haemost . 2014;112:427–431. Gasiorowska A, Faas R. Current approach to dysphagia. Gastroenterol Hepatol . 2009;5:269–279. Golden CB, Feusner JH. Malignant abdominal masses in children: quick guide to evaluation and diagnosis. Pediatr Clin North Am . 2002;49:1369–1392. Hasosah MY, Abdul-Wahab AA, Bin-Yahab SA, et al. Blue rubber bled nevus syndrome: extensive small bowel vascular lesions responsible for gastrointestinal bleeding. J Paediatr Child Health . 2010;46:63–65. Kirkham SE, Lindley KJ, Elawad MA, et al. Treatment of multiple small bowel angiodysplasias causing severe lifethreatening bleeding with thalidomide. J Pediatr Gastroenterol Nutr . 2006;42(5):585–587. Koppen IJ, Nurko S, Saps M, et al. The Pediatric Rome IV criteria: what's new? Expert Rev Gastroenterol Hepatol . 2017;11(3):193–201. Li BU, Misiewicz L. Cylic vomiting syndrome: a brain-gut disorder. Gastroenterol Clin North Am . 2003;32:997–1019. Mulvaney S, Lombert EW, Garber J, et al. Trajectories of symptoms and impairment for pediatric patients with

functional abdominal pain. J Am Acad Child Adolesc Psychiatry . 2006;45:737–744. Nurko S, Rosen R, Furuta GT. Esophageal dysmotility in children with eosinophilic esophagitis: a study using prolonged esophageal manometry. Am J Gastroenterol . 2009;104(12):3050–3057; 10.1038/ajg.2009.543 [Epub 2009 Sep 15]. Parashette KR, Croffie J. Vomiting. Pediatr Rev . 2013;34:307– 320. Pennazlo M. Small-intestinal pathology on capsule endoscopy: spectrum of vascular lesions. Endoscopy . 2005;37:864–869. Pfau BT, Li BUK, Murray RD, et al. Differentiating cyclic from chronic vomiting patterns in children: quantitative criteria and diagnostic implications. Pediatrics . 1996;97:364–368. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology . 2006;130:1527–1537. Rome Foundation for Functional Gastrointestinal Disorders: home page (website) . http://www.romecriteria.org . Rubin G. Constipation in children. Clin Evid . 2003;10:369– 374. Sami SS, Al-Araji SA, Ragunath K. Review article: gastrointestinal angiodysplasia—pathogenesis, diagnosis and management. Aliment Pharmacol Ther . 2014;39:15–34. Siawash M, de Jager-Kievit JWA, Ten WTA, et al. Prevalence of anterior cutaneous nerve entrapment syndrome in a pediatric population with chronic abdominal pain. J Pediatr Gastroenterol Nutr . 2016;62(3):399–402. Strate LL, Gralnek IM. ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding. Am J Gastroenterol . 2016;111(4):459–474. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Consensus statement on the

diagnosis and management of cyclical vomiting. J Pediatr Gastroenterol Nutr . 2008;47:379–393.

SECTION 2

The Oral Cavity OUTLINE Chapter 333 Development and Developmental Anomalies of the Teeth Chapter 334 Disorders of the Oral Cavity Associated With Other Conditions Chapter 335 Malocclusion Chapter 336 Cleft Lip and Palate Chapter 337 Syndromes With Oral Manifestations Chapter 338 Dental Caries Chapter 339 Periodontal Diseases Chapter 340 Dental Trauma Chapter 341 Common Lesions of the Oral Soft Tissues Chapter 342 Diseases of the Salivary Glands and Jaws Chapter 343 Diagnostic Radiology in Dental Assessment

CHAPTER 333

Development and Developmental Anomalies of the Teeth Vineet Dhar

Newborn infants do not have teeth for about first 6 mo after birth (predentate period). At this stage, the upper and lower alveolar ridges in the mouth, also known as gum pads, house the primary (deciduous) and some permanent tooth buds. The primary dentition period starts with eruption of the first primary tooth; all 20 primary teeth erupt by 3 yr of age. The permanent teeth start erupting around age of 6 yr, and the transition to full permanent dentition is completed by 13 yr of age. The transition time between primary and permanent dentition, when a mix of primary and permanent teeth are present, is referred to as mixed dentition.

Development of Teeth Initiation The primary teeth form in dental crypts that arise from a band of epithelial cells incorporated into each developing jaw. By 12 wk of fetal life, each of these epithelial bands (dental laminae) has 5 areas of rapid growth on each side of the maxilla and the mandible, seen as rounded, budlike enlargements. Organization of adjacent mesenchyme takes place in each area of epithelial growth, and the 2 elements together are the beginning of a tooth. After the formation of these crypts for the 20 primary teeth, another generation of tooth buds forms lingually (toward the tongue); these will develop into the succeeding permanent incisors, canines, and premolars that eventually replace the primary teeth. This process takes place from approximately 5 mo of gestation for the central incisors to approximately 10 mo of age for the second

premolars. On the other hand, the permanent first, second, and third molars arise from extension of the dental laminae distal to the second primary molars; buds for these teeth develop at approximately 4 mo of gestation, 1 yr of age, and 4-5 yr of age, respectively.

Histodifferentiation–Morphodifferentiation As the epithelial bud proliferates, the deeper surface invaginates and a mass of mesenchyme becomes partially enclosed. The epithelial cells differentiate into the ameloblasts that lay down an organic matrix that forms enamel; the mesenchyme forms the dentin and dental pulp.

Calcification After the organic matrix has been laid down, the deposition of the inorganic mineral crystals takes place from several sites of calcification that later coalesce. The characteristics of the inorganic portions of a tooth can be altered by disturbances in formation of the matrix, decreased availability of minerals, or the incorporation of foreign materials. Such disturbances can affect the color, texture, or thickness of the tooth surface. Calcification of primary teeth begins at 3-4 mo in utero and concludes postnatally at approximately 12 mo, with mineralization of the second primary molars (Table 333.1 ). Table 333.1

Calcification, Crown Completion, and Eruption TOOTH FIRST EVIDENCE OF CALCIFICATION PRIMARY DENTITION Maxillary Central incisor 3-4 mo in utero Lateral incisor 4.5 mo in utero Canine 5.5 mo in utero First molar 5 mo in utero Second molar 6 mo in utero Mandibular Central incisor 4.5 mo in utero Lateral incisor 4.5 mo in utero

CROWN COMPLETED

ERUPTION

4 mo 5 mo 9 mo 6 mo 10-12 mo

7.5 mo 8 mo 16-20 mo 12-16 mo 20-30 mo

4 mo mo

6.5 mo 7 mo

Canine 5 mo in utero First molar 5 mo in utero Second molar 6 mo in utero PERMANENT DENTITION

9 mo 6 mo 10-12 mo

16-20 mo 12-16 mo 20-30 mo

Maxillary Central incisor Lateral incisor Canine First premolar

3-4 mo 10 mo 4-5 mo 1.5 yr

4-5 yr 4-5 yr 6-7 yr 5-6 yr

7-8 yr 8-9 yr 11-12 yr 10-11 yr

Second premolar

2-

6-7 yr

10-12 yr

First molar Second molar Third molar Mandibular Central incisor Lateral incisor Canine First premolar

At birth 2.5-3 yr 7-9 yr

2.5-3 yr 7-8 yr 12-16 yr

6-7 yr 12-13 yr 17-21 yr

3-4 mo 3-4 mo 4-5 mo -2 yr

4-5 yr 4-5 yr 6-7 yr 5-6 yr

6-7 yr 7-8 yr 9-10 yr 10-12 yr

6-7 yr

11-12 yr

2.5-3 yr 7-8 yr 12-16 yr

6-7 yr 11-13 yr 17-21 yr

Second premolar First molar Second molar Third molar

yr

-2.5 yr At birth 2.5-3 yr 8-10 yr

Modified from Logan WHG, Kronfeld R: Development of the human jaws and surrounding structures from birth to age 15 years. J Am Dent Assoc 20:379, 1993.

Eruption At the time of tooth bud formation, each tooth begins a continuous movement toward the oral cavity. Table 333.1 lists the times of eruption of the primary and permanent teeth. Anomalies Associated With Eruption Pattern: Delayed eruption of the 20 primary teeth can be familial or indicate systemic or nutritional disturbances such as hypopituitarism, hypothyroidism, cleidocranial dysplasia, trisomy 21, and multiple other syndromes. Failure of eruption of single or small groups of teeth can arise from local causes such as malpositioned teeth, supernumerary teeth, cysts, or retained primary teeth. Premature loss of primary teeth is most commonly caused by premature eruption of the permanent teeth. If the entire dentition is advanced for age and sex, precocious puberty or hyperthyroidism should be considered. Natal teeth are observed in approximately 1 in 2,000 newborn infants, usually in the position of the mandibular central incisors. Natal teeth are present at birth, whereas neonatal teeth erupt in the first mo of life. Attachment of natal and neonatal teeth is generally limited to the gingival margin, with little root formation or bony support. They may be a supernumerary or a prematurely erupted primary tooth. A radiograph can easily differentiate between the 2

conditions. Natal teeth are associated with cleft palate, Pierre Robin syndrome, Ellis-van Creveld syndrome, Hallermann-Streiff syndrome, pachyonychia congenita, and other anomalies. A family history of natal teeth or premature eruption is present in 15–20% of affected children. Natal or neonatal teeth occasionally result in pain and refusal to feed and can produce maternal discomfort because of abrasion or biting of the nipple during nursing. If the tooth is mobile, there is a danger of detachment, with aspiration of the tooth. Because the tongue lies between the alveolar processes during birth, it can become lacerated (Riga-Fede disease ). Decisions regarding extraction of prematurely erupted primary teeth must be made on an individual basis. Exfoliation failure occurs when a primary tooth is not shed before the eruption of its permanent successor. Most often the primary tooth exfoliates eventually, but in some cases the primary tooth needs to be extracted. This occurs most commonly in the mandibular incisor region.

Anomalies Associated With Tooth Development Both failures and excesses of tooth initiation are observed. Developmentally missing teeth can result from environmental insult, a genetic defect involving only teeth, or the manifestation of a syndrome. Anomalies of Number: Anodontia, or absence of teeth, occurs when no tooth buds form (ectodermal dysplasia, or familial missing teeth) or when there is a disturbance of a normal site of initiation (the area of a palatal cleft). The teeth that are most commonly absent are the third molars, the maxillary lateral incisors, and the mandibular second premolars. If the dental lamina produces more than the normal number of buds, supernumerary teeth occur, most often in the area between the maxillary central incisors. Because they tend to disrupt the position and eruption of the adjacent normal teeth, their identification by radiographic examination is important. Supernumerary teeth also occur with cleidocranial dysplasia (see Chapter 337 ) and in the area of cleft palates. Anomalies of Size: Twinning, in which 2 teeth are joined together, is most often observed in the mandibular incisors of the primary dentition. It can result from gemination, fusion, or concrescence. Gemination is the result of the division of one tooth germ to form a bifid crown on a single root with a common pulp canal; an extra tooth appears to be present in the dental arch. Fusion is the joining of incompletely developed teeth that, owing to pressure, trauma, or

crowding, continue to develop as 1 tooth. Fused teeth are sometimes joined along their entire length; in other cases a single wide crown is supported on 2 roots. Concrescence is the attachment of the roots of closely approximated adjacent teeth by an excessive deposit of cementum. This type of twinning, unlike the others, is found most often in the maxillary molar region. Disturbances during differentiation can result in alterations in dental morphology, such as macrodonti a (large teeth) or microdontia (small teeth). The maxillary lateral incisors can assume a slender, tapering shape (peg-shaped laterals). Anomalies of Shape: Dens in Dente or Dens Invaginatus presents as tooth within tooth appearance, which results from invagination of inner enamel epithelium caused by disruption during morphodifferentiation, Dens Evaginatus presents as an extra cusp on anterior or posterior teeth, which contains enamel, dentin, and sometimes even pulp tissue. In the anterior teeth the cusp is talon shaped and presents in the cingulum area. Taurodontism is more common in permanent molars and is characterized by elongated pulp chamber with short stunted roots due to failure or late invagination of Hertwig epithelial root sheath. It may be associated with several syndromic conditions such as Down syndrome, trichodento-osseous syndrome, ectodermal dysplasia (hypohidrotic), and amelogenesis imperfecta (hypomaturation-hypoplastic type). Dilaceration is an abnormal bend or curve in root possibly due to trauma. It may be subsequent to injury to the primary predecessor tooth. Anomalies of Structure: Amelogenesis imperfecta represents a group of hereditary conditions that manifest in enamel defects of the primary and permanent teeth without evidence of systemic disorders (Fig. 333.1 ). The teeth are covered by only a thin layer of abnormally formed enamel through which the yellow underlying dentin is seen. The primary teeth are generally affected more than the permanent teeth. Susceptibility to caries is low, but the enamel is subject to destruction from abrasion. Complete coverage of the crown may be indicated for dentin protection, to reduce tooth sensitivity, and for improved appearance.

FIG. 333.1 Amelogenesis imperfecta, hypoplastic type. The enamel defect results in areas of missing or thin enamel, as well as grooves and pits.

Dentinogenesis imperfecta, or hereditary opalescent dentin, is a condition analogous to amelogenesis imperfecta in which the odontoblasts fail to differentiate normally, resulting in poorly calcified dentin (Fig. 333.2 ). This autosomal dominant disorder can also occur in patients with osteogenesis imperfecta. The enamel-dentin junction is altered, causing enamel to break away. The exposed dentin is then susceptible to abrasion, in some cases worn to the gingiva. The teeth are opaque and pearly, and the pulp chambers are generally obliterated by calcification. Both primary and permanent teeth are usually involved. If there is excessive wear of the teeth, selected complete coverage of the teeth may be indicated to prevent further tooth loss and improve appearance.

FIG. 333.2 Dentinogenesis imperfecta. The bluish, opalescent sheen on several of these teeth results from genetically defective dentin. This condition may be associated with osteogenesis imperfecta. (From Nazif MM, Martin BS, McKibben DH, et al: Oral disorders. In Zitelli BJ, Davis HW, editors: Atlas of pediatric physical diagnosis, ed 4, Philadelphia, 2002, Mosby, p 703.)

Localized disturbances of calcification that correlate with periods of illness, malnutrition, premature birth, or birth trauma are common. Hypocalcification appears as opaque white patches or horizontal lines on the tooth; hypoplasia is more severe and manifests as pitting or areas devoid of enamel. Systemic conditions, such as renal failure and cystic fibrosis, are associated with enamel defects. Local trauma to the primary incisors can also affect calcification of permanent incisors. Fluorosis (mottled enamel) can result from systemic fluoride consumption >0.05 mg/kg/day during enamel formation. This high fluoride consumption can be caused by residing in an area of high fluoride content of the drinking water (>2.0 ppm), swallowing excessive fluoridated toothpaste, or inappropriate fluoride prescriptions. Excessive fluoride during enamel formation affects ameloblastic function, resulting in inconspicuous white, lacy patches on the enamel to severe brownish discoloration and hypoplasia. The latter changes are usually seen with fluoride concentrations in the drinking water >5.0 ppm. Anomalies of Color: Discolored teeth can result from incorporation of foreign substances into developing enamel. Neonatal hyperbilirubinemia can produce blue to black discoloration of the primary teeth. Porphyria produces a red-brown discoloration. Tetracyclines are extensively incorporated into bones and teeth and, if administered during the period of formation of enamel, can result in brown-yellow discoloration and hypoplasia of the enamel. Such teeth fluoresce under ultraviolet light. The period at risk extends from approximately 4 mo of gestation to 7 yr of life. Repeated or prolonged therapy with tetracycline

carries the highest risk. Teething is associated with primary tooth eruption and may manifest with benign symptoms such as gingival hyperemia, irritability, sucking fingers, and drooling; some infants have no symptoms or symptoms not identified by their parents. Low-grade fever is an inconsistent finding. The treatment of symptoms of teething is often unnecessary but could include oral analgesics and iced teething rings. “Natural” (homeopathic) teething remedies may contain toxic additives and should be avoided.

Bibliography

Dummett CO, Thikkurissy S. Anomalies of the developing dentition IN pediatric dentistry: infancy through adolescence . ed 5. Elsevier/Saunders: St. Louis; 2013:54–64. Food and Drug Administration / FDA News Release. FDA confirms elevated levels of belladonna in certain homeopathic teething products . https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm5 . Food and Drug Administration / FDA News Release. FDA warns against the use of homeopathic teething tablets and gels . https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm5 . Massignan C, Cardoso M, Porporatti AL, et al. Signs and symptoms of primary tooth eruption: a meta-analysis. Pediatrics . 2016;137(3):e20153501. Tinanoff N. Use of fluoride. Berg J, Slayton R. Early childhood oral health . Wiley-Blackwell: Ames, Iowa; 2009:92–109.

CHAPTER 334

Disorders of the Oral Cavity Associated With Other Conditions Vineet Dhar

Disorders of the teeth and surrounding structures can occur in isolation or in combination with other systemic conditions (Table 334.1 ). Most commonly, medical conditions that occur during tooth development can affect tooth formation or appearance. Damage to teeth during their development is permanent. Table 334.1 Dental Problems Associated With Selected Medical Conditions MEDICAL CONDITION Cleft lip and palate Kidney failure Cystic fibrosis Immunosuppression Low birthweight

COMMON ASSOCIATED DENTAL OR ORAL FINDINGS Missing teeth, extra (supernumerary) teeth, shifting of arch segments, feeding difficulties, speech problems Mottled enamel (permanent teeth), facial dysmorphology Stained teeth with extensive medication, mottled enamel Oral candidiasis with potential for systemic candidiasis, cyclosporineinduced gingival hyperplasia Palatal groove, narrow arch with prolonged oral intubation; enamel defects of primary teeth Bacteremia from dental procedures or trauma

Heart defects with susceptibility to bacterial endocarditis Neutrophil chemotactic deficiency Aggressive periodontitis (loss of supporting bone around teeth) Diabetes mellitus type I (uncontrolled) Aggressive periodontitis Neuromotor dysfunction Oral trauma from falling; malocclusion (open bite); gingivitis from lack of hygiene Prolonged illness (generalized) during Enamel hypoplasia of crown portions forming during illness tooth formation Seizures Gingival enlargement if phenytoin is used Maternal infections Syphilis: abnormally shaped teeth Vitamin D–dependent rickets Enamel hypoplasia

CHAPTER 335

Malocclusion Vineet Dhar

The oral cavity is essentially a masticatory instrument. The purpose of the anterior teeth is to bite off large portions of food. The posterior teeth reduce foodstuff to a soft, moist bolus. The cheeks and tongue force the food onto the areas of tooth contact. Establishing a proper relationship between the mandibular and maxillary teeth is important for both physiologic and cosmetic reasons.

Variations in Growth Patterns Growth patterns are classified into 3 main types of occlusion, determined when the jaws are closed and the teeth are held together (Fig. 335.1 ). According to the Angle classification of malocclusion, in class I occlusion (normal), the cusps of the posterior mandibular teeth interdigitate ahead of and inside of the corresponding cusps of the opposing maxillary teeth. This relationship provides a normal facial profile.

FIG. 335.1 Angle classification of occlusion. The typical correspondence between the facial-jaw profile and molar relationship is shown. (Data from Borrie FR, Bearn DR,

Innes NP, Iheozor-Ejiofor Z: Interventions for the cessation of non-nutritive sucking habits in children. Cochrane Database Syst Rev 31(3):CD008694, 2015. doi: 10.1002/14651858.CD008694.pub2.)

In class II malocclusion, buck teeth , the cusps of the posterior mandibular teeth are behind and inside the corresponding cusps of the maxillary teeth. This common occlusal disharmony is found in approximately 45% of the population. The facial profile can give the appearance of a receding chin (retrognathia) (mandibular deficiency) or protruding front teeth. The resultant increased space between upper and lower anterior teeth encourage finger sucking and tonguethrust habits. In addition, children with pronounced class II malocclusions are at greater risks of damage to the incisors as a consequence of trauma. Treatment includes orthodontic retraction of the maxilla or stimulation of the mandible. In class III malocclusion, underbite , the cusps of the posterior mandibular teeth interdigitate a tooth or more ahead of their opposing maxillary counterparts. The anterior teeth appear in crossbite with the mandibular incisors protruding beyond the maxillary incisors. The facial profile gives the appearance of a protruding chin (prognathia) with or without an appearance of maxillary deficiency. If necessary, treatment includes mandibular excess reduction osteotomy or orthodontic maxillary facial protrusion.

Crossbite Normally, the mandibular teeth are in a position just inside the maxillary teeth, so that the outside mandibular cusps or incisal edges meet the central portion of the opposing maxillary teeth. A reversal of this relation is referred to as a crossbite. Crossbites can be anterior, involving the incisors; can be posterior, involving the molars; or can involve single or multiple teeth.

Open and Closed Bites If the posterior mandibular and maxillary teeth make contact with each other, but the anterior teeth are still apart, the condition is called an open bite. Open bites can result from skeletal growth pattern or digit sucking. If digit sucking is terminated before skeletal and dental growth is complete, the open bite might resolve naturally. If mandibular anterior teeth occlude inside the maxillary anterior teeth in an overclosed position, the condition is referred to as a closed or deep bite.

Treatment of open and closed bites consists of orthodontic correction, generally performed in the preteen or teenage years. Some cases require orthognathic surgery to position the jaws optimally in a vertical direction.

Dental Crowding Overlap of incisors can result when the jaws are too small or the teeth are too large for adequate alignment of the teeth. Growth of the jaws is mostly in the posterior aspects of the mandible and maxilla, and therefore inadequate space for the teeth at 7 or 8 yr of age will not resolve with growth of the jaws. Spacing in the primary dentition is normal and favorable for adequate alignment of successor teeth.

Digit Sucking Various and conflicting etiologic theories and recommendations for correction have been proposed for digit sucking in children. Prolonged digit sucking can cause flaring of the maxillary incisor teeth, an open bite, and a posterior crossbite. The prevalence of digit sucking decreases steadily from the age of 2 yr to approximately 10% by the age of 5 yr. The earlier the habit is discontinued after the eruption of the permanent maxillary incisors (age 7-8 yr), the greater the likelihood that there will be lessening effects on the dentition. A variety of treatments have been suggested, from behavioral modification to insertion of an appliance with extensions that serves as a reminder when the child attempts to insert the digit. Unfortunately, a systematic review has found only low-quality evidence of the effectiveness of interventions such as orthodontic appliances and psychological interventions. The greatest likelihood of success occurs in cases in which the child desires to stop. Stopping of the habit will not rectify a malocclusion caused by a prior deviant growth pattern.

CHAPTER 336

Cleft Lip and Palate Vineet Dhar

Clefts of the lip and palate are distinct entities which are closely related embryologically, functionally, and genetically. It is thought that cleft of the lip appears because of hypoplasia of the mesenchymal layer, resulting in a failure of the medial nasal and maxillary processes to join. Cleft of the palate results from failure of palatal shelves to approximate or fuse.

Incidence and Epidemiology The incidence of cleft lip with or without cleft palate is approximately 1 in 750 white births; the incidence of cleft palate alone is approximately 1 in 2,500 white births. Clefts of the lip are more common in males. Possible causes include maternal drug exposure, a syndrome-malformation complex, or genetic factors. Although clefts of lips and palates appear to occur sporadically, the presence of susceptible genes appears important. There are approximately 400 syndromes associated with cleft lip and palates. There are families in which a cleft lip or palate, or both, is inherited in a dominant fashion (van der Woude syndrome ), and careful examination of parents is important to distinguish this type from others, because the recurrence risk is 50%. Ethnic factors also affect the incidence of cleft lip and palate; the incidence is highest among Asians (~1 in 500) and Native Americans (~1 in 300) and lowest among blacks (~1 in 2,500). Cleft lip may be associated with other cranial facial anomalies, whereas cleft palate may be associated with central nervous system anomalies.

Clinical Manifestations

Cleft lip can vary from a small notch in the vermilion border to a complete separation involving skin, muscle, mucosa, tooth, and bone. Clefts of the lip may be unilateral (more often on the left side) or bilateral and can involve the alveolar ridge (Fig. 336.1 ).

FIG. 336.1 Nonsyndromic orofacial clefts. A, Cleft lip and alveolus. B, Cleft palate. C, Incomplete unilateral cleft lip and palate. D, Complete unilateral cleft lip and palate. E, Complete bilateral cleft lip and palate. (From Shaw WC: Orthodontics and occlusal management . Oxford, UK, 1993, Butterworth-Heinemann.)

Isolated cleft palate occurs in the midline and might involve only the uvula or can extend into or through the soft and hard palates to the incisive foramen. When associated with cleft lip, the defect can involve the midline of the soft palate and extend into the hard palate on one or both sides, exposing one or both of the nasal cavities as a unilateral or bilateral cleft palate. The palate can also have a submucosal cleft indicated by a bifid uvula, partial separation of muscle with intact mucosa, or a palpable notch at the posterior of the palate (see Fig. 336.1 ).

Treatment A complete program of habilitation for the child with a cleft lip or palate can require years of special treatment by a team consisting of a pediatrician, plastic surgeon, otolaryngologist, oral and maxillofacial surgeon, pediatric dentist, prosthodontist, orthodontist, speech therapist, geneticist, medical social worker, psychologist, and public health nurse. The immediate problem in an infant born with a cleft lip or palate is feeding. Although some advocate the construction of a plastic obturator to assist in feedings, most believe that, with the use of soft artificial nipples with large openings, a squeezable bottle, and proper instruction, feeding of infants with clefts can be achieved.

Surgical closure of a cleft lip is usually performed by 3 mo of age, when the infant has shown satisfactory weight gain and is free of any oral, respiratory, or systemic infection. Modification of the Millard rotation–advancement technique is the most commonly used technique; a staggered suture line minimizes notching of the lip from retraction of scar tissue. The initial repair may be revised at 4 or 5 yr of age. Corrective surgery on the nose may be delayed until adolescence. Nasal surgery can also be performed at the time of the lip repair. Cosmetic results depend on the extent of the original deformity, healing potential of the individual patient, absence of infection, and the skill of the surgeon. Because clefts of the palate vary considerably in size, shape, and degree of deformity, the timing of surgical correction should be individualized. Criteria such as width of the cleft, adequacy of the existing palatal segments, morphology of the surrounding areas (width of the oropharynx), and neuromuscular function of the soft palate and pharyngeal walls affect the decision. The goals of surgery are the union of the cleft segments, intelligible and pleasant speech, reduction of nasal regurgitation, and avoidance of injury to the growing maxilla. In an otherwise healthy child, closure of the palate is usually done before 1 yr of age to enhance normal speech development. When surgical correction is delayed beyond the 3rd yr, a contoured speech bulb can be attached to the posterior of a maxillary denture so that contraction of the pharyngeal and velopharyngeal muscles can bring tissues into contact with the bulb to accomplish occlusion of the nasopharynx and help the child to develop intelligible speech. A cleft palate usually crosses the alveolar ridge and interferes with the formation of teeth in the maxillary anterior region. Teeth in the cleft area may be displaced, malformed, or missing. Missing teeth or teeth that are nonfunctional are replaced by prosthetic devices.

Postoperative Management During the immediate postoperative period, special nursing care is essential. Gentle aspiration of the nasopharynx minimizes the chances of the common complications of atelectasis or pneumonia. The primary considerations in postoperative care are maintenance of a clean suture line and avoidance of tension on the sutures. The infant is fed with a specially designed bottle and the arms are restrained with elbow cuffs. A fluid or semifluid diet is maintained for 3

wk. The patient's hands, toys, and other foreign bodies must be kept away from the surgical site.

Sequelae Recurrent otitis media and subsequent hearing loss are frequent with cleft palate. Displacement of the maxillary arches and malposition of the teeth usually require orthodontic correction. Misarticulations and velopharyngeal dysfunction are often associated with cleft lip and palate and may be present or persist because of physiologic dysfunction, anatomic insufficiency, malocclusion, or inadequate surgical closure of the palate. Such speech is characterized by the emission of air from the nose and by a hypernasal quality with certain sounds, or by compensatory misarticulations (glottal stops). Before and sometimes after palatal surgery, the speech defect is caused by inadequacies in function of the palatal and pharyngeal muscles. The muscles of the soft palate and the lateral and posterior walls of the nasopharynx constitute a valve that separates the nasopharynx from the oropharynx during swallowing and in the production of certain sounds. If the valve does not function adequately, it is difficult to build up enough pressure in the mouth to make such explosive sounds as p, b, d, t, h, y, or the sibilants s, sh, and ch, and such words as “cats,” “boats,” and “sisters” are not intelligible. After operation or the insertion of a speech appliance, speech therapy is necessary.

Velopharyngeal Dysfunction The speech disturbance characteristic of the child with a cleft palate can also be produced by other osseous or neuromuscular abnormalities where there is an inability to form an effective seal between oropharynx and nasopharynx during swallowing or phonation. In a child who has the potential for abnormal speech, adenoidectomy can precipitate overt hypernasality. If the neuromuscular function is adequate, compensation in palatopharyngeal movement might take place and the speech defect might improve, although speech therapy is necessary. In other cases, slow involution of the adenoids can allow gradual compensation in palatal and pharyngeal muscular function. This might explain why a speech defect does not become apparent in some children who have a submucous cleft palate or similar anomaly predisposing to palatopharyngeal incompetence.

Clinical Manifestations Although clinical signs vary, the symptoms of velopharyngeal dysfunction are similar to those of a cleft palate. There may be hypernasal speech (especially noted in the articulation of pressure consonants such as p, b, d, t, h, v, f, and s); conspicuous constricting movement of the nares during speech; inability to whistle, gargle, blow out a candle, or inflate a balloon; loss of liquid through the nose when drinking with the head down; otitis media; and hearing loss. Oral inspection might reveal a cleft palate or a relatively short palate with a large oropharynx; absent, grossly asymmetric, or minimal muscular activity of the soft palate and pharynx during phonation or gagging; or a submucous cleft. Velopharyngeal dysfunction may also be demonstrated radiographically. The head should be carefully positioned to obtain a true lateral view; one film is obtained with the patient at rest and another during continuous phonation of the vowel u as in “boom.” The soft palate contacts the posterior pharyngeal wall in normal function, whereas in velopharyngeal dysfunction such contact is absent. In selected cases of velopharyngeal dysfunction, the palate may be retropositioned or pharyngoplasty may be performed using a flap of tissue from the posterior pharyngeal wall. Dental speech appliances have also been used successfully. The type of surgery used is best tailored to the findings on nasoendoscopy.

Bibliography Berg E, Haaland OA, Feragen KB, et al. Health status among adults born with an oral cleft in Norway. JAMA Pediatr . 2016;170(11):1063–1070. Kasten EF, Schmidt SP, Zickler CF, et al. Team care of the patient with cleft lip and palate. Curr Probl Pediatr Adolesc Health Care . 2008;38:133–164. Lam DJ, Chiu LL, Sie KCY, et al. Impact of cleft width in clefts of secondary palate on the risk of velopharyngeal insufficiency. Arch Facial Plast Surg . 2012;14:360–364. Mossey PA, Little J, Munger RG, et al. Cleft lip and palate. Lancet . 2009;374:1773–1782.

Rittler M, Lopez-Camelo JS, Castilla EE, et al. Preferential associations between oral clefts and other major congenital anomalies. Cleft Palate Craniofac J . 2008;45:525–532.

CHAPTER 337

Syndromes With Oral Manifestations Vineet Dhar

Many syndromes have distinct or accompanying facial, oral, and dental manifestations (see Apert syndrome, Chapter 609.11 ; Crouzon disease, Chapter 609.11 ; Down syndrome, Chapter 98.2 ). Osteogenesis imperfecta is often accompanied by effects on the teeth, termed dentinogenesis imperfecta (see Chapter 333 , Fig. 333.2 ). Depending on the severity of presentation, treatment of the dentition varies from routine preventive and restorative monitoring to covering affected posterior teeth with stainless steel crowns, to prevent further tooth loss and improve appearance. Dentinogenesis imperfecta can also occur in isolation without the bony effects. Another syndrome, cleidocranial dysplasia, has orofacial features such as frontal bossing, hypoplastic maxilla, and supernumerary teeth. The primary teeth can be overretained, and the permanent teeth remain unerupted. Supernumerary teeth are common, especially in the premolar area. Extensive dental rehabilitation may be needed to correct severe tooth crowding and unerupted and supernumerary teeth. Ectodermal dysplasias are a heterogeneous group of conditions in which oral manifestations range from little or no involvement (the dentition is completely normal) to cases in which the teeth can be totally or partially absent or malformed (Chapter 668 ). Because alveolar bone does not develop in the absence of teeth, the alveolar processes can be either totally or partially absent, and the resultant overclosure of the mandible causes the lips to protrude. Facial development is otherwise not disturbed. Teeth, when present, can range from normal to small and conical. If aplasia of the buccal and labial salivary glands is present, dryness and irritation of the oral mucosa can occur. People with ectodermal dysplasia might need partial or full dentures, even at a very young age. The vertical height between the jaws is thus restored, improving the position

of the lips and facial contours, as well as restoring masticatory function. Pierre Robin syndrome consists of micrognathia and is usually accompanied by a high arched or cleft palate (Fig. 337.1 ). The tongue is usually of normal size, but the floor of the mouth is foreshortened. The air passages can become obstructed, particularly on inspiration, usually requiring treatment to prevent suffocation. The infant should be maintained in a prone or partially prone position so that the tongue falls forward to relieve respiratory obstruction. Some patients require tracheostomy. Mandibular distraction procedures in the neonate can improve mandibular size, enhance respiration, and facilitate oral feedings.

FIG. 337.1 Pierre Robin syndrome. (From Clark DA: Atlas of neonatology, ed 7, Philadelphia, 2000, WB Saunders, p 144.)

Sufficient spontaneous mandibular growth can take place within a few months to relieve the potential airway obstruction. Often the growth of the mandible

achieves a normal profile in 4-6 yr. Of children with Pierre Robin syndrome, 30– 50% have Stickler syndrome (types I-VI), an autosomal dominant condition that includes other findings such as prominent joints, arthritis, hypotonia, hypermobile joints, mitral valve prolapse, hearing loss, spine problems (scoliosis, kyphosis, platyspondyly), and ocular problems (high myopia, glaucoma, cataracts, retinal detachment). Symptoms may vary greatly even with a family. Mutations are noted in the genes that produce collagen (COL2A1 in most; COL11A1 in others) in many, but not all, patients with Stickler syndrome. Other syndromes are associated with Pierre Robin syndrome, including 22Q11.2 deletion syndrome (velocardiofacial syndrome). Mandibulofacial dysostosis (Treacher Collins syndrome or Franceschetti syndrome) is an autosomal dominant syndrome that primarily affects the face. The facial appearance varies but is characterized by downward-sloping palpebral fissures, colobomas of the lower eyelids, sunken cheekbones, blind fistulas opening between the angles of the mouth and the ears, deformed pinnae, atypical hair growth extending toward the cheeks, receding chin, and large mouth. Facial clefts, abnormalities of the ears, and deafness are common. The mandible is usually hypoplastic; the ramus may be deficient, and the coronoid and condylar processes are flat or even aplastic. The palatal vault may be either high or cleft. Dental malocclusions are common. The teeth may be missing, hypoplastic, or displaced or be in an open bite position. Initially, the primary concern is breathing and feeding problems. Surgery to restore normal structure of the face can be performed, which may include repair of cleft palate, zygomatic and orbit reconstruction, reconstruction of the lower eyelid, external ear reconstruction, and orthognathic surgery. Hemifacial microsomia presentation can be quite variable but is usually characterized by unilateral hypoplasia of the mandible and can be associated with partial paralysis of the facial nerve, underdeveloped ear, and blind fistulas between the angles of the mouth and the ears. Severe facial asymmetry and malocclusion can develop because of the absence or hypoplasia of the mandibular condyle on the affected side. Congenital condylar deformity tends to increase with age. Early craniofacial surgery may be indicated to minimize the deformity. This disorder can be associated with ocular and vertebral anomalies (oculoauriculovertebral spectrum, including Goldenhar syndrome); therefore radiographs of the vertebrae and ribs should be considered to determine the extent of skeletal involvement.

Bibliography Buchenau W, Urschitz MS, Sautermeister J, et al. A randomized clinical trial of a new orthodontic appliance to improve upper airway obstruction in infants with pierre robin sequence. J Pediatr . 2007;151:145–149. Chang CC, Steinbacker DM. Treacher collins syndrome. Semin Plast Surg . 2012;26:83–90.

CHAPTER 338

Dental Caries Vineet Dhar

Etiology The development of dental caries depends on interrelationships among the tooth surface, dietary carbohydrates, and specific oral bacteria. Organic acids produced by bacterial fermentation of dietary carbohydrates reduce the pH of dental plaque adjacent to the tooth to a point where demineralization occurs. The initial demineralization appears as an opaque white spot lesion on the enamel, and with progressive loss of tooth mineral, cavitation of the tooth occurs (Fig. 338.1 ).

FIG. 338.1 Initial carious lesions (white spot lesions) around the necks of the maxillary central incisors.

The group of microorganisms, mutans streptococci, is associated with the development of dental caries. These bacteria have the ability to adhere to

enamel, produce abundant acid, and survive at low pH. Once the enamel surface cavitates, other oral bacteria (lactobacilli) can colonize the tooth, produce acid, and foster further tooth demineralization. Demineralization from bacterial acid production is determined by the frequency of carbohydrate consumption and by the type of carbohydrate. Sucrose is the most cariogenic sugar because one of its by-products during bacterial metabolism is glucan, a polymer that enables bacteria to adhere more readily to tooth structures. Dietary behaviors, such as consuming sweetened beverages in a nursing bottle or frequently consuming sticky candies, increase the cariogenic potential of foods because of the long retention of sugar in the mouth.

Epidemiology As per the 2011–2012 National Health and Nutrition Examination Survey (NHANES), approximately 15% of children ranging from 2 to 8 yr of age had one or more primary teeth affected by dental caries (Fig. 338.2 ). In the permanent dentition, over 10% of children aged 12-15 yr had dental caries and one-fourth of children were affected by age 16-19 yr (Fig. 338.3 ).

Prevalence* of untreated dental caries† in primary teeth§

FIG. 338.2 among children aged 2-8 yr, by age group and race/Hispanic origin— National Health and Nutrition Examination Survey, 2011-2014. *With 95% confidence intervals indicated with error bars. † Untreated dental caries is defined as tooth decay (dental cavities) that have not received appropriate treatment. Data were collected by dentists in the mobile examination center

as part of the oral health component of the National Health and Nutrition Examination Survey. § Primary teeth are the first teeth (baby teeth), which are shed and replaced by permanent teeth. (From Centers for Disease Control and Prevention: Prevalence of untreated dental caries in primary teeth among children aged 2-8 years, by age group and race/Hispanic origin—National Health and Nutrition Examination Survey, 2011–2014. MMWR 66(9):261, 2017.)

FIG. 338.3 Prevalence* of untreated dental caries† in permanent teeth among children and adolescents aged 6-19 yr, by age group—National Health and Nutrition Examination Survey, United States, 2011-2014. *With 95% confidence intervals indicated with error bars. † Untreated dental caries (i.e., dental cavities) are defined as tooth decay that has not received appropriate treatment. Data were collected by dentists in the mobile examination center as part of the oral health component of the National Health and Nutrition Examination Survey. (From Centers for Disease Control and Prevention: Prevalence of untreated dental caries in permanent teeth among children and adolescents aged 6-19 years, by age group—National Health and Nutrition Examination Survey, United States, 2011–2014. MMWR 66(1):36, 2017.)

Clinical Manifestations Dental caries of the primary dentition usually begins in the pits and fissures.

Small lesions may be difficult to diagnose by visual inspection, but larger lesions are evident as darkened or cavitated lesions on the tooth surfaces (Fig. 338.4 ). Rampant dental caries in infants and toddlers, referred to as early childhood caries , is the result of early colonization of the child with cariogenic bacteria and the frequent ingestion of sugar, either in the bottle or in solid foods. The carious process in this situation is initiated earlier and consequently can affect the maxillary incisors first and then progress to the molars as they erupt.

FIG. 338.4 Rampant caries in a 3 yr old child. Note darkened and cavitated lesions on the fissure surfaces of mandibular molars.

The prevalence of untreated caries was significantly higher in children between 3 and 9 yr of age living at or below 100% of federal poverty level compared with those above the poverty level. Besides high frequency of sugar consumption and colonization with cariogenic bacteria, other enabling factors include low socioeconomic status of the family, other family member with carious teeth, recent immigrant status of the child, and the visual presence of dental plaque on the child's teeth. Children who develop caries at a young age are known to be at high risk for developing further caries as they get older. Therefore the appropriate prevention of early childhood caries can result in the elimination of major dental problems in toddlers and less decay in later childhood. Among adolescents, the prevalence of dental caries experience was higher in age group 16-19 yr (67%) compared with age group 12-15 yr (50%). Overall, the caries experience did not significantly differ by race, Hispanic origin, and poverty levels.

Complications Left untreated, dental caries usually destroy most of the tooth and invade the dental pulp (Fig. 338.5 ), leading to an inflammation of the pulp (pulpitis) and significant pain. Pulpitis can progress to pulp necrosis, with bacterial invasion of the alveolar bone causing a dental abscess (Fig. 338.6 ). Red flags for serious spreading of dental infection are noted in Table 338.1 . Infection of a primary tooth can disrupt normal development of the successor permanent tooth. In some cases, this process leads to spread of infection to other facial spaces (Fig. 338.7 ).

FIG. 338.5 Basic dental anatomy: 1, enamel; 2, dentin; 3, gingival margin; 4, pulp; 5, cementum; 6, periodontal ligament; 7, alveolar bone; 8, neurovascular bundle.

FIG. 338.6 Facial swelling from an abscessed primary molar. Resolution of the inflammation can be achieved by a course of antibiotics, followed by either extraction or root canal of the offending tooth.

Table 338.1

Red Flags Suggestive of a Spreading Dental Infection • Pyrexia • Tachycardia or tachypnea • Trismus; may be relative due to pain or absolute due to a collection within the muscle causing muscle spasm in cases of masticator space involvement • Raised tongue and floor of mouth, drooling • Periorbital cellulitis • Difficulty with speaking, swallowing, and breathing • Hypotension • Increased white blood cell count • Lymphadenopathy • Dehydration

From Robertson DP, Keys W, Rautemaa-Richardson R, et al: Management of severe acute dental

infections. BMJ 350:h1300, 2015 (Box 3, p. 151).

FIG. 338.7 Spread of infection in the maxillofacial region is complicated by the variety of vital structures. Routes of spread are determined by fascial planes and this affects the presentation and management of each subdivision of cervicofacial infection. (From Robertson DP, Keys W, Rautemaa-Richardson R, et al: Management of severe acute dental infections. BMJ 350:h1300, 2015. Fig. 3, p. 151.)

Treatment The age at which dental caries occurs is important in dental management. Children younger than 3 yr of age lack the developmental ability to cooperate with dental treatment and often require sedation or general anesthesia to repair carious teeth. After age 4 yr, children can generally cope with dental restorative care with the use of local anesthesia. Children with neurologic impairment or developmental delay may require general anesthesia for dental procedures at

older ages. Dental treatment, using silver amalgam, plastic composite, or stainless-steel crowns, can restore most teeth affected with dental caries. If caries involves the dental pulp, a partial removal of the pulp (pulpotomy) or complete removal of the pulp (pulpectomy) may be required. If a tooth requires extraction, a space maintainer may be indicated to prevent migration of teeth, which subsequently leads to malposition of permanent successor teeth. Clinical management of the pain and infection associated with untreated dental caries varies with the extent of involvement and the medical status of the patient. Dental infection localized to the dentoalveolar unit can be managed by local measures (extraction, pulpectomy). Oral antibiotics are indicated for dental infections associated with fever, cellulitis, and facial swelling or if it is difficult to anesthetize the tooth in the presence of inflammation. Penicillin is the antibiotic of choice, except in patients with a history of allergy to this agent. Clindamycin and erythromycin are suitable alternatives. Oral analgesics, such as ibuprofen, are usually adequate for pain control.

Prevention Dental caries screening, risk assessment, and preventive management in young children needs to be part of the scope of medical providers because children younger than 3 yr often are not under the care of a dentist. Prevention of early childhood caries is critical because, if primary dental care is not initiated or does not succeed, teeth may develop dental caries requiring restorative care. Dental restorative care to treat caries in young children may require the use of sedation or general anesthesia with its associated high costs and possible health risks, and there is high recurrence of carious lesions once they develop. Because they are seeing infants and toddlers on a periodicity schedule, physicians have an important role in screening children younger than 3 yr of age for dental caries; providing preventive instructions; applying preventive measures, such as fluoride varnish; and referring the child to a dentist if problems exist.

Fluoride The most effective preventive measure against dental caries is communal water supplies with optimal fluoride content. Water fluoridation at the level of 0.7-1.2

mg fluoride per liter (ppm F) was introduced in the United States in the 1940s. Because fluoride from water supplies is now one of several sources of fluoride, the Department of Health and Human Services proposes to not have a fluoride range, but instead to limit the recommendation to the lower limit of 0.7 ppm F. The rationale is to balance the benefits of preventing dental caries with reducing the chance of fluorosis. Children who reside in areas with fluoride-deficient water supplies or who consume primarily bottled water, and are at risk for caries, benefit from dietary fluoride supplements (Table 338.2 ). If the patient uses a private water supply, it is necessary to get the water tested for fluoride levels before prescribing fluoride supplements. To avoid potential overdoses, no fluoride prescription should be written for more than a total of 120 mg of fluoride. However, because of confusion regarding fluoride supplements among practitioners and parents, association of supplements with fluorosis, and lack of parent compliance with the daily administration, supplements may no longer be the first-line approach for preventing caries in preschool-aged children. Table 338.2

Supplemental Fluoride Dosage Schedule AGE 6 mo-3 yr 3-6 yr 6-16 yr

FLUORIDE IN HOME WATER 0.6 (PPM) 0 0 0

* Milligrams of fluoride per day.

Topical fluoride on a daily basis can be achieved by using fluoridated toothpaste. Supervised use of less than a pea-sized amount of toothpaste (approximately 0.25 g) on the toothbrush in children between 3 and 6 yr of age reduces the risk of fluorosis. Children younger than 3 yr of age should brush with less than a smear or grain-sized amount of fluoridated toothpaste. Professional topical fluoride applications performed semiannually reportedly reduce caries by approximately 30%. Fluoride varnish is ideal for professional applications in preschool children because of ease of use, even with non–dental health providers, and its safety because of single-dose dispensers. Products that are available come in containers of 0.25, 0.4, or 0.6 mL of varnish, corresponding to 5.6, 9.0, and 13.6 mg fluoride, respectively. Fluoride varnish should be administered twice a year for preschool children at moderate caries

risk and 4 times a year for children at high caries risk.

Oral Hygiene Daily brushing, especially with fluoridated toothpaste, helps to prevent dental caries. Most children younger than 8 yr of age do not have the coordination required for adequate tooth brushing. Accordingly, parents should assume responsibility for the child's oral hygiene, with the degree of parental involvement appropriate to the child's changing abilities.

Diet Frequent consumption of sweetened fruit drinks is not generally recognized by parents for its high cariogenic potential. Consuming sweetened beverages in a nursing bottle or sippy cup should be discouraged and special efforts made to instruct parents that their child should consume sweetened beverages only at meal times and not exceed 6 oz/day.

Dental Sealant Plastic dental sealants have been shown to be effective in preventing caries on the pit and fissure of the primary and permanent molars. Sealants are most effective when placed soon after teeth erupt and used in children with deep grooves and fissures in the molar teeth. Sealants have been shown to reduce caries incidence by 85% over 7 yr.

Bibliography

American Academy of Pediatric Dentistry Reference Manual. Guideline on fluoride therapy. Pediatr Dent . 2016\2017;38:181–184 [or] http://www.aapd.org/media/Policies_Guidelines/G_FluorideTherapy1.pdf . American Academy of Pediatric Dentistry Reference Manual. Policy on early childhood caries (ECC): classification, consequences, and preventive strategies. Pediatr Dent .

2016\2017;38:52–54 [or] http://www.aapd.org/media/Policies_Guidelines/P_ECCClassifications1.p . Centers for Disease Control and Prevention. Populations receiving optimally fluoridated public drinking water— United States, 1992–2006. MMWR MORB MORTAL WKLY REP . 2008;57(27):737–740. Centers for Disease Control and Prevention. Prevalence of untreated dental caries in permanent teeth among children and adolescents aged 6-19 years, by age group—national health and nutrition examination survey, United States, 20112014. MMWR MORB MORTAL WKLY REP . 2017;66(1):36. Centers for Disease Control and Prevention. Prevalence of untreated dental caries in primary teeth among children aged 2-8 years, by age group and race/hispanic origin—national health and nutrition examination survey, 2011-2014. MMWR MORB MORTAL WKLY REP . 2017;66(9):261. Clark MB, Slayton RL. AAP section on oral health: fluoride use in caries prevention in the primary care setting. Pediatrics . 2014;134:626–633. Dye BA, Thornton-Evans G, Li X, Iafolla TJ. Dental caries and sealant prevalence in children and adolescence in the United States, 2011-2012. NCHS data brief no 191 . National Center for Health Statistics.: Hyattsville, MD; 2015 [As accessed on October 3, 2016 at] http://www.cdc.gov/nchs/data/databriefs/db191.pdf . Dye BA, Thornton-Evans G, Li X. Oral health disparities as determined by selected healthy people 20202 oral health objectives for United States, 2009-2010. NCHS data brief no 104 . National Center for Health Statistics.: Hyattsville, MD; 2012 [As accessed on December 28, 2016 at] https://www.cdc.gov/nchs/data/databriefs/db104.pdf . Griffin SO, Wei L, Gooch BF, et al. Vital signs: dental sealant

use and untreated tooth decay among U.S. school-aged children. MMWR MORB MORTAL WKLY REP . 2016;65(41):1141–1145. Krol DM, Segura A, Boulter S, et al. Maintaining and improving the oral health of young children. Pediatrics . 2014;134:1224–1229. Moyer VA, US Preventive Services Task Force. Prevention of dental caries in children from birth through age 5 years: US preventive services task force recommendation statement. Pediatrics . 2014;133:1102–1111. Peres KG, Nascimento GG, Peres MA, et al. Impact of prolonged breastfeeding on dental caries: a population-based birth cohort study. Pediatrics . 2017;140(1):e20162943. Robertson DP, Keys W, Rautemaa-Richardson R, et al. Management of severe acute dental infections. BMJ . 2015;350:h1300. Ryan P, McMahon G. Severe dental infections in the emergency department. Eur J Emerg Med . 2012;19:208–213. Tinanoff N. Use of fluoride. Berg J, Slayton R. Early childhood oral health . Wiley-Blackwell: Ames, IA; 2009:92–109. Warnke PH, Becker ST, Springer ING, et al. Penicillin compared with other advanced broad-spectrum antibiotics regarding antibacterial activity against oral pathogens isolated from odontogenic abscesses. J Craniomaxillofac Surg . 2008;36:462–467.

CHAPTER 339

Periodontal Diseases Vineet Dhar

The periodontium includes the gingiva, alveolar bone, cementum, and periodontal ligament (see Fig. 338.5 ).

Gingivitis Poor oral hygiene results in the accumulation of dental plaque at the toothgingival interface that activates an inflammatory response, expressed as localized or generalized reddening and swelling of the gingiva. More than half of American school children experience gingivitis. In severe cases, the gingiva spontaneously bleeds and there is oral malodor. Treatment is proper oral hygiene (careful tooth brushing and flossing); complete resolution can be expected. Fluctuations in hormonal levels during the onset of puberty can increase inflammatory responses to plaque. Gingivitis in healthy children is unlikely to progress to periodontitis (inflammation of the periodontal ligament resulting in loss of alveolar bone).

Aggressive Periodontitis in Children (Prepubertal Periodontitis) Periodontitis in children before puberty is a rare disease that often begins between the time of eruption of the primary teeth and the age of 4 or 5 yr. The disease occurs in localized and generalized forms. There is rapid bone loss, often leading to premature loss of primary teeth. It is often associated with systemic problems, including neutropenia, leukocyte adhesion or migration defects, hypophosphatasia, Papillon-Lefèvre syndrome, leukemia, and Langerhans cell

histiocytosis. However, in many cases, there is no apparent underlying medical problem. Nonetheless, diagnostic workups are necessary to rule out underlying systemic disease. Treatment includes aggressive professional teeth cleaning, strategic extraction of affected teeth, and antibiotic therapy. There are few reports of long-term successful treatment to reverse bone loss surrounding primary teeth.

Aggressive Periodontitis in Adolescents Localized aggressive periodontitis (LAgP) in adolescents is characterized by rapid attachment and alveolar bone loss, on at least 2 first molars and incisors. Overall prevalence in the United States is 90% have an associated tracheoesophageal fistula (TEF). In the most common form of EA, the upper esophagus ends in a blind pouch and the TEF is connected to the distal esophagus (type C). Fig. 345.1 shows the types of EA and TEF and their relative frequencies. The exact cause is still unknown; associated features include advanced maternal age, European ethnicity, obesity, low socioeconomic status, and tobacco smoking. This defect has survival rates of >90%, owing largely to improved neonatal intensive care, earlier recognition, and appropriate intervention. Infants weighing 90%. An unprepared contrast enema is most likely to aid in the diagnosis in children older than 1 mo of age because the proximal ganglionic segment might not be significantly dilated in the first few wk of life. Classic findings are based on the presence of an abrupt narrow transition zone between the normal dilated proximal colon and a smaller-caliber obstructed distal aganglionic segment. In the absence of this finding, it is imperative to compare the diameter of the rectum to that of the sigmoid colon, because a rectal diameter that is the same as or smaller than the sigmoid colon suggests Hirschsprung disease. Radiologic evaluation should be performed without prior preparation (i.e., unprepped contrast enema study ) to prevent transient dilation of the aganglionic segment. As many as 10% of newborns with Hirschsprung disease have a normal contrast study. This diagnostic test is most valuable in the disease that involves the distal colon, and specifically, the rectosigmoid. A transition zone may not be readily identifiable in total bowel aganglionosis. Twenty-four-hour delayed films are helpful in showing retained contrast (see Fig. 358.4 ). If significant barium is still present in the colon, it increases the suspicion of Hirschsprung disease even if a transition zone is not identified. Barium enema examination is useful in determining the extent of aganglionosis before surgery and in evaluating other diseases that manifest as lower bowel obstruction in a neonate. The sensitivity (~70%) and specificity (50–80%) of barium enema studies diagnosing

Hirschsprung disease is lower than other methodologies. Full-thickness rectal biopsies can be performed at the time of surgery to confirm the diagnosis, level of involvement and to differentiate other disorders (see Fig. 358.5 ).

Treatment Once the diagnosis is established, the definitive treatment is operative intervention. Previously, a temporary ostomy was placed, and definitive surgery was delayed until the child was older. Currently, many infants undergo a primary pull-through procedure unless there is associated enterocolitis or other complications, when a decompressing ostomy is usually required. There are essentially three surgical options. The first successful surgical procedure, described by Swenson, was to excise the aganglionic segment and anastomose the normal proximal bowel to the rectum 1-2 cm above the dentate line. The operation is technically difficult and led to the development of two other procedures. Duhamel described a procedure to create a neorectum, bringing down normally innervated bowel behind the aganglionic rectum. The neorectum created in this procedure has an anterior aganglionic segment with normal sensation and a posterior ganglionic segment with normal propulsion. The endorectal pull-through procedure described by Soave involves stripping the mucosa from the aganglionic rectum and bringing normally innervated colon through the residual muscular cuff, thus bypassing the abnormal bowel from within. Advances in techniques have led to successful laparoscopic single-stage endorectal pull-through procedures, which are the treatment of choice. In ultrashort-segment Hirschsprung disease , also known as anal achalasia , the aganglionic segment is limited to the internal sphincter. The clinical symptoms are similar to those of children with functional constipation. Ganglion cells are present on rectal suction biopsy, but the anorectal manometry is abnormal, with failure of relaxation of the internal anal sphincter in response to rectal distention. Current treatment, although controversial, includes anal botulism injection to relax the anal sphincter and anorectal myectomy if indicated. Long-segment Hirschsprung disease involving the entire colon and, at times, part of the small bowel presents a difficult problem. Anorectal manometry and rectal suction biopsy demonstrate findings of Hirschsprung disease, but radiologic studies are difficult to interpret because a colonic transition zone cannot be identified. The extent of aganglionosis can be determined accurately

by biopsy at the time of laparotomy. When the entire colon is aganglionic, often together with a length of terminal ileum, ileal-anal anastomosis is the treatment of choice, preserving part of the aganglionic colon to facilitate water absorption, which helps the stools to become firm. The prognosis of surgically treated Hirschsprung disease is generally satisfactory; the great majority of patients achieve fecal continence. Long-term postoperative problems include constipation, recurrent enterocolitis, stricture, prolapse, perianal abscesses, and fecal soiling. Some children require myectomy or a redo pull-through procedure. Hirschsprung disease–associated enterocolitis can occur at any time prior to or following surgery and is the leading cause of death in these patients. Dysmotility related to partial obstruction, underlying disease, impaired immune function, and the intestinal microbiome may all contribute to this pathophysiologic process. Explosive, foul-smelling and/or bloody diarrhea, abdominal distention, explosive discharge of rectal contents on digital examination, diminished peripheral perfusion, lethargy, and fever are all ominous signs. Management principles include hydration, decompression from above and below (nasogastric Salem Sump, rectal tube, rectal irrigation), and the use of broad-spectrum antibiotics.

Bibliography Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet . 2008;45:1–14. Arshad A, Powell C, Tighe MP. Hirschsprung's disease. BMJ . 2012;345:47–49. Bonnard A, Zeidan S, Degas V, et al. Outcomes of Hirschsprung's disease associated with Mowat-wilson syndrome. J Pediatr Surg . 2009;44:587–591. Dasgupta R, Langer J. Evaluation and management of persistent problems after surgery for hirschsprung disease in a child. J Pediatr Gastroenterol Nutr . 2008;46(1):13–19. Dasgupta R, Langer J. Hirschsprung disease. Curr Probl Surg . 2004;41:942–988.

DeLorijn F, Reitsma JB, Voskuijl WP, et al. Diagnosis of Hirschsprung's disease: a prospective comparative accuracy study of common tests. J Pediatr . 2005;146:787–792. Friedmacher F, Puri P. Classification and diagnostic criteria of variants of Hirschsprung's disease. Pediatr Surg Int . 2013;29:855–872. Hackam D, Reblock K, Barksdale E, et al. The influence of Down's syndrome on the management and outcome of children with Hirschsprung's disease. J Pediatr Surg . 2003;38:946–949. Haricharan R, Georgeson K. Hirschsprung disease. Semin Pediatr Surg . 2008;17:266–275. Heuckeroth RO. Hirschsprung disease. Faure C, et al. Pediatric neurogastroenterology . Springer Science + Business Media: New York; 2013. Gastrointestinal Motility and Functional Disorders in Children, Clinical Gastroenterology . . Keshtgar AS, Ward HC, Clayden GS, et al. Investigations for incontinence and constipation after surgery for Hirschsprung's disease in children. Pediatr Surg Int . 2003;19:4–8. Langer JC, Durrant AC, de la Torre L, et al. One-stage transanal soave pull through for hirschsprung disease: a multicenter experience with 141 children. Ann Surg . 2003;238:569–583 [discussion 583–585]. Langer JC. Hirschsprung disease. Curr Opin Pediatr . 2013;25:368–374. Moore SW. Chromosomal and related mendelian syndromes associated with Hirschsprung's disease. Pediatr Surg Int . 2012;28:1045–1058. Morris M, Soglio D, Quimet A, et al. A study of calretinin in hirschsprung disease pathology, particularly total colonic hirschsprung disease. J Pediatr Surg . 2013;48(5):1037–1043. Ozyurek H, Kayacik OE, Gunger O, et al. Rare association of

Hirschsprung's disease and joubert syndrome. Eur J Pediatr . 2008;167:475–477. Pensabene L, Youssef NN, Griffiths JM, et al. Colonic manometry in children with defecatory disorders. Role in diagnosis and management. Am J Gastroenterol . 2003;98:1052–1057. Prato AP, Musso M, Ceccherini I, et al. Hirschsprung disease and congenital anomalies of the kidney and urinary tract (CAKUT). Medicine (Baltimore) . 2009;88:83–90. Walker WA, Goulet O, Kleinman R, et al. Pediatric gastrointestinal disease . ed 4. BC Decker: Hamilton, Ontario; 2004.

358.5

Intestinal Neuronal Dysplasia Asim Maqbool, Chris A. Liacouras

Intestinal neuronal dysplasia (IND) describes different quantitative (hypoganglionosis or hyperganglionosis) and qualitative (immature or heterotropic ganglion cells) abnormalities of the myenteric and/or submucosal plexus. The typical histology is that of hyperganglionosis and giant ganglia. Type A occurs very rarely and is characterized by congenital aplasia or hypoplasia of the sympathetic innervation. Patients present early in the neonatal period with episodes of intestinal obstruction, diarrhea, and bloody stools. This type B, which accounts for more than 95% of cases, is characterized by malformation of the parasympathetic submucous and myenteric plexus with giant ganglia and thickened nerve fibers, increased acetylcholinesterase staining, and isolated ganglion cells in the lamina propria. IND type B mimics Hirschsprung disease, and patients present with chronic constipation (see Table

358.6 and Fig. 358.5 ). Clinical manifestations include abdominal distention, constipation, and enterocolitis. Various lengths of bowel may be affected from segmental to the entire intestinal tract. IND has been observed in an isolated form and proximal to an aganglionic segment. Other intraintestinal and extraintestinal manifestations are present in patients with IND. It has been reported in all age groups, most commonly in infancy, but is also seen in adults who have had constipation not dating back to childhood. Associated diseases and conditions include Hirschsprung disease, prematurity, small left colon syndrome, and meconium plug syndrome. Studies have identified a deficiency in substance P in patients with IND. Type A IND may be inherited in a familial, autosomal recessive pattern. Most cases of IND type B are sporadic, with few familial clusters, suggesting autosomal dominant inheritance. Management includes that for functional constipation, and, if unsuccessful, surgery is indicated.

Bibliography

Hutson J, McNamara J, Shin Y. Review article: slow transit constipation in children. J Paediatr Child Health . 2001;37:426–430. Kapur R. Neuropathology of paediatric chronic intestinal pseudo-obstruction and related animal models. J Pathol . 2001;194:277–288. Montedonico S, Acevedo S, Fadda B. Clinical aspects of intestinal neuronal dysplasia. J Pediatr Surg . 2002;37(12):1772–1774. Neuronal Intestinal Dysplasia. Online Mendelian Inheritance in Man Database . https://www.omim.org/entry/601223? search=intestinal%20neuronal%20dysplasia&highlight=neuronic%20dys . Walker WA, Goulet O, Kleinman R, et al. Pediatric gastrointestinal disease . ed 4. BC Decker: Hamilton, Ontario; 2004.

358.6

Superior Mesenteric Artery Syndrome (Wilkie Syndrome, Cast Syndrome, Arteriomesenteric Duodenal Compression Syndrome) Asim Maqbool, Chris A. Liacouras

Superior mesenteric artery syndrome results from compression of the third duodenal segment by the artery against the aorta. Malnutrition or catabolic states may cause mesenteric fat depletion, which collapses the duodenum within a narrowed aortomesenteric angle. Other etiologies include extraabdominal compression (e.g., body cast) and mesenteric tension, as can occur from ileoanal pouch anastomosis. Rapid weight loss and immobilization are risk factors. Symptoms include intermittent epigastric pain, anorexia, nausea, and vomiting. Risk factors include thin body habitus, prolonged bed rest, abdominal surgery, and exaggerated lumbar lordosis. Onset can be within weeks of a trigger, but some patients have chronic symptoms that evade diagnosis. A classic example is an underweight adolescent who begins vomiting 1-2 wk following scoliosis surgery or spinal fusion. Recognition may be delayed in the context of an eating disorder. The diagnosis is established radiologically by demonstrating a duodenal cutoff just right of midline along with proximal duodenal dilation, with or without gastric dilation. Although the upper gastrointestinal series remains a mainstay, modalities including CT, MR angiography, or ultrasound may be more appropriate if there is concern for other etiologies such as malignancy. Upper endoscopy should be considered to rule out intraluminal pathology. Treatment focuses on obstructive relief, nutritional rehabilitation, and correction of associated fluid and electrolyte abnormalities. Lateral or prone positioning can shift the duodenum away from obstructing structures and allow

resumption of oral intake. If repositioning is unsuccessful, patients require nasojejunal enteral nutrition past the obstruction or parenteral nutrition if this is not tolerated. This management is successful in the vast majority of cases, with eventual withdrawal of tube feeding once weight has been regained and enteral feeding tolerance orally has been gradually and fully restored. Patients with refractory courses may require surgery to bypass the obstruction.

Acknowledgment Andrew Chu contributed to the previous version of this chapter.

Bibliography Biank V, Werlin S. Superior mesenteric artery syndrome in children: a 20-year experience. J Pediatr Gastroenterol Nutr . 2006;42:522–525. Merrett ND, Wilson RB, Cosman P, et al. Superior mesenteric artery syndrome: diagnosis and treatment strategies. J Gastrointest Surg . 2009;13:287–292. Welsch T, Büchler MW, Kienle P. Recalling superior mesenteric artery syndrome. Dig Surg . 2007;24(3):149–156 [Epub 2007 Apr 27].

CHAPTER 359

Ileus, Adhesions, Intussusception, and Closed-Loop Obstructions 359.1

Ileus Asim Maqbool, Chris A Liacouras

Ileus is the failure of intestinal peristalsis caused by loss of coordinated gut motility without evidence of mechanical obstruction. In children, it is most often associated with abdominal surgery or infection (gastroenteritis, pneumonia, peritonitis). Ileus also accompanies metabolic abnormalities (e.g., uremia, hypokalemia, hypercalcemia, hypermagnesemia, acidosis) or administration of certain drugs, such as opiates, vincristine, and antimotility agents such as loperamide when used during gastroenteritis. Ileus manifests with nausea, vomiting, feeding intolerance, abdominal distention with associated pain, and delayed passage of stool and bowel gas. Bowel sounds are minimal or absent, in contrast to early mechanical obstruction, when they are hyperactive. Abdominal radiographs demonstrate multiple airfluid levels throughout the abdomen. Serial radiographs usually do not show progressive distention as they do in mechanical obstruction. Contrast radiographs, if performed, demonstrate slow movement of barium through a patent lumen. Ileus after abdominal surgery generally resolves in within 72 hr. Treatment involves correcting the underlying abnormality, supportive care of comorbidities, and mitigation of iatrogenic contributions. Electrolyte abnormalities should be identified and corrected, and narcotic agents, when

used, should be weaned as tolerated. Nasogastric decompression can relieve recurrent vomiting or abdominal distention associated with pain; resultant fluid losses should be corrected with isotonic crystalloid solution. Prokinetic agents such as erythromycin are not routinely recommended. Selective peripheral opioid antagonists such as methylnaltrexone hold promise in decreasing postoperative ileus, but pediatric data are lacking.

Bibliography Vather R, Bissett I. Management of prolonged post-operative ileus: evidence-based recommendations. ANZ J Surg . 2013;83:319–324.

359.2

Adhesions Asim Maqbool, Chris A Liacouras

Adhesions are fibrous tissue bands that result from peritoneal injury. They can constrict hollow organs and are a major cause of postoperative small bowel obstruction. Most remain asymptomatic, but problems can arise any time after the 2nd postoperative wk to yr after surgery, regardless of surgical extent. In one study, the 5-yr readmission risk because of adhesions varied by operative region (2.1% for colon to 9.2% for ileum) and procedure (0.3% for appendectomy to 25% for ileostomy formation/closure). The overall risk was 5.3% excluding appendectomy and 1.1% when appendectomy was included. The diagnosis is suspected in patients with abdominal pain, constipation, emesis, and a history of intraperitoneal surgery. Nausea and vomiting quickly follow onset of pain. Initially, bowel sounds are hyperactive, and the abdomen is flat. Subsequently, bowel sounds disappear, and bowel dilation can cause abdominal distention. Fever and leukocytosis suggest bowel necrosis and

peritonitis. Plain radiographs demonstrate obstructive features, and a CT scan or contrast studies may be needed to define the etiology. Management includes nasogastric decompression, intravenous fluid resuscitation, and broad-spectrum antibiotics in preparation for surgery. Nonoperative intervention is contraindicated unless a patient is stable with obvious clinical improvement. In children with repeated obstruction, fibrin-glued plication of adjacent small bowel loops can reduce the risk of recurrent problems. Long-term complications include female infertility, failure to thrive, and chronic abdominal and/or pelvic pain.

Acknowledgment Andrew Chu, MD contributed to the prior version of this chapter.

Bibliography Grant HW, Parker MC, Wilson MS, et al. Adhesions after abdominal surgery in children. J Pediatr Surg . 2008;43:152– 156.

359.3

Intussusception Asim Maqbool, Chris A Liacouras

Intussusception occurs when a portion of the alimentary tract is telescoped into an adjacent segment. It is the most common cause of intestinal obstruction between 5 mo and 3 yr of age and the most common abdominal emergency in children younger than 2 yr of age. Sixty percent of patients are younger than 1 yr of age and 80% of the cases occur before age 24 mo; it is rare in neonates. The incidence varies from 1 to 4 per 1,000 live births. The male:female ratio is 3 : 1.

Many small bowel–small bowel and a few small bowel–colonic intussusceptions reduce spontaneously; if left untreated, ileal-colonic intussusception may lead to intestinal infarction, perforation, peritonitis, and death.

Etiology and Epidemiology Approximately 90% of cases of intussusception in children are idiopathic. The seasonal incidence has peaks in fall and winter. Correlation with prior or concurrent respiratory adenovirus (type C) infection has been noted, and the condition can complicate otitis media, gastroenteritis, Henoch-Schönlein purpura, or other upper respiratory tract infections. A slight increase in intussusception has been noted to occur within 3 wk of the rotavirus vaccine (especially after the first dose), but this is a very rare side effect. It is postulated that gastrointestinal infection or the introduction of new food proteins results in swollen Peyer patches in the terminal ileum. Lymphoid nodular hyperplasia is another related risk factor. Prominent mounds of lymph tissue lead to mucosal prolapse of the ileum into the colon, thus causing an intussusception. In 2–8% of patients, recognizable lead points for the intussusception are found, such as a Meckel diverticulum, intestinal polyp, neurofibroma, intestinal duplication cysts, inverted appendix stump, leiomyomas, hamartomas, ectopic pancreatic tissue, anastomotic suture line, enterostomy tube, posttransplant lymphoproliferative disease, hemangioma, or malignant conditions such as lymphoma or Kaposi sarcoma. Gastrojejunal and jejunostomy tubes can also serve as lead points for intussusception. Lead points are more common in children older than 2 yr of age; the older the child, the higher the risk of a lead point. In adults, lead points are present in 90%. Intussusception can complicate mucosal hemorrhage, as in Henoch-Schönlein purpura, idiopathic thrombocytopenic purpura, or hemophilia. Cystic fibrosis, celiac disease, and Crohn disease are other risk factors. Postoperative intussusception is ileoileal and usually occurs within several days of an abdominal operation. Anterograde intussusception may occur rarely following bariatric surgery with a Roux-en-Y gastric bypass and is noteworthy that there does not seem to be a lead point in these cases. Intrauterine intussusception may be associated with the development of intestinal atresia. Intussusception in premature infants is rare. Ileal-ileal intussusception may be more common than previously believed, is often idiopathic or associated with Henoch-Schönlein purpura, and usually

resolves spontaneously.

Pathology Intussusceptions are most often ileocolic, less commonly cecocolic, and occasionally ileal. Very rarely, the appendix forms the apex of an intussusception. The upper portion of bowel, the intussusceptum, invaginates into the lower, the intussuscipiens, pulling its mesentery along with it into the enveloping loop. Constriction of the mesentery obstructs venous return; engorgement of the intussusceptum follows, with edema, and bleeding from the mucosa leads to a bloody stool, sometimes containing mucus. The apex of the intussusception can extend into the transverse, descending, or sigmoid colon, even to and through the anus in neglected cases. This presentation must be distinguished from rectal prolapse. Most intussusceptions do not strangulate the bowel within the first 24 hr but can eventuate in intestinal gangrene and shock.

Clinical Manifestations In typical cases, there is sudden onset, in a previously well child, of severe paroxysmal colicky pain that recurs at frequent intervals and is accompanied by straining efforts with legs and knees flexed and loud cries. The infant may initially be comfortable and play normally between the paroxysms of pain, but if the intussusception is not reduced, the infant becomes progressively weaker and lethargic. At times, the lethargy is often disproportionate to the abdominal signs. With progression, a shock-like state, with fever and peritonitis, can develop. The pulse becomes weak and thready, the respirations become shallow and grunting, and the pain may be manifested only by moaning sounds. Vomiting occurs in most cases and is usually more frequent in the early phase. In the later phase, the vomitus becomes bile stained. Stools of normal appearance may be evacuated in the first few hr of symptoms. After this time, fecal excretions are small or more often do not occur, and little or no flatus is passed. Blood is generally passed in the first 12 hr but at times not for 1-2 days and infrequently not at all; 60% of infants pass a stool containing red blood and mucus, the currant jelly stool. Some patients have only irritability and alternating or progressive lethargy. The classic triad of pain, a palpable sausage-shaped abdominal mass, and bloody or currant jelly stool is seen in 90%; the presence of rectal bleeding increases this to approximately 100%. Palpation of the abdomen usually reveals a slightly tender sausage-shaped mass, sometimes ill defined, which might increase in size and firmness during a paroxysm of pain and is most often in the right upper abdomen, with its long axis cephalocaudal. If it is felt in the epigastrium, the long axis is transverse. Approximately 30% of patients do not have a palpable mass. The presence of bloody mucus on rectal examination supports the diagnosis of intussusception. Abdominal distention and tenderness develop as intestinal obstruction becomes more acute. On rare occasions, the advancing intestine prolapses through the anus. This prolapse can be distinguished from prolapse of the rectum by the separation between the protruding intestine and the rectal wall, which does not exist in prolapse of the rectum. Ileoileal intussusception in children younger than 2 yr can have a less-typical clinical picture, the symptoms and signs being chiefly those of small intestinal obstruction; these often resolve without treatment. Recurrent intussusception is noted in 5–8% and is more common after hydrostatic than surgical reduction. Chronic intussusception, in which the symptoms exist in milder form at recurrent intervals, is more likely to occur with or after acute enteritis and can arise in older children as well as in infants.

Diagnosis When the clinical history and physical findings suggest intussusception, an ultrasound is typically performed. A plain abdominal radiograph might show a density in the area of the intussusception. Screening ultrasounds for suspected intussusception increases the yield of diagnostic or therapeutic enemas and reduces unnecessary radiation exposure in children with negative ultrasound examinations. The diagnostic findings of intussusception on ultrasound include a tubular mass in longitudinal views and a doughnut or target appearance in transverse images (Fig. 359.1 ). Ultrasound has a sensitivity of approximately 98–100% and a specificity of approximately 98% in diagnosing intussusception. Air, hydrostatic (saline), and, less often, water-soluble contrast enemas have replaced barium examinations. Contrast enemas demonstrate a filling defect or cupping in the head of the contrast media where its advance is obstructed by the intussusceptum (Fig. 359.2 ). A central linear column of contrast media may be

visible in the compressed lumen of the intussusceptum, and a thin rim of contrast may be seen trapped around the invaginating intestine in the folds of mucosa within the intussuscipiens (coiled-spring sign), especially after evacuation. Retrogression of the intussusceptum under pressure and visualized on x-ray or ultrasound documents successful reduction. Air reduction is associated with fewer complications and lower radiation exposure than traditional contrast hydrostatic techniques.

FIG. 359.1 Transverse image of an ileocolic intussusception. Note the loops within the loops of bowel.

FIG. 359.2 Intussusception in an infant. The obstruction is evident in the proximal transverse colon. Contrast material between the intussusceptum and the intussuscipiens (arrows) is responsible for the coiled-spring appearance.

Differential Diagnosis It may be particularly difficult to diagnose intussusception in a child who already has gastroenteritis; a change in the pattern of illness, in the character of pain, or in the nature of vomiting or the onset of rectal bleeding should alert the physician. The bloody stools and abdominal cramps that accompany enterocolitis can usually be differentiated from intussusception because in enterocolitis the pain is less severe and less regular, there is diarrhea, and the infant is recognizably ill between pains. Bleeding from a Meckel diverticulum is usually painless. Joint symptoms, purpura, or hematuria usually but not invariably accompany the intestinal hemorrhage of Henoch-Schönlein purpura. Because intussusception can be a complication of this disorder, ultrasonography may be needed to distinguish the conditions. It is important in patients with cystic fibrosis to distinguish intussusception from distal intestinal obstruction syndrome. Distal intestinal obstruction syndrome requires antegrade treatment, which would be harmful if there was an intussusception.

Treatment Reduction of an acute intussusception is an emergency procedure and should be performed immediately after diagnosis in preparation for possible surgery. In patients with prolonged intussusception and signs of shock, peritoneal irritation, intestinal perforation, or pneumatosis intestinalis, hydrostatic reduction should not be attempted. The success rate of radiologic hydrostatic reduction under fluoroscopic or ultrasonic guidance is approximately 80–95% in patients with ileocolic intussusception. Spontaneous reduction of intussusception occurs in approximately 4–10% of patients. Bowel perforations occur in 0.5–2.5% of attempted barium and hydrostatic (saline) reductions. The perforation rate with air reduction is 0.1–0.2%. Surgical reduction is indicated in the presence of refractory shock, suspected bowel necrosis or perforation, peritonitis, and multiple recurrences (suspected lead point). An ileoileal intussusception is best demonstrated by abdominal ultrasonography. Reduction by instillation of contrast agents, saline, or air might not be possible. Such intussusceptions can develop insidiously after bowel surgery and require reoperation if they do not spontaneously reduce. Ileoileal disease is common with Henoch-Schönlein purpura and other unidentifiable disorders and usually resolves without the need for any specific treatment. If manual operative reduction is impossible or the bowel is not viable, resection of the intussusception is necessary, with end-to-end anastomosis.

Prognosis Untreated ileal-colonic intussusception in infants is usually fatal; the chances of recovery are directly related to the duration of intussusception before reduction. Most infants recover if the intussusception is reduced in the first 24 hr, but the mortality rate rises rapidly after this time, especially after the 2nd day. Spontaneous reduction during preparation for operation is not uncommon. The recurrence rate after reduction of intussusceptions is approximately 10%, and after surgical reduction it is 2–5%; none has recurred after surgical resection. Most recurrences occur within 72 hr of reduction. Corticosteroids may reduce the frequency of recurrent intussusception but are rarely used for this purpose. Repeated reducible episodes caused by lymphonodular hyperplasia may respond to treatment of identifiable food allergies if present. A single recurrence

of intussusception can usually be reduced radiologically. In patients with multiple ileal-colonic recurrences, a lead point should be suspected and laparoscopic surgery considered. It is unlikely that an intussusception caused by a lesion such as lymphosarcoma, polyp, or Meckel diverticulum will be successfully reduced by radiologic intervention. With adequate surgical management, laparoscopic reduction carries a very low mortality.

Bibliography Bajaj L, Roback MG. Post-reduction management of intussusception in a children's hospital emergency department. Pediatrics . 2003;112:1302–1307. Bines JE, Kohl KS, Forster J, et al. Acute intussusception in infants and children as an adverse event following immunizations: case definition and guidelines of data collection, analysis, and presentation. Vaccine . 2004;22:569– 574. Bines JE, Liem NT, Justice FA, et al. Risk factors for intussusception in infants in Vietnam and Australia: adenovirus implicated, but not rotavirus. J Pediatr . 2006;149:452–460. Bonnard A, Demarche M, Dimitriu C, et al. Indications for laparoscopy in the management of intussusception. A multicenter retrospective study conducted by the French study group for pediatric laparoscopy (GECI). J Pediatr Surg . 2008;43:1249–1253. Buettcher M, Baer G, Bonhoeffer J, et al. Three-year surveillance of intussusception in children in Switzerland. Pediatrics . 2007;120:473–480. Burke MS, Ragi JM, Karamanoukian HL, et al. New strategies in nonoperative management of meconium ileus. J Pediatr Surg . 2002;37:760–764. Centers for Disease Control and Prevention. Postmarketing monitoring of intussusception after Rota Teg vaccination—

United States, February 1, 2006–February 15, 2007. MMWR Morb Mortal Wkly Rep . 2007;56:218–222. Crystal P, Hertzanu Y, Farber B, et al. Sonographically guided hydrostatic reduction of intussusception in children. J Clin Ultrasound . 2002;30:343–348. Fischer TK, Bihrmann K, Perch M, et al. Intussusception in early childhood: a cohort study of 1.7 million children. Pediatrics . 2004;114:782–785. Greenberg D, Givon-Lavi N, Newman N, et al. Intussusception in children in southern Israel: disparity between 2 populations. Pediatr Infect Dis J . 2008;27:236–240. Haber P, Patel M, Pan Y, et al. Intussusception after rotavirus vaccines reported to US VAERS, 2006–2012. Pediatrics . 2013;131:1042–1049. Henrikson S, Blane CE, Koujok K, et al. The effect of screening sonography on the positive rate of enemas for intussusception. Pediatr Radiol . 2003;33:190–193. Henry MCW, Brever CK, Tashjian DB, et al. The appendix sign: a radiographic marker for irreducible intussusception. J Pediatr Surg . 2006;41:487–489. Hughes UM, Connolly BL, Chait PG, Muraca S. Further report of small-bowel intussusceptions related to gastrojejunostomy tubes. Pediatr Radiol. 2000;30(9):614–617. Hui GC, Gerstle JT, Weinstein M, Connolly B. Small-bowel intussusception around a gastrojejunostomy tube resulting in ischemic necrosis of the intestine. Pediatr Radiol. 2004;34(11):916–918. Koumanidou C, Vakaki M, Pitsoulakis G, et al. Sonographic detection of lymph nodes in the intussusception of infants and young children: clinical evaluation and hydrostatic reduction. AJR Am J Roentgenol . 2002;178:445–450. Krishna S, Prabhu R, Thangavelu S, Shenoy R. Jejuno-jejunal intussusception: an unusual complication of feeding

jejunostomy. BMJ Case Rep . 2013;27:1–3. Reilly NR, Aguilar KM, Green PH. Should intussusception in children prompt screening for celiac disease? J Pediatr Gastroenterol Nutr . 2013;56(1):56–59. Shaw D, Huddleston S, Beilman G. Anterograde intussusception following laparoscopic Roux-en-Y gastric bypass: a case report and review of the literature. Obes Surg. 2010;20(8):1191–1194. Sorantin E, Lindbichler F. Management of intussusception. Eur Radiol . 2004;14:146–154. Stolz LA, Kizza H, Little K, et al. Intussusception detected with ultrasound in a resource-limited setting. Lancet . 2013;381:2054. Williams H. Imaging and intussusception. Arch Dis Child Educ Pract Ed . 2008;93:30–36.

359.4

Closed-Loop Obstructions Asim Maqbool, Chris A Liacouras

Closed-loop obstructions (i.e., internal hernia ) result from bowel loops that enter windows created by mesenteric defects or adhesions and become trapped. Vascular engorgement of the strangulated bowel results in intestinal ischemia and necrosis unless promptly relieved. Prior abdominal surgery is an important risk factor. Symptoms include abdominal pain, distention, and bilious emesis. Symptoms can be intermittent if the herniated bowel slides in and out of the defect. Peritoneal signs suggest ischemic bowel. Plain radiographs demonstrate signs of small bowel obstruction or free air if the bowel has perforated. CT scan can identify and delineate internal hernias. Supportive management includes

intravenous fluids, antibiotics, and nasogastric decompression. Prompt surgical relief of the obstruction is indicated to prevent bowel necrosis.

Bibliography Hongo N, Mori H, Matsumoto S, et al. Internal hernias after abdominal surgeries: MDCT features. Abdom Imaging . 2011;36:349–362.

CHAPTER 360

Foreign Bodies and Bezoars 360.1

Foreign Bodies in the Stomach and Intestine Asim Maqbool, Chris A. Liacouras

Once in the stomach, 95% of all ingested objects pass without difficulty through the remainder of the gastrointestinal tract. Perforation after ingestion of a foreign body is estimated to be 20 mm in diameter) remains in the stomach for longer than 48 hr, or if a lithium battery is ingested, the battery should be removed. Batteries larger than 15 mm that do not pass the pylorus within 48 hr are less likely to pass spontaneously and generally require removal. In children younger than 6 yr of age, batteries larger than 15 mm are not likely to pass spontaneously and should be removed endoscopically. If the patient develops peritoneal signs, surgical removal is required. Batteries beyond the duodenum pass per rectum in 85% within 72 hr. The battery should be identified by size and imprint code or by evaluation of a duplicate measurement of the battery compartment. The National Button Battery Ingestion Hotline (202-625-3333) can be called for help in identification. The Poison Control Center (800-222-1222) can be called as well for ingestion of batteries and caustic materials. Lithium batteries result in more severe injury than a button alkali battery, with damage occurring in minutes. Button batteries in a symptomatic child should be removed, or if there are multiple batteries, they should be removed. In older children and adults, oval objects larger than 5 cm in diameter or 2 cm in thickness tend to lodge in the stomach and should be endoscopically retrieved. Thin long objects >6 cm in length fail to negotiate the pylorus or duodenal sweep and should also be removed. In infants and toddlers, objects >3 cm in length or >20 mm in diameter do not usually pass through the pylorus and should be removed. An open safety pin presents a major problem and requires urgent endoscopic removal if within reach. Razor blades can be managed with a rigid endoscope by pulling the blade into instrument. The endoscopist can alternatively use a rubber hood on the head of the endoscope to protect the esophagus. Other sharp objects (needles, bones, pins) usually pass the stomach, but complications may be as high as 35%; if possible, they should be removed by endoscope if in the stomach or proximal duodenum. If sharp objects are not able to be removed but no progress is observed in location during 3 days,

surgical removal is indicated. Drugs (aggregated iron pills, cocaine) may have to be surgically removed; initial management can include oral polyethylene glycol lavage. Drug body packing (heroin, cocaine) is usually seen on kidneys-uretersbladder or CT imaging and often passes without incident. Endoscopic procedures may rupture the material, causing severe toxicity. Surgery is indicated if toxicity develops, if the packages fail to progress, or if there are signs of obstruction. Ingestion of magnets poses a danger to children. The number of magnets is thought to be critical. If a single magnet is ingested, there is the least likelihood of complications. If 2 or more magnets are ingested, the magnetic poles are attracted to each other and create the risk of obstruction, fistula development, and perforation. Endoscopic retrieval is emergent after films are taken when multiple magnets are ingested. Abdominal pain or peritoneal signs require urgent surgical intervention. If all magnets are located in the stomach, immediate endoscopic removal is indicated. If the ingestion occurred greater than 12 hr prior to evaluation, or if the magnets are beyond the stomach and the patient is symptomatic, general surgery should be consulted. If the patient is asymptomatic, endoscopic or colonoscopic removal may be considered, along with a surgical evaluation. Lead-based foreign bodies can cause symptoms from lead intoxication. Early endoscopic removal is indicated of an object suspected to contain lead. A lead level should be obtained. Water-absorbing polymer balls (beads) can expand to approximately 400 times their starting size and if ingested may produce intestinal obstruction. Initially of a small diameter, they pass the pylorus only to rapidly enlarge in the small intestine. Surgical removal is indicated. Children occasionally place objects in their rectum. Small blunt objects usually pass spontaneously, but large or sharp objects typically need to be retrieved. Adequate sedation is essential to relax the anal sphincter before attempting endoscopic or speculum removal. If the object is proximal to the rectum, observation for 12-24 hr usually allows the object to descend into the rectum.

Bibliography ASGE Standards of Practice Committee. Management of ingested foreign bodies and food impactions. Gastrointest

Endosc . 2011;73:1085–1091. Centers for Disease Control and Prevention (CDC). Injuries from batteries among children aged 50% by 5 yr); the risk of requiring additional surgery increases with each operation. Potential complications of surgery include development of fistula or stricture, anastomotic leak, postoperative partial small bowel obstruction secondary to adhesions, and short bowel syndrome. Surgery is the treatment of choice for localized disease of small bowel or colon that is unresponsive to medical treatment, bowel perforation, fibrosed stricture with symptomatic partial small bowel obstruction, and intractable bleeding. Intraabdominal or liver abscess sometimes is successfully treated by ultrasonographic or CT-guided catheter drainage and concomitant intravenous antibiotic treatment. Open surgical drainage is necessary if this approach is not successful. Growth retardation was once considered an indication for resection; without other indications, trial of medical and/or nutritional therapy is currently preferred. Perianal abscess often requires drainage unless it drains spontaneously. In general, perianal fistulas should be managed by a combined medical and surgical approach. Often, the surgeon places a seton through the fistula to keep the tract open and actively draining while medical therapy is administered, to help prevent the formation of a perianal abscess. A severely symptomatic perianal fistula can require fistulotomy, but this procedure should be considered only if the location allows the sphincter to remain undamaged. The surgical approach for Crohn disease is to remove as limited a length of bowel as possible. There is no evidence that removing bowel up to margins that are free of histologic disease has a better outcome than removing only grossly involved areas. The latter approach reduces the risk of short bowel syndrome. Laparoscopic approach is increasingly being used, with decreased postoperative recovery time. One approach to symptomatic small bowel stricture has been to perform a strictureplasty rather than resection. The surgeon makes a longitudinal incision across the stricture but then closes the incision with sutures in a transverse fashion. This is ideal for short strictures without active disease. The reoperation rate is no higher with this approach than with resection, whereas bowel length is preserved. Postoperative medical therapy with agents such as mesalamine, metronidazole, azathioprine, and, more recently, infliximab, is often given to decrease the likelihood of postoperative recurrence. Severe perianal disease can be incapacitating and difficult to treat if unresponsive to medical management. Diversion of fecal stream can allow the area to be less active, but on reconnection of the colon, disease activity usually recurs.

Support Psychosocial issues for the child with Crohn disease include a sense of being different, concerns about body image, difficulty in not participating fully in ageappropriate activities, and family conflict brought on by the added stress of this disease. Social support is an important component of the management of Crohn disease. Parents are often interested in learning about other children with similar problems, but children may be hesitant to participate. Social support and individual psychologic counseling are important in the adjustment to a difficult problem at an age that by itself often has difficult adjustment issues. Patients who are socially “connected” fare better. Ongoing education about the disease is an important aspect of management because children generally fare better if they understand and anticipate problems. The Crohn and Colitis Foundation of America has local chapters throughout the United States and supports several regional 1-wk camps for children with Crohn disease.

Prognosis Crohn disease is a chronic disorder that is associated with high morbidity but low mortality. Symptoms tend to recur despite treatment and often without apparent explanation. Weight loss and growth failure can usually be improved with treatment and attention to nutritional needs. Up to 15% of patients with early growth retardation secondary to Crohn disease have a permanent decrease in linear growth. Osteopenia is particularly common in those with chronic poor nutrition and frequent exposure to high doses of corticosteroids. Dual energy xray absorptiometry can help identify patients at risk for developing osteopenia. Steroid-sparing agents, weight bearing exercise, and improved nutrition, including supplementation with vitamin D and calcium, can improve bone mineralization. Some of the extraintestinal manifestations can, in themselves, be major causes of morbidity, including sclerosing cholangitis, chronic active hepatitis, pyoderma gangrenosum, and ankylosing spondylitis. The region of bowel-involved and complications of the inflammatory process tend to increase with time and include bowel strictures, fistulas, perianal disease, and intraabdominal or retroperitoneal abscess. Most patients with Crohn disease eventually require surgery for one of its many complications; the rate of reoperation is high. Surgery is unlikely to be curative and should be avoided except for the specific indications noted previously. An earlier, most aggressive

medical treatment approach, with the goal of exacting mucosal healing may improve long-term prognosis, and this is an active area of investigation. The risk of colon cancer in patients with long-standing Crohn colitis approaches that associated with ulcerative colitis, and screening colonoscopy after 8-10 yr of colonic disease is indicated. Despite these complications, most children with Crohn disease lead active, full lives with intermittent flare-up in symptoms.

Bibliography Absah I, Stephens M. Adjunctive treatment to antitumor necrosis factor in pediatric patients with refractory Crohn's disease. Curr Opin Pediatr . 2013;25:624–628. Ananthakrishnan AN. Filgotinib for Crohn's disease— expanding treatment options. Lancet . 2017;389:228–229. Ardizzone S, Maconi G, Sampietro GM, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for crohn disease. Gastroenterology . 2004;127:730– 740. Ashton JJ, Ennis S, Beattie RM. Early-onset paediatric inflammatory bowel disease. Lancet . 2017;1:147–158. Barrett JC, Hansoul S, Nicolae DI, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet . 2008;40:955–962. Baumgart DC, Sandborn WJ. Crohn's disease. Lancet . 2012;380:1590–1602. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet . 2009;374:1617–1624. Biancheri P, Di Sabatino A, Rovedatti L, et al. Effect of tumor necrosis factor-alpha blockade on mucosal addressin celladhesion molecule-1 in Crohn's disease. Inflamm Bowel Dis . 2013;19(2):259–264.

Borelli O, Cordischi L, Cirulli M, et al. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn's disease: a randomized controlled open-label trial. Clin Gastroenterol Hepatol . 2006;4:744–753. Catalano OA, Gee MS, Nicolai E, et al. Evaluation of quantitative PET/MR enterography biomarkers for discrimination of inflammatory strictures from fibrotic strictures in crohn disease. Radiology . 2016;278(3):792–800. Cheifetz AS. Management of active crohn disease. JAMA . 2013;309:2150–2158. Ciccocioppo R, Corazza GR. Mesenchymal stem cells for fistulizing Crohn's disease. Lancet . 2016;388:1251–1252. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn's disease (CALM): a multicenter, randomized, controlled phase 3 trial. Lancet . 2017;390:27792788. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med . 2010;362(15):1383–1394. D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomized trial. Lancet . 2008;371:660–667. De Felice KM, Katzka DA, Raffals LE. Crohn's disease of the esophagus: clinical features and treatment outcomes in the biologic era. Inflamm Bowel Dis . 2005;21(9):2106–2113 [2– 15]. DeBoer MD, Denson LA. Delays in puberty, growth, and accrual of bone mineral density in pediatric Crohn's disease: despite temporal changes in disease severity, the need for monitoring remains. J Pediatr . 2013;163:17–22. Feagan BG, Sandborn WJ, D'Haens G, et al. Induction therapy with the selective interleukin-23-inhibitor risankizumab in

patients with moderate-to-severe Crohn's disease: a randomized, double-blind, placebo-controlled phase 2 study. Lancet . 2017;389:1699–1708. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med . 2016;375(20):1946–1960. Gentile NM, Murray JA, Pardi DS. Autoimmune enteropathy: a review and update of clinical management. Curr Gastroenterol Rep . 2012;14:380–385. Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet . 2010;375:657–662. Gupta K, Noble A, Kachelries KE, et al. A novel enteral nutrition protocol for the treatment of pediatric Crohn's disease. Inflamm Bowel Dis . 2013;19:1374–1378. Hanauer SB. Targeting interleukin 23 for Crohn's disease: finding the right drug for the right patient. Lancet . 2017;389:1671–1672. Hyams J, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology . 2012;143:365–374. Kabi A, Nickerson KP, Homer CR, et al. Digesting the genetics of inflammatory bowel disease: insights from studies of autophagy risk genes. Inflamm Bowel Dis . 2012;18:782–792. Kanneganti TD. Inflammatory bowel disease and the NLRP3 inflammasome. N Engl J Med . 2017;377(7):694–696. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence of geographic distribution of Crohn's disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol . 2007;5:1424–1429. Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomized controlled trial. Lancet .

2015;386:1825–1834. Kugathasan S, Denson LA, Walters TW, et al. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicenter inception cohort study. Lancet . 2017;389:1710–1718. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in wisconsin: a statewide population-based study. J Pediatr . 2003;143:525–531. Laakso S, Valta H, Verkasalo M, et al. Impaired bone health in inflammatory bowel disease: a case-control study in 80 pediatric patients. Calcif Tissue Int . 2012;91(2):121–130. Lazzerini M, Martelossi S, Magazzu G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory crohn disease—a randomized clinical trial. JAMA . 2013;310(20):2164–2173. Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med . 2015;372(12):1104–1113. Oliva-Hemker M, Huftless S, Al Kazzi ES, et al. Clinical presentation and five-year therapeutic management of very early-onset inflammatory bowel disease in a large north American cohort. J Pediatr . 2015;167:527–532. Pellino G, Nicolai E, Catalano OA, et al. PET/MR versus PET/CT imaging: impact on the clinical management of small-bowel Crohn's disease. J Crohn Colitis . 2017;10(3):277–285. Qiu Y, Li MY, Feng T, et al. Systematic review with metaanalysis: the efficacy and safety of stem cell therapy for Crohn's disease. Sten Cell Res Ther . 2017;8:136. Riguero M, Schraut W, Baidoo L, et al. Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology . 2009;136:441–450.

Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med . 2013;369(8):711–721. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med . 2012;367:1519–1528. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med . 2004;350:876–885. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology . 2014;147(3):618–627. Seemann NM, Elkadri A, Walters TD, Langer JC. The role of surgery for children with perianal Crohn's disease. J Pediatr Surg . 2015;50:140–143. Sentongo TA, Semeao EJ, Piccoli DA, et al. Growth, body composition, and nutritional status in children and adolescents with Crohn's disease. J Pediatr Gastroenterol Nutr . 2002;31:33–40. Singer AAM, Gadepalli SK, Eder SJ, Adler J. Fistulizing Crohn's disease presenting after surgery on a perianal lesion. Pediatrics . 2016;137(3):e20152878. Sinha R, Nwokolo C, Murphy PD. Magnetic resonance imaging in Crohn's disease. BMJ . 2008;336:273–276. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. Lancet . 2017;389:1741–1754. Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol . 2007;102:2804–2812. Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut . 2013;62:1795–1805.

Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomized, placebo-controlled trial. Lancet . 2017;389:266–274. Walters TD, Kim MO, Denson LA, et al. Increased effectiveness of early therapy with anti-tumor necrosis factoralpha vs an immunomodulator in children with Crohn's disease. Gastroenterology . 2014;146(2):383–391. Zimmermann EM, Al-Hawary MM. MRI of the small bowel in patients with Crohn's disease. Curr Opin Gastroenterol . 2011;27:132–138.

362.3

Very Early Onset Inflammatory Bowel Disease Ronen E. Stein, Robert N. Baldassano

Keywords immunodeficiency monogenic indeterminate colitis Crohn disease ulcerative colitis infant toddler

IBD may be classified according to age at onset: pediatric onset (0.8. The neurologic disease can be prevented with the use of an oral water-soluble vitamin E preparation (TPGS, Liqui-E) at a dose of 25-50 IU/day in neonates and 15-25 IU/kg/day in children. Vitamin K deficiency can occur as a result of cholestasis and poor fat absorption. In children with liver disease it is very important to differentiate between the coagulopathy related to vitamin K malabsorption and one secondary to the synthetic failure of the liver. A single dose of vitamin K administered intravenously does not correct the prolonged prothrombin time in liver failure, but the deficiency state responds within a few hours. Easy bruising may be the first sign. In neonatal cholestasis, coagulopathy as a result of vitamin K deficiency can manifest with intracranial bleeds with devastating consequences, and prothrombin time should be routinely measured to monitor for deficiency in children with cholestasis. All children with cholestasis should receive regular vitamin K supplementation. Vitamin A deficiency is rare and is associated with night blindness, xerophthalmia, and increased mortality if patients contract measles. Serum vitamin A levels should be monitored and adequate supplementation considered; caution should be observed as high levels of vitamin A can cause liver damage.

364.11

Rare Inborn Defects Causing

Malabsorption Corina Hartman, Raanan Shamir

Keywords Fanconi-Bickel syndrome Cystinuria Lysinuric protein intolerance Hartnup disease Blue diaper syndrome Iminoglycinuria Dicarboxylic aminoaciduria Vitamin B12 Cobalamin malabsorption Megaloblastic anemia Imerslund-Grasbeck syndrome Folate Folate malabsorption Congenital chloride diarrhea Secretory diarrhea Congenital sodium diarrhea Acrodermatitis enteropathica Menkes disease Occipital horn syndrome Familial hypomagnesemia Intestinal iron absorption Hemochromatosis Refractory iron-deficiency anemia Congenital (primary) malabsorption disorders originate from multitude types of defects including structural or functional defects of enterocytes or disorders involving other cellular lineages of the GI tract such as enteroendocrine or

immune cells (see Chapter 364.3 and 367 ). Integral membrane proteins, which fulfill a transport function as receptor or channel across the apical or basolateral membrane of enterocytes for nutritional components, are another class of disorders associated with primary disorders of malabsorption. Histologic examination of the small and large bowel is typically normal. Most of these disorders are inherited in an autosomal recessive pattern. Most are rare, and patients present with a broad phenotypic heterogeneity as a result of modifier genes and nutritional and other secondary factors.

Disorders of Carbohydrate Absorption These are described in Chapter 364.9 . Patients with Fanconi-Bickel syndrome present with tubular nephropathy; rickets; hepatomegaly; glycogen accumulation in liver, kidney, and small bowel; failure to thrive; fasting hypoglycemia and postprandial hyperglycemia. The disorder is caused by homozygous mutations of GLUT2 (SLC2A2), the facilitative monosaccharides transporter at the basolateral membrane of enterocytes, hepatocytes, renal tubules, pancreatic islet cells, and cerebral neurons. The patients exhibit postprandial hyperglycemia secondary to low insulin secretion (impaired glucose-sensing mechanisms in beta-cells) and fasting hypoglycemia due to altered glucose transport out of the liver. The increased intracellular glucose level inhibits glycogen degradation leading to glycogen accumulation and hepatomegaly. Similarly, altered monosaccharides transport out of enterocytes may be responsible for the putative glycogen accumulation and as a consequence, for diarrhea and malabsorption observed in some patients. Therapy includes the substitution of electrolyte losses and vitamin D, and supplying uncooked cornstarch to prevent hypoglycemia. Patients who present in the neonatal period need frequent small meals and galactose-free milk.

Disorders of Amino Acid and Peptide Absorption Protein digestion and absorption in the intestine is accomplished by a combination of proteases, peptidases, and peptide and amino acid transporters. Amino acid transporters are essential for the absorption of amino acids from nutrients, mediate the inter-organ, intercellular transfer of amino acids and the

transport of amino acids between cellular compartments. Owing to their ontogenic origins, enterocytes and renal tubules share similar amino acid transporters. Their highest intestinal transporter activity is found in the jejunum. The transporters causing Hartnup disease, cystinuria, iminoglycinuria, and dicarboxylic aminoaciduria are located in the apical membrane, and those causing lysinuric protein intolerance (LPI) and blue diaper syndrome are anchored in the basolateral membrane of the intestinal epithelium. Dibasic amino acids, including cystine, ornithine, lysine, and arginine are taken up by the Na-independent SLC3A1/SLC7A9, which is defective in cystinuria. Cystinuria is the most common primary inherited aminoaciduria. This disorder is not associated with any GI or nutritional consequences because of compensation by an alternative transporter. However, hypersecretion of cystine in the urine leads to recurrent cystine stones, which account for up to 6–8% of all urinary tract stones in children. Ample hydration, urine alkalinization, and cystine-binding thiol drugs can increase the solubility of cystine. Cystinuria type I (SLC3A1) is inherited as an autosomal recessive trait, whether the transmission of non-type I cystinuria (SLC7A9) is autosomal dominant with incomplete penetrance. Cystinuria type I has been described in association with 2p21 deletion syndrome and hypotonia-cystinuria syndrome. LPI is the second most common disorder of amino acids transport (see Chapter 103.14 ). LPI is caused by y+ LAT-1 (SLC7A7) carrier at the basolateral membrane of the intestinal and renal epithelium and the failure to deliver cytosolic dibasic cationic amino acids into the paracellular space. This defect is not compensated by the SLC3A1/SLC7A9 transporter at the apical membrane. The symptoms of LPI, which appear after weaning, include diarrhea, failure to thrive, hepatosplenomegaly, nephritis, respiratory insufficiency, alveolar proteinosis, pulmonary fibrosis, and osteoporosis. Abnormalities of bone marrow have also been described in a subgroup of LPI patients. The disorder is characterized by low plasma concentrations of dibasic amino acids (in contrast to high levels of citrulline, glutamine, and alanine) and massive excretion of lysine (as well as orotic acid, ornithine, and arginine in moderate excess) in the urine. Hyperammonemia and coma usually develop after episodic attacks of vomiting, after fasting, or following the administration of large amounts of protein (or alanine load), possibly because of a deficiency of intramitochondrial ornithine. Some patients show moderate retardation. Cutaneous manifestations can include alopecia, perianal dermatitis, and sparse hair. Some patients avoid protein-containing food. Immune dysfunction potentially attributable to nitric

oxide overproduction secondary to arginine intracellular trapping might be the pathophysiological route explaining many LPI complications, including hemophagocytic lymphohistiocytosis, various autoimmune disorders, and an incompletely characterized immune deficiency. Treatment includes dietary protein restriction (90 mmol/L and exceed the sum of fecal sodium and potassium. Early diagnosis and aggressive lifelong enteral substitution of KCl in combination with NaCl (chloride doses of 6-8 mmol/kg/day for infants and 3-4 mmol/kg/day for older patients) prevent mortality and long-term complications (such as urinary infections, hyperuricemia with renal calcifications, renal insufficiency, and hypertension) and allow normal growth and development. Orally administered proton pump inhibitors, cholestyramine, and butyrate can reduce the severity of diarrhea. The diarrheal symptoms usually tend to regress with age. However, febrile diseases are likely to exacerbate symptoms as a consequence of severe dehydration and electrolyte imbalances. (See Chapter 71 for fluid and electrolyte management.) The classic form of congenital sodium diarrhea (CSD) manifests with polyhydramnios, massive secretory diarrhea , severe metabolic acidosis, alkaline stools (fecal pH > 7.5) and hyponatremia because of fecal losses of Na+ (fecal Na+ > 70 mmol/L). Urinary secretion of sodium is low to normal. CSD is clinically and genetically heterogeneous. A syndromic form of CSD with superficial punctate keratitis, choanal or anal atresia, hypertelorism, and corneal erosions has been related to mutations of SPINT2, encoding a serine–protease inhibitor, whose pathophysiologic action on intestinal Na+ absorption is unclear. This form of CSD is also referred to as CTE (intestinal epithelial dysplasia), as it often shows clustered enterocytes that form “tufts” with branching crypts on histology (described in Chapter 364.3 ). Two genetic defects have been identified so far in several patients with the non-syndromic form of CSD. Dominant activating mutations in receptor guanylate cyclase C (GUCY2C) were found to

cause a spectrum of secretory diarrheas including nonsyndromic CSD in 4 patients. These mutations were associated with elevated intracellular cyclic guanosine monophosphate (cGMP) levels that induced inhibition of NHE3 exchanger via its phosphorylation by cGMP kinase II. Mutations in SLC9A3 , the gene encoding the Na+ /H+ antiporter 3 (NHE3), the major intestinal brushborder Na+ /H+ exchanger, were identified in 9 patients with non-syndromic CSD. IBD developed in a number of patients with dominant GC-C mutations, and also in 2 of 9 patients with recessive SLC9A3 mutations, implicating NHE3 in the pathogenesis of IBD in a subset of patients. The congenital form of acrodermatitis enteropathica manifests with severe deficiency of body zinc soon after birth in bottle-fed children, or after weaning from breastfeeding. Clinical signs of this disorder are anorexia, diarrhea, failure to thrive, humoral and cell-mediated immunodeficiency (poor wound healing, recurrent infections), male hypogonadism, skin lesions (vesicobullous dermatitis on the extremities and perirectal, perigenital, and perioral regions, and alopecia), and neurologic abnormalities (tremor, apathy, depression, irritability, nystagmus, photophobia, night blindness, and hypogeusia). The genetic defect of acrodermatitis enteropathica is caused by a mutation in the Zrt-Irt-like protein 4 (ZIP4, SLC39A4), normally expressed on the apical membrane, which enables the uptake of zinc into the cytosol of enterocytes. The zinc-dependent alkaline phosphatase and plasma zinc levels are low. Paneth cells in the crypt of the small intestinal mucosa show inclusion bodies. Acrodermatitis enteropathica requires long-term treatment with elemental zinc at 1 mg/kg/day. Maternal zinc deficiency impairs embryonic, fetal, and postnatal development. Chapter 67 describes the acquired forms of zinc deficiency. Transient neonatal zinc deficiency is an autosomal dominant disorder with similar manifestations as AE. The disease is caused by mutations in ZnT2, the transporter responsible for supplying human milk with zinc. Menkes disease and occipital horn syndrome are both caused by mutations in the gene encoding Cu2+ transporting adenosine triphosphatase (ATPase), αpolypeptide (ATP7A), also called Menkes or MNK protein. ATP7A is mainly expressed by enterocytes, placental cells, and the central nervous system, and is localized in the trans -Golgi network for copper transfer to enzymes in the secretory pathway or to endosomes to facilitate copper efflux. Copper values in liver and brain are low in contrast to an increase in mucosal cells, including enterocytes and fibroblasts. Plasma copper and ceruloplasmin levels decline postnatally. Clinical features of Menkes disease are progressive cerebral

degeneration (convulsions), feeding difficulties, failure to thrive, hypothermia, apnea, infections (urinary tract), peculiar facies, hair abnormalities (kinky hair), hypopigmentation, bone changes, and cutis laxa. Patients with the classic form of Menkes disease usually die before the age of 3 yr. A therapeutic trial with copper-histidinase should start before the age of 6 wk. In contrast to Menkes disease, occipital horn syndrome usually manifests during adolescence with borderline intelligence, craniofacial abnormalities, skeletal dysplasia (short clavicles, pectus excavatum, genu valgum), connective tissue abnormalities, chronic diarrhea, orthostatic hypotension, obstructive uropathy, and osteoporosis. It should be differentiated from Ehlers-Danlos syndrome type V. Active calcium absorption is mediated by the transient receptor potential channel 6 (TRPV6) at the brush border membrane, calbindin, and the CaATPase, or the Na+ -Ca++ exchanger for calcium efflux at the basolateral membrane within the proximal small bowel. A congenital defect of these transporters has not yet been described. Intestinal absorption of dietary magnesium, which occurs via the transient receptor potential channel TRPM6 at the apical membrane, is impaired in familial hypomagnesemia with secondary hypocalcemia , which manifests with neonatal seizures and tetany. Intestinal iron absorption consists of several complex regulated processes starting with the uptake of heme-containing iron by heme carrier protein 1 (HCP1) and Fe2+ (after luminal reduction of oxidized Fe3+ ) by the divalent metal transporter 1 (DMT1) at the apical membrane, followed by the efflux of Fe2+ by ferroportin 1 (also called the iron-regulated transporter) at the basolateral membrane of duodenal enterocytes. Hepatic hormone hepcidin has a key role in iron homeostasis by interacting with ferroportin. When it binds to ferroportin, hepcidin induces phosphorylation of the iron exporter, causing its internalization and degradation. A decrease in the ferroportin protein level on the cell surface inhibits iron export from intracellular pools. Thus, hepcidin controls plasma iron levels by reducing iron absorption in the gut, lowering iron release from hepatocytes, and preventing iron recycling by macrophages Hepcidin deficiency causes iron overload in hereditary hemochromatosis and iron-loading anemias, whereas hepcidin excess causes or contributes to the development of iron-restricted anemia in inflammatory diseases, infections, some cancers, and chronic kidney disease. Mutations of the ferroportin 1 gene have been found in the autosomal dominant form of hemochromatosis type 4. Mutations within the hemochromatosis (HFE) gene (Cys282 Tyr, His63Asn, Ser65Cys) of classic

hemochromatosis reduce the endocytic uptake of diferric transferrin by the transferrin receptor-1 at the basolateral membrane of the intestinal epithelium. Hepcidin is the defective gene of juvenile hemochromatosis (type 2, subtype B). Elevated hepcidin results in hypoferremia and insufficient supply of iron for erythropoiesis, leading to different types of anemia. The underlying causes of hepcidin elevation in iron-restricted anemias are varied. An example of a genetic cause of hepcidin increase is the familial iron-refractory iron deficiency anemia (IRIDA), an autosomal recessive disorder caused by a mutation in matriptase-2 (TMPRSS6) , a negative regulator of hepcidin expression. This anemia is characterized by very low plasma iron levels, unresponsiveness to oral iron therapy and partial correction by parenteral iron. Mutations in DMT1 transporter (SLC11A2) are another cause of IRIDA . The development of severe microcytic, hypochromic anemia typifies these patients; however, surprisingly, some of them load iron in the liver.

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CHAPTER 365

Intestinal Transplantation in Children With Intestinal Failure Jorge D. Reyes, André A.S. Dick

The introduction of tacrolimus and the development of the abdominal multiorgan procurement techniques allowed the tailoring of various types of intestine grafts that can contain other intraabdominal organs, such as the liver, pancreas, and stomach. The understanding that the liver protects the intestine against rejection demonstrates the interaction between recipient and donor immunocytes (hostversus-graft and graft-versus-host) which under the cover of immunosuppression allows varying degrees of graft acceptance and eventual minimization of drug therapy. Over the past several years the number of patients placed on the list for and those undergoing intestinal transplantation has decreased, which may be a result of (1) improvements in the care of patients with intestinal failure under a multidisciplinary intestinal care team management, (2) the introduction of new lipid management strategies for the treatment of cholestatic liver disease, and (3) corrective surgery enhancing absorptive surface and motility, which has led to increased survival and decreased morbidity.

Indications for Intestinal Transplant Intestinal failure describes a patient who has lost the ability to maintain nutritional support and adequate fluid requirements, needed to sustain growth, with their own intestine and is permanently dependent on total parenteral nutrition (TPN). The majority of these patients have short bowels as a result of a congenital deficiency or acquired condition (see Chapter 364.07 ). In others, the cause of intestinal failure is a functional disorder of motility or absorption (Table 365.1 ). Rarely do patients receive intestinal transplants for benign neoplasms.

The complications of intestinal failure include loss of venous access, lifethreatening infections, and TPN-induced cholestatic liver disease. Table 365.1

Causes of Intestinal Failure in Children Requiring Transplantation SHORT BOWEL • Congenital disorders • Volvulus • Gastroschisis • Necrotizing enterocolitis • Intestinal atresia • Trauma INTESTINAL DYSMOTILITY • Intestinal pseudoobstruction • Intestinal aganglionosis (Hirschsprung disease) ENTEROCYTE DYSFUNCTION • Microvillus inclusion disease • Tufting enteropathy • Autoimmune disorders • Crohn disease TUMORS • Familial polyposis • Inflammatory pseudotumor

Paucity of Venous Access Administration of TPN requires the insertion of a centrally placed venous catheter, there being only 6 readily accessible sites (bilateral internal jugulars, subclavians, iliac veins). The loss of venous access generally occurs in the setting of recurrent catheter sepsis and thrombosis; clinical convention suggests that loss of 50% of these venous access sites places the patient at risk of not being able to be treated with TPN.

Life-Threatening Infections Life-threatening infections are usually catheter-related; the absence of significant lengths of intestine may be associated with abnormal motility of the residual bowel (producing both delayed or rapid emptying), with varying degrees of bacterial overgrowth and possible bacterial or fungal translocation as a consequence of loss of intestinal barrier function and/or loss of gut immunity.

This situation can produce cholestatic liver disease, multisystem organ failure, and metastatic infectious foci in lungs, kidneys, liver, and the brain.

Liver Disease The development of cholestatic liver disease is the most serious complication of intestinal failure and may be a consequence of the toxic drug effects of TPN on hepatocytes, a disruption of bile flow and bile acid metabolism, and the frequent occurrence of bacterial translocation and sepsis with endotoxin release into the portal circulation. This complication varies in frequency depending on the patient's age and the etiology of the intestinal failure; it is most common in neonates with extreme short gut. The effects on the liver include fatty transformation, steatohepatitis and necrosis, fibrosis, and then cholestasis. The development of clinical jaundice (total bilirubin > 3 mg/dL) and thrombocytopenia are significant risk factors for poor outcome, because these changes portend the development of portal hypertensive gastroenteropathy, hypersplenism, coagulopathy, and uncontrollable bleeding.

Transplantation Operation Donor Selection Intestinal grafts are usually procured from hemodynamically stable, ABOidentical brain-dead donors who have minimal clinical or laboratory evidence suggesting intraabdominal ischemia; size matching varies according to age of the recipients; present surgical techniques allow for significant reductions of the graft in order to achieve abdominal closure. Human leukocyte antigen has been random, and cross matching has not been a determinant of graft acceptance. Exclusion criteria include a history of malignancy and intraabdominal evidence of infection; systemic viral or bacterial infections are not excluded. Donor preparation has been limited to the administration of systemic and enteral antibiotics. Prophylaxis for graft-versus-host disease with graft pretreatment using irradiation or a monoclonal antilymphocyte antibody has varied over time. Grafts have been preserved with the University of Wisconsin solution, as is the case with other types of abdominal organs.

Types of Intestinal Grafts

Intestinal allografts are used in various forms, either alone (as an isolated intestine graft ) or as a composite graft, which can include the liver, duodenum, and pancreas (liver–intestine graft ); when this composite graft includes the stomach, and the recipient operation requires the removal of all of the patient's gastrointestinal tract (as with intestinal pseudoobstruction) and liver, then this replacement graft is known as a multivisceral graft . The procurement of these various types of grafts focuses on the preservation of the arterial vessels of celiac and/or superior mesenteric arteries, as well as appropriate venous outflow, which would include the superior mesenteric vein or the hepatic veins in the composite grafts. The larger composite grafts inherently retain the celiac and superior mesenteric arteries; this includes multivisceral grafts, liver plus small bowel grafts, and modified multivisceral grafts in which the liver is excluded but the entire gastrointestinal tract is replaced, including the stomach. The isolated intestine graft retains the superior mesenteric artery and vein; this graft can be accomplished with preservation of the vessels going to the pancreas, when that organ has been allocated to another recipient. The graft that is to be used in a particular recipient is dissected out in situ and then removed after cardiac arrest of the donor, with core cooling of the organs, using an infusion of preservation solution (Fig. 365.1 ).

FIG. 365.1 The various abdominal organs can be dissected in situ, providing isolated or composite grafts to fit the individual patient's needs. Separation of intestine and pancreas is feasible, with preservation of the inferior pancreaticoduodenal artery (IPDA) and vein (IPDV). The use of vascular grafts from the donor allow connections to the superior mesenteric pedicle (artery [SMA] and vein [SMV] ) to aorta and inferior vena cava (IVC) or portal vein (inset). MCA, Major coronary artery. (From Abu-Elmagd K, Fung J, Bueno J, et al: Logistics and technique for procurement of intestinal, pancreatic and hepatic grafts from the same donor, Ann Surg 232:680–697, 2000.)

Various modifications in these grafts have included the preservation of visceral ganglia at the base of the arteries, the inclusion of donor duodenum and pancreas for the liver and intestine graft, the inclusion of colon, the reduction of the liver graft (into left or right side) and variable reduction of the intestine graft, and the development of living donor intestine grafts.

The Recipient Operation Because many children have had multiple previous abdominal operations, intestinal transplantation can be a formidable technical challenge; most children require replacement of the liver because of TPN-induced disease and often

present with advanced liver failure. Transplantation of an isolated intestinal allograft involves exposure of the lower abdomen, infrarenal aorta, and inferior vena cava. Placement of vascular homografts using donor iliac artery and vein to these vessels allows arterialization and venous drainage of the intestinal graft. In patients who have retained their intestine and then undergo an enterectomy at the time of transplantation, use of the native superior mesenteric vessels is feasible. Transplantation of a larger composite graft requires the removal and replacement of the native liver in the liver with intestine transplant, and complete abdominal exenteration in the multivisceral transplant. In a similar fashion, the infrarenal aorta is exposed for placement of an arterial conduit graft (donor thoracic aorta) for arterialization of the graft. The venous drainage is achieved to the retained hepatic veins, which are fashioned to a single conduit for anastomosis to the allograft liver. The intestinal anastomosis to native proximal and distal bowel is performed, leaving an enterostomy of distal allograft ileum; this will be used for routine posttransplantation surveillance endoscopy and biopsy. This ostomy is closed 36 mo after transplantation (Fig. 365.2 ).

FIG. 365.2 The three basic intestinal transplant procedures (the graft is shaded ). With the isolated intestine, the venous outflow may be to the recipient portal vein (main figure), inferior vena cava (inset left), or superior mesenteric vein (inset right). With the composite grafts, which include the liver, the arterialization is from the aorta with venous drainage out from the liver graft to the recipient inferior vena cava.

Postoperative Management Immunosuppression Successful immunosuppression for intestinal transplantation is initiated with tacrolimus and corticosteroids. This required high levels of tacrolimus (in the nephrotoxic range), and although initial success rates were high they were followed by rejection rates of > 80%, infection, and late drug toxicities, resulting in a gradual loss of grafts and patients. The next generation of protocols incorporated the addition of other agents, such as azathioprine, cyclophosphamide, induction with an interleukin-2 antibody antagonist, mycophenolate mofetil, and rapamycin. This modification resulted in a decreased incidence in the severity of initial rejection; the ability to decrease immunosuppression later did not allow for stabilization of long-term survival. The introduction of recipient pretreatment using antilymphocyte antibodies and the elimination of recipient therapy with steroids have resulted in improved transplant survival as a result of a significant decrease in the incidence of rejection and infection, permitting the gradual decrease of immunosuppressive drug therapy within 3 mo, and a decline in drug toxicity events. The most common induction regimen used is T cell depleting agents followed by -2 receptor antagonists (Fig. 365.3 ). A mainstay of maintenance immunosuppression is tacrolimus and prednisone dual therapy. By 1 yr the majority of patients are on tacrolimus monotherapy (Fig. 365.4 ).

FIG. 365.3 Induction agents used in intestinal transplant recipients. Immunosuppression at transplant reported to the OPTN. IL2-RA , interleukin-2 receptor antagonist. (From Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2016 Annual Data Report. Fig IN28. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration; 2018. Available at https://srtr.transplant.hrsa.gov/annual_reports/Default.aspx )

FIG. 365.4 Calcineurin inhibitor use in intestine transplant recipients. Immunosuppression at transplant reported to the OPTN. (From Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2016 Annual Data Report. Fig IN29. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration; 2018. Available at https://srtr.transplant.hrsa.gov/annual_reports/Default.aspx )

Allograft Assessment There are no simple laboratory tools that allow assessment of the intestinal allograft. The gold standard for diagnosis of intestinal allograft rejection has been serial endoscopic surveillance and biopsies through the allograft ileostomy. Clinical signs and symptoms of rejection or infection of the allograft can overlap and mimic each other, producing either rapid diarrhea or complete ileus with pseudoobstruction syndromes, or gastrointestinal bleeding. Any changes in clinical status should warrant thorough evaluation for rejection with endoscopic biopsies and an evaluation for opportunistic infection, malabsorption, and other enteral infections. The diagnosis of acute rejection is based on seeing destruction of crypt epithelial cells from apoptosis, in association with a mixed lymphocytic infiltrate. These histologic findings may or may not correlate with endoscopic evidence of injury, which varies from diffuse erythema and friability to ulcers and, in cases of severe rejection, exfoliation of the intestinal mucosa. Chronic rejection of the allograft can be diagnosed only through full-thickness sampling of the intestine, which shows the typical vasculopathy that can result in progressive ischemia of the allograft.

Rejection and Graft-Versus-Host Disease Acute rejection rates for the intestinal allograft are significantly higher than with any other organ, in the range of 80–90%, and severe rejection requiring the use of antilymphocyte antibody preparations may be as high as 30%. Triple-drug regimens and the use of interleukin-2 antibody inhibitors have resulted in significant decreases in rejection rates; nonetheless, the amount of immunosuppression was incompatible with improvements in long-term patient and graft survival. Rejection rates of 40% are achievable with the use of antilymphocyte globulin. These protocols induce varying degrees of proper tolerance , which can eventually allow for minimization of immunosuppression, thus reducing the risk of drug toxicity and infection. Vascular rejection has been an uncommon occurrence, and chronic rejection has been seen in approximately 15% of cases. Graft-versus-host disease is infrequent but potentially life-threatening; the mortality rate exceeds 80% and most recipients die from infectious complications from bone marrow failure. The incidence seen in intestinal transplantation is 5–6%. Although no standard treatment is available, early diagnosis, prevention of infection, and initiation of treatment as soon as possible may improve outcomes.

Infections Infectious complications are the most significant cause of morbidity and mortality after intestinal transplantation. The most common infections (bacterial, fungal, polymicrobial) occur as a result of the continuing need for venous catheter placement for as long as 1 yr posttransplantation. Infections as a consequence of immunosuppressive drug management are from cytomegalovirus (CMV) infection (22% incidence), Epstein-Barr virus (EBV)–induced infections (21% incidence), and adenovirus enteritis (40% incidence). Despite improvements in monitoring and preventative measures, CMV remains the most common viral infection postintestinal transplantation. CMV may be acquired from blood transfusions, reactivation of endogenous viruses, or the donated allograft. The highest-risk recipients for CMV infection are those who are immunologically naïve and receive an allograft from a donor who is seropositive. The 2 CMV prevention strategies commonly employed are universal prophylaxis and preemptive therapy. Consensus guidelines recommend

prophylaxis treatment for high-risk patients (donor+/recipient−). The preferred drugs for CMV prophylaxis are ganciclovir and oral valganciclovir. Patients at the highest risk for EBV infection are those who are seronegative at the time of transplantation and those requiring a high-burden immunosuppressive therapy to maintain their graft. EBV disease varies from asymptomatic viremia to posttransplant lymphoproliferative disorder (PTLD). The incidence of EBV-related PTLD is highest in patients receiving intestinal allografts compared to liver, heart, or kidney. Children have a higher incidence of PTLD compared to adults, and are most likely to have EBV+PTLD. Early diagnosis and prevention of PTLD is essential and the mainstay of therapy is to reduce immunosuppression, although some patients have required chemotherapy. The use of anti–B-cell monoclonal antibodies, such as the anti-CD20 antibody rituximab, in PTLD has been successful as noted in anecdotal reports. Successful management of these viral infections is achieved through early detection and preemptive therapy, for both CMV and EBV, before the development of a serious life-threatening infection. This approach has improved outcomes for CMV, eliminating the mortality in the pediatric patient population (see Chapters 205 , 281 , and 282 ).

Outcomes Intestinal transplantation is the standard of care for children with intestinal failure who have significant complications of TPN and can no longer tolerate such therapy. Data from the Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) Annual Report 2015, and center-specific data reports have documented significant improvements with short- and long-term survivals for transplantations occurring principally in the last 10 yr; isolated intestinal transplantation graft failure rates for deceased donor transplants in 2013-2014 were 24.5% at 1 yr, 42.4% at 3 yr for transplants in 2011-2012, and 54% at 5 yr for transplants in 2009-2010 (Fig. 365.5 ). For liver-intestine recipients during the same time period graft failure rates were 27% at 1 yr, 33.3% at 3 yr, 48.7% at 5 yr, and 51% at 10 yr for transplants 2003-2004 (Fig. 365.6 ). It is hoped that with the minimization strategies currently used the long-term survival will plateau as occurs with other organ transplants; rehabilitation and quality-of-life studies have shown that more than 80% of survivors reach total independence from TPN and have meaningful life activities. Consequently, there has been a shift in efforts to improve long-

term outcomes and quality of life.

FIG. 365.5 Graft failure among transplant recipients of intestine without liver. All recipients of deceased donor intestines, including multiorgan transplants. Patients are followed until the earliest of retransplant, graft failure, death, or December 31, 2016. Estimates computed with Cox proportional hazards models adjusted for age, sex, and race. (From Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2016 Annual Data Report. Fig IN37. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration; 2018. Available at https://srtr.transplant.hrsa.gov/annual_reports/Default.aspx )

FIG. 365.6 Graft failure among transplant recipients of intestine with liver. All recipients of deceased donor intestines, including multiorgan transplants. Patients are followed until the earliest of retransplant, graft failure, death, or December 31, 2016. Estimates computed with Cox proportional hazards models adjusted for age, sex, and race. (From Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2016 Annual Data Report. Fig IN38. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration; 2018. Available at https://srtr.transplant.hrsa.gov/annual_reports/Default.aspx )

Bibliography Abu-Elmagd K, Fung J, Bueno J, et al. Logistics and technique for procurement of intestinal, pancreatic and hepatic grafts from the same donor. Ann Surg . 2000;232:680–697. Berg CL, Steffick DE, Edwards EB, et al. Liver and intestine transplantation in the United States 1998–2007. Am J Transplant . 2009;9(4 Pt 2):907–931. Bond G, Reyes J, Mazariegos G, et al. The impact of positive Tcell lymphocytotoxic crossmatch on intestinal allograft rejection and survival. Transplant Proc . 2000;32:1197–1198. Choquet S, Oertel S, LeBlond V, et al. Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution. Ann Hematol . 2007;86:599–607. Fishbein TW, Matsumoto CS. Intestinal replacement therapy: timing and indications for referral of patients to an intestinal rehabilitation and transplant program. Gastroenterology . 2006;130:S147–S151. Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the intestine transplant registry: a new era has dawned. Ann Surg . 2005;241:607–613. Green M, Reyes J, Webber S, et al. The role of antiviral and immunoglobulin therapy in the prevention of Epstein-barr virus infection and post-transplant lymphoproliferative disease following solid organ transplantation. Transpl Infect Dis . 2001;3:97–103. Kauffman SS, Atkinson JB, Bianchi A, et al. Indications for pediatric intestinal transplantation. Pediatr Transplant . 2001;5:80–87. Kelly DA. Intestinal failure associated liver disease: what do we know today? Gastroenterology . 2006;130(2 Suppl 1):S70– S77.

Organ Procurement and Transplantation Network. Data (website) . http://optn.transplant.hrsa.gov/data/ . Puntis J, Jenkins HR. Intestinal failure. Arch Dis Child . 2009;94:919–920. Reyes J, Mazariegos GV, Abu-Elmagd K, et al. Intestinal transplantation under tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti-thymocyte globulin (thymoglobulin). Am J Transplant . 2005;5:1430– 1436. Reyes J, Mazariegos GV, Bond GM, et al. Pediatric intestinal transplantation: historical notes, principles and controversies. Pediatr Transplant . 2002;6:193–207. Rogers J, Bueno J, Shapiro R, et al. Results of simultaneous and sequential pediatric liver and kidney transplantation. Transplantation . 2001;72:1666–1670. Salvia G, Guarino A, Terrin G, et al. Neonatal onset intestinal failure: an Italian multicenter study. J Pediatr . 2008;153:674–676. Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the causes of protracted diarrhea of infancy. J Pediatr Gastroenterol Nutr . 2004;38:16–26. Singh N, Paterson DL, Gayowski T, et al. Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus i.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, controlled trial. Transplantation . 2000;70:717. Smith JM, Skeans MA, Horslen SP, et al. OPTN?SRTR 2015 annual data report: intestine. Am J Transplant . 2017;17(Suppl 1):252–285. Squires RH, Duggan C, Teitelbaum DH, et al. Natural history of pediatric intestinal failure: initial report from the pediatric intestinal failure consortium. J Pediatr . 2012;161:723–728. Starzl TE, Demtris AJ, Trucco M, et al. Cell migration and

chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology . 1993;17:1127–1156. Testa G, Holterman M, John E, et al. Combined living donor liver/small bowel transplantation. Transplantation . 2005;27:1401–1404.

CHAPTER 366

Acute Gastroenteritis in Children Karen L. Kotloff

The term gastroenteritis denotes inflammation of the gastrointestinal tract, most commonly the result of infections with bacterial, viral, or parasitic pathogens (Tables 366.1 to 366.3 ). Many of these infections are foodborne illnesses (Table 366.4 ). Several clinical syndromes are often described because they have different (albeit overlapping) etiologies, outcomes, and treatments. Acute gastroenteritis (AGE) captures the bulk of infectious cases of diarrhea. The most common manifestations are diarrhea and vomiting, which can also be associated with systemic features such as abdominal pain and fever. Dysentery refers to a syndrome characterized by frequent small stools containing visible blood, often accompanied by fever, tenesmus, and abdominal pain. This should be distinguished from bloody diarrhea (larger volume bloody stools with less systemic illness) because the etiologies may differ. Prolonged (lasting 7-13 days) and persistent diarrhea (lasting 14 days or longer) are important because of their impact on growth and nutrition. Table 366.1

Etiologies of Viral Gastroenteritis COMMERCIALLY AVAILABLE DIAGNOSTIC TEST Person-to-person Very No. Testing of (fecal-oral and contagious stool or vomitus aerosolized vomit), (chlorine using real time and food, water, and heat reverse and fomites resistant); transcriptase contaminated with produces (RT)human feces. large quantitative outbreaks in PCR is the

ACUTE DURATION PRINCIPAL INCUBATION RISK ETIOLOGY SIGNS AND OF VEHICLE AND PERIOD FACTORS SYMPTOMS ILLNESS TRANSMISSION Caliciviruses 12-48 hr (including noroviruses and sapoviruses)

Nausea, vomiting, abdominal cramping, diarrhea, fever, myalgia, and some

1-3 days

headache

Rotavirus 2-4 days (groups AC), astrovirus, and enteric adenovirus (serotypes 40 and 41)

Often begins 3-8 days with vomiting, followed by watery diarrhea, lowgrade fever

closed settings such as cruise ships, and restaurants.

Person-to-person (fecal-oral), fomites. Aerosol transmission of rotavirus may be possible.

preferred method, available in public health laboratories. Immunoassays for norovirus have poor sensitivity. FDA-cleared multiplex PCR assays are available to detect these organisms. Norovirus genotyping (GI and GII) is performed by CDC. Nearly all Yes. Rotavirus: infants and immunoassay children (preferred), latex worldwide agglutination, and were immuneinfected by chromatography of 2 yr of age stool. Enteric before adenovirus: vaccine immunoassay. FDAintroduction. cleared multiplex PCR assays are available to detect these organisms.

CDC, Centers for Disease Control and Prevention. Modified from Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1–33, 2004.

Table 366.2

Etiologies of Bacterial Gastroenteritis ETIOLOGY

INCUBATION ACUTE SIGNS PERIOD AND SYMPTOMS

Bacillus cereus 1-6 hr (preformed emetic toxin) Bacillus cereus (enterotoxins formed in vivo)

8-16 hr

Sudden onset of severe nausea and vomiting; diarrhea may be present Abdominal cramps, watery diarrhea; nausea and vomiting

DURATION PRINCIPAL OF VEHICLE AND RISK FACTORS ILLNESS TRANSMISSION 24 hr

Soil and water

Improperly refrigerated cooked or fried rice, meats

1-2 days

Soil and water

Meats, stews, gravies, vanilla sauce

Campylobacter jejuni

Clostridium difficile toxin

Clostridium perfringens toxin

may be present Diarrhea, (10–20% of episodes are prolonged), cramps, fever, and vomiting; bloody diarrhea, bacteremia, extraintestinal infections, severe disease in immunocompromised Unknown—can Mild to moderate appear weeks watery diarrhea that after antibiotic can progress to cessation severe, pseudomembranous colitis with systemic toxicity. 8-16 hr Watery diarrhea, nausea, abdominal cramps; fever is rare 1-5 days

Enterohemorrhagic 1-9 days Escherichia coli (usually 3-4 (EHEC) including days) E. coli O157:H7 and other Shiga toxin–producing E. coli (STEC)

Watery diarrhea that becomes bloody in 1-4 days in ~40% of infections; in contrast to dysentery, bloody stools are large volume and fever/toxicity are minimal. More common in children 10 days) usually selflimiting

Wild and domestic animals and animal products, including pets

Raw and undercooked poultry, unpasteurized milk, untreated surface water

Variable

Person-person (fecal-oral), mostly within healthcare facilities

Immunosuppression, intestinal disease or surgery, prolonged hospitalization, antibiotics

1-2 days

Environment, Meats, poultry, human and animal gravy, dried or intestines precooked foods with poor temperature control Food and water Undercooked beef contaminated with especially feces from hamburger, ruminants; infected unpasteurized milk people and animals and juice, raw fruits (fecal-oral); and petting zoos, predominantly recreational high-resource swimming, daycare. countries Antimotility agents and antibiotics increase risk of hemolytic uremic syndrome

4-7 days

3-7 days

5-7 days (sometimes >10 days) usually selflimiting

5-7 days

Water or food contaminated with human feces Domestic poultry, cattle, reptiles, amphibians, birds

Infected people or fecally contaminated surfaces (fecaloral)

Infants and young children in LMIC and travelers Ingestion of raw or undercooked food, improper food handling, travelers, immunosuppression, hemolytic anemia, achlorhydria, contact with infected animal Poor hygiene and sanitation, crowding, travelers, daycare, MSM, prisoners

Staphylococcus 1-6 hr aureus (preformed enterotoxin)

Vibrio cholerae O1 1-5 days and O139

Vibrio parahaemolyticus

2-48 hr

Vibrio vulnificus

1-7 days

Yersinia 1-5 days enterocolitica and Yersinia pseudotuberculosis

manifestation or proceed to dysentery. Sudden onset of 1-3 days severe nausea and vomiting Abdominal cramps Diarrhea and fever may be present Watery diarrhea and 3-7 days vomiting, that can be profuse and lead to severe dehydration and death within hours.

Watery diarrhea, abdominal cramps, nausea, vomiting. Bacteremia and wound infections occur uncommonly, especially in high-risk patients, e.g., with liver disease and diabetes. Vomiting, diarrhea, abdominal pain. Bacteremia and wound infections, particularly in patients with chronic liver disease (presents with septic shock and hemorrhagic bullous skin lesions) Diarrhea, (10–20% prolonged), cramps, fever, and vomiting; bloody diarrhea, bacteremia, extraintestinal infections, severe disease in immunocompromised; pseudoappendicitis occurs primarily in older children.

Birds, mammals, dairy, and environment

Unrefrigerated or improperly refrigerated meats, potato and egg salads, cream pastries

Food and water Contaminated water, contaminated with fish, shellfish, human feces street-vended food from endemic or epidemic settings; blood group O, vitamin A deficiency

2-5 days

Estuaries and marine environments; currently undergoing pandemic spread

Undercooked or raw seafood, such as fish, shellfish

2-8 days

Estuaries and marine environments

Undercooked or raw shellfish, especially oysters, other contaminated seafood, and open wounds exposed to seawater

5-7 days (sometimes >10 days) usually selflimiting

Swine products, occasionally person-to-person and animal-tohumans, waterborne, bloodborne (can multiply during refrigeration)

Undercooked pork, improper food handling, unpasteurized milk, tofu, contaminated water, transfusion from a bacteremic person, cirrhosis, chelation therapy.

† FDA-cleared multiplex PCR assays are available but generally not recommended for diagnosis

in individual patients because of inability to determine antimicrobial susceptibility to guide treatment or speciate the organism for outbreak investigation. FDA, Food and Drug Administration; LMIC, low and middle-income countries; MSM, men who have sex with men; PCR, polymerase chain reaction; TCBS, thiosulfate-citrate-bile salts-sucrose. Modified from Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1–33, 2004.

Table 366.3

Etiologies of Parasitic Gastroenteritis ETIOLOGY

COMMERCIALLY AVAILABLE DIAGNOSTIC TEST Diarrhea 1-2 wk; may be Person-to-person Infants 6-18 mo Request specific (usually watery), remitting and (fecal-oral), of age living in microscopic bloating, relapsing over Contaminated food endemic examination of stool flatulence, weeks to months and water settings in with special stains cramps, (including LMIC, patients (direct fluorescent malabsorption, municipal and with AIDS, antibody staining is weight loss, and recreational water childcare preferable to fatigue may wax contaminated with settings, modified acid fast) and wane. human feces. drinking for Cryptosporidium. Persons with unfiltered Immunoassays and AIDS or surface water, PCR malnutrition MSM, IgA sensitive than have more deficiency microscopy. severe disease. Same as Same as Fresh produce Travelers, Cryptosporidium Cryptosporidium (imported berries, consumption of lettuce) fresh produce imported from the tropics.

ACUTE SIGNS INCUBATION DURATION AND PERIOD OF ILLNESS SYMPTOMS

Cryptosporidium 1-11 days

Cyclospora cayetanensis

1-11 days

Entamoeba histolytica

2-4 wk

Gradual onset of cramps, watery diarrhea and often dysentery with cramps but rarely fever. Can wax and wane with weight loss.

Variable; may be protracted (several weeks to several months)

PRINCIPAL RISK VEHICLE AND FACTORS TRANSMISSION

Fecal-oral transmission Any uncooked food or food contaminated by an ill food handler after cooking;

Persons living in or traveling to LMIC, institutionalized persons, MSM.

Giardia intestinalis

1-4 wk

Dissemination to live and other organs can occur. Diarrhea, 2-4 wk stomach cramps, gas, weight loss; symptoms may wax and wane.

drinking water

Any uncooked food or food contaminated by an ill food handler after cooking; drinking water

Hikers drinking unfiltered surface water, persons living in or traveling to LMIC, MSM, IgA deficiency

Microscopic examination of stool for ova and parasites may need at least 3 samples; immunoassay is more sensitive. Multiplex PCR.

† FDA-cleared multiplex PCR assays are available.

IgA, Immunoglobulin A; LMID, low- and middle-income countries; MSM, men who have sex with men; PCR, polymerase chain reaction. Modified from Centers for Disease Control and Prevention: Diagnosis and management of foodborne illnesses, MMWR 53(RR-4):1–33, 2004.

Table 366.4

Incidence of Bacterial and Parasitic Food-Borne Infections in 2017 and Percentage Change Compared With 2014-2016 Average Annual Incidence by Pathogen FoodNet Sites,* 2014-2017 † PATHOGEN Bacteria Campylobacter Salmonella Shigella Shiga toxin–producing E. coli ** Yersinia Vibrio Listeria Parasites Cryptosporidium Cyclospora

2017 NO. OF CASES

INCIDENCE RATE §

2017 VERSUS 2014-2016 % CHANGE ¶ (95% CI)

9,421 7,895 2,132 2,050 489 340 158

19.1 16.0 4.3 4.2 1.0 0.7 0.3

10 −5 −3 28 166 54 26

(2 to 18) (−11 to 1) (−25 to 25) (9 to 50) (113 to 234) (26 to 87) (2 to 55)

1,836 163

3.7 0.3

10 489

(−16 to 42) (253 to 883)

* Connecticut, Georgia, Maryland, Minnesota, New Mexico, Oregon, Tennessee, and selected

counties in California, Colorado, and New York. † Data for 2017 are preliminary. § Per 100,000 population. ¶ Percentage change reported as increase or decrease.

** For Shiga toxin–producing E. coli , all serogroups were combined because it is not possible to

distinguish between serogroups using culture-independent diagnostic tests. Reports that were only Shiga toxin–positive from clinical laboratories and were Shiga toxin–negative at a public health laboratory were excluded (n = 518). When these were included, the incidence rate was 5.2, which was a 57% increase (CI = 33–85%). CI, confidence interval; FoodNet, CDC's Foodborne Diseases Active Surveillance Network. From Marder EP, Griffin PM, Cieslak PR, et al: Preliminary incidence and trends of infections with pathogens transmitted commonly through food—foodborne diseases active surveillance network, 10 U.S. sites, 2006-2017, MMWR 67(11):324–328, 2018 (Table 1, p. 325).

Burden of Childhood Diarrhea Although global mortality due to diarrheal diseases has declined substantially (39%) during the past 2 decades, it remains unacceptably high. In 2015, diarrheal disease caused an estimated 499,000, or 8.6% of all childhood deaths, making it the 4th most common cause of child mortality worldwide. Over the same period, a smaller decline (10%) was observed in the incidence of diarrhea disease among children younger than 5 yr. Almost 1.0 billion episodes occurred in 2015 worldwide, resulting in an estimated 45 million childhood disabilityadjusted life years. Approximately 86% of the episodes occurred in Africa and South Asia (63% and 23%, respectively). The decline in diarrheal mortality, despite the lack of significant changes in incidence, is the result of preventive rotavirus vaccination and improved case management of diarrhea, as well as improved nutrition of infants and children. These interventions have included widespread home- and hospital-based oral rehydration solution (ORS) therapy and improved nutritional management of children with diarrhea. In addition to the risk of mortality, high rates of diarrhea can be associated with long-term adverse outcomes. Diarrheal illnesses, especially episodes among young children that are recurrent, prolonged, or persistent, can be associated with malnutrition, stunting, micronutrient deficiencies, and significant deficits in psychomotor and cognitive development.

Pathogens Rotavirus is the most common cause of AGE among children throughout the world. Several other viruses occur less frequently. Norovirus and sapovirus are the 2 genera of Caliciviruses that cause AGE. Norovirus genogroup II, genotype

4 (GII.4) has predominated globally during the past decade. Among the more than 50 serotypes of adenovirus, 40 and 41 are most often associated with diarrhea. Astroviruses are identified less often (see Table 366.1 ). The major bacterial pathogens that cause AGE are nontyphoidal Salmonella (NTS), Shigella, Campylobacter , and Yersinia (see Table 366.2 ). Five pathotypes of Escherichia coli infect humans: Shiga toxin–producing (STEC), also known as enterohemorrhagic (EHEC), enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroaggregative (EAEC), and enteroinvasive (EIEC). Two serogroups of Vibrio cholerae (O1 and O139) produce epidemic cholera and cause nearly all sporadic cases. Clostridium difficile disease can be both nosocomial and community acquired in children. Bacterial pathogens that cause foodborne illness due to their ability to produce emetic and/or enterotoxins include Bacillus cereus , Clostridium perfringens , and Staphylococcus aureus. The significance of isolating Aeromonas and Plesiomonas in a diarrheal stool remains uncertain. Giardia intestinalis, Cryptosporidium spp., Cyclospora cayetanensis , and Entamoeba histolytica are the most common parasites that cause diarrhea in the United States (see Table 366.3 ). At least 13 species of Cryptosporidium are associated with human disease, but C. hominis and to a less extent C. parvum are most common. The genus Entamoeba comprises 6 species that colonize humans, but only E. histolytica is considered a human pathogen. G. intestinalis (formerly G. lamblia and G. duodenalis ) is a flagellate protozoan that infects the small intestine and biliary tract. Other protozoa that uncommonly cause AGE are Isospora belli (now designated Cystoisospora belli ) and Blastocystic hominis.

Epidemiology in the United States and Other Middle- and High-Income Countries Risk Factors Related to Economic Development. Insufficient access to adequate hygiene, sanitation, and clean drinking water are the main factors leading to the heavy burden of AGE in developing countries. Nonetheless, infectious AGE remains ubiquitous in middle- and high- income countries, although the severe consequences have become uncommon. In fact, economic development poses its own risks for transmission of enteric pathogens. The

ability to mass-produce and widely distribute food has led to large multistate outbreaks of AGE due to NTS, STEC, and other agents. Globalization has cultivated a taste for tropical fruits and vegetables, creating a mechanism for importation of novel pathogens. The increasing frequency of antimicrobial resistance among bacteria that causes AGE has been linked to the use of antibiotics as growth-promotors for animals bred for food. Recreational swimming facilities and water treatment systems have provided a vehicle for massive outbreaks of Cryptosporidium , a chlorine-resistant organism. Venues serving catered food to large groups of people, such as hotels and cruise ships, are conducive to outbreaks, as are institutions where hygiene is compromised, such as daycare centers, prisons, and nursing homes. Hospitalization and modern medical therapy have created a niche for nosocomial C. difficile toxin infection (Table 366.5 ). Table 366.5

Exposure or Condition Associated With Pathogens Causing Diarrhea EXPOSURE OR CONDITION FoodBorne Foodborne outbreaks in hotels, cruise ships, resorts, restaurants, catered events Consumption of unpasteurized milk or dairy products Consumption of raw or undercooked meat or poultry Consumption of fruits or unpasteurized fruit juices, vegetables, leafy greens, and sprouts Consumption of undercooked eggs Consumption of raw shellfish Exposure or Contact Swimming in or drinking untreated fresh water Swimming in recreational water facility with treated water Healthcare, long-term care,

PATHOGEN(S) Norovirus, nontyphoidal Salmonella , Clostridium perfringens , Bacillus cereus , Staphylococcus aureus , Campylobacter spp., ETEC, STEC, Listeria , Shigella , Cyclospora cayetanensis , Cryptosporidium spp. Salmonella , Campylobacter , Yersinia enterocolitica , S. aureus toxin, Cryptosporidium , and STEC. Listeria is infrequently associated with diarrhea, Brucella (goat milk cheese), Mycobacterium bovis , Coxiella burnetii STEC (beef), C. perfringens (beef, poultry), Salmonella (poultry), Campylobacter (poultry), Yersinia (pork, chitterlings), S. aureus (poultry), and Trichinella spp. (pork, wild game meat) STEC, nontyphoidal Salmonella , Cyclospora , Cryptosporidium , norovirus, hepatitis A, and Listeria monocytogenes

Salmonella , Shigella (egg salad) Vibrio species, norovirus, hepatitis A, Plesiomonas

Campylobacter , Cryptosporidium , Giardia , Shigella , Salmonella , STEC, Plesiomonas shigelloides Cryptosporidium and other potentially waterborne pathogens when disinfectant concentrations are inadequately maintained Norovirus, Clostridium difficile , Shigella , Cryptosporidium , Giardia , STEC,

prison exposure, or employment Childcare center attendance or employment Recent antimicrobial therapy Travel to resourcechallenged countries Exposure to house pets with diarrhea Exposure to pig feces in certain parts of the world Contact with young poultry or reptiles Visiting a farm or petting zoo Exposure or Condition Age group

Underlying immunocompromising condition Hemochromatosis or hemoglobinopathy AIDS, immunosuppressive therapies Anal-genital, oral-anal, or digital-anal contact

rotavirus Rotavirus, Cryptosporidium , Giardia , Shigella , STEC C. difficile , multidrug-resistant Salmonella Escherichia coli (enteroaggregative, enterotoxigenic, enteroinvasive), Shigella , typhi and nontyphoidal Salmonella , Campylobacter , Vibrio cholerae , Entamoeba histolytica , Giardia , Blastocystis , Cyclospora , Cystoisospora , Cryptosporidium Campylobacter , Yersinia Balantidium coli Nontyphoidal Salmonella STEC, Cryptosporidium , Campylobacter

Rotavirus (6-18 mo of age), nontyphoidal Salmonella (infants from birth to 3 mo of age and adults >50 yr with a history of atherosclerosis), Shigella (1-7 yr of age), Campylobacter (young adults) Nontyphoidal Salmonella , Cryptosporidium , Campylobacter , Shigella , Yersinia

Y. enterocolitica , Salmonella Cryptosporidium , Cyclospora , Cystoisospora , microsporidia, Mycobacterium avium –intercellulare complex, cytomegalovirus Shigella , Salmonella , Campylobacter , E. histolytica , Giardia lamblia , Cryptosporidium

ETEC, enterotoxigenic Escherichia coli ; STEC, Shiga toxin–producing Escherichia coli . From Shane AL, Mody RK, Crump JA, et al: 2017 Infectious Diseases Society for America clinical practice guidelines for the diagnosis and management of infectious diarrhea, Clin Infect Dis 65(12):e45–80, 2017 (Table 2, p. e48).

Endemic Diarrhea. In the United States, rotavirus was the most common cause of medically attended AGE among children younger than 5 yr until the introduction of rotavirus vaccine for routine immunization of infants. Annual epidemics swept across the country beginning in the southwest in November and reaching the northeast by May, affecting nearly every child by the age of 2 yr. Since vaccine introduction, healthcare utilization for AGE has decreased markedly. Norovirus is the leading cause of AGE among children in the United States seeking healthcare, followed by sapovirus, adenovirus 40 and 41, and astrovirus (see Table 366.1 ). Foodborne Transmission. The most comprehensive resource for describing the burden of bacterial and protozoal diarrhea in the United States is the Foodborne Diseases Active Surveillance Network (FoodNet) maintained by the Centers for Disease Control and Prevention (CDC) (see Table 366.4 ). FoodNet

performs active laboratory-based surveillance of 9 bacterial and protozoal enteric infections commonly transmitted by food. Among children 0-19 yr of age in 2015, NTS was most common, followed by Campylobacter and Shigella , then STEC and Cryptosporidium . Vibrio, Yersinia, and Cyclospora were the least common (see Table 366.5 ). Children younger than 5 yr have the highest incidence of disease, and the elderly have the highest frequency of hospitalization and death. Only 5% of these infections are associated with recognized outbreaks. Noninfectious agents may also cause foodborne gastrointestinal symptoms due to a direct toxic effect of the food (mushrooms) or contamination (heavy metals) (Table 366.6 ). Table 366.6

Foodborne Noninfectious Illnesses ETIOLOGY

INCUBATION SIGNS AND PERIOD SYMPTOMS

DURATION OF ILLNESS Usually selflimited

ASSOCIATED LABORATORY TREATMENT FOODS TESTING

Antimony

5 min-8 hr usually 18,000, CRP > 4 mg/dL). Reports of this approach suggest a more rapid return to full activities and lower costs associated with the hospitalization for nonoperative management; however, others have reported that

patients with nonoperative management had more subsequent ED visits, advanced imaging studies, and hospitalizations compared with those managed operatively at the first visit.

Recurrent Appendicitis Prospective studies of the incidence of early recurrent appendicitis (within 1 yr) describe a range between 10 to 20% in patients initially managed nonoperatively. The lifetime risk of recurrent appendicitis in children treated nonoperatively is unknown. Controversies remain in the initial nonoperative management of PA. Most studies have reported significantly fewer overall complications (wound infections, intraabdominal abscesses, bowel obstruction, re-operations) in patients with initial nonoperative management of PA compared to patients with PA managed with upfront appendectomy; other reviews have supported early appendectomy in PA because initial nonoperative management and delayed appendectomy was associated with a significantly longer time to return to normal activities and an adverse event rate of 30% versus 55% in the initial nonoperative cohort. The initial nonoperative management and delayed appendectomy patients also incurred higher costs. Currently under review is the need for delayed appendectomy IA in patients with complicated appendicitis initially managed nonoperatively. While the trend in cases of PA at presentation is toward initial nonoperative management, the data remains uncertain, and there is no convincing data to recommend one approach in all patients.

Interval Appendectomy In patients with PA initially treated nonoperatively, the decision to proceed with IA, typically in 4-6 wk, is another area of management lacking consensus. Traditionally, most surgeons recommended IA to avoid recurrent appendicitis and to confirm the original diagnosis, citing reports which demonstrated an incidence of unexpected pathology in 30% of IA specimens. This has been questioned with nonoperative management of simple appendicitis gaining acceptance and many debating the risk of recurrent appendicitis (5–20%), believing it to be lower. The lifetime risk of recurrent appendicitis is unknown. Decision-making for IA must be individualized to balance the risks of recurrent appendicitis with the risks of anesthesia and comorbid conditions such as

obesity, congenital heart disease, chronic respiratory conditions, and others.

Incidental Appendicoliths The question of the incidental appendicolith is an intriguing one for pediatric practitioners. These are patients who do not have appendicitis but are found to have an appendicolith on imaging studies. An appendicolith is defined as a calcification within the appendiceal lumen. In adults, incidental appendicoliths identified by CT scans vary in incidence from ALT (150 µm in diameter are

found, postoperative establishment of bile flow is likely. The success rate for establishing good bile flow after the Kasai operation is much higher (90%) if performed before 8 wk of life. Therefore, early referral and prompt evaluation of infants with suspected biliary atresia is important. Educating parents, increased awareness among healthcare providers, and broader implementation of the stool card program are imperative to avoid delayed diagnosis and achieve favorable outcomes. Some patients with biliary atresia, even of the noncorrectable type, derive long-term benefits from interventions such as the Kasai procedure. In most, a degree of hepatic dysfunction persists. Patients with biliary atresia usually have persistent inflammation of the intrahepatic biliary tree, which suggests that biliary atresia reflects a dynamic process involving the entire hepatobiliary system. This might account for the ultimate development of complications such as portal hypertension. The short-term benefit of hepatoportoenterostomy is decompression and drainage sufficient to forestall the onset of cirrhosis and sustain growth until a successful liver transplantation can be done. The use of steroids following the Kasai procedure has not been shown to improve the patient or the native liver survival rates. Similarly, there is no convincing data to support the use of antibiotics or choleretic agents after surgery.

Management of Chronic Cholestasis With any form of neonatal cholestasis, whether the primary disease is idiopathic neonatal hepatitis, intrahepatic cholestasis, or biliary atresia, affected patients are at increased risk for progression and complications of chronic cholestasis. These reflect various degrees of residual hepatic functional capacity and are due directly or indirectly to diminished bile flow. Any substance normally excreted into bile is retained in the liver, with subsequent accumulation in tissue and in serum. Involved substances include bile acids, bilirubin, cholesterol, and trace elements. Decreased delivery of bile acids to the proximal intestine leads to inadequate digestion and absorption of dietary long-chain triglycerides and fatsoluble vitamins. Impairment of hepatic metabolic function can alter hormonal balance and utilization of nutrients. Progressive liver damage can lead to biliary cirrhosis, portal hypertension, and liver failure. Treatment of patients with cholestasis is empirical and is guided by careful monitoring (Table 383.7 ). No therapy is known to be effective in halting the progression of cholestasis or in preventing further hepatocellular

damage and cirrhosis. Growth failure is a major concern and is related in part to malabsorption and malnutrition resulting from ineffective digestion and absorption of dietary fat. Use of a medium-chain triglyceride-containing formula can improve caloric balance. With chronic cholestasis and prolonged survival, children with hepatobiliary disease can experience deficiencies of the fat-soluble vitamins (A, D, E, and K). Metabolic bone disease is common. It is essential to monitor the fat-soluble vitamin status in patients. Table 383.7

Suggested Medical Management of Persistent Cholestasis CLINICAL IMPAIRMENT Malnutrition resulting from malabsorption of dietary long-chain triglycerides Fat-soluble vitamin malabsorption Vitamin A deficiency (night blindness, thick skin) Vitamin E deficiency (neuromuscular degeneration)

MANAGEMENT Replace with dietary formula or supplements containing medium-chain triglycerides

Replace with 10,000-15,000 IU/day as Aquasol A Replace with 50-400 IU/day as oral α-tocopherol or TPaGS Vitamin D deficiency (metabolic bone disease) Replace with 5,000-8,000 IU/day of D2 or 3-5 µg/kg/day of 25-hydroxycholecalciferol Vitamin K deficiency (hypoprothrombinemia) Replace with 2.5-5.0 mg every other day as watersoluble derivative of menadione Micronutrient deficiency Calcium, phosphate, or zinc supplementation Deficiency of water-soluble vitamins Supplement with twice the recommended daily allowance Retention of biliary constituents such as cholesterol (itch Administer choleretic bile acids (ursodeoxycholic acid, or xanthomas) 15-30 mg/kg/day) Progressive liver disease; portal hypertension (variceal Interim management (control bleeding; salt restriction; bleeding, ascites, hypersplenism) spironolactone) End-stage liver disease (liver failure) Transplantation

TPGS , D-α-tocopherol polyethylene glycol 1000 succinate.

A degenerative neuromuscular syndrome is found in patients with chronic cholestasis, caused by vitamin E deficiency; affected children experience progressive areflexia, cerebellar ataxia, ophthalmoplegia, and decreased vibratory sensation. Specific morphologic lesions were found in the central nervous system, peripheral nerves, and muscles. These lesions are preventable and are not commonly seen today; they were potentially reversible in children younger than 3-4 yr of age. Affected children have low serum vitamin E concentrations, increased hydrogen peroxide hemolysis, and low ratios of serum vitamin E to total serum lipids (20 mg/dL without hemolysis after the 1st wk of life should suggest the syndrome.

Diagnosis The diagnosis of CN type I is based on the early age of onset and the extreme level of bilirubin elevation in the absence of hemolysis. In affected infants, bile contains no bilirubin glucuronide and bilirubin concentration in bile is 75% of the total. Cholangiography fails to visualize the biliary tract and x-ray of the gallbladder is also abnormal. Liver histology demonstrates normal architecture, but hepatocytes contain black pigment similar to melanin. Liver function is normal and prognosis is excellent. The most commonly reported symptoms are abdominal pain and fatigue, jaundice, dark urine, and slight enlargement of the liver. Jaundice fluctuates in intensity and is aggravated by intercurrent disease. Rarely, Dubin-Johnson can present in the neonatal period with severe conjugated hyperbilirubinemia with serum bilirubin >20 mg/dL and hepatosplenomegaly. No treatment is indicated for disease which presents outside of the neonatal period.

Rotor Syndrome Rotor Syndrome is an autosomal recessive disease resulting from biallelic inactivating mutations in SLCO1B1 and SLCO1B3 result in functional deficiencies of both OATP1B1 and OATP1B protein. Importantly, these mutations may confer significant drug toxicity risk. These patients present similarly to Dubin-Johnson syndrome, with asymptomatic mild and fluctuating conjugated hyperbilirubinemia, with total serum bilirubin levels between 2 and 5 mg/dL. Unlike Dubin-Johnson syndrome, total urinary coproporphyrin excretion is elevated with a relative increase in the amount of the coproporphyrin I isomer. If liver biopsy is performed, there is no abnormal pigmentation in contrast to

Dubin-Johnson. The gallbladder is normal by roentgenography. Rotor syndrome is benign and no treatment is indicated.

Bibliography Canu G, Minucci A, Zuppi C, et al. Gilbert and crigler najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. Blood Cells Mol Dis . 2013;50(4):273–280. Claridge LC, Arnstrong MJ, Booth C, et al. Gilbert's syndrome. BMJ . 2011;342:975–976. Farrar JS, Palais RA, Wittwer CT. Snapback primer genotyping of the gilbert syndrome UGT1A1 (TA)n promoter polymorphism by high-resolution melting. Clin Chem . 2011;57:1303–1310. Hafkamp AM. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-najjar disease: a randomized controlled trial. Pediatr Res . 2007;62:725–730. Hsieh TY, Shiu TY, Huang SM, et al. Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmacogenet Genomics . 2007;17:229–236. Hughes RD, Mitry RR, Dhawan A. Current status of hepatocyte transplantation. Transplantation . 2012;93:342–347. Memon N, Weinberger BI, Hegyi T, et al. Inherited disorders of bilirubin clearance. Ped Res . 2015;79(3):378–386. Ribes-Koninckx C, Ibars EP, Calzado Agrasot MA, et al. Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant . 2012;21:2267–2282. Uchiumi T, Tanamachi H, Kuchiwaki K, et al. Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin-johnson syndrome. Hepatol

Res . 2013;43(5):569–575. Van de Steeg E, Stranecky V, Hartmannova H, et al. Complete OATP1B1 and OAT1b3 deficiency causes human rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest . 2012;122:519–528.

384.2

Wilson Disease Anna L. Peters, William F. Balistreri

Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder that can be associated with liver disease, degenerative changes in the brain, and Kayser-Fleischer (K-F) rings in the cornea (Fig. 384.1 ). The incidence is approximately 1/30,000 births worldwide. Specific treatment is available; however this disease is progressive and potentially fatal if untreated. Prompt diagnostic evaluation for Wilson disease in all patients over age 5 yr presenting with any form of liver disease facilitates expeditious initiation of treatment of the disease, appropriate genetic counseling, screening of firstdegree relatives, and also allows appropriate treatment of non-Wilsonian liver disease once copper toxicosis is ruled out.

FIG. 384.1 Kayser-Fleischer ring. There is a brown discoloration at the outer margin of the cornea because of the deposition of copper in Descemet's membrane. Here it is clearly seen against the light green iris. Slit-lamp examination is required for secure detection. (From Ala A, Walker AP, Ashkan K, et al: Wilson's disease, Lancet 369:397–408, 2007.)

Pathogenesis The abnormal gene for Wilson disease is found on chromosome 13 (13q14.3), and encodes ATP7B , a copper transporting P-type adenosine triphosphatase (ATPase) which is mainly expressed in hepatocytes and is critical for biliary copper excretion and for copper incorporation into ceruloplasmin. Absence or malfunction of ATP7B results in decreased biliary copper excretion and diffuse accumulation of copper in the cytosol of hepatocytes. With time, liver cells become overloaded and copper is redistributed to other tissues, including the brain and kidneys, causing toxicity, primarily as a potent inhibitor of enzymatic processes. Ionic copper inhibits pyruvate oxidase in brain and ATPase in membranes, leading to decreased adenosine triphosphate-phosphocreatine and potassium content of tissue. More than 500 mutations have been identified, of which >380 have a confirmed role in disease pathogenesis; genetic testing should be able to identify a pathologic variant. Most patients are compound heterozygotes. Mutations that abolish gene function are associated with an onset of disease symptoms as early as 3 yr of age, when Wilson disease might not typically be considered in the differential diagnosis. Milder mutations can be associated with neurologic symptoms or liver disease as late as 80 yr of age. The most commonly occurring disease-causing ATP7B mutations result in a protein which binds copper but is unable to effectively traffic to the apical surface of hepatocytes to perform its

copper-exporting function. Pharmacologic inhibition of p38 and Jun N-terminal kinase mitogen-activated protein kinase (JNK MAPK) signaling pathways in vitro can rescue this defect and are potential new therapeutic targets.

Clinical Manifestations Forms of Wilsonian hepatic disease include asymptomatic hepatomegaly (with or without splenomegaly), subacute or chronic hepatitis, and acute hepatic failure (with or without hemolytic anemia). Cryptogenic cirrhosis, portal hypertension, ascites, edema, variceal bleeding, or other effects of hepatic dysfunction (delayed puberty, amenorrhea, coagulation defects) can be manifestations of Wilson disease. Disease presentations are variable, with a tendency to familial patterns. Liver disease is the most common disease manifestation in children and can precede neurologic symptoms by as long as 10 yr. Females are 3 times more likely than males to present with acute hepatic failure. When Wilson disease presents after age 20, neurologic symptoms are the most common manifestation. Neurologic disorders can develop insidiously or precipitously, with intention tremor, dysarthria, rigid dystonia, Parkinsonism, choreiform movements, lack of motor coordination, deterioration in school performance, psychosis, or behavioral changes. K-F rings are absent in young patients with hepatic Wilson disease up to 50% of the time but are present in 95% of patients with neurologic symptoms. Psychiatric manifestations include depression, personality changes, anxiety, obsessive-compulsive behavior, or psychosis. Coombs-negative hemolytic anemia may be an initial manifestation, possibly related to the release of large amounts of copper from damaged hepatocytes; this form of Wilson disease is usually fatal without transplantation. During hemolytic episodes, urinary copper excretion and serum free copper levels are markedly elevated. Manifestations of renal Fanconi syndrome and progressive renal failure with alterations in tubular transport of amino acids, glucose, and uric acid may be present. Unusual manifestations include arthritis, pancreatitis, nephrolithiasis, infertility or recurrent miscarriages, cardiomyopathy, and hypoparathyroidism.

Pathology All grades of hepatic injury occur in patients with Wilson disease with steatosis,

hepatocellular ballooning and degeneration, glycogen granules, minimal inflammation, and enlarged Kupffer cells being most common. The earliest histologic feature of Wilson disease is mild steatosis which may mimic nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. Additionally, the lesion may be indistinguishable from that of autoimmune hepatitis. With progressive parenchymal damage, fibrosis and cirrhosis develop. Ultrastructural changes primarily involve the mitochondria and include increased density of the matrix material, inclusions of lipid and granular material, and increased intracristal space with dilation of the tips of the cristae.

Diagnosis Wilson disease should be considered in children and teenagers with unexplained acute or chronic liver disease, neurologic symptoms of unknown cause, acute hemolysis, psychiatric illnesses, behavioral changes, Fanconi syndrome, or unexplained bone (osteoporosis, fractures) or muscle disease (myopathy, arthralgia). The clinical suspicion is confirmed by study of indices of copper metabolism. Most patients with Wilson disease have decreased serum ceruloplasmin levels (1.6 µmol/L), and urinary copper excretion (normally 100 µg/day and often up to 1,000 µg or more per day. Typical urinary copper excretion in patients with untreated Wilson disease is >1.6 µmol/24 hr. in adults and >0.64 µmol/24 hr in children. In equivocal cases, the response of urinary copper output to chelation may be of diagnostic help. Prior to a 24 hr urine collection patients are given 2 500 mg oral doses of D -penicillamine 12 hr apart; affected patients excrete >1,600 µg/24 hr. Demonstration of K-F rings, which might not be present in younger children,

requires a slit-lamp examination by an ophthalmologist. After adequate treatment, K-F rings resolve. Liver biopsy can determine the extent and severity of liver disease and for measuring the hepatic copper content (normally 250 µg/g dry weight (>4 µmol/g dry weight) is the best biochemical evidence for Wilson disease, but lowering the threshold to 1.2 µmol/g dry weight improves sensitivity without significantly affecting specificity. Intermediate levels of hepatic copper may be present in asymptomatic carriers. In later stages of Wilson disease, hepatic copper content can be unreliable because cirrhosis leads to variable hepatic copper distribution and sampling error. First-degree relatives of patients with Wilson disease should be screened for presymptomatic disease. This screening should include determination of the serum ceruloplasmin level and 24-hr urinary copper excretion. If these results are abnormal or equivocal, liver biopsy should be carried out to determine morphology and hepatic copper content. Genetic screening by either linkage analysis or direct DNA mutation analysis is possible, especially if the mutation for the proband case is known or the patient is from an area where a specific mutation is prevalent, such as in central and eastern Europe where the H1069Q mutation is present in 50–80% of patients.

Treatment Once the diagnosis of Wilson disease is made, lifelong treatment should be initiated and is focused on limiting copper uptake and promoting copper excretion through dietary and pharmacologic measures. The normal diet contains 2-5 mg of copper per day. For patients with Wilson disease, the dietary intake of copper should be restricted to 30%, and liver transplantation is the only effective intervention. Supportive care aimed at sustaining patients and early referral to a liver transplantation center can be lifesaving. As mentioned, HBV infection can also result in chronic hepatitis, which can lead to cirrhosis, end-stage liver disease complications, and HCC. Membranous glomerulonephritis with deposition of complement and HBeAg in glomerular capillaries is a rare complication of HBV infection.

Treatment Treatment of acute HBV infection is largely supportive. Close monitoring for liver failure and extrahepatic morbidities is key. Treatment of chronic HBV infection is in evolution; no 1 drug currently achieves consistent, complete eradication of the virus. The natural history of chronic HBV infection in children is complex, and there is a lack of reliable long-term outcome data on which to base treatment recommendations. Treatment of chronic HBV infection in children should be individualized and done under the care of a pediatric

hepatologist experienced in treating the disease. The goal of treatment is to reduce viral replication defined by having undetectable HBV DNA in the serum and development of anti-HBe, termed seroconversion. The development of anti-HBe transforms the disease into an inactive form, thereby decreasing infectivity, active liver injury and inflammation, fibrosis progression, and the risk of HCC. Treatment is only indicated for patients in the immune-active form of the disease, as evidenced by elevated ALT and/or AST, who have fibrosis on liver biopsy, putting the child at higher risk for cirrhosis during childhood.

Treatment Strategies Interferon-α2b (IFN-α2b) has immunomodulatory and antiviral effects (Table 385.7 ). It has been used in children, with long-term viral response rates similar to the 25% rate reported in adults. Interferon (IFN) use is limited by its subcutaneous administration, treatment duration of 24 wk, and side effects (flulike symptoms, marrow suppression, depression, retinal changes, autoimmune disorders). IFN is further contraindicated in decompensated cirrhosis. One advantage of IFN, compared to other treatments, is that viral resistance does not develop with its use. Table 385.7

Positive and Negative Factors to Consider in the Decision to Treat Hepatitis B With Peginterferon or a Nucleoside or Nucleotide Analog AGENT Peginterferon

Nucleoside or nucleotide analog

POSITIVE FACTORS Finite duration of treatment Durable off-treatment response More rapid disappearance of HBsAg Immunostimulatory as well as intrinsically antiviral Better tolerability compared with its use in hepatitis C Negligible side effects Convenience; ready acceptance by patients Potent inhibition of virus replication Reduced drug resistance with the third-generation nucleoside analogs

NEGATIVE FACTORS Inconvenience of subcutaneous injection Frequent side effects Clearance of HBsAg in a small minority of patients depending on genotype Potential risk of ALT flares in patients with advanced liver fibrosis Relative contraindication in patients older than age 60 or those with comorbid illnesses Slight risk of nephropathy with nucleotide analogs (adefovir, tenofovir) Drug expense can be considerable during long-term use Long or indefinite treatment needed for both HBeAg-positive and HBeAg-negative patients Access issues in developing nations

HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen. From Wells JT, Perillo R: Hepatitis B. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's gastrointestinal and liver disease , 10/e, Philadelphia, 2016, Elsevier, Table 79.4.

Lamivudine is an oral synthetic nucleoside analog that inhibits the viral enzyme reverse transcriptase. In children older than 2 yr of age, its use for 52 wk resulted in HBeAg clearance in 34% of patients with an ALT >2 times normal; 88% remained in remission at 1 yr. It has a good safety profile. Lamivudine has to be used for ≥ 6 mo after viral clearance, and the emergence of a mutant viral strain (YMDD) poses a barrier to its long-term use. Combination therapy in children using IFN and lamivudine did not seem to improve the rates of response in most series. Adefovir (a purine analog that inhibits viral replication) is approved for use in children older than 12 yr of age, in whom a prospective 1-yr study showed 23% seroconversion. No viral resistance was noted in that study but has been reported in adults. Entecavir (a nucleoside analog that inhibits replication) is currently approved for use in children older than 2 yr of age. Prospective data has shown a 21% seroconversion rate in adults with minimal resistance developing. Patients in whom resistance to lamivudine developed have an increased risk of resistance developing to entecavir. Tenofovir (a nucleotide analog that inhibits viral replication) is also approved for use in children older than 12 yr of age. Prospective data have shown a 21% seroconversion rate with a very low rate of resistance developing. Patients with lamivudine-resistant mutations do not appear to have an increased rate of resistance. Concern exists over long-term use and bone mineral density. Peginterferon-α2 has the same mechanism of action as IFN but is given once weekly. This formulation has not been approved in the United States but is recommended for the treatment of chronic HBV in other countries. Patients most likely to respond to currently available drugs have low serum HBV DNA titers, are HBeAg-positive, have active hepatic inflammation (ALT greater than twice the upper limit of normal for at least 6 mo), and recently acquired disease. Immune tolerant patients—those with normal ALT and AST, who are HBeAgpositive with elevated viral load—are currently not considered for treatment, although the emergence of new treatment paradigms is promising for this large, yet hard-to-treat, subgroup of patients.

Prevention The most effective prevention strategies have resulted from the screening of pregnant mothers and the use of HBIG and hepatitis B vaccine in infants (Tables 385.8 to 385.11 ). In HBsAg-positive and HBeAg-positive mothers, a 10% risk of chronic HBV infection exists compared to 1% in HBeAg-negative mothers. This knowledge offers screening strategies that may affect both mother and infant by using antiviral medications during the third trimester. Guidelines suggest that mothers with an HBV DNA viral load >200,000 IU/mL receive an antiviral such as telbivudine, lamivudine, or tenofovir during the third trimester, especially if they had a previous child who developed chronic HBV after receiving HBIG and the hepatitis B vaccine. This practice has proven safe with normal growth and development in infants of treated mothers. Table 385.8

Strategy to Eliminate Hepatitis B Virus Transmission in the United States* • Screening of all pregnant women for HBsAg HBV DNA testing for HBsAg-positive pregnant women, with suggestion of maternal antiviral therapy to reduce perinatal transmission when HBV DNA is >200,000 IU/mL Prophylaxis (HepB vaccine and hepatitis B immunoglobulin) for infants born to HBsAg-positive † women • Universal vaccination of all infants beginning at birth ‡ , § as a safeguard for infants born to HBV-infected mothers not identified prenatally • Routine vaccination of previously unvaccinated children aged 20 mg/dL but unaccompanied by severe pain or fever. There is no change in hematocrit or reticulocyte count nor any association with a hemolytic crisis.

Histiocytic Disorders Langerhans cell histiocytosis (Chapter 534.1 ), the most common of the histiocytoses, typically affects the bone and skin. However, it can cause infiltration of high-risk organs such as the liver resulting in periportal inflammation and sclerosing cholangitis. Liver involvement often results in worse outcomes. Hemophagocytic lymphohistiocytosis (HLH) (Chapter 534.2 ) is a multiorgan, severe, and potentially fatal inflammatory process associated with activation of macrophages that mimics sepsis. The hepatic manifestation of HLH is usually acute liver failure with portal inflammatory infiltrates and hemophagocytosis noted on liver biopsy.

387.1

Nonalcoholic Fatty Liver Disease

Bernadette E. Vitola, William F. Balistreri

Nonalcoholic fatty liver disease (NAFLD) , a spectrum of liver diseases strongly associated with obesity, is the most common chronic liver disease in children. NAFLD can range from fatty liver alone to a triad of fatty infiltration, inflammation, and fibrosis termed nonalcoholic steatohepatitis (NASH) , which resembles alcoholic liver disease but occurs with little or no exposure to ethanol. Unlike adults, NASH in children has 2 distinct histologic types. Type 1 NASH resembles adult histologic findings with steatosis and balloon degeneration of hepatocytes and/or periportal fibrosis. Type 2 NASH includes steatosis and portal inflammation. Many patients with NAFLD are asymptomatic. Liver histology, obtained from autopsy data, suggest that 10% of children and 38% of obese children aged 2-19 yr old have NAFLD. The risk is lower in African-American children. Elevated serum aminotransferase levels are not sensitive or specific markers for NAFLD. A normal serum ALT level is present in 21–23% of pediatric patients with NAFLD. Although ultrasonography detects NAFLD, no current imaging modalities distinguish between simple steatosis and NASH. A liver biopsy may be required for a delimiting diagnosis. There are no reliable biomarkers available to serve as an alternative to liver biopsy. The estimated prevalence of fatty liver disease in adults is thought to be as high as 15–20% for NAFLD overall and 2–4% for NASH. Risk factors in pediatric cohorts include obesity, male gender, white or Hispanic ethnicity, hypertriglyceridemia, and insulin resistance. Hepatic steatosis alone may be benign, but up to a quarter of patients with NASH can develop progressive fibrosis with resultant cirrhosis. The long-term prognosis of NASH that has developed in childhood is unknown. Children diagnosed with NAFLD should be screened for comorbid conditions, including diabetes, hypertension, dyslipidemia, and obstructive sleep apnea. Obese and overweight children with other risk factors >3 yr of age should be screened for NAFLD by checking aminotransferase levels and liver ultrasound, even though neither is highly sensitive or specific. MRI is in use for clinical trials, but further studies are needed prior to its standard use in patient care. Lysosomal acid lipase deficiency (LAL-D) , an autosomal recessive disorder due to mutations in LIPA may produce a hepatic steatosis like syndrome. In contrast to NAFLD, patients with LAL-D usually demonstrate microvesicular or

mixed micro- and macrovesicular steatosis not macrovesicular changes. Therapeutic trials in children and adolescents with biopsy-proven NAFLD/NASH are rare. Although there is no definitive treatment for NAFLD, gradual weight loss is effective in normalizing serum ALT levels and improving NAFLD. Low glycemic index foods and substituting polyunsaturated fatty acids for saturated fats may help. Vitamin E and vitamin C provide no additional benefit to the efficacy of lifestyle intervention (diet and exercise) in improving steatosis or biochemical abnormalities in pediatric NAFLD. However, vitamin E has been shown to improve balloon degeneration in children with NASH. Metformin has produced mixed results in the treatment of NAFLD. Thiazolidinediones (pioglitazone, rosiglitazone) improve liver histology in adults with NASH but have not been studied in children. In view of the potential role of the gut microbiome in contributing to the pathogenesis of NAFLD, the role of probiotics as an adjunct to lifestyle changes is under investigation. A preliminary study using ω-3 docosahexaenoic acid in children showed improved insulin sensitivity, ALT, triglycerides, BMI, and histology in children with NAFLD. Cysteamine bitartrate (slow release), a potential precursor of glutathione, an antioxidant, may reduce liver enzyme levels, as well as serum leptin and adiponectin levels, and is also a potential candidate for the treatment of NAFLD. GLP-1 is a neuropeptide (incretin) that has an antihyperglycemic effect. A metaanalysis demonstrated decreased ALT and improved imaging findings, as well as histologic features in adults with NAFLD and diabetes treated with GLP-1 agonists. In adults, a fibroblast growth factor 19 (FGF-19)-like agent has shown preliminary positive results. FGF-19 regulates bile acid, carbohydrate and energy metabolism.

Bibliography Abdou RM, Zhu L, Baker RD, et al. Gut Microbiota of nonalcoholic fatty liver disease. Dig Dis Sci . 2016;61(5):1268–1281 [PMID] 26898658. Africa JA, Newton KP, Schwimmer JB. Lifestyle interventions including nutrition, exercise, and supplements for nonalcoholic fatty liver disease in children. Dig Dis Sci . 2016;61(5):1375–1386 [PMID] 27041377. Carbone LJ, Angus PW, Yeomans ND. Incretin-based therapies

for the treatment of non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol . 2016;31(1):23–31 [PMID] 26111358. Della Corte C, Mazzotta AR, Nobili V. Fatty liver disease and obesity in youth. Curr Open Endocrinol Obes . 2016;23(1):66–71 [PMID] 26702852. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med . 2017;377(21):2063–2072. Harrison SA, Rinella ME, Abdelmalek MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicenter, ransomised, double-blind, placebo-controlled, phase 2 trial. Lancet . 2018;391:1174–1184. Himes RW, Barlow SE, Bove K, et al. Lysosomal acid lipase deficiency unmasked in two children with nonalcoholic fatty liver disease. Pediatrics . 2016;138(4):e20160214. Kohli R, Sunduram S, Mouzaki M, et al. Pediatric nonalcoholic fatty liver disease: a report from the expert committee on nonalcoholic fatty liver disease (ECON). J Pediatr . 2016;172:9–13. Schwimmer JB. Clinical advances in pediatric nonalcoholic fatty liver disease. Hepatology . 2016;63(5):1718–1725 [PMID] 27100147. Yan Y, Hou D, Zhao X, et al. Childhood adiposity and nonalcoholic fatty liver disease in adulthood. Pediatrics . 2017;139(4):e20162738.

Bibliography Aubart M, Ou P, Elie C, et al. Longitudinal MRI and ferritin monitoring of iron overload in chronically transfused and chelated children with sickle cell anemia and thalassemia major. J Pediatr Hematol Oncol . 2016;38(7):497–502

[PMID] 27548334. Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis and treatment. J Pediatr . 2013;163(5):1253–1259 [PMID] 23953723. Franceschet I, Cazzagon N, Del Ross T, et al. Primary Sclerosing cholangitis associated with inflammatory bowel disease: an observational study in a Southern Europe population focusing on new therapeutic options. Eur J Gastroenterol Hepatol . 2016;28(5):508–513 [PMID] 26872110. Lee WS, Sokol RJ. Intestinal Microbiota, Lipids, and the Pathogenesis of Intestinal Failure–Associated Liver Disease. J Pediatr . 2015;167(3):519–526. Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol . 2015;12(10):561–571 [PMID] 26260366. Myers KC, Dandoy C, El-Bietar J, et al. Veno-occlusive disease of the liver in the absence of elevation in bilirubin in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant . 2015;21(2):379–381 [PMID] 25300869. Pichler J, Simchowitz V, Macdonald S, et al. Comparison of liver function with two new/mixed intravenous lipid emulsions in children with intestinal failure. Eur J Clin Nutr . 2014;68(10):1161–1167 [PMID] 24961544. Pundi K, Pundi KN, Kamath PS, et al. Liver disease in patients after the Fontan operation. Am J Cardiol . 2016;117(3):456– 460 [PMID] 26704027. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe vena-occlusive and multiorgan failure. Blood . 2016;127(13):1656–1665 [PMID] 26825712.

Sathe MN, Freeman AJ. Gastrointestinal, pancreatic and hepatibiliary manifestations of cystic fibrosis. Pediatr Clin North Am . 2016;63(4):679–698 [PMID] 27469182. Thorvaldson L, Remberger M, Winiarski J, et al. HLA, GVHD, and parenteral nutrition are risk factors for hepatic complications in pediatric HSCT. Pediatr Transplant . 2016;20(1):96–104 [PMID] 26518451.

CHAPTER 388

Mitochondrial Hepatopathies Samar H. Ibrahim, William F. Balistreri

A wide variety of mitochondrial disorders are associated with liver disease. Hepatocytes contain a high density of mitochondria because the liver, with its biosynthetic and detoxifying functions, is highly dependent on adenosine triphosphate. Defects in mitochondrial function can lead to impaired oxidative phosphorylation, increased generation of reactive oxygen species, impairment of other metabolic pathways, and activation of mechanisms of cellular death. Mitochondrial disorders can be divided into primary, in which the mitochondrial defect is the primary cause of the disorder, and secondary, in which mitochondrial function is affected by exogenous injury or a genetic mutation that affects nonmitochondrial proteins (see Chapter 105.4 ). Primary mitochondrial disorders can be caused by mutations affecting mitochondrial DNA (mtDNA) or by nuclear genes that encode mitochondrial proteins or cofactors (see Chapter 383 —Table 383.3 and Table 388.1 ). Specific patterns may be noted (Table 388.2 ). Secondary mitochondrial disorders include diseases with an uncertain etiology, such as Reye syndrome; disorders caused by endogenous or exogenous toxins, drugs, or metals; and other conditions in which mitochondrial oxidative injury may be involved in the pathogenesis of liver injury. Table 388.1

Genotypic Classification of Primary Mitochondrial Hepatopathies and Organ Involvement GENE Deletion

RESPIRATORY HEPATIC CHAIN HISTOLOGY COMPLEX Multiple Steatosis,

OTHER ORGANS INVOLVED Kidney, heart,

CLINICAL FEATURES Sideroblastic anemia, variable

(Pearson)

fibrosis

MPV17

I, III, IV

Steatosis

DGUOK

I, III, IV

MPV17

I, III, IV

SUCLG1

I, III, IV

Steatosis, fibrosis Steatosis, fibrosis Steatosis

POLG1

I, III, IV

Steatosis, fibrosis

C10orf2/Twinkle I, III, IV

Steatosis

BCS1L

III (GRACILE)

SCO1

IV

TRMU

I, III, IV

EFG1

I, III, IV

Steatosis, fibrosis Steatosis, fibrosis Steatosis

EFTu

I, III, IV

Unknown

CNS, muscle

thrombocytopenia and neutropenia, persistent diarrhea CNS, muscle, Adult-onset multisystemic involvement: gastrointestinal myopathy, ophthalmoplegia, severe tract constipation, parkinsonism Kidneys, CNS, Nystagmus, hypotonia, renal Fanconi muscle syndrome, acidosis CNS, PNS Hypotonia Kidneys, CNS, Myopathy, sensorineural hearing loss, muscle respiratory failure CNS, muscle Liver failure preceded by neurologic symptoms, intractable seizures, ataxia, psychomotor regression CNS, muscle Infantile-onset spinocerebellar ataxia, loss of skills CNS ±, muscle Fanconi-type renal tubulopathy ±, kidneys Muscle

CNS CNS

Infantile liver failure with subsequent recovery Severe, rapidly progressive encephalopathy Severe lactic acidosis, rapidly fatal encephalopathy

CNS, central nervous system; GRACILE, growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death; PNS, peripheral nervous system. From Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics, therapeutic approaches and outcomes, J Pediatr 163:942–948, 2013 (Table 2, p. 944).

Table 388.2

Hepatic Phenotypes of Mitochondrial Cytopathies • Infantile liver failure • Neonatal cholestasis • Pearson syndrome • Alpers disease • Chronic liver disease • Drug-induced mitochondrial toxicity

From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease , ed 5, Philadelphia, 2016, Elsevier (Box 71.2, p. 876).

Epidemiology Mitochondrial respiratory chain disorders of all types affect 1 in 20,000 children

younger than 16 yr of age; liver involvement has been reported in 10–20% of patients with respiratory chain defect. Primary mitochondrial disorders, including mtDNA depletion syndromes (MDSs), occur in 1 in 5,000 live births and are a known cause of acute liver failure in children 25), and a raised ratio of β-hydroxybutyrate to acetoacetate

(>4.0). Symptoms are nonspecific and include lethargy and vomiting. Most patients additionally have neurologic involvement that manifests as a weak suck, recurrent apnea, or myoclonic epilepsy. Liver biopsy shows predominantly microvesicular steatosis, cholestasis, bile duct proliferation, glycogen depletion, and iron overload. With standard therapy the prognosis is poor, and most patients die from liver failure or infection in the first few months of life.

Alpers Syndrome (Alpers-Huttenlocher Syndrome or Alpers Hepatopathic Poliodystrophy) Diagnostic criteria include refractory mixed-type seizures with a focal component; psychomotor regression that is episodic and triggered by intercurrent infections; and hepatopathy with or without acute liver failure. Alpers syndrome manifests from infancy up to 8 yr of age with seizures, hypotonia, feeding difficulties, psychomotor regression, and ataxia. Patients develop hepatomegaly and jaundice and have a slower progression to liver failure than those with cytochrome-c oxidase deficiency. Elevated blood or cerebrospinal fluid lactate and pyruvate levels are supportive of the diagnosis, in addition to characteristic electroencephalographic findings (high-amplitude slow activity with polyspikes), asymmetric abnormal visual evoked responses, and low-density areas or atrophy in the occipital or temporal lobes on computed tomography scanning of the brain. In some patients complex I deficiency has been found in liver or muscle mitochondria. The disease is inherited in an autosomal recessive fashion; mutations in the catalytic subunit of the nuclear gene mtDNA POLG have been identified in multiple families with Alpers syndrome, leading to the advent of molecular diagnosis for Alpers syndrome. Patients with POLG mutations are susceptible to valproate-induced liver dysfunction.

Mitochondrial DNA Depletion Syndrome MDS is characterized by a tissue-specific reduction in mtDNA copy number, leading to deficiencies in complexes I, III, and IV. MDS manifests with phenotypic heterogeneity; multisystem and localized disease forms include myopathic, hepatocerebral, and liver-restricted presentations. Infants with the hepatocerebral form present in the neonatal period. The first symptoms are

metabolic; these rapidly progress to hepatic failure with hypoglycemia and vomiting. This stage is followed by neurologic involvement affecting the central and peripheral systems. Laboratory studies are characterized by lactic acidosis, hypoglycemia, and markedly elevated α-fetoprotein in plasma. In some patients, iron overload has been found with elevated transferrin saturation, high ferritin levels, and iron accumulation in hepatocytes and Kupffer cells. Death usually occurs by 1 yr of age. Spontaneous recovery has been reported in a patient with liver-restricted disease. Inheritance is autosomal recessive and mutations in the nuclear deoxyguanosine kinase gene (DGUOK) have been identified in many patients with hepatocerebral MDS. Thymidine kinase 2 has been implicated in the myopathic form; no known genetic defect has been identified in liverrestricted MDS. Multiple other nuclear genes including POLG, MPV17, Twinkle helicase gene, and SUCLG1 have been implicated in hepatocerebral MDS. Liver biopsies of patients with MDS show microvesicular steatosis, cholestasis, focal cytoplasmic biliary necrosis, and cytosiderosis in hepatocytes and sinusoidal cells. Ultrastructural changes are characteristic, with oncocytic transformation of mitochondria, which is characterized by mitochondria with sparse cristae, granular matrix, and dense or vesicular inclusions. If the native DNA-encoded complex II is normal and the activities of the other complexes are decreased, one should investigate mtDNA copy numbers for a MDS. Diagnosis is established by the demonstration of a low ratio of mtDNA (40%. Although mortality has not changed, the prevalence has decreased from >500 cases in 1980 to approximately 35 cases per year since. The decline in the reported incidence of Reye syndrome may be partially related to more accurate modern diagnosis of infectious, metabolic, or toxic disease, thus reducing the percentage of idiopathic or true cases of Reye syndrome. Reye syndrome is precipitated in a genetically susceptible person by the interaction of a viral infection (influenza, varicella) and salicylate and/or antiemetic use. Clinically it is characterized by a preceding viral illness that appears to be resolving and the acute onset of vomiting and encephalopathy (see Table 388.3 ). Neurologic symptoms can rapidly progress to seizures, coma, and death. Liver dysfunction is invariably present when vomiting develops, with coagulopathy and elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and ammonia. Importantly, patients remain anicteric and serum bilirubin levels are normal. Liver biopsies show microvesicular steatosis without evidence of liver inflammation or necrosis. Death is usually secondary to increased intracranial pressure and cerebral herniation. Patients who survive have full recovery of liver function but should be carefully screened for fatty-acid oxidation and fatty-acid transport defects (Table 388.4 ).

Table 388.3

Clinical Staging of Reye Syndrome and Reye-Like Diseases Symptoms at the time of admission: I. Usually quiet, lethargic and sleepy, vomiting, laboratory evidence of liver dysfunction II. Deep lethargy, confusion, delirium, combativeness, hyperventilation, hyperreflexia III. Obtunded, light coma ± seizures, decorticate rigidity, intact pupillary light reaction IV. Seizures, deepening coma, decerebrate rigidity, loss of oculocephalic reflexes, fixed pupils V. Coma, loss of deep tendon reflexes, respiratory arrest, fixed dilated pupils, flaccidity/decerebration (intermittent); isoelectric electroencephalogram

Table 388.4

Diseases That Present a Clinical or Pathologic Picture Resembling Reye Syndrome • Metabolic disease • Organic aciduria • Disorders of oxidative phosphorylation • Urea cycle defects (carbamoyl phosphate synthetase, ornithine transcarbamylase) • Defects in fatty acid oxidation metabolism • Acyl–coenzyme A dehydrogenase deficiencies • Systemic carnitine deficiency • Hepatic carnitine palmitoyltransferase deficiency • 3-OH, 3-methylglutaryl-coenzyme A lyase deficiency • Fructosemia • Infantile liver failure syndrome 1. Caused by leucyl-tRNA synthetase (LARS) gene mutations • Central nervous system infections or intoxications (meningitis), encephalitis, toxic encephalopathy • Hemorrhagic shock with encephalopathy • Drug or toxin ingestion (salicylate, valproate)

Acquired abnormalities of mitochondrial function can be caused by several drugs and toxins, including valproic acid, cyanide, amiodarone, chloramphenicol, iron, the emetic toxin of Bacillus cereus, and nucleoside analogs. Valproic acid is a branched fatty acid that can be metabolized into the mitochondrial toxin 4-envalproic acid. Children with underlying respiratory chain defects appear more sensitive to the toxic effects of this drug, and valproic acid is reported to precipitate liver failure in patients with Alpers syndrome and cytochrome-c oxidase deficiency. Nucleoside analogs directly inhibit mitochondrial respiratory chain complexes. The reverse transcriptase inhibitors zidovudine, didanosine, stavudine, and zalcitabine―used to treat HIV-infected patients―inhibit DNA POLG of mitochondria and can block elongation of mtDNA, leading to mtDNA depletion. Other conditions that can lead to mitochondrial oxidative stress include cholestasis, nonalcoholic steatohepatitis,

α1 -antitrypsin deficiency, and Wilson disease.

Diagnostic Evaluation Screening tests include common biochemical tests (comprehensive metabolic profile, INR, α-fetoprotein, CPK, phosphorus, complete blood cell count, ammonia, lactate, pyruvate, serum ketone bodies: both quantitative 3hydroxybutyrate and quantitative acetoacetate, total free fatty acids, serum acylcarnitine profile; serum-free and total carnitines, urine organic acids, and serum amino acids) (Table 388.5 ). These results will guide subsequent confirmatory testing to establish a molecular diagnosis. Genotyping, including single gene or panel screening for common mitochondrial disease, is used in clinical practice. Whole exome or genome sequencing is also helpful and is replacing single gene or gene panel testing. However, the identification of multiple gene variants of uncertain significance will require detailed clinical and biochemical confirmation for interpretation. Tissue (liver biopsy, skin fibroblast, and muscle biopsy) may be needed to make a specific biochemical diagnosis. Table 388.5 Tiered Investigations in Suspected Mitochondrial Liver Disease TIER 1 Pre-/postprandial plasma lactate, glucose, FFA, and 3-OH Plasma carnitine, acylcarnitines Plasma amino acids, creatine kinase, thymidine Urinary organic acids, amino acids, tubular resorption phosphate, albumin/creatinine ratio CSF lactate/protein (if feasible) Electrocardiography and echocardiography Electroencephalography and visual-evoked potentials Common mutations in POLG, DGUOK, MPV17, and TRMU TIER 2 Tissue analysis Liver biopsy : (if feasible). Tissue for light microscopy, electron microscopy, and Oil Red O stain Frozen tissue for respiratory chain enzyme activity analysis and mtDNA copy number Muscle biopsy : Tissue for light microscopy, electron microscopy, Oil Red O stain, and histochemistry for respiratory chain complexes Frozen tissue for respiratory chain enzyme activity analysis and mtDNA copy number

Skin biopsy: set up for fibroblast culture TIER 3 Cranial MRI/MRS TIER 4 Extended molecular screening. This will be guided by the clinical phenotype, results of the tissue analysis, and local facilities Currently suggested genes should include SUCLG1, BCS1L, SOC1, TFSM, TWINKLE, ACAD9, EARS2, GFM1, RRM2B, TK2 , and SUCLA2

From Wyllie R, Hyams JS, Kay M, editors: Pediatric gastrointestinal and liver disease , ed 5, Philadelphia, 2016, Elsevier (Box 71-3, p. 876).

Treatment of Mitochondrial Hepatopathies There is no effective therapy for most patients with mitochondrial hepatopathies; neurologic involvement often precludes orthotopic liver transplantation. Patients with mitochondrial disorders remain at risk for transplant-related worsening of their underlying metabolic disease, especially patients with POLG -related disease. Several therapeutic drug combinations―including antioxidants, vitamins, cofactors, and electron acceptors―have been proposed, but no randomized controlled trials have been completed to evaluate them. Treatment strategies are supportive and include the infusion of sodium bicarbonate for acute metabolic acidosis, transfusions for anemia and thrombocytopenia, and exogenous pancreatic enzymes for pancreatic insufficiency. It is important to discontinue or avoid medications that may exacerbate hepatopathy, including sodium valproate, tetracycline, and macrolide antibiotics, azathioprine, chloramphenicol, quinolones, and linezolid. Ringer lactate should be avoided because patients with liver dysfunction may not be able to metabolize lactate. Propofol should be avoided during anesthesia because of potential interference with mitochondrial function. In patients with lactic acidosis, lactate levels should be monitored during procedures. It is important to maintain anabolism using a balanced intake of fat and carbohydrates while avoiding unbalanced intakes (e.g., glucose only at a high intravenous rate) or fasting for >12 hr.

Bibliography Al-Hussaini A, Faqeih E, El-Hattab AW, et al. Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure. J Pediatr . 2014;164:553–559. Casey JP, McGettigan P, Lynam-Lennon N, et al. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Mol Genet Metab . 2012;106(3):351–358 [10967192] Casey yr]. Casteels-Van Daele M, Van Geet C, Wounter C, et al. Reyes syndrome revisited: a descriptive term covering a group of heterogeneous disorders. Eur J Pediatr . 2000;159:641–648. Ducluzeau PH, Lachaux A, Bouvier R, et al. Progressive reversion of clinical and molecular phenotype in a child with liver mitochondrial DNA depletion. J Hepatol . 2002;36:698– 703. Feldman AG, Sokol RJ, et al. Lactate and lactate: pyruvate ratio in the diagnosis and outcomes of pediatric acute liver failure. J Pediatr . 2017 [Jan 12. pii: S0022-3476(16)31430-5]. Hazard FK, Ficicioglu CH, Ganesh J, Ruchelli ED. Liver pathology in infantile mitochondrial DNA depletion syndrome. Pediatr Dev Pathol . 2013;16:415–424. Karadimus CL, Vu TH, Holve SA, et al. Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Am J Hum Genet . 2006;79:544–548. Lee WS, Sokol RJ. Mitochondrial hepatopathies: advances in genetics and pathogenesis. Hepatology . 2007;45:1555–1565. Lee WS, Sokol RJ. Mitochondrial hepatopathies: advances in genetics, therapeutic approaches and outcomes. J Pediatr . 2013;163:942–948. Mancuso M, Filosto M, Tsujino S, et al. Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in

both the myophosphorylase and deoxyguanosine kinase genes. Arch Neurol . 2003;60:1445–1447. Marzia B, Teresa R, Daniela V, et al. Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy. Biochem Biophys Res Commun . 2011;415:300–304. McFarland R, Hudson G, Taylor RW, et al. Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase γ (POLG1). Arch Dis Child . 2008;93:151–153. Molleston JP1, Sokol RJ, Karnsakul W, et al. Evaluation of the child with suspected mitochondrial liver disease. J Pediatr Gastroenterol Nutr . 2013;57(3):269–276; 10.1097/MPG.0b013e31829ef67a . Nguyen RK, Sharief FS, Chan SSL, et al. Molecular diagnosis of Alpers syndrome. J Hepatol . 2006;45:108–116. Parikh S, et al. Solid organ transplantation in primary mitochondrial disease: proceed with caution. Mol Genet Metab . 2016;118(3):178–184; 10.1016/j.ymgme.2016.04.009 . Rahman S. Gastrointestinal and hepatic manifestations of mitochondrial disorders. J Inherit Metab Dis . 2013;36:659– 673. Spinazzola A, Santer R, Akman OH, et al. Hepatocerebral form of mitochondrial DNA depletion syndrome. Arch Neurol . 2008;65(8):1108–1113. Vineta F, Heike K. Mitochondrial hepatopathies in the newborn period. Semin Fetal Neonatal Med . 2011;16:222–228.

CHAPTER 389

Autoimmune Hepatitis Benjamin L. Shneider, Frederick J. Suchy

Autoimmune Hepatitis Chronic Liver Disease Autoimmune hepatitis is a chronic hepatic inflammatory process manifested by elevated serum aminotransaminase concentrations, liver-associated serum autoantibodies, and/or hypergammaglobulinemia. The serological autoantibody profile defines 2 main types of autoimmune hepatitis: AIH type 1, with positivity for anti-nuclear antibodies (ANA) and/or anti–smooth muscle antibody (SMA) and AIH type 2, with positivity for anti–liver kidney microsomal type 1 antibody (anti-LKM-1). The targets of the inflammatory process can include hepatocytes and to a lesser extent bile duct epithelium. Chronicity is determined either by duration of liver disease (typically >3-6 mo) or by evidence of chronic hepatic decompensation (hypoalbuminemia, thrombocytopenia) or physical stigmata of chronic liver disease (clubbing, spider telangiectasia, splenomegaly, ascites). The severity is variable; the affected child might have only biochemical evidence of liver dysfunction, might have stigmata of chronic liver disease, or can present in hepatic failure. Chronic hepatitis can also be caused by persistent viral infection (see Chapter 358 ), drugs (see Chapter 363 ), metabolic diseases (see Chapter 361 ), fatty liver disease, or idiopathic disorders, which may have features of autoimmunity (Table 389.1 ). More than 90% of hepatitis B infections in the 1st yr of life become chronic, compared with 5–10% among older children and adults. Chronic hepatitis develops in >50% of acute hepatitis C virus infections. Transmission can occur during the perinatal period from an infected mother or in adolescents from parenteral drug abuse. Hepatitis A does not lead to chronic liver disease. Hepatitis E can become chronic in immunosuppressed patients.

Drugs commonly used in children that can cause chronic liver injury, which can mimic autoimmune hepatitis, include isoniazid, methyldopa, pemoline, nitrofurantoin, dantrolene, minocycline, pemoline, and the sulfonamides. Metabolic diseases can lead to chronic hepatitis, including α1 -antitrypsin deficiency, inborn errors of bile acid biosynthesis, and Wilson disease. Nonalcoholic steatohepatitis, usually associated with obesity and insulin resistance, is another common cause of chronic hepatitis. It can progress to cirrhosis but responds to weight reduction. In many cases the cause of chronic hepatitis is unknown; in some, an autoimmune mechanism is suggested by the finding of serum antinuclear and anti–SMAs and by multisystem involvement (arthropathy, thyroiditis, rashes, Coombs-positive hemolytic anemia). Table 389.1

Disorders Producing Chronic Hepatitis • Chronic viral hepatitis • Hepatitis B • Hepatitis C • Hepatitis D • Autoimmune hepatitis • Anti–actin antibody-positive • Anti–liver-kidney microsomal antibody-positive • Anti–soluble liver antigen antibody-positive • Others (includes antibodies to liver-specific lipoproteins or asialoglycoprotein) • Overlap syndrome with sclerosing cholangitis and autoantibodies • Systemic lupus erythematosus • Celiac disease • Drug-induced hepatitis • Metabolic disorders associated with chronic liver disease • Wilson disease • Nonalcoholic steatohepatitis • α1 -Antitrypsin deficiency • Tyrosinemia • Niemann-Pick disease type 2 • Glycogen storage disease type IV • Cystic fibrosis • Galactosemia • Bile acid biosynthetic abnormalities

Autoimmune hepatitis is a clinical constellation that suggests an immunemediated process; it is responsive to immunosuppressive therapy (Table 389.2 ). Autoimmune hepatitis typically refers to a primarily hepatocyte-specific process, whereas autoimmune cholangiopathy and sclerosing cholangitis predominately involve intrahepatic and extrahepatic bile duct injury. Overlap of the process

involving both hepatocyte and bile duct–directed injury may be more common in children. De novo hepatitis can be seen in a subset of liver transplant recipients whose initial disease was not autoimmune. Table 389.2

Classification of Autoimmune Hepatitis VARIABLE

TYPE 1 AUTOIMMUNE HEPATITIS

Characteristic autoantibodies Antinuclear antibody*

TYPE 2 AUTOIMMUNE HEPATITIS Antibody against liver-kidney microsome type 1*

Smooth-muscle antibody* Antiactin antibody †

Geographic variation Age at presentation Gender of patients Association with other autoimmune diseases Clinical severity Histopathologic features at presentation Treatment failure Relapse after drug withdrawal Need for long-term maintenance

Antibody against liver cytosol type 1* Autoantibodies against soluble liver antigen and Antibody against liver-kidney liver-pancreas antigen ‡ microsomal type 3 Atypical perinuclear antineutrophil cytoplasmic antibody Worldwide Worldwide; rare in North America Any age Predominantly childhood and young adulthood Female in ~75% of cases Female in ~95% of cases Common Common § Broad range, variable Broad range, mild disease to cirrhosis

Generally severe Generally advanced

Infrequent Variable

Frequent Common

Variable

~100%

* The conventional method of detection is immunofluorescence. † Tests for this antibody are rarely available in commercial laboratories. ‡ This antibody is detected by enzyme-linked immunosorbent assay. § Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is seen only in patients with

type 2 disease. Modified from Krawitt EL: Autoimmune hepatitis, N Engl J Med 354:54–66, 2006.

Etiology T Lymphocytes

Autoimmune Regulator Gene Autoimmune hepatitis arises in a genetically predisposed host after an unknown trigger leads to a T cell–mediated immune response targeting liver autoantigens. A dense portal mononuclear cell infiltrate invades the surrounding parenchyma and comprises T and B lymphocytes, macrophages, and plasma cells. The immunopathogenic mechanisms underlying autoimmune hepatitis are unsettled. Triggering factors can include molecular mimicry, infections, drugs, and the environment (toxins) in a genetically susceptible host. Several human leukocyte antigen class II molecules―particularly DR3, DR4, and DR7 isoforms―confer susceptibility to autoimmune hepatitis. Self-antigenic peptides are processed by populations of antigen-presenting cells and presented to CD4 and CD8 effector T cells. CD4+ T lymphocytes recognizing a self-antigenic liver peptide orchestrate liver injury. Cell-mediated injury by cytokines released by CD8+ cytotoxic T cells and/or antibody-mediated cytotoxicity can be operative. There is also evidence that regulatory T cells from patients with autoimmune hepatitis are impaired in their ability to control the proliferation of CD4 and CD8 effector cells. Cytochrome P450 2D6 is the main autoantigen in type 2 autoimmune hepatitis. Antibody-coated hepatocytes may be lysed by complement or Fc-bearing natural killer lymphocytes. Heterozygous mutations in the autoimmune regulator gene (AIRE), which encodes a transcription factor controlling the negative selection of autoreactive thymocytes, can be found in some children with autoimmune hepatitis types 1 and 2. AIRE mutations also cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (also called autoimmune polyendocrinopathy syndrome), in which autoimmune hepatitis occurs in approximately 20% of patients.

Pathology The histologic features common to untreated cases include inflammatory infiltrates, consisting of lymphocytes and plasma cells that expand portal areas and often penetrate the lobule (interface hepatitis); moderate to severe piecemeal necrosis of hepatocytes extending outward from the limiting plate; variable necrosis, fibrosis, and zones of parenchymal collapse spanning neighboring portal triads or between a portal triad and central vein (bridging necrosis); and variable degrees of bile duct epithelial injury. Distortion of hepatic architecture

can be severe; cirrhosis may be present in children at the time of diagnosis. Histologic features in acute liver failure may be obscured by massive necrosis and multilobular collapse. Other histologic features may suggest an alternative diagnosis: characteristic periodic acid–Schiff-positive, diastase-resistant granules are seen in α1 -antitrypsin deficiency, and macrovesicular and microvesicular steatosis is found in nonalcoholic steatohepatitis and often in Wilson disease. Bile duct injury can suggest an autoimmune cholangiopathy or an overlap syndrome. Ultrastructural analysis might suggest distinct types of storage disorders.

Clinical Manifestations The clinical features and course of autoimmune hepatitis are extremely variable. Signs and symptoms at the time of presentation comprise a wide spectrum of disease including a substantial number of asymptomatic patients and some who have an acute, even fulminant, onset. In 25–30% of patients with autoimmune hepatitis, particularly children, the illness mimics acute viral hepatitis. In most the onset is insidious. Patients can be asymptomatic or have fatigue, malaise, behavioral changes, anorexia, and amenorrhea, sometimes for many months before jaundice or stigmata of chronic liver disease are recognized. Extrahepatic manifestations can include arthritis, vasculitis, nephritis, thyroiditis, Coombspositive anemia, and rash. Some patients’ initial clinical features reflect cirrhosis (ascites, hypersplenism, bleeding esophageal varices, or hepatic encephalopathy). There may be mild to moderate jaundice in severe cases. Spider telangiectasias and palmar erythema may be present. The liver may be tender and slightly enlarged but might not be felt in patients with cirrhosis. The spleen is commonly enlarged. Edema and ascites may be present in advanced cases.

Laboratory Findings The findings are related to the severity of presentation. In many asymptomatic cases, serum aminotransferase ranges between 100 and 300 IU/L, whereas levels in excess of 1,000 IU/L can be seen in young symptomatic patients. Serum bilirubin concentrations may be normal in mild cases but are commonly 2-10 mg/dL in more severe cases. Serum alkaline phosphatase and γ-glutamyl

transpeptidase activities are normal to slightly increased but may be more significantly elevated in autoimmune cholangiopathy or in the setting of overlap with sclerosing cholangitis. Serum γ-globulin levels can show marked polyclonal elevations. Hypoalbuminemia is common. The prothrombin time is prolonged, most often as a result of vitamin K deficiency but also as a reflection of impaired hepatocellular function. A normochromic normocytic anemia, leukopenia, and thrombocytopenia are present and become more severe with the development of portal hypertension and hypersplenism. Most patients with autoimmune hepatitis have hypergammaglobulinemia. Serum immunoglobulin G levels usually exceed 16 g/L. Characteristic patterns of serum autoantibodies define distinct subgroups of autoimmune hepatitis (see Table 389.2 ). The most common pattern (type 1) is associated with the formation of non–organ-specific antibodies, such as antiactin (smooth muscle) and ANA. Approximately 50% of these patients are 10-20 yr of age. High titers of a liver-kidney microsomal antibody are detected in another form (type 2) that usually affects children 2-14 yr of age. A subgroup of primarily young women might demonstrate autoantibodies against a soluble liver antigen but not against nuclear or microsomal proteins. Antineutrophil cytoplasmic antibodies may be seen more commonly in autoimmune cholangiopathy. Autoantibodies are rare in healthy children, so that titers as low as 1 : 40 may be significant, although nonspecific elevation in autoantibodies can be observed in a variety of liver diseases. Up to 20% of patients with apparent autoimmune hepatitis might not have autoantibodies at presentation but have histological features and clinical course consistent with the disorder. Other, less common autoantibodies include rheumatoid factor, antiparietal cell antibodies, antithyroid antibodies, and anti– liver cytosol type 1 antibody (anti-LC-1). A Coombs-positive hemolytic anemia may be present.

Diagnosis There is no specific test for autoimmune hepatitis; it is a clinical diagnosis based on certain diagnostic criteria. Diagnostic criteria with scoring systems have been developed for adults and modified slightly for children, although these scoring systems were developed as research rather than diagnostic tools. Important positive features include female gender, primary elevation in transaminases and not alkaline phosphatase (or GGT), elevated γ-globulin levels, the presence of autoantibodies (most commonly antinuclear, smooth muscle, or liver-kidney

microsome), and characteristic histologic findings (Fig. 389.1 ). Important negative features include the absence of viral markers (hepatitides B, C, D) of infection, absence of a history of drug or blood product exposure, and negligible alcohol consumption.

FIG. 389.1 Autoimmune hepatitis. Liver biopsy showing fibrous expansion of the portal tracts with moderate portal lymphocytic infiltrates rich in plasma cells (arrowhead). There is extensive interface hepatitis (arrows). Original magnification ×20. (Courtesy Margret Magid, Mount Sinai School of Medicine.)

Common conditions that might lead to chronic hepatitis should be excluded (see Table 389.1 ). The differential diagnosis includes α1 -antitrypsin deficiency (see Chapter 357 ) and Wilson disease (see Chapter 357.2 ). The former disorder must be excluded by performing α1 -antitrypsin phenotyping and the latter by measuring serum ceruloplasmin and 24-hr urinary copper excretion and/or hepatic copper levels. Chronic hepatitis may occur in patients with inflammatory bowel disease, but liver dysfunction in such patients is more commonly caused by pericholangitis or sclerosing cholangitis. Celiac disease (see Chapter 338 ) is associated with liver disease that is akin to autoimmune hepatitis, and appropriate serologic testing should be performed, including assays for anti– tissue transglutaminase antibodies or antiendomysial antibodies. An ultrasonogram should be done to identify a choledochal cyst or other structural disorders of the biliary system. Magnetic resonance (MR) cholangiography may be very useful for screening for evidence of sclerosing cholangitis. An overlap syndrome with features of primary sclerosing cholangitis and autoimmune

hepatitis is being increasingly recognized with wider application of MR cholangiography (Table 389.3 ). Patients with primary sclerosing cholangitis can have elevated γ-globulin levels and autoantibodies; therefore liver biopsy findings in these children may be especially important. Dilated or obliterated veins on ultrasonography suggest the possibility of the Budd-Chiari syndrome. Diagnosis of autoimmune liver disease in the setting of acute liver failure is difficult and care should be taken in applying standardized approaches. “Seronegative” autoimmune hepatitis has been described, so absence of classic autoimmune markers does not exclude this diagnosis. Table 389.3

Overlap Syndromes of Autoimmune Hepatitis AUTOIMMUNE HEPATITIS WITH OVERLAPPING FEATURES OF: Primary Sclerosing Primary Biliary Cholangitis* Cholestasis Cholangitis Clinical AMA + AMA − AMA − and Serum AP frequently > 2-fold ULN Serum AP frequently > 2- Serum AP frequently > 2-fold ULN laboratory fold ULN features IBD common No UC Abnormal cholangiogram Normal cholangiogram (except in small-duct disease) Histology Destructive cholangitis Ductopenia Lymphoplasmacytic portal and acinar infiltrates Ductopenia Cholangiolar Lymphocytic destructive cholangitis proliferation Cholestasis Swollen fibrotic portal Swollen hepatocytes tracts Treatment Prednisone (10 mg daily) in Prednisone (10 mg daily) Prednisone (10 mg daily) in combination with azathioprine (50 in combination with combination with azathioprine (50 mg daily) if AP ≤ 2 × ULN azathioprine (50 mg mg daily) and/or low-dose UDCA daily) and low-dose (13-15 mg/kg daily) depending on UDCA (13-15 mg/kg AP level and histologic features daily) Prednisone (10 mg daily) in combination with azathioprine (50 mg daily) and low-dose UDCA (1315 mg/kg daily) if AP > 2 × ULN and/or florid duct lesions * Primary biliary cholangitis formerly called primary biliary cirrhosis.

AMA , antimitochondrial antibodies; AP , alkaline phosphatase level; UDCA , ursodeoxycholic acid; ULN , upper limit of normal. From Czaja AJ: Autoimmune hepatitis. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's gastrointestinal and liver disease , ed 10, Philadelphia, 2016: Elsevier

(Table 90.4).

Treatment Prednisone, with or without azathioprine or 6-mercaptopurine, improves the clinical, biochemical, and histologic features in most patients with autoimmune hepatitis and prolongs survival in most patients with severe disease. The goal is to suppress or eliminate hepatic inflammation with minimal side effects. Prednisone at an initial dose of 1-2 mg/kg/24 hr is continued until aminotransferase values return to less than twice the upper limit of normal. The dose should then be lowered in 5-mg decrements over 2-4 mo until a maintenance dose of 0.1-0.3 mg/kg/24 hr is achieved. In patients who respond poorly, who experience severe side effects, or who cannot be maintained on lowdose steroids, azathioprine (1.5-2.0 mg/kg/24 hr, up to 100 mg/24 hr) can be added, with frequent monitoring for bone marrow suppression. Measurement of thiopurine methyltransferase activity should be done prior to beginning treatment with the thiopurine drugs azathioprine and 6-mercaptopurine. Patients with low activity (10% prevalence) or absent activity (prevalence 0.3%) are at risk for developing severe drug-induced myelotoxicity from accumulation of the unmetabolized drug. Measurement of the drug metabolites, 6-thioguanine nucleotide and 6-methylmercaptopurine, is useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression and hepatotoxicity. Single-agent therapy with alternate-day corticosteroids should be used with great caution, although addition of azathioprine to alternate-day steroids can be an effective approach that minimizes corticosteroid-related toxicity. In patients with a mild and relatively asymptomatic presentation, some favor a lower starting dose of prednisone (10-20 mg) coupled with the simultaneous early administration of either 6-mercaptopurine (1.0-1.5 mg/kg/24 hr) or azathioprine (1.5-2.0 mg/kg/24 hr). Patients with primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome respond similarly to immunosuppressive therapy. Precise diagnostic criteria for autoimmune disease in the setting of sclerosing cholangitis do not exist. Autoimmune markers and immunoglobulin levels are often elevated in children with sclerosing cholangitis and do not necessarily indicate a diagnosis of coincident autoimmune hepatitis. The choleretic agent, ursodeoxycholic acid, is often used in biliary tract disease, but trials in adults with primary sclerosing

cholangitis have not shown efficacy, and patients have experienced toxicity at higher doses. There is a potential role for budesonide combined with azathioprine in treatment of noncirrhotic patients. Budesonide is a corticosteroid with high first-pass clearance by the liver and fewer systemic side effects including suppression of hypothalamic–pituitary axis. Cyclosporine, tacrolimus, mycophenolate mofetil, and sirolimus have been used in the management of cases refractory to standard therapy. Use of these agents should be reserved for practitioners with extensive experience in their administration, because the agents have a more restricted therapeutic to toxic ratio. Histologic progress does not necessarily need to be assessed by sequential liver biopsies, although biochemical remission does not ensure histologic resolution. Follow-up liver biopsy is an important consideration in patients for whom consideration is given to discontinuing corticosteroid therapy. In patients with disappearance of symptoms and biochemical abnormalities and resolution of the necroinflammatory process on biopsy, an attempt at gradual discontinuation of medication is justified. There is a high rate of relapse after discontinuation of therapy. Relapse can require reinstitution of induction dosing of immunosuppression to control disease relapse.

Prognosis The initial response to therapy in autoimmune hepatitis is generally prompt, with a >75% rate of remission. Transaminases and bilirubin fall to near-normal levels, often in the first 1-3 months. When present, abnormalities in serum albumin and prothrombin time respond over a longer period (3-9 mo). In patients meeting the criteria for tapering and then withdrawal of treatment (25–40% of children), 50% are weaned from all medication; in the other 50%, relapse occurs after a variable period. Relapse usually responds to retreatment. Many children will not meet the criteria for an attempt at discontinuation of immunosuppression and should be maintained on the smallest dose of prednisone that minimizes biochemical activity of the disease. A careful balance of the risks of continued immunosuppression and ongoing hepatitis must be continually evaluated. This requires continual screening for complications of medical therapy (monitoring of linear growth velocity, ophthalmologic examination, bone density measurement, blood pressure monitoring). Intermittent flares of hepatitis can occur and can necessitate recycling of prednisone therapy.

Some children have a relatively steroid-resistant form of hepatitis. More extensive evaluations of the etiology of their hepatitis should be undertaken, directed particularly at reassessing for the presence of either sclerosing cholangitis or Wilson disease. Nonadherence to medical therapy is one of the most common causes of “resistance” to medical therapy. Progression to cirrhosis can occur in autoimmune hepatitis despite a good response to drug therapy and prolongation of life. Corticosteroid therapy in fulminant autoimmune disease may be useful, although it should be administered with caution, given the predisposition of these patients to systemic bacterial and fungal infections. Liver transplantation has been successful in patients with end-stage or fulminant liver disease associated with autoimmune hepatitis (see Chapter 368 ). Disease recurs after transplantation in approximately 30% of patients and is associated with increased concentrations of serum autoantibodies and interface hepatitis on liver biopsy. Patients generally respond well to an increase in immunosuppression, particularly to the addition of azathioprine.

Bibliography Jimenez-Rivera C, Ling SC, Ahmed N, et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics . 2015;136:e1237–e1248. Kerkar N, Yanni G. ‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: a comprehensive review. J Autoimmun . 2016;66:17–24. Liberal R, Grant CR, Longhi MS, et al. Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev . 2014;13:435–440. Liberal R, Krawitt EL, Vierling JM, et al. Cutting edge issues in autoimmune hepatitis. J Autoimmun . 2016;75:6–19. Longhi MS, Mieli-Vergani G, Vergani D. Autoimmune hepatitis. Curr Pediatr Rev . 2014;10:268–274. Maggiore G, Socie G, Sciveres M, et al. Seronegative autoimmune hepatitis in children: spectrum of disorders. Dig Liver Dis . 2016;48:785–791. Rodrigues AT, Liu PM, Fagundes ED, et al. Clinical characteristics and prognosis in children and adolescents with

autoimmune hepatitis and overlap syndrome. J Pediatr Gastroenterol Nutr . 2016;63:76–81. Zizzo AN, Valentino PL, Shah PS, Kamath BM. Second-line agents in pediatric patients with autoimmune hepatitis: a systematic review and Meta-analysis. J Pediatr Gastroenterol Nutr . 2017;65(1):6–15.

CHAPTER 390

Drug- and Toxin-Induced Liver Injury Frederick J. Suchy, Amy G. Feldman

The liver is the main site of drug metabolism and is particularly susceptible to structural and functional injury after the ingestion, parenteral administration, or inhalation of chemical agents, drugs, plant derivatives (home remedies), herbal or nutritional supplements, or environmental toxins. The possibility of drug use or toxin exposure at home or in the parents’ workplace should be explored for every child with liver dysfunction. The clinical spectrum of illness can vary from asymptomatic biochemical abnormalities of liver function to fulminant failure. Liver injury may be the only clinical feature of an adverse drug reaction or may be accompanied by systemic manifestations and damage to other organs. In hospitalized patients, clinical and laboratory findings may be confused with the underlying illness. After acetaminophen, antimicrobials, supplements, and central nervous system agents are the most commonly implicated drug classes causing liver injury in children. There is growing concern about environmental hepatotoxins that are insidious in their effects. Many environmental toxins―including the plasticizers, biphenyl A, and the phthalates―are ligands for nuclear receptors that transcriptionally activate the promoters of many genes involved in xenobiotic and lipid metabolism and may contribute to obesity and nonalcoholic fatty liver disease. Some herbal, weight loss, and body building supplements have been associated with hepatic injury or even liver failure (Table 390.1 ) related to their intrinsic toxicity or because of contamination with fungal toxins, pesticides, or heavy metals. Table 390.1

Hepatotoxic Herbal Remedies, Dietary Supplements, and Weight Loss Products REMEDY Ayurvedic herbal medicine

POPULAR USES Multiple

SOURCE Multiple

Barakol

Anxiolytic

Cassia siamea

Black cohosh

Menopausal symptoms Fever

Cimicifuga racemosa

“Bush tea”

Cascara Chaparral leaf (greasewood, creosote bush) Chaso/onshido Chinese medicines (traditional) Jin bu huan

Laxative “Liver tonic,” burn salve, weight loss Weight loss

Senecio, Heliotropium, Crotalaria spp. Cascara sagrada Larrea tridenta

—

HEPATOTOXIC COMPONENT Uncertain (may contain heavy metal contaminants) Uncertain

TYPE OF LIVER INJURY Hepatitis

Anthracene glycoside Nordihydroguaiaretic acid

Cholestatic hepatitis Acute and chronic hepatitis, FHF

N -nitro-fenfluramine

Acute hepatitis, FHF

Reversible hepatitis or cholestasis Uncertain Hepatitis (causality uncertain) Pyrrolizidine alkaloids SOS

Sleep aid, analgesic Weight loss Anti-aging, neuroprotection, laxative Multiple

Lycopodium serratum Levotetrahydropalmitine Ephedra spp. Ephedrine Polygonum Anthraquinone multiflorum Thunb (fleeceflower root) Scutellaria root Diterpenoids

Comfrey Germander

Herbal tea Weight loss, fever

Greater celandine

Gallstones, IBS

Symphytum spp. Teucrium chamaedry, T. capitatum, T. polium Chelidonium majus

Green tea leaf extract Herbalife

Multiple

Camellia sinensis —

Hydroxycut

Nutritional supplement, weight loss Weight loss

Impila Kava

Multiple Anxiolytic

Camellia sinensis , among other constituents Callilepsis laureola Piper methysticum

Kombucha Limbrel (Flavocoxid)

Weight loss Osteoarthritis

Lichen alkaloid Plant bioflavonoids

Ma huang Shou-wu-pian

Syo-saiko-to

Acute or chronic hepatitis or cholestasis, steatosis Severe hepatitis, FHF Acute hepatitis or cholestasis

Hepatocellular necrosis, cholestasis, steatosis, granulomas Pyrrolizidine alkaloid Acute SOS, cirrhosis Diterpenoids, epoxides Acute and chronic hepatitis, FHF, autoimmune injury Isoquinoline alkaloids Cholestatic hepatitis, fibrosis Catechins Hepatitis (causality questioned) Various; ephedra Severe hepatitis, FHF

Uncertain

Acute hepatitis, FHF

Potassium atractylate Kava lactone, pipermethystine Usnic acid Baicalin, epicatechin

Hepatic necrosis Acute hepatitis, cholestasis, FHF Acute hepatitis Acute mixed hepatocellular-cholestatic injury

Lipokinetix

Weight loss

Lichen alkaloid

Usnic acid

Mistletoe

Asthma, infertility Dental pain Abortifacient

Viscus album

Uncertain

Prostatism Herbal tea Laxative

Various foods, oils Hedeoma pulegoides, Mentha pulegium Multiple Sassafras albidum Cassia angustifolia

Anxiolytic Sedative

Scutellaria Valeriana officinalis

Eugenol Pulegone, monoterpenes Uncertain Safrole Sennoside alkaloids; anthrone Diterpenoids Uncertain

Oil of cloves Pennyroyal (squawmint oil) Prostata Sassafras Senna Skullcap Valerian

Acute hepatitis, jaundice, FHF Hepatitis (in combination with skullcap) Zonal necrosis Severe hepatocellular necrosis Chronic cholestasis HCC (in animals) Acute hepatitis Hepatitis Elevated liver enzymes

FHF, fulminant hepatic failure; HCC, hepatocellular carcinoma; SOS, sinusoidal obstruction syndrome. From Lewis JH: Liver disease caused by anesthetics, chemicals, toxins, and herbal preparations. In Feldman M, Friedman LS, Brandt LJ, editors: Sleisenger and Fordtran's gastrointestinal and liver disease , ed 10, Philadelphia, 2016, Elsevier, (Table 89.6).

Hepatic metabolism of drugs and toxins is mediated by a sequence of enzymatic reactions that in large part transform hydrophobic, less-soluble molecules into more nontoxic, hydrophilic compounds that can be readily excreted in urine or bile (see Chapter 72 ). Relative liver size, liver blood flow, and extent of protein binding also influence drug metabolism. Phase 1 of the process involves enzymatic activation of the substrate to reactive intermediates containing a carboxyl, phenol, epoxide, or hydroxyl group. Mixed-function monooxygenase, cytochrome-c reductase, various hydrolases, and the cytochrome P450 (CYP) system are involved in this process. Nonspecific induction of these enzymatic pathways, which can occur during intercurrent viral infection, with starvation, and with the administration of certain drugs such as anticonvulsants, can alter drug metabolism and increase the potential for hepatotoxicity. A single agent can be metabolized by more than 1 biochemical reaction. The reactive intermediates that are potentially damaging to the cell are enzymatically conjugated in phase 2 reactions with glucuronic acid, sulfate, acetate, glycine, or glutathione. Some drugs may be directly metabolized by these conjugating reactions without first undergoing phase 1 activation. Phase 3 is the energy-dependent excretion of drug metabolites and their conjugates by an array of membrane transporters in the liver and kidney such as the multidrug resistant protein 1. Pathways for biotransformation are expressed early in the fetus and infant, but many phase 1 and phase 2 enzymes are immature, particularly in the 1st yr of life. CYP3A4 is the primary hepatic CYP expressed postnatally and metabolizes

more than 75 commonly used therapeutic drugs and several environmental pollutants and procarcinogens. Hepatic CYP3A4 activity is poorly expressed in the fetus but increases after birth to reach 30% of adult values by 1 mo and 50% of adult values between 6 and 12 mo of age. CYP3A4 can be induced by a number of drugs, including phenytoin, phenobarbital, and rifampin. Enhanced production of toxic metabolites can overwhelm the capacity of phase 2 reactions. Conversely, numerous inhibitors of CYP3A4 from several different drug classes, such as erythromycin and cimetidine, can lead to toxic accumulations of CYP3A4 substrates. By contrast, although CYP2D6 is also developmentally regulated (maturation by 10 yr of age), its activity depends more on genetic polymorphisms than on sensitivity to inducers and inhibitors because more than 70 allelic variants of CYP2D6 significantly influence the metabolism of many drugs. Uridine diphosphate glucuronosyltransferase 1A6, a phase 2 enzyme that glucuronidates acetaminophen, is also absent in the human fetus, increases slightly in the neonate, but does not reach adult levels until sometime after 10 yr of age. Mechanisms for the uptake and excretion of organic ions can also be deficient early in life. Impaired drug metabolism via phase 1 and phase 2 reactions present in the 1st few months of life is followed by a period of enhanced metabolism of many drugs in children through 10 yr of age compared with adults. Genetic polymorphisms in genes encoding enzymes and transporters mediating phases 1, 2, and 3 reactions can also be associated with impaired drug metabolism and an increased risk of hepatotoxicity. Some cases of idiosyncratic hepatotoxicity can occur as a result of aberrations (polymorphisms) in phase 1 drug metabolism, producing intermediates of unusual hepatotoxic potential combined with developmental, acquired, or relative inefficiency of phase 2 conjugating reactions. Genome-wide association studies have identified HLA associations in certain cases of drug- and toxin-induced liver injury (DILI ). Children may less susceptible than adults to hepatotoxic reactions; liver injury after the use of the anesthetic halothane is rare in children, and acetaminophen toxicity is less common in infants than in adolescents, whereas most cases of fatal hepatotoxicity associated with sodium valproate use have been reported in children. Excessive or prolonged therapeutic administration of acetaminophen combined with reductions in caloric or protein intake can produce hepatotoxicity in children. In this setting, acetaminophen metabolism may be impaired by reduced synthesis of sulfated and glucuronated metabolites and reduced stores of glutathione. Immaturity of hepatic drug metabolic pathways can prevent

degradation of a toxic agent; under other circumstances, the same immaturity might limit the formation of toxic metabolites. Severe sodium valproate hepatotoxicity is often associated with an underlying inherited mitochondrial disorder (Alper syndrome). Chemical hepatotoxicity can be predictable or idiosyncratic. Predictable hepatotoxicity implies a high incidence of hepatic injury in exposed persons depending on dose. It is understandable that only a few drugs in clinical use fall into this category. These agents might damage the hepatocyte directly through alteration of membrane lipids (peroxidation) or through denaturation of proteins; such agents include carbon tetrachloride and trichloroethylene. Indirect injury can occur through interference with metabolic pathways essential for cell integrity or through distortion of cellular constituents by covalent binding of a reactive metabolite; examples include the liver injury produced by acetaminophen or by antimetabolites such as methotrexate or 6-mercaptopurine. Idiosyncratic hepatotoxicity is unpredictable and accounts for the majority of adverse reactions. In contrast to previous dogma that idiosyncratic reactions are independent of dose, there is new information that higher doses of drugs metabolized in the liver pose a greater risk for hepatotoxicity. Idiosyncratic drug reactions in certain patients can reflect aberrant pathways for drug metabolism, possibly related to genetic polymorphisms, with production of toxic intermediates (isoniazid and sodium valproate can cause liver damage through this mechanism). Duration of drug use before liver injury varies (weeks to ≥1 yr) and the response to reexposure may be delayed. An idiosyncratic reaction can also be immunologically mediated as a result of prior sensitization (hypersensitivity); extrahepatic manifestations of hypersensitivity can include fever, rash, arthralgia, and eosinophilia. Duration of exposure before reaction is generally 1-4 wk, with prompt recurrence of injury on reexposure. Studies indicate that arene oxides, generated through oxidative (CYP) metabolism of aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine), can initiate the pathogenesis of some hypersensitivity reactions. Arene oxides, formed in vivo, can bind to cellular macromolecules, thus perturbing cell function and possibly initiating immunologic mechanisms of liver injury. Although the generation of chemically reactive metabolites has received great attention in the pathogenesis of hepatoxicity, increasing evidence now exists for the multifactorial nature of the process, in particular the role played by the host immune system. Activation of liver nonparenchymal Kupffer cells and

infiltration by neutrophils perpetuate toxic injury by many drugs by release of reactive oxygen and nitrogen species as well as cytokines. Stellate cells can also be activated, potentially leading to hepatic fibrosis and cirrhosis. The pathologic spectrum of drug-induced liver disease is extremely wide, is rarely specific, and can mimic other liver diseases (Table 390.2 ). Predictable hepatotoxins, such as acetaminophen, produce centrilobular necrosis of hepatocytes. Steatosis is an important feature of tetracycline (microvesicular) and ethanol (macrovesicular) toxicities. A cholestatic hepatitis can be observed, with injury caused by erythromycin estolate and chlorpromazine. Cholestasis without inflammation may be a toxic effect of estrogens and anabolic steroids. Use of oral contraceptives and androgens has also been associated with benign and malignant liver tumors. Some idiosyncratic drug reactions can produce mixed patterns of injury, with diffuse cholestasis and cell necrosis. Chronic hepatitis has been associated with the use of methyldopa and nitrofurantoin. Table 390.2

Patterns of Hepatic Drug Injury DISEASE Centrilobular necrosis

Microvesicular steatosis

Acute hepatitis

General hypersensitivity

Fibrosis Cholestasis

Sinusoidal obstruction syndrome (venoocclusive disease)

DRUG Acetaminophen Carbon tetrachloride Cocaine Ecstasy Iron Halothane Valproic acid Tetracycline Toluene Methotrexate Isoniazid Anti–tumor necrosis factor agents Valproic acid Sulfonamides Phenytoin Minocycline Methotrexate Chlorpromazine Aniline Erythromycin Paraquat Estrogens Sertraline Irradiation plus busulfan Arsenic

Portal and hepatic vein thrombosis Biliary sludge Hepatic adenoma or hepatocellular carcinoma

Cyclophosphamide Estrogens Androgens Ceftriaxone Oral contraceptives Anabolic steroids

Clinical manifestations can be mild and nonspecific, such as fever and malaise. Fever, rash, and arthralgia may be prominent in cases of hypersensitivity. In ill hospitalized patients, the signs and symptoms of hepatic drug toxicity may be difficult to separate from the underlying illness. The differential diagnosis should include acute and chronic viral hepatitis, biliary tract disease, septicemia, ischemic and hypoxic liver injury, malignant infiltration, and inherited metabolic liver disease. The laboratory features of drug- or toxin-related liver disease are extremely variable. Hepatocyte damage can lead to elevations of serum aminotransferase activities and serum bilirubin levels and to impaired synthetic function as evidenced by decreased serum coagulation factors and albumin. Hyperammonemia can occur with liver failure or with selective inhibition of the urea cycle (sodium valproate). Toxicologic screening of blood and urine specimens can aid in the detecting drug or toxin exposure. Percutaneous liver biopsy may be necessary to distinguish drug injury from complications of an underlying disorder or from intercurrent infection. Vanishing bile duct syndrome can be seen in a small portion of patients with idiosyncratic DILI. Slight elevation of serum aminotransferase activities (generally 1.5 not corrected by vitamin K in the presence of clinical hepatic encephalopathy, or a PT >20 sec or INR >2 regardless of the presence of clinical hepatic encephalopathy. Liver failure in the perinatal period can be associated with prenatal liver injury and even cirrhosis. Examples include gestational alloimmune liver disease (GALD), tyrosinemia, familial hemophagocytic lymphohistiocytosis (HLH), and some cases of congenital viral (herpes simplex virus [HSV]) infection. Liver disease may be noticed at birth or after several days of apparent well-being. Fulminant Wilson disease and fulminant autoimmune hepatitis also occurs in older children who were previously asymptomatic but, by definition, have preexisting liver disease. Other forms of acute-on-chronic liver failure can occur when a patient with an underlying liver disease such as biliary atresia develops hepatic decompensation after viral or drug-induced hepatic injury. In some cases of liver failure, particularly in the idiopathic form of acute hepatic failure, the onset of encephalopathy occurs later, from 8 to 28 wk after the onset of jaundice.

Etiology Infection Acute hepatic failure can be a complication of viral hepatitis (A, B, D, and rarely E), Epstein-Barr virus, herpes simplex virus, adenovirus, enterovirus, influenza A, cytomegalovirus, parvovirus B19, human herpesvirus-6, varicella zoster infection, parechovirus, and other respiratory illnesses. An unusually high rate of fulminant hepatic failure occurs in young people who have combined infections with the hepatitis B virus (HBV) and hepatitis D. Mutations in the precore and/or promoter region of HBV DNA are associated with fulminant and severe hepatitis. HBV is also responsible for some cases of fulminant liver failure in the absence of serologic markers of HBV infection but with HBV DNA found in the liver. Hepatitis E virus is an uncommon cause of fulminant hepatic failure in the United States, but can occur in pregnant women, in whom mortality rates rise dramatically to up to 25%. Patients with chronic hepatitis C are at risk if they have superinfection with hepatitis A virus.

Autoimmune Hepatitis Acute hepatic failure is caused by autoimmune hepatitis in approximately 5% of cases. Patients have a positive autoimmune marker (e.g., antinuclear antibody, anti–smooth muscle antibody, liver-kidney microsomal antibody, or soluble liver antigen) and possibly an elevated serum immunoglobulin G level. If a biopsy can be performed, liver histology often demonstrates interface hepatitis and a plasma cell infiltrate.

Metabolic Diseases Metabolic disorders associated with hepatic failure include Wilson disease, acute fatty liver of pregnancy, galactosemia, hereditary tyrosinemia, hereditary fructose intolerance, defects in β-oxidation of fatty acids, and deficiencies of mitochondrial electron transport, in particular mitochondrial DNA depletion disorders. Patients with Wilson disease who present in acute liver failure often have high bilirubin levels, low alkaline phosphatase levels, low uric acid levels, aspartate aminotransferase levels that are higher than alanine aminotransferase levels, and a Coombs-negative hemolytic anemia.

Neoplasm Acute liver failure can occur with malignancies including leukemia, lymphoma, and familial HLH . Acute liver failure is a common feature of HLH caused by several gene defects, infections by mostly viruses of the herpes group, and a variety of other conditions including organ transplantation and malignancies. Impaired function of natural killer cells and cytotoxic T-lymphocyte cells with uncontrolled hemophagocytosis and cytokine overproduction is characteristic for genetic and acquired forms of HLH. Patients with HLH present with a combination of fever, splenomegaly, cytopenias, high triglyceride levels, very high ferritin levels, low natural killer cell activity, high soluble CD25 levels; they may also have hemophagocytosis on bone marrow or liver biopsy (see Chapter 534 ).

Gestational Alloimmune Liver Disease GALD is the most common cause of acute liver failure in the neonate. In this alloimmune process, maternal immunoglobulin (Ig) G antibodies bind to fetal liver antigens and activate the terminal complement cascade resulting in hepatocyte injury and death. Infants with GALD present with low/normal aminotransferases that are out of proportion to their degree of liver failure. They may have significant hypoglycemia, jaundice, coagulopathy, and hypoalbuminemia. Alpha fetoprotein levels are typically high as are serum ferritin levels.

Drug-Induced Liver Injury Various hepatotoxic drugs and chemicals can also cause drug-induced liver injury and acute hepatic failure. Predictable liver injury can occur after exposure to carbon tetrachloride, Amanita phalloides mushrooms or after acetaminophen overdose. Acetaminophen is the most common identifiable etiology of acute hepatic failure in children and adolescents in the United States and England. In addition to the acute intentional ingestion of a massive dose, a therapeutic misadventure leading to severe liver injury can also occur in ill children given doses of acetaminophen exceeding weight-based recommendations for many days. Such patients can have reduced stores of glutathione after a prolonged illness and a period of poor nutrition. Idiosyncratic damage can follow the use of drugs such as halothane, isoniazid, ecstasy, or sodium valproate. Herbal and

weight loss supplements are additional causes of hepatic failure (see Chapter 390 ).

Vascular Ischemia and hypoxia resulting from hepatic vascular occlusion, severe heart failure, cyanotic congenital heart disease, or circulatory shock can produce liver failure.

Idiopathic Acute Liver Failure Idiopathic acute liver failure accounts for 40–50% of acute hepatic failure cases in children. The disease occurs sporadically and usually without the risk factors for common causes of viral hepatitis. It is likely that the etiology of these cases is heterogeneous, including unidentified or variant viruses, excessive immune activation, and undiagnosed genetic or metabolic disorders. There is increasing recognition of some children presenting with indeterminate acute hepatitis or acute liver failure who have evidence of immune activation including markedly elevated sIL-2R levels but never fulfilling diagnostic criteria for HLH. Recurrent, acute liver failure has been reported with onset in infancy due to mutations of the neuroblastoma amplified sequence gene (NBAS) . Episodes are usually precipitated by fever and characterized by bouts of vomiting and lethargy. Massively elevated aminotransferase levels and coagulopathy are present. Microvesicular steatosis is prominent on liver biopsy. Most patients recovered with restoration of normal liver function after control of fever and maintenance of energy balance with the infusion of intravenous glucose. The function of NBAS protein remains uncertain but it appears to be involved in retrograde transport between the endoplasmic reticulum and Golgi apparatus.

Pathology Liver biopsy usually reveals patchy or confluent massive necrosis of hepatocytes. Multilobular or bridging necrosis can be associated with collapse of the reticulin framework of the liver. There may be little or no regeneration of hepatocytes. A zonal pattern of necrosis may be observed with certain insults. Centrilobular damage is associated with acetaminophen hepatotoxicity or with circulatory shock. Evidence of severe hepatocyte dysfunction rather than cell

necrosis is occasionally the predominant histologic finding (microvesicular fatty infiltrate of hepatocytes is observed in Reye syndrome, β-oxidation defects, and tetracycline toxicity).

Pathogenesis The mechanisms that lead to acute hepatic failure are poorly understood. It is unknown why only approximately 1–2% of patients with viral hepatitis experience liver failure. Massive destruction of hepatocytes might represent both a direct cytotoxic effect of the virus and an immune response to the viral antigens. Of patients with HBV-induced liver failure, – become negative for serum hepatitis B surface antigen within a few days of presentation and often have no detectable HBV antigen or HBV DNA in serum. These findings suggest a hyperimmune response to the virus that underlies the massive liver necrosis. Formation of hepatotoxic metabolites that bind covalently to macromolecular cell constituents is involved in the liver injury produced by drugs such as acetaminophen and isoniazid; acute hepatic failure can follow depletion of intracellular substrates involved in detoxification, particularly glutathione. Whatever the initial cause of hepatocyte injury, various factors can contribute to the pathogenesis of liver failure, including impaired hepatocyte regeneration, altered parenchymal perfusion, endotoxemia, and decreased hepatic reticuloendothelial function.

Clinical Manifestations Acute hepatic failure can be the presenting feature of liver disease or it can complicate previously known liver disease (acute-on-chronic liver failure). A history of developmental delay and/or neuromuscular dysfunction can indicate an underlying mitochondrial or β-oxidation defect. A child with acute hepatic failure has usually been previously healthy and most often has no risk factors for liver disease such as exposure to toxins or blood products. Progressive jaundice, fetor hepaticus, fever, anorexia, vomiting, and abdominal pain are common. A rapid decrease in liver size without clinical improvement is an ominous sign. A hemorrhagic diathesis and ascites can develop. Patients should be closely observed for hepatic encephalopathy, which is initially characterized by minor disturbances of consciousness or motor function.

Irritability, poor feeding, and a change in sleep rhythm may be the only findings in infants; asterixis may be demonstrable in older children. Patients are often somnolent, confused, or combative on arousal and can eventually become responsive only to painful stimuli. Patients can rapidly progress to deeper stages of coma in which extensor responses and decerebrate and decorticate posturing appear. Respirations are usually increased early, but respiratory failure can occur in stage IV coma (Table 391.1 ). The pathogenesis of hepatic encephalopathy is likely related to increased serum levels of ammonia, false neurotransmitters, amines, increased γ-aminobutyric acid receptor activity, or increased circulating levels of endogenous benzodiazepine-like compounds. Decreased hepatic clearance of these substances can produce marked central nervous system dysfunction. The mechanisms responsible for cerebral edema and intracranial hypertension in acute liver failure (ALF) suggest both cytotoxic and vasogenic injury. There is increasing evidence for an inflammatory response (synthesis and release of inflammatory factors from activated microglia and endothelial cells) which acts in synergy with hyperammonemia to cause severe astrocyte swelling/brain edema. Table 391.1

Stages of Hepatic Encephalopathy

Symptoms

Signs

STAGES I Periods of lethargy, euphoria; reversal of day-night sleeping; may be alert Trouble drawing figures, performing mental tasks

Electroencephalogram Normal

II Drowsiness, inappropriate behavior, agitation, wide mood swings, disorientation Asterixis, fetor hepaticus, incontinence

Generalized slowing, q waves

III Stupor but arousable; confused, incoherent speech Asterixis, hyperreflexia, extensor reflexes, rigidity Markedly abnormal triphasic waves

IV Coma: IVa responds to noxious stimuli; IVb no response Areflexia, no asterixis, flaccidity

Markedly abnormal bilateral slowing, d waves, electrocortical silence

Laboratory Findings Serum direct and indirect bilirubin levels and serum aminotransferase activities

may be markedly elevated. Serum aminotransferase activities do not correlate well with the severity of the illness and can decrease as a patient deteriorates. The blood ammonia concentration is usually increased, but hepatic coma can occur in patients with a normal blood ammonia level. PT and the INR are prolonged and often do not improve after parenteral administration of vitamin K. Hypoglycemia can occur, particularly in infants. Hypokalemia, hyponatremia, metabolic acidosis, or respiratory alkalosis can also develop.

Treatment Specific therapies for identifiable causes of acute liver failure include N acetylcysteine (acetaminophen), acyclovir (herpes simplex virus), penicillin (Amanita mushrooms), nucleos(t)ide analogs such as entecavir (hepatitis B virus [HBV]), and prednisone (autoimmune hepatitis). Immunosuppression with corticosteroids should also be considered in children with the indeterminate form of fulminant hepatic failure with immune activation to avoid progression to liver transplantation or death. However, controlled trials have shown a worse outcome in patients treated with corticosteroids in patients without an immune basis for liver injury. Treatment of GALD involves a combination of double-volume exchange transfusion to remove existing reactive antibody followed immediately by administration of high-dose intravenous immunoglobulin (IVIG) (1 g/kg) to block antibody induced complement activation. Management of other types of acute hepatic failure is supportive. No therapy is known to reverse hepatocyte injury or to promote hepatic regeneration. An infant or child with acute hepatic failure should be cared for in an institution able to perform a liver transplantation if necessary and managed in an intensive care unit with continuous monitoring of vital functions. Endotracheal intubation may be required to prevent aspiration, to reduce cerebral edema by hyperventilation, and to facilitate pulmonary toilet. Mechanical ventilation and supplemental oxygen are often necessary in advanced coma. Sedatives should be avoided unless needed in the intubated patient because these agents can aggravate or precipitate encephalopathy. Opiates may be better tolerated than benzodiazepines. Prophylactic use of proton pump inhibitors should be considered because of the high risk of gastrointestinal bleeding. Hypovolemia should be avoided and treated with cautious infusions of isotonic fluids and blood products. Renal dysfunction can result from dehydration, acute tubular necrosis, or functional renal failure (hepatorenal

syndrome). Electrolyte and glucose solutions should be administered intravenously to maintain urine output, to correct or prevent hypoglycemia, and to maintain normal serum potassium concentrations. Hyponatremia is common and should be avoided; it is usually dilutional and not a result of sodium depletion. Parenteral supplementation with calcium, phosphorus, and magnesium may be required. Hypophosphatemia, probably a reflection of liver regeneration, and early phosphorus administration are associated with a better prognosis in acute liver failure, whereas hyperphosphatemia predicts a failure of spontaneous recovery. Coagulopathy should be treated with parenteral administration of vitamin K. Fresh-frozen plasma, cryoprecipitate, platelets, activated factor VII, or prothrombin complex concentrates can be used to treat clinically significant bleeding or can be given if an invasive procedure such as placement of a central line or an intracranial monitor needs to be performed. Plasmapheresis can permit temporary correction of the bleeding diathesis without resulting in volume overload. Continuous hemofiltration is useful for managing fluid overload, acute renal failure, and hyperammonemia. Patients should be monitored closely for infection, including sepsis, pneumonia, peritonitis, and urinary tract infections. At least 50% of patients experience serious infection. Gram-positive organisms (Staphylococcus aureus, Staphylococcus epidermidis) are the most common pathogens, but Gramnegative and fungal infections are also observed. Gastrointestinal hemorrhage, infection, constipation, sedatives, electrolyte imbalance, and hypovolemia can precipitate encephalopathy and should be identified and corrected. Protein intake should be initially restricted or eliminated, depending on the degree of encephalopathy. If encephalopathy or hyperammonemia develops, lactulose or rifaximin can be administered. N acetylcysteine is not effective in improving the outcome of patients with acute liver failure not associated with acetaminophen. Cerebral edema is an extremely serious complication of hepatic encephalopathy that responds poorly to measures such as corticosteroid administration and osmotic diuresis. Monitoring intracranial pressure can be useful in preventing severe cerebral edema, in maintaining cerebral perfusion pressure, and in establishing the suitability of a patient for liver transplantation. Temporary liver support continues to be evaluated as a bridge for the patient with liver failure to liver transplantation or regeneration. Nonbiologic systems, essentially a form of liver dialysis with an albumin-containing dialysate, and biologic liver support devices that involve perfusion of the patient's blood

through a cartridge containing liver cell lines or porcine hepatocytes can remove some toxins, improve serum biochemical abnormalities, and, in some cases, improve neurologic function, but there has been little evidence of improved survival, and few children have been treated. Orthotopic liver transplantation can be lifesaving in patients who reach advanced stages (III, IV) of hepatic coma. Reduced-size allografts and living donor transplantation have been important advances in the treatment of infants with hepatic failure. Partial auxiliary orthotopic or heterotopic liver transplantation is successful in a small number of children, and in some cases it has allowed regeneration of the native liver and eventual withdrawal of immunosuppression. Orthotopic liver transplantation should not be done in patients with liver failure and neuromuscular dysfunction secondary to a mitochondrial disorder because progressive neurologic deterioration is likely to continue after transplantation.

Prognosis Children with acute hepatic failure fare better than adults. Improved survival can be attributed to careful intensive care and if necessary liver transplantation. In the largest prospective study from the Pediatric Acute Liver Failure Study Group, 709 children were assessed at 21 days: 50.3% of patients survived with supportive care alone, 36.2% survived after liver transplantation, and 13.4% died. A scoring system based on peak values of total serum bilirubin, PT, and plasma ammonia concentration predicted transplant-free survival. Prognosis varies considerably with the cause of liver failure and stage of hepatic encephalopathy. Survival rates with supportive care may be as high as 90% in acetaminophen overdose and with fulminant hepatitis A. By contrast, spontaneous recovery can be expected in only approximately 40% of patients with liver failure caused by the idiopathic (indeterminate) form of acute liver failure or an acute onset of Wilson disease. Prognosis is also poor for spontaneous recovery in patients with mitochondrial deficits, hemophagocytic syndromes, herpes simplex disease, and idiosyncratic drug reactions. In patients who progress to stage IV coma (see Table 391.1 ), the prognosis is extremely poor. Brain stem herniation is the most common cause of death. Major complications such as sepsis, severe hemorrhage, or renal failure increase the mortality. The prognosis is particularly poor in patients with liver necrosis and multiorgan failure.

Age 4, PT >90 sec, low factor V levels, and the need for dialysis before transplantation are associated with increased mortality. Pretransplantation serum bilirubin concentration or the height of hepatic enzymes is not predictive of posttransplantation survival. A plasma ammonia concentration >200 µmol/L is associated with a 5-fold increased risk of death. Children with acute hepatic failure are more likely to die while on the waiting list compared to children with other liver transplant requiring diagnoses. Owing to the severity of their illness, the 6 mo post–liver transplantation survival of approximately 75% for acute liver failure is significantly lower than the 90% achieved in children with chronic liver disease. Patients who recover from fulminant hepatic failure with only supportive care do not usually develop cirrhosis or chronic liver disease. Aplastic anemia occurs in approximately 10% of children with the idiopathic form of fulminant hepatic failure and is often fatal without bone marrow transplantation. Long-term survivors demonstrate average IQ and visual spatial ability but greater than expected impairments in motor skills, attention, executive function, and healthrelated quality of life.

Bibliography Asrani SK, Simonetto DA, Kamath PS. Acute-on-chronic liver failure. Clin Gastroenterol Hepatol . 2015;13:2128–2139. Bigelow AM, Scott JP, Hong JC, et al. Human parechovirus as a cause of isolated pediatric acute liver failure. Pediatrics . 2016;138(5):e20160233. Bitar R, Thwaites R, Davison S, et al. Liver failure in early infancy: aetiology, Presentation, and outcome. J Pediatr Gastroenterol Nutr . 2017;64:70–75. Cardenas V, DiPaola F, Adams SD, et al. Acute liver failure secondary to neuroblastoma amplified sequence deficiency. J Pediatr . 2017;186:179–182. Feldman AG, Sokol RJ, Hardison RM, et al. Lactate and lactate: pyruvate ration in the diagnosis and outcomes of pediatric acute liver failure. J Pediatr . 2017;182:217–222. Feldman AG, Whitington PF. Neonatal hemochromatosis. J

Clin Exp Hepatol . 2013;3:313–320. Jain V, Dhawan A. Prognostic modeling in pediatric acute liver failure. Liver Transplant . 2016;22:1418–1430. Jimenez-Rivera C, Nightingale S, Benchimol EI, et al. Outcomes in infants listed for liver transplantation: a retrospective cohort study using the united network for organ sharing database. Pediatr Transplant . 2016;20:904–911. Kathemann S, Bechmann LP, Sowa JP, et al. Etiology, outcome and prognostic factors of childhood acute liver failure in a german single center. Ann Hepatol . 2015;14:722–728. Li R, Belle SH, Horslen S, et al. Clinical course among cases of acute liver failure of indeterminate diagnosis. J Pediatr . 2016;171:163–170. Li R, Belle SH, Horslen S, et al. Pediatric acute liver failure study G. Clinical course among cases of acute liver failure of indeterminate diagnosis. J Pediatr . 2016;171:163–170 [e161–e163]. Lu BR, Gralla J, Liu E, et al. Evaluation of a scroing system for assessing prognosis in pediatric acute liver failure. Clin Gastroenterol Hepatol . 2008;6(10):1140–1145. Narkewicz MR, Horslen S, Belle SH, et al. Prevalence and significance of autoantibodies in children with acute liver failure. J Pediatr Gastroenterol Nutr . 2017;64:210–217. Ng VL, Li R, Loomes KM, et al. Outcomes of children with and without hepatic encephalopathy from the pediatric acute liver failure study group. J Pediatr Gastroenterol Nutr . 2016;63:357–364. Sorensen LG, Neighbors K, Zhang S, et al. Neuropsychological functioning and health-related quality of life: pediatric acute liver failure study group results. J Pediatr Gastroenterol Nutr . 2015;60:75–83. Staufner C, Haack TB, Kopke MG, et al. Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum,

disease mechanisms, and therapeutic concepts. J Inherit Metab Dis . 2016;39:3–16. Taylor SA, Whitington PF. Neonatal acute liver failure. Liver Transpl . 2016;22:677–685. Uchida H, Sakamoto S, Fukuda A, et al. Sequential analysis of variable markers for predicting outcomes in pediatric patients with acute liver failure. Hepatology Res . 2017;47:1241– 1251. Wijdicks EFM. Hepatic encephalopathy. N Engl J Med . 2016;375(17):1660–1670. Zamora R, Vodovotz Y, Mi Q, et al. Data-driven modeling for precision medicine in pediatric acute liver failure. Mol Med . 2016;22.

CHAPTER 392

Cystic Diseases of the Biliary Tract and Liver Frederick J. Suchy, Amy G. Feldman

Cystic lesions of liver may be initially recognized during infancy and childhood. Hepatic fibrosis can also occur as part of an associated developmental defect (Table 392.1 ). Cystic renal disease is usually associated and often determines the clinical presentation and prognosis. Virtually all proteins encoded by genes mutated in combined cystic diseases of the liver and kidney are at least partially localized to primary cilia in renal tubular cells and cholangiocytes. Table 392.1 Syndromes Associated With Congenital Hepatic Fibrosis DISORDER Autosomal recessive polycystic kidney disease Autosomal dominant polycystic kidney disease Autosomal dominant polycystic liver disease Jeune syndrome Joubert syndrome COACH syndrome Meckel-Gruber syndrome Carbohydrate-deficient glycoprotein syndrome type 1b Ivemark syndrome type 2 Nephronophthisis type 3 Bardet-Biedl syndrome Oral-facial-digital syndrome type 1

ASSOCIATED FEATURES Ductal plate malformation, Caroli syndrome Ductal plate malformation, Caroli syndrome Rarely, congestive heart failure Asphyxiating thoracic dystrophy, with cystic renal tubular dysplasia, Caroli syndrome Central nervous system defects, cardiac malformations C erebellar vermis hypoplasia, o ligophrenia, congenital a taxia, ocular c oloboma, h epatic fibrosis Cystic renal dysplasia, abnormal bile duct development with fibrosis, posterior encephalocele, polydactyly Phosphomannose isomerase 1 deficiency chronic diarrhea, protein-losing enteropathy Autosomal-recessive renal-hepatic-pancreatic dysplasia Tapetoretinal degeneration Retinal degeneration, obesity, limb deformities, hypogonadism Oral clefts, hamartomas or cysts of the tongue, digital anomalies pancreatic cysts

Miscellaneous syndromes

Intestinal lymphangiectasia, enterocolitis, cystic short rib (Beemer-Langer) syndrome, osteochondrodysplasia

After Suchy FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children, ed 3, New York, 2014, Cambridge University Press, p. 713.

A solitary, congenital liver cyst (nonparasitic) can occur in childhood and has been identified in some cases on prenatal ultrasound. Abdominal distention and pain may be present, and a poorly defined right-upper-quadrant mass may be palpable. These benign lesions are best left undisturbed unless they compress adjacent structures or a complication occurs, such as hemorrhage into the cyst. Operative management is generally reserved for symptomatic patients and enlarging cysts.

Choledochal Cysts Choledochal cysts are congenital dilatations of the common bile duct that can cause progressive biliary obstruction and biliary cirrhosis. Cylindrical (fusiform) and spherical (saccular) cysts of the extrahepatic ducts are the most common types (see Table 392.1 ). Choledochal cysts are classified according to the Todani method (Fig. 392.1 ). Type 1 choledochal cysts, the most common variant, involve a saccular or fusiform dilation of the common bile duct. Type II cysts are congenital diverticula protruding from the common bile duct. Type III cysts or choledochoceles involve a herniation of the intraduodenal segment of the common bile duct into the duodenum. Type IVa cysts or Caroli disease involve multiple intrahepatic and extrahepatic cysts. Type IVb cysts involve only the extrahepatic duct. Solitary liver cysts (type V) are very rare.

FIG. 392.1 Classification of choledochal cysts according to Todani and colleagues. Ia, common type; Ib, segmental dilation; Ic, diffuse dilation; II, diverticulum; III, choledochocele; IVa, multiple cysts (intra- and extrahepatic); IVb, multiple cysts (extrahepatic); V, single or multiple dilations of the intrahepatic ducts (Caroli disease). (From Savader SJ, Benenati JF, Venbrux AC, et al. Choledochal cysts: Classification and cholangiographic appearance. AJR Am J Roentgenol 1991;156:327-31.)

The pathogenesis of choledochal cysts remains uncertain. Some reports suggest that junction of the common bile duct and the pancreatic duct before their entry into the sphincter of Oddi might allow reflux of pancreatic enzymes into the common bile duct, causing inflammation, localized weakness, and dilation of the duct. It has also been proposed that a distal congenital stenotic segment of the biliary tree leads to increased intraluminal pressure and proximal biliary dilation. Other possibilities are that choledochal cysts represent malformations of the common duct or that they occur as part of the spectrum of an infectious disease that includes neonatal hepatitis and biliary atresia. Approximately 75% of cases appear during childhood. The infant typically presents with cholestatic jaundice; severe liver dysfunction including ascites and coagulopathy can rapidly evolve if biliary obstruction is not relieved. An abdominal mass is rarely palpable. In an older child, the classic triad of

abdominal pain, jaundice, and mass occurs in 500 cells/mm3 , a negative culture, no intraabdominal source of infection, and no prior treatment with antibiotics. It should be treated in a similar manner as primary peritonitis.

Bibliography Runyon BA. Management of adult patients with ascites due to cirrhosis: an update. Hepatology . 2009;49:2087–2107. Singh S, Khardori NM. Intra-abdominal and pelvic emergencies. Med Clin North Am . 2012;96:1171–1191.

398.2

Acute Secondary Peritonitis Asim Maqbool, Jessica W. Wen, Chris A. Liacouras

Acute secondary peritonitis most often results from entry of enteric bacteria into the peritoneal cavity through a necrotic defect in the wall of the intestines or other viscus as a result of obstruction or infarction or after rupture of an

intraabdominal visceral abscess. It most commonly follows perforation of the appendix. Other causes include incarcerated hernias, rupture of a Meckel diverticulum, midgut volvulus, intussusception, hemolytic uremic syndrome, peptic ulceration, inflammatory bowel disease, necrotizing cholecystitis, necrotizing enterocolitis, typhlitis, and traumatic perforation. Peritonitis in the neonatal period most often occurs as a complication of necrotizing enterocolitis but may be associated with meconium ileus or spontaneous (or indomethacin-induced) rupture of the stomach or intestines. In postpubertal girls, bacteria from the genital tract (Neisseria gonorrhoeae, Chlamydia trachomatis) can gain access to the peritoneal cavity via the fallopian tubes, causing secondary peritonitis. The presence of a foreign body, such as a ventriculoperitoneal catheter or peritoneal dialysis catheter, can predispose to peritonitis, with skin microorganisms, such as Staphylococcus epidermidis, Staphylococcus aureus, and Candida albicans , contaminating the shunt. Secondary peritonitis results from direct toxic effects of bacteria as well as local and systemic release of inflammatory mediators in response to organisms and their products (lipopolysaccharide endotoxin). The development of sepsis depends on various host and disease factors, as well as promptness of antimicrobial and surgical intervention.

Clinical Manifestations Similar to primary peritonitis, characteristic symptoms include fever, diffuse abdominal pain, nausea, and vomiting. Physical findings of peritoneal inflammation include rebound tenderness, abdominal wall rigidity, a paucity of body motion (lying still), and decreased or absent bowel sounds from paralytic ileus. Massive exudation of fluid into the peritoneal cavity, along with the systemic release of vasodilative substances, can lead to the rapid development of shock. A toxic appearance, irritability, and restlessness are common. Basilar atelectasis as well as intrapulmonary shunting can develop, with progression to acute respiratory distress syndrome. Laboratory studies reveal a peripheral WBC count >12,000 cells/mm3 , with a marked predominance of polymorphonuclear forms. X-rays of the abdomen can reveal free air in the peritoneal cavity, evidence of ileus or obstruction, peritoneal fluid, and obliteration of the psoas shadow. Other peritoneal fluid findings suggestive of secondary peritonitis include elevated total protein (>1 g/dL), and low glucose (50% is usually symptomatic and often requires treatment. As with all cases of upper airway obstruction, tracheostomy is avoided when possible. Subglottic stenosis is typically measured using the Myer-Cotton system, with grade I through grade IV subglottic stenosis indicating the severity of narrowing. Dilation and endoscopic laser surgery can be attempted in grade I and II, although they may not be effective because most congenital stenoses are cartilaginous. Anterior cricoid split or laryngotracheal reconstruction with cartilage graft augmentation is typically used in grade III and IV subglottic stenosis. The differential diagnosis includes other anatomic anomalies, as well as a hemangioma or papillomatosis.

FIG. 413.2 Subglottic stenosis. (Courtesy Rn Cantab, Wikipedia Commons.)

Bibliography Myer CM, O'Conner DM, Cotton RT. Proposed grading system for subglottic stenosis based on endotracheal tube sizes. Ann Otol Rhinol Laryngol . 1994;103(4 Pt 1):319–323. Sandu K, Monnier P. Cricotracheal resection. Otolaryngol Clin North Am . 2008;41:988–998. Schroeder JW Jr, Holinger LD. Congenital laryngeal stenosis. Otolaryngol Clin North Am . 2008;41:865–875.

413.3

Vocal Cord Paralysis Jill N. D'Souza, James W. Schroeder Jr

Keywords vocal cord paralysis bilateral unilateral clinical manifestations Vocal cord paralysis is the third most common congenital laryngeal anomaly that produces stridor in infants and children. Congenital central nervous system lesions such as Chiari malformation, myelomeningocele, and hydrocephalus or birth trauma may be associated with bilateral paralysis. Bilateral vocal cord paralysis produces airway obstruction manifested by respiratory distress and high-pitched inspiratory stridor, aphonatory or dysphonic sound, or inspiratory weak cry. Unilateral vocal cord paralysis is most often iatrogenic, as a result of surgical treatment for aerodigestive (tracheoesophageal fistula) and cardiovascular (patent ductus arteriosus repair) anomalies, although they may also be idiopathic. Unilateral paralysis causes aspiration, coughing, and choking; the cry is weak and breathy, but stridor and other symptoms of airway obstruction are less common. Vocal cord paralysis in older children may be due to a Chiari malformation or tumors compressing the vagus or recurrent laryngeal nerve.

Diagnosis The diagnosis of vocal cord paralysis is made by awake flexible laryngoscopy. The examination will demonstrate an inability or weakness to abduct the involved vocal cord. A thorough investigation for the underlying primary cause is indicated. Because of the association with other congenital lesions, evaluation includes neurology and cardiology consultations, imaging of the course of the recurrent laryngeal nerve, and diagnostic endoscopy of the larynx, trachea, and bronchi.

Treatment Treatment is based on the severity of the symptoms. Idiopathic vocal cord paralysis in infants usually resolves spontaneously within 6-12 mo. If it is not

resolved by 2-3 yr of age, function typically does not recover. For unilateral vocal cord paralysis, injection laterally to the paralyzed vocal cord moves it medially to reduce aspiration and related complications. Reinnervation procedures using the ansa cervicalis have been successful in regaining some function of unilateral vocal cord. Bilateral paralysis may require temporary tracheotomy in 50% of patients. Airway augmentation procedures in bilateral vocal cord paralysis typically focus on widening the posterior glottis, such as an endoscopically placed or open posterior glottis cartilage graft, arytenoidectomy, or arytenoid lateralization. These procedures are generally successful in reducing the obstruction; however, they may result in dysphagia and aspiration.

Bibliography Zur K, Carrol L. Recurrent laryngeal nerve reinnervation in children: acoustic and endoscopic characteristics Preintervention and Post-intervention. A comparison of treatment options. Laryngoscope . 2015;Supp 125(11):S1– S15.

413.4

Congenital Laryngeal Webs and Atresia Jill N. D'Souza, James W. Schroeder Jr

Keywords laryngeal web

glottis web laryngeal atresia Congenital laryngeal webs are typically located in the anterior glottis with subglottic extension and associated subglottic stenosis, and they result from incomplete recanalization of the laryngotracheal tube. They may be asymptomatic. Thick webs may be suspected in lateral radiographs of the airway. Chromosomal and cardiovascular anomalies, as well as chromosome 22q11 deletion, are common in patients with congenital laryngeal web. Diagnosis is made by direct laryngoscopy (Fig. 413.3 ). Treatment might require only incision or dilation. Webs with associated subglottic stenosis are likely to require cartilage augmentation of the cricoid cartilage (laryngotracheal reconstruction). Laryngeal atresia occurs as a complete glottic web due to failure of laryngeal and tracheal recanalization and may be associated with tracheal agenesis and tracheoesophageal fistula. Laryngeal atresia may be detected in the prenatal period, and preparations should be made for establishment of definitive airway at birth. Other times, congenital laryngeal atresia is a cause of respiratory distress in the newborn and is diagnosed only upon initial direct laryngoscopy.

FIG. 413.3 Anterior glottic web, endoscopic view. (Courtesy Dr. Jeff Rastatter, Division of Pediatric Otolaryngology, Lurie Children's Hospital, Chicago, IL.)

Bibliography Ambrosiom A, Magit A. Respiratory distress of the newborn: congenital laryngeal atresia. Int J Pediatr Otorhinolaryngol . 2012;76(11):1685–1687. McElhinney DB, Jacobs I, McDonald-McGinn DM, et al. Chromosomal and cardiovascular anomalies associated with congenital laryngeal web. Int J Pediatr Otorhinolaryngol . 2002;66(1):23–27. Shah J, White K, Dohar J. Vocal characteristics of congenital anterior glottic webs in children: a case report. Int J Pediatr Otorhinolaryngol . 2015;79(6):941–945.

413.5

Congenital Subglottic Hemangioma Jill N. D'Souza, James W. Schroeder Jr

Keywords subglottic hemangioma beard distribution vascular lesions biphasic stridor Subglottic hemangioma is a rare cause of early infancy respiratory distress. Symptoms typically present within the 1st 2-6 mo of life. The most common presenting symptom is biphasic stridor, somewhat more prominent during inspiration. This is exacerbated by crying and acute viral illnesses. A barking cough, hoarseness, and symptoms of recurrent or persistent croup are typical.

Only 1% of children who have cutaneous hemangiomas will have a subglottic hemangioma. However, 50% of those with a subglottic hemangioma will have a cutaneous hemangioma. A facial hemangioma is not always present, but when it is evident, it is in the beard distribution, and thus, respiratory distress in a child with a vascular lesion in this area should prompt further investigation. Chest and neck radiographs can show the characteristic asymmetric narrowing of the subglottic larynx. Airway vascular lesions may also be associated with PHACES syndrome , characterized by Posterior Fossa Malformations, Hemangioma, Arterial lesions of head and neck, Cardiac anomalies, Eye Anomalies, and Sternal cleft. More than 50% of children with PHACES syndrome have an airway vascular lesion. Treatment options range from conservative monitoring, steroid injection to tracheotomy and airway reconstruction. Propranolol has become a mainstay in initial therapy of subglottic hemangioma; however, it is estimated that up to 50% of patients with subglottic hemangioma may not have a long-term response to propranolol, indicating a need for close airway monitoring in these patients (Fig. 413.4 ). Treatment is further discussed in Chapter 417.3 .

FIG. 413.4 A and B, Case of tracheal hemangioma prepropranolol and postpropranolol therapy (pictures 2 wk apart). (From Bush A, Abel R, Chitty L, et al: Congenital lung disease. In Wilmott RW, Deterding R, Li A, et al, editors: Kendig's disorders of the respiratory tract in children , ed 9, Philadelphia, 2019, Elsevier, Fig. 18.18, p. 308.)

Bibliography

Durr ML, Meyer NK, Huoh KC, et al. Airway hemangiomas in PHACE syndrome. Laryngoscope . 2012;122:2323–2329. Hardison S, Wan W, Dodson KM. The use of propranolol in the treatment of subglottic hemangiomas: a literature review and Meta-analysis. Int J Pediatr Otorhinolaryngol . 2016;90:175– 180. Rahbar R, et al. The biology and management of subglottic hemangioma: past, Present, Future. Laryngoscope . 2004;114(11):1880–1891. Saetti R, Silvestrini M, Cutrone C, et al. Treatment of congenital subglottic hemangiomas: our experience compared with reports in the literature. Arch Otolaryngol Head Neck Surg . 2008;134(8):848–851. Siegel B, Mehta D. Open airway surgery for subglottic hemangioma in the era of propranolol: is it still indicated. Int J Pediatr Otorhinolaryngol . 2015;79(7):1124–1127.

413.6

Laryngoceles and Saccular Cysts Jill N. D'Souza, James W. Schroeder Jr

Keywords laryngocele saccular cyst A laryngocele is an abnormal air-filled dilation of the laryngeal saccule that arises vertically between the false vocal cord, the base of the epiglottis, and the

inner surface of the thyroid cartilage. It communicates with the laryngeal lumen and, when intermittently filled with air, causes hoarseness and dyspnea. A saccular cyst (congenital cyst of the larynx) is distinguished from the laryngocele in that its lumen is isolated from the interior of the larynx and it contains mucus, not air. In infants and children, laryngoceles cause hoarseness and dyspnea that may increase with crying. Saccular cysts may cause respiratory distress and stridor at birth and may require early airway intervention. Intubation can be challenging because the supraglottic and laryngeal anatomy may be distorted. In addition, complete airway obstruction may occur on induction with neuromuscular blockade acting on laryngeal tone. A saccular cyst may be visible on radiography, but the diagnosis is made by laryngoscopy (Fig. 413.5 ). Needle aspiration of the cyst confirms the diagnosis but rarely provides a cure. Surgical excision is the therapy of choice for management of saccular cysts and laryngoceles. Approaches include endoscopic CO2 laser excision, endoscopic extended ventriculotomy (marsupialization or unroofing), or, traditionally, external excision.

FIG. 413.5 Endoscopic photograph of a saccular cyst. (From Ahmad SM, Soliman AMS: Congenital anomalies of the larynx, Otolaryngol Clin North Am 40:177–191, 2007, Fig. 3.)

Bibliography Civantos FJ, Holinger LD. Laryngoceles and saccular cysts in infants and children. Arch Otolaryngol Head Neck Surg . 1992;118:296–300. Kirse DJ, Rees CJ, Celmer AW, et al. Endoscopic extended ventriculotomy for congenital saccular cysts of the larynx in infants. Arch Otolaryngol Head Neck Surg . 2006;132(7):724–728. Parkes WJ, Propst EJ. Advances in the diagnosis, Management, and treatment of neonates with laryngeal disorders. Semin Fetal Neonatal Med . 2016 http://dx.doi.org.10.1016/j.siny.2016.03.003 .

413.7

Posterior Laryngeal Cleft and Laryngotracheoesophageal Cleft Jill N. D'Souza, James W. Schroeder Jr

The posterior laryngeal cleft is characterized by aspiration and is the result of a deficiency in the midline of the posterior larynx. Posterior laryngeal clefts are categorized into 4 types. Type 1 clefts are mild and the interarytenoid notch extends only down to the level of the true vocal cords; 60% of these will cause no symptoms and will not require surgical repair. In severe cases, the cleft (type 4) extends inferiorly into the cervical or thoracic trachea so there is no separation between the trachea and esophagus, creating a laryngotracheoesophageal cleft. Laryngeal clefts can occur in families and are likely to be associated with tracheal agenesis, tracheoesophageal fistula, and multiple congenital anomalies,

as with G syndrome, Opitz-Frias syndrome, and Pallister-Hall syndrome. Initial symptoms are those of aspiration and recurrent respiratory infections. Esophagogram is undertaken to evaluate presence of aspiration or laryngeal penetration of ingested contrast material. A FEES exam may be undertaken by an otolaryngologist with assistance of a speech language and pathology team to observe pattern of liquid spillage during swallow and may identify a cleft. However, the gold standard of diagnosis remains operative laryngoscopy and bronchoscopy with palpation of the posterior larynx. This assists in determining length of the cleft and guides treatment options. A type I cleft extends to, but not beyond, the vocal cords. A type II cleft extends beyond the vocal cords to, but not through, the cricoid cartilage. A type III cleft extends through cricoid into cervical trachea. A type IV cleft extends into thoracic trachea. Treatment is based on the cleft type and the symptoms; in general, a type I cleft may be managed endoscopically, whereas higher grades may require an open procedure. Stabilization of the airway is the first priority. Gastroesophageal reflux must be controlled and a careful assessment for other congenital anomalies is undertaken before repair. Several endoscopic and open cervical and transthoracic surgical repairs have been described.

Bibliography Alexander NS, et al. Postoperative observation of children after endoscopic type I posterior laryngeal cleft repair. Otolaryngol Head Neck Surg . 2015;152(1):153–158. Moungthong G, Holinger LD. Laryngotracheoesophageal clefts. Ann Otol Rhinol Laryngol . 1997;106:1002–1011. Rahbar R, Roullon I, Roger G, et al. The presentation and management of laryngeal cleft. Arch Otolaryngol Head Neck Surg . 2006;132:1335–1341. Shehab ZP, Bailey CM. Type IV laryngotracheoesophageal clefts—recent 5 year experience at great ormond street hospital for children. Int J Pediatr Otorhinolaryngol . 2001;60(1):1–9.

413.8

Vascular and Cardiac Anomalies Jill N. D'Souza, James W. Schroeder Jr

Keywords vascular ring vascular compression tracheobronchomalacia Aberrant cardiopulmonary vascular anatomy may directly impact the trachea and bronchi. The aberrant innominate artery is the most common cause of secondary tracheomalacia (see Chapter 459 ). It may be asymptomatic and discovered incidentally, or it may cause severe symptoms. Expiratory wheezing and cough occur and, rarely, reflex apnea or “dying spells.” Surgical intervention is rarely necessary. Infants are most commonly treated expectantly because the problem is often self-limited. The term vascular ring is used to describe vascular anomalies that result from abnormal development of the aortic arch complex. The double aortic arch is the most common complete vascular ring, encircling both the trachea and esophagus, compressing both. With few exceptions, these patients are symptomatic by 3 mo of age. Respiratory symptoms predominate, but dysphagia may be present. The diagnosis is established by barium esophagogram that shows a posterior indentation of the esophagus by the vascular ring (see Fig. 459.2 in Chapter 459 ). CT or MRI with angiography provides the surgeon the information needed. Other vascular anomalies include the pulmonary artery sling, which also requires surgical correction. The most common open (incomplete) vascular ring is the left aortic arch with aberrant right subclavian artery. Although common, it is usually asymptomatic, although dysphagia lusoria may be described. This is characterized as dysphagia caused by an aberrant subclavian coursing behind the

esophagus, leading to esophageal compression and difficulty with bolus transit. Congenital cardiac defects are likely to compress the left main bronchus or lower trachea. Any condition that produces significant pulmonary hypertension increases the size of the pulmonary arteries, which in turn cause compression of the left main bronchus. Surgical correction of the underlying pathology to relieve pulmonary hypertension relieves the airway compression.

Bibliography Backer CL, Monge MC, Popescu AR, et al. Vascular rings. Semin Pediatr Surg . 2016;25(3):165–175. Backer CM, Mavroudis C, Gerber ME, et al. Tracheal surgery in children: an 18-year review of four techniques. Eur J Cardiothorac Surg . 2001;19:777–784. Hannemann K, Newman B, Chan F. Congenital variants and anomalies of the aortic arch. Radiographics . 2017;37(1):32– 51. Hofferberth SG, Watters K, Rahbar R, Fynn-Thompson F: Management of congenital tracheal stenosis.

413.9

Tracheal Stenoses, Webs, and Atresia Jill N. D'Souza, James W. Schroeder Jr

Long segment congenital tracheal stenosis with complete tracheal rings typically occurs within the 1st yr of life, usually after a crisis has been precipitated by an acute respiratory illness. The diagnosis may be suggested by plain radiographs. CT with contrast delineates associated intrathoracic anomalies such as the pulmonary artery sling, which occurs in one third of patients; one-fourth have

associated cardiac anomalies. Bronchoscopy is the best method to define the degree and extent of the stenosis and the associated abnormal bronchial branching pattern. Treatment of clinically significant stenosis involves tracheal resection of short segment stenosis, slide tracheoplasty for long segment stenosis or tracheal rings. Congenital soft tissue stenosis and thin webs are rare. Dilation may be all that is required.

Bibliography Ywakim R, El-Hakim H. Congenital tracheal stenosis managed conservatively: systematic review of the literature. J Otolaryngol Head Neck Surg . 2012;41(4):288–302.

413.10

Foregut Cysts Jill N. D'Souza, James W. Schroeder Jr

The embryologic foregut gives rise to the pharynx, lower respiratory tract, esophagus, stomach, duodenum, and hepatobiliary tract, and duplication cysts can occur anywhere along this tract. Foregut duplications account for approximately one third of all duplications. The bronchogenic cyst, intramural esophageal cyst (esophageal duplication), and enteric cyst can all produce symptoms of respiratory obstruction and dysphagia. The diagnosis is suspected when chest radiographs or CT scan delineate the mass and, in the case of enteric cyst, the associated vertebral anomaly. The treatment of all foregut cysts is surgical excision.

Bibliography Barnes NA, Pilling DW. Bronchopulmonary foregut

malformations: embryology, radiology and quandary. Eur Radiol . 2003;13(12):2659–2673. Hills S, Maddalozzo J. Congenital lesions of epithelial origin. Otolaryngol Clin North Am . 2015;48(1):209–223.

413.11

Tracheomalacia and Bronchomalacia See Chapter 416 .

Bibliography Lyons M, Vlastarakos PV, Nikolopoulos TP. Congenital and acquired developmental problems of the upper airway in newborns and infants. Early Hum Dev . 2012;88(12):951– 955. Ryan G, Somme S, Crombleholme TM. Airway compromise in the fetus and neonate: prenatal assessment and perinatal management. Semin Fetal Neonatal Med . 2016;21:230–239. Zoumalan R, Maddalozzo J, Holinger LD. Etiology of stridor in infants. Ann Otol Rhinol Laryngol . 2007;116:329–334.

CHAPTER 414

Foreign Bodies in the Airway Allison R. Hammer, James W. Schroeder Jr

Epidemiology and Etiology Choking is a leading cause of morbidity and mortality among children, especially those younger than 4 yr of age. Most victims of foreign body aspiration are older infants and toddlers (Fig. 414.1 ); males have been found to be victims up to 1.7 times more likely than females. Studies show that children younger than 4 yr of age account for 61.7–70% of airway foreign body cases. The most common objects on which children choke are food items (59.5–81% of all choking cases). Nuts, seeds, hot dogs, hard candy, gum, bones, and raw fruits and vegetables are the most frequently aspirated food items. From 2001 to 2009, an average of 12,435 children ages 0-14 yr in the United States were treated in emergency departments for choking on food without fatality. Common inorganic objects on which children choke include coins, latex balloons, pins, jewelry, magnets, pen caps, and toys. Globular, compressible, or round objects such as hot dogs, grapes, nuts, balloons, marshmallows, meats, and candies are particularly hazardous due to their ability to completely occlude the airway.

FIG. 414.1 Number of fatalities versus victim age, all fatality types. (From Milkovich SM, Altkorn R, Chen X, et al: Development of the small parts cylinder: lessons learned, Laryngoscope 118[11]:2082–2086, 2008.)

Young children are more at risk to aspirate a foreign body largely because of their developmental vulnerabilities and their underdeveloped ability to swallow food. Infants and toddlers often use their mouths to explore their surroundings, and children generally are more likely to be distracted, playing, or ambulatory while eating. An infant is able to suck and swallow and is equipped with involuntary reflexes (gag, cough, and glottis closure) that help to protect against aspiration during swallowing. Dentition develops at approximately 6 mo of age with the eruption of the incisors. Molars do not erupt until approximately 1.5 yr of age; mature mastication takes longer to develop. Despite a strong gag reflex, a child's airway is more vulnerable to obstruction than an adult's airway. Young children are more likely to experience significant blockage by small foreign bodies due to their smaller airway diameter. Mucus and secretions may form a seal around the foreign body, making it more difficult to dislodge by forced air. In addition, the force of air generated by an infant or young child's cough is less effective in dislodging an airway obstruction. It is recommended that children younger than 5 yr of age should avoid hard candy and chewing gum and that raw fruits and vegetables be cut into small pieces. Other factors, such as developmental delays or disorders causing neurologic or muscular issues, can also put children at higher risk for foreign body aspiration.

Clinical Manifestations Foreign bodies of the airway have variable presentations and complications,

depending on the characteristics, duration, and location of the foreign body. The clinical manifestations range from an asymptomatic state to severe respiratory distress. The most serious complication of foreign body aspiration is complete obstruction of the airway, which may be recognized in the conscious child as sudden respiratory distress followed by an inability to speak or cough. There are typically three stages of symptoms that result from aspiration of an object into the airway: 1. Initial event: Paroxysms of coughing, choking, gagging, and possibly airway obstruction occur immediately after aspiration of the foreign body. The child is sometimes able to expel the foreign body during this stage. 2. Asymptomatic interval: The foreign body becomes lodged, reflexes fatigue, and the immediate irritating symptoms subside. The lack of symptoms can be particularly misleading to the provider when a child presents in this stage and accounts for a large percentage of delayed diagnoses and overlooked foreign bodies . A large meta-analysis of more than 30,000 patients showed that diagnosis is delayed more than 25 hr in almost 40% of airway foreign body cases. 3. Complications: Obstruction, erosion, or infection develops, which again directs attention to the presence of a foreign body. In this third stage, complications include fever, cough, hemoptysis, pneumonia, and atelectasis. Acute or chronic complications have been reported in almost 15% of cases of foreign bodies of the airway.

Diagnosis History is the most important factor in determining the need for bronchoscopy. A positive history must never be ignored, but a negative history can be misleading. Because nuts and seeds are the most common bronchial foreign bodies, the physician should specifically question the child's parents about these items, and bronchoscopy should be carried out promptly. A comprehensive physical exam is also essential, including examination of the nose, oral cavity, pharynx, neck, and lungs. Choking or coughing episodes accompanied by new-onset wheezing and asymmetric breath sounds are highly suggestive of foreign body in the airway. In addition to history and physical examination, radiology studies have

an important role in diagnosing foreign bodies in the airway. Plain films are typically recommended first, although many foreign bodies are radiolucent (80– 96%), and therefore providers often must rely on secondary findings (such as air trapping, asymmetric hyperinflation, obstructive emphysema, atelectasis, mediastinal shift, and consolidation) to indicate suspicion of a foreign body. Expiratory or lateral decubitus films can assist in revealing these suggestive secondary findings. The indication for computed tomography of the chest is currently being explored due to its high sensitivity and specificity, its ability to detect radiolucent objects, and its potential to eliminate the need for an anesthesia and procedure. However, the known risks of radiation must certainly be considered. If there is a high index of suspicion despite negative or inconclusive imaging, bronchoscopy should be performed.

Treatment The treatment of choice for airway foreign bodies is prompt endoscopic removal with rigid instruments by a specialist (otolaryngologist or pulmonologist). Bronchoscopy is deferred only until providers have obtained preoperative studies and the patient has been prepared by adequate hydration and emptying of the stomach. Airway foreign bodies are usually removed the same day the diagnosis is first considered. As with any treatment modality, providers must give careful consideration to the risks and benefits of the bronchoscopy procedure when diagnosis is unclear. Potential complications of rigid bronchoscopy include bronchospasm, desaturation, bleeding, and airway edema, in addition to the inherent risks of anesthesia. Beyond the understanding of diagnosis and management of airway foreign bodies, there is a strong need and push for awareness, education, and prevention among caregivers, healthcare providers, and manufacturers of food and toys.

414.1

Laryngeal Foreign Bodies Allison R. Hammer, James W. Schroeder Jr

Although laryngeal foreign bodies are less common (2–12% of cases) than bronchial or tracheal foreign bodies, they are particularly dangerous due to risk of complete laryngeal obstruction, which can asphyxiate the child unless it is promptly relieved with the Heimlich maneuver (see Chapter 81 and Figs. 81.6 and 81.7 ). Objects that are partially obstructive of the larynx are usually flat and thin and lodge between the vocal cords in the sagittal plane, causing symptoms of croup, hoarseness, cough, stridor, and dyspnea.

414.2

Tracheal Foreign Bodies Allison R. Hammer, James W. Schroeder Jr

Tracheal foreign bodies account for 3–12% of airway foreign body cases. Children who have tracheal foreign bodies can present with dysphonia, dysphagia, dry cough, or biphasic stridor. Posteroanterior and lateral soft tissue neck radiographs (airway films) are abnormal in 92% of children, whereas chest radiographs are abnormal in only 58% of these cases.

414.3

Bronchial Foreign Bodies Allison R. Hammer, James W. Schroeder Jr

Most airway foreign bodies lodge in a bronchus (80–90% of cases). Occasionally, fragments of a foreign body may produce bilateral involvement or

shifting infiltrates if they move from lobe to lobe. Some children with bronchial foreign bodies present asymptomatically, whereas others have asymmetric breath sounds, coughing, and wheezing. Posteroanterior and lateral chest radiographs (including the abdomen) are standard in the assessment of infants and children suspected of having aspirated a foreign object. An expiratory posteroanterior chest film is most helpful. During expiration, the bronchial foreign body obstructs the exit of air from the obstructed lung, producing obstructive emphysema and air trapping. The persistent inflation of the obstructed lung causes shift of the mediastinum toward the opposite side (Fig. 414.2 ). Air trapping is an immediate complication, whereas atelectasis is a late finding. Lateral decubitus chest films or fluoroscopy can provide the same information as expiratory films but are often unnecessary. History and physical examination, not radiographs, determine the indication for bronchoscopy.

FIG. 414.2 A, Normal inspiratory chest radiograph in a toddler with a peanut fragment in the left main bronchus. B, Expiratory radiograph of the same child showing the classic obstructive emphysema (air trapping) on the involved (left) side. Air leaves the normal right side allowing, the lung to deflate. The medium shifts toward the unobstructed side.

Bibliography

American Academy of Pediatrics. Committee on injury, violence, and poison prevention: prevention of choking among children. Pediatrics . 2010;125:601–607. Archarya K. Rigid bronchoscopy in airway foreign bodies: value of the clinical and radiological signs. Int Arch Otorhinolaryngol . 2016;20:196–201. Chapin MM, Rochette LM, Annest JL, et al. Nonfatal choking on food among children 14 years or younger in the United States, 2001–2009. Pediatrics . 2013;132:275–281. Foltran F, Ballali S, Passali FM, et al. Foreign bodies in the airways: a meta-analysis of published papers. Int J Pediatr Otorhinolaryngol . 2012;76S:S12–S19. Friedman EM, Anthony MD. A five-year analysis of airway foreign body management: toward a better understanding of negative bronchoscopies. Ann Otol Rhinol Laryngol . 2016;125(7):591–595. Lowe DA, Vasquez R, Maniaci V. Foreign body aspiration in children. Clin Ped Emerg Med . 2015;16(3):140–148. Maraynes M, Agoritsas K. Inhaled foreign bodies in pediatric patients: proven management techniques in the emergency department. Pediatr Emerg Med Pract . 2015;12(10):1–14. Rodríguez H, Passali GC, Gregori D, et al. Management of foreign bodies in the airway and oesophagus. Int J Pediatr Otorhinolaryngol . 2012;76(Suppl 1):S84–S91.

CHAPTER 415

Laryngotracheal Stenosis and Subglottic Stenosis Taher Valika, James W. Schroeder Jr

Laryngotracheal stenosis is the second most common cause of stridor in neonates and is the most common cause of airway obstruction requiring tracheostomy in infants. The glottis (vocal cords) and the upper trachea are compromised in most laryngeal stenosis, particularly those that develop following endotracheal intubation. Subglottic stenosis is a narrowing of the subglottic larynx, which is the space extending from the undersurface of the true vocal cords to the inferior margin of the cricoid cartilage. Subglottic stenosis is considered congenital when there is no other apparent cause such as a history of laryngeal trauma or intubation. Approximately 90% of cases manifest in the 1st yr of life. Management relies on fine-tuning the airway, while ensuring the patient continues to grow. Knowledge of preventative measures is imperative to all healthcare members.

415.1

Congenital Subglottic Stenosis Keywords subglottic stenosis

See Chapter 413.2 .

415.2

Acquired Laryngotracheal Stenosis Taher Valika, James W. Schroeder Jr

Keywords subglottic stenosis laryngotracheal stenosis Ninety percent of acquired stenoses are a result of endotracheal intubation. The narrowest portion of the pediatric larynx is the subglottic region due to the narrow cricoid cartilage. When the pressure of the endotracheal tube against the cricoid mucosa is greater than the capillary pressure, ischemia occurs, followed by necrosis and ulceration. Secondary infection and perichondritis develop with exposure of cartilage (Fig. 415.1 ). Granulation tissue forms around the ulcerations. These changes and edema throughout the larynx usually resolve spontaneously after extubation. Chronic edema and fibrous stenosis develop in only a small percentage of cases.

FIG. 415.1 Bronchoscopy in a 2 mo old infant showing mucosal erosion and cartilage exposure in the subglottic region. Child was intubated with an age-appropriate tube but with an excess of air in cuff. (Courtesy Dr. Taher Valika, Division of Pediatric Otolaryngology, Ann & Robert H. Lurie Children's Hospital of Chicago.)

A number of factors predispose to the development of laryngeal stenosis. Laryngopharyngeal reflux of acid and pepsin from the stomach is known to exacerbate endotracheal tube trauma. More damage is caused in areas left unprotected, owing to loss of mucosa. Congenital subglottic stenosis narrows the larynx which makes the patient more likely to develop acquired subglottic stenosis because significant injury is more likely to occur with use of an endotracheal tube of age-appropriate size. Other risk factors for the development of acquired subglottic stenosis include sepsis, malnutrition, chronic inflammatory disorders, and immunosuppression. An oversized endotracheal tube is the most common factor contributing to laryngeal injury. A tube that allows a small air leak at the end of the inspiratory cycle minimizes potential trauma. Other extrinsic factors—traumatic intubation, multiple reintubations, movement of the endotracheal tube, and duration of intubation—can contribute to varying degrees in individual patients.

Clinical Manifestations

Symptoms of acquired and congenital stenosis are similar. Spasmodic croup, the sudden onset of severe croup in the early morning hours, is usually caused by laryngopharyngeal reflux with transient laryngospasm and subsequent laryngeal edema. These frightening episodes resolve rapidly, often before the family and child reach the emergency department. Other presentations can also involve neonates who fail extubation, despite multiple attempts, and children with permanent dyspnea, stridor, or dysphonia.

Diagnosis The diagnosis can be made by posteroanterior and lateral airway radiographs. The gold standard to confirm the diagnosis is via direct laryngoscopy and bronchoscopy in the operating room. High-resolution CT imaging and ultrasonography are of limited value. This is similar to the workup associated with congenital subglottic stenosis.

Treatment The severity, location, and type (cartilaginous or soft tissue) of the stenosis determine the treatment. Mild cases can be managed without operative intervention because the airway will improve as the child grows. Moderate soft tissue stenosis is treated by endoscopy using gentle dilations or CO2 laser. Severe laryngotracheal stenosis is likely to require laryngotracheal reconstructive (expansion) surgery or resection of the narrowed portion of the laryngeal and tracheal airway (cricotracheal resection). Every effort is made to avoid tracheotomy using endoscopic techniques or open surgical procedures. Fundamental knowledge of the airway can help to reduce the incidence of stenoses. The use of age-appropriate tubes and cuffless tubes, treatment of gastroesophageal reflux, and reducing the duration of mechanical ventilation have led to an overall decrease in laryngotracheal stenoses in the past decade.

Bibliography Benjamin B, Holinger LD. Laryngeal complications of endotracheal intubation. Ann Otol Rhinol Laryngol .

2008;117(Suppl 200):1–20. Ida JB, Thompson DM. Pediatric stridor. Otolaryngol Clin North Am . 2014;47(5):795–819. Markovitz BP, Randolph AG, Khemanu RG. Corticosteroids for the prevention and treatment of post-extubation stridor in neonates, children and adults. Cochrane Database Syst Rev . 2008;(2) [CD001000]. Rizzi MD, Thorne MC, Zur KB, et al. Laryngotracheal reconstruction with posterior cartilage grafts. Otolaryngol Head Neck Surg . 2009;140:348–353.

CHAPTER 416

Bronchomalacia and Tracheomalacia Jonathan D. Finder

Tracheomalacia and bronchomalacia refer to chondromalacia of a central airway, leading to insufficient cartilage to maintain airway patency throughout the respiratory cycle. These are common causes of persistent wheezing in infancy. Tracheomalacia and bronchomalacia can be either primary or secondary (Table 416.1 ). Primary tracheomalacia and bronchomalacia are often seen in premature infants, although most affected patients are born at term. Secondary tracheomalacia and bronchomalacia refer to the situation in which the central airway is compressed by an adjacent structure (e.g., vascular ring; see Chapter 345 ) or deficient in cartilage because of tracheoesophageal fistula (see Chapter 345 ). Bronchomalacia is common following lung transplantation, assumed to be secondary to the loss of bronchial artery supply leading to ischemia of the bronchial cartilage. This form of bronchomalacia may take months to present following transplantation. Laryngomalacia can accompany primary bronchomalacia or tracheomalacia. Involvement of the entire central airway (laryngotracheobronchomalacia) is also seen. Table 416.1

Classification of Tracheomalacia PRIMARY TRACHEOMALACIA Congenital absence of tracheal-supporting cartilages SECONDARY TRACHEOMALACIA Esophageal atresia, tracheoesophageal fistula Vascular rings (double aortic arch) Tracheal compression from an aberrant innominate artery Tracheal compression from mediastinal masses Abnormally soft tracheal cartilages associated with connective tissue disorders Prolonged mechanical ventilation, chronic lung disease

From McNamara VM, Crabbe DC: Tracheomalacia, Paediatr Respir Rev 5:147–154, 2004.

Clinical Manifestations Primary tracheomalacia and bronchomalacia are principally disorders of infants, with a male:female ratio of 2 : 1. The dominant finding, low-pitched monophonic wheezing heard predominantly during expiration, is most prominent over the central airways. Parents often describe persistent respiratory congestion even in the absence of a viral respiratory infection. When the lesion involves only one main bronchus (more commonly the left), the wheezing is louder on that side and there may be unilateral palpable fremitus. In cases of tracheomalacia, the wheeze is loudest over the trachea. Hyperinflation and/or subcostal retractions do not occur unless the patient also has concurrent asthma, viral bronchiolitis, or other causes of peripheral airways obstruction. In the absence of asthma, patients with tracheomalacia and bronchomalacia are not helped by administration of a bronchodilator. Acquired tracheomalacia and bronchomalacia are seen in association with vascular compression (vascular rings, slings, and innominate artery compression) or in association with the loss of bronchial artery supply in lung transplantation. Tracheomalacia is the rule following correction of tracheoesophageal fistula. Other causes of acquired tracheomalacia, which may persist after surgical correction include cardiomegaly. The importance of the physical exam cannot be understated; one study found that pediatric pulmonologists made a correct assessment of malacia based on symptoms, history, and lung function prior to bronchoscopy in 74% of cases.

Diagnosis Definitive diagnoses of tracheomalacia and bronchomalacia are established by flexible or rigid bronchoscopy (Fig. 416.1 ). The lesion is difficult to detect on plain radiographs. Although fluoroscopy can demonstrate dynamic collapse and avoid the need for invasive diagnostic techniques, it is poorly sensitive. Pulmonary function testing can show a pattern of decreased peak flow and flattening of the flow-volume loop. Other important diagnostic modalities include MRI and CT scanning. MRI with angiography is especially useful when there is a possibility of vascular ring and should be performed when a right

aortic arch is seen on plain film radiography.

FIG. 416.1 Four examples of tracheomalacia appearances. A, Commashaped trachea caused by innominate artery compression requiring aortopexy. B, Bunched-up trachealis muscle and compressed trachea caused by a double aortic arch. C, Flattened trachea and increased trachealis diameter with a tracheoesophageal fistula in the posterior wall. D, Ovoid-shaped trachea from external compression by innominate artery. (From Deacon JWF, Widger J, Soma MA: Paediatric tracheomalacia—A review of clinical features and comparison of diagnostic imaging techniques, Int J Pediatr Otorhinolaryngol 98:75–81, 2017.)

Treatment Postural drainage can help with clearance of secretions. β-Adrenergic agents should be avoided in the absence of asthma because they can exacerbate loss of airway patency due to decreased airway tone. Nebulized ipratropium bromide may be useful. Endobronchial stents have been used in severely affected patients but have a high incidence of complications, ranging from airway obstruction due to granulation tissue to erosion into adjacent vascular structures. Continuous positive airway pressure via tracheostomy may be indicated for severe cases. A surgical approach (aortopexy and bronchopexy) is rarely required and only for patients who have life-threatening apnea, cyanosis, and bradycardia (cyanotic spells) from airway obstruction and/or who demonstrated vascular compression. Reports of creation and use of 3-dimensional (3D) printed, bioresorbable external tracheobronchial stents in pediatric patients with life-threatening tracheobronchomalacia have shown great promise.

Prognosis Primary bronchomalacia and tracheomalacia have excellent prognoses because

airflow improves as the child and the airways grow. Patients with primary airway malacia usually take longer to recover from common respiratory infections. Wheezing at rest usually resolves by age 3 yr. Prolonged bacterial bronchitis has been reported as a complication of bronchomalacia. Prognosis in secondary and acquired forms varies with cause. Patients with concurrent asthma need considerable supportive treatment and careful monitoring of respiratory status.

Bibliography Anton-Pacheco JL, Cabezali D, Tejedor R, et al. The role of airway stenting in pediatric tracheobronchial obstruction. Eur J Cardiothorac Surg . 2008;33:1069–1075. Boogaard R, Huijsmans SH, Pijnenburg MW, et al. Tracheomalacia and bronchomalacia in children: incidence and patient characteristics. Chest . 2005;128:3391–3397. Carden KA, Boiselle PM, Waltz DA, et al. Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest . 2005;127:984–1005. Kompare M, Weinberger M. Protracted bacterial bronchitis in young children: association with airway malacia. J Pediatr . 2012;160:88–92. Mahajan AK, Folch E, Khandhar SJ, et al. The diagnosis and management of airway complications following lung transplantation. Chest . 2017 [pii: S0012-3692(17)30265-9]. Masters IB, Zimmerman PV, Pandeya N, et al. Quantified tracheobronchomalacia disorders and their clinical profiles in children. Chest . 2008;133:461–467. McNamara VM, Crabbe DC. Tracheomalacia. Paediatr Respir Rev . 2004;5:147–154. Morrison RJ, Hollister SJ, Niedner MF. Mitigation of tracheobronchomalacia with 3d-printed personalized medical devices in pediatric patients. Sci Transl Med . 2015;7(285):285ra64. Sanchez MO, Greer MC, Masters IB, et al. A comparison of

fluoroscopic airway screening with flexible bronchoscopy for diagnosing tracheomalacia. Pediatr Pulmonol . 2012;47:63– 67.

CHAPTER 417

Neoplasms of the Larynx, Trachea, and Bronchi Saied Ghadersohi, James W. Schroeder Jr

417.1

Vocal Nodules Saied Ghadersohi, James W. Schroeder Jr

Keywords Vocal nodules Vocal abuse Voice therapy Vocal nodules , which are not true neoplasms, are the most common cause of chronic hoarseness in children. Chronic vocal abuse or misuse (i.e., frequent yelling and screaming) produces localized vascular congestion, edema, hyalinization, and epithelial thickening in the bilateral vocal cords. This grossly appears as nodules that disrupt the normal vibration of the cords during phonation. Vocal abuse is the main factor, and the voice is worse in the evenings. Differential can include unilateral lesions such as vocal cord cysts and polyps; however, these usually have an acute inciting event and are rarer in

children. Treatment is primarily nonsurgical with voice therapy used in children >4 yr of age who can participate in therapy, and clinical monitoring with behavioral therapy in younger children or those with developmental delay. In addition, laryngopharyngeal reflux commonly exacerbates vocal abuse–induced irritation of the cord, Therefore antireflux therapy can also be implemented (see Chapter 349 ). Surgical excision of vocal cord lesions in children is controversial and is rarely indicated but may be necessary if the child is unable to communicate adequately, becomes aphonic, or requires tension and straining to make any utterance whatsoever.

417.2

Recurrent Respiratory Papillomatosis Saied Ghadersohi, James W. Schroeder Jr

Keywords Recurrent Respiratory Papillomas HPV Papillomas are the most common respiratory tract neoplasms in children, occurring in 4.3 in 100,000. They are simply warts—benign tumors— caused by the human papillomavirus (HPV), most commonly types 6 and 11 (see Chapter 293 ). Seventy-five percent of recurrent respiratory papilloma cases occur in children younger than age 5 yr, but the diagnosis may be made at any age. In general, neonatal-onset disease is a negative prognostic factor with higher mortality and need for tracheostomy. Sixty-seven percent of children with RRP are born to mothers who had condylomas during pregnancy or parturition. The mode of HPV transmission is still not clear. Neonates have been reported to have RRP, suggesting intrauterine transmission of HPV. Despite close association with

vaginal condylomata, only 1 in 231 to 400 vaginal births go on to develop respiratory papillomatosis. Therefore other risk factors contribute to transmission, and C-section delivery for prevention cannot be recommended. However, preventive measures can include the prospective widespread use of the quadrivalent HPV vaccine to help eliminate maternal and paternal HPV reservoirs and possibly decrease cases of RRP caused by HPV 6 and 11.

Clinical Manifestations The clinical course involves remissions and exacerbations of recurrent papillomas most commonly on the larynx (usually the vocal cords), causing progressively worsening hoarseness, sleep-disordered breathing, exertional dyspnea, stridor, and, if left untreated, eventually severe airway obstruction (Fig. 417.1 ). Although it is a benign disease, lesions can spread throughout the aerodigestive tract in 31% of patients, most commonly the oral cavity, trachea, and bronchi. Rarely these lesions can undergo malignant conversion (1.6%); however, some patients may have spontaneous remission. Patients may be initially diagnosed with asthma, croup, vocal nodules, or allergies.

FIG. 417.1 Laryngoscopic view of respiratory papillomas causing near complete obstruction at glottic level. (From Derkay CS, Wiatrak B: Recurrent respiratory papillomatosis: a review, Laryngoscope 118:1236– 1245, 2008.)

Treatment The treatment of RRP is endoscopic surgical removal with three goals. First, debulking/complete removal of the lesions, secondly, preservation of normal structures, and finally, prevention of scar formation in the affected areas. Most surgeons in North America prefer the microdebrider, although microsurgery, CO2 , and KTP laser techniques have been described. Despite these techniques, some form of adjunct therapy may be needed in up to 20% of cases. The most widely accepted indications for adjunct therapy are a need for more than four surgical procedures per year, rapid regrowth of papillomata with airway compromise, or distal multisite spread of disease. Adjunct therapies can be inhaled or administered intralesionally or systemically and include antiviral modalities (interferon, ribavirin, acyclovir, cidofovir), antiangiogenic agents such as bevacizumab (Avastin), photodynamic therapy, dietary supplement (indole-3-carbinol), nonsteroidal antiinflammatory drugs (COX2 inhibitors, Celebrex), retinoids, and mumps vaccination.

Bibliography Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope . 2008;118:1236–1245. Hawks M, Campisi P, Zafar R, et al. Time course of juvenile onset recurrent respiratory papillomatosis caused by human papillomavirus. Pediatr Infect Dis J . 2008;27:149–154. Maturo SC, Hartnick CJ. Juvenile-onset recurrent respiratory papillomatosis. Adv Otorhinolaryngol . 2012;73:105–108. Shah KV, Stern WF, Shah FK, et al. Risk factors for juvenile onset recurrent respiratory papillomatosis. Pediatr Infect Dis J . 1998;17:372 [PMID] 9613648. Syrjanen S. HPV in head and neck cancer. J ClinVirol. 2005;32(Suppl 1):S59–S66. Zeitels SM, Barbu AM, Landau-Zemer T, et al. Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study. Ann Otol Rhinol Laryngol .

2011;120(10):627–634 [PMID] 22097147.

417.3

Congenital Subglottic Hemangioma Saied Ghadersohi, James W. Schroeder Jr

Keywords congenital infantile hemangioma stridor

Clinical Manifestations Typically, congenital subglottic hemangiomas are symptomatic within the first 2 mo of life, almost all occurring before 6 mo of age. Much like the cutaneous infantile hemangiomas, these lesions have 2 phases: a proliferative phase with rapid growth in the first 6 mo of life, then they stabilize by 1 yr, and a slow involution phase typically by age 3. Patients present with usually inspiratory but sometimes biphasic stridor. The infant can have a barking cough and temporarily respond to steroids, similar to persistent croup. Fifty percent of congenital subglottic hemangiomas are associated with facial lesions, but the converse is not true. Radiographs classically delineate an asymmetric subglottic narrowing. The diagnosis is made by direct laryngoscopy.

Treatment The medical treatment of hemangiomas traditionally was with long-term

systemic steroids, which often had severe side effects, including growth retardation and adrenal suppression. Prednisone 2-4 mg/kg/day is given orally for 4-6 wk, typically with partial regression of the lesion. The dosage is then tapered. If there is no response, the drug is discontinued. Propranolol was introduced in 2008 and rapidly became the first-line treatment of infantile and subglottic hemangiomas, including in a recent randomized clinical trial comparing it with systemic steroids. The mechanism is thought to be through VEGF or adrenergic vasoconstriction pathways and can involute the lesion in a few days. Typically, treatment is with 1-3 mg/kg/day of propranolol for 4-12 mo, based on clinical monitoring as noted in a 2011 consensus guideline. Prescreening patients with cardiology workup (i.e., electrocardiogram) is advised. Side effects include hypotension, bradycardia, bronchospasm, and hypoglycemia; children treated with propranolol need to be monitored closely. Surgical management can range from intralesional steroid injection to avoid systemic steroid side effects, CO2 , or KTP laser endoscopic excision, and ultimately as a last resort tracheostomy can establish a safe airway, allowing time for the lesion to involute per its natural course.

Bibliography Bauman N, McCarter R, Guzzetta P, et al. Propranolol vs prednisolone for symptomatic proliferating infantile hemangiomas: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg . 2014;140(4):323. Drolet BA, et al. Initiation and use of propranolol for infantile hemangioma: a report of a consensus conference. Pediatrics . 2013;131:128–140 [PMID] 23266923. England R, Banerjee D, Shawber C, et al. Propranolol action is mediated via the beta-2 adrenergic receptor in hemangioma stem cells. Plast Reconstr Surg . 2013;131(5):62. Hoff SR, Rastatter JC, Richter GT. Head and neck vascular lesions. Otolaryngol Clin North Am . 2015;48(1):29–45.

417.4

Vascular Anomalies Saied Ghadersohi, James W. Schroeder Jr

Keywords Vascular malformations Vascular tumors Based on the International Society for the Study of Vascular Anomalies classification system, these lesions can be classified into vascular malformations and vascular tumors. The most common vascular tumors are infantile/subglottic hemangiomas and were previously discussed. Vascular malformations are not true neoplastic lesions. They have a normal rate of endothelial turnover and various channel abnormalities. They are subcategorized based on high or low flow and by their predominant type (capillary, venous, arterial, lymphatic, or a combination thereof). Overall, vascular malformations are uncommon, and they rarely occur in the larynx and airway. When they do occur, they are often an extension from elsewhere in the head and neck. It should be noted that these lesions can expand with a viral upper respiratory infection. They can be diagnosed with direct visualization during laryngoscopy or bronchoscopy or seen on CT/MRI imaging. Treatment usually entails a multidisciplinary team approach with early surgical or laser resection or sclerotherapy.

Bibliography Behr GG, Johnson C. Vascular anomalies: hemangiomas and beyond—part 1, Fast-flow lesions. AJR Am J Roentgenol . 2013;200(2):414–422. Behr GG, Johnson CM. Vascular anomalies: hemangiomas and

beyond—part 2, Slow-flow lesions. AJR Am J Roentgenol . 2013;200(2):423–436. Hoff SR, Rastatter JC, Richter GT. Head and neck vascular lesions. Otolaryngol Clin North Am . 2015;48(1):29–45.

417.5

Other Laryngeal Neoplasms James W. Schroeder Jr, Lauren D. Holinger

Keywords Neurofibromatosis Rhabdomyosarcoma Neurofibromatosis (see Chapter 614.1 ) rarely involves the larynx. When children are affected, limited local resection is undertaken to maintain an airway and optimize the voice. Complete surgical extirpation is virtually impossible without debilitating resection of vital laryngeal structures. Most surgeons select the option of less-aggressive symptomatic surgery because of the poorly circumscribed and infiltrative nature of these fibromas. Rhabdomyosarcoma (see Chapter 527 ) and other malignant tumors of the larynx are rare. Symptoms of hoarseness and progressive airway obstruction prompt initial evaluation by flexible laryngoscopy in the office.

417.6

Tracheal Neoplasms

Saied Ghadersohi, James W. Schroeder Jr, Lauren D. Holinger

Keywords Inflammatory pseudotumor hamartomas Tracheal tumors are extremely rare and include malignant and benign neoplasms; they may initially be misdiagnosed as asthma. The 2 most common benign tumors are inflammatory pseudotumor and hamartoma. The inflammatory pseudotumor is probably a reaction to a previous bronchial infection or traumatic insult. Growth is slow, and the tumor may be locally invasive. Hamartomas are tumors of primary tissue elements that are abnormal in proportion and arrangement. Tracheal neoplasms manifest with stridor, wheezing, cough, or pneumonia and are rarely diagnosed until 75% of the lumen has been obstructed (Fig. 417.2 ). Chest radiographs or airway films can identify the obstruction. Pulmonary function studies demonstrate an abnormal flow-volume loop. A mild response to bronchodilator therapy may be misleading. Treatment is based upon the histopathology.

FIG. 417.2 A CT scan of the trachea with a circumscribed intraluminal tracheal mass (arrow) in the tracheal wall. (From Venizelos I, Papathomas T, Anagnostou E, et al: Pediatric inflammatory myofibroblastic tumor of the trachea: a case report and review of the literature, Pediatr Pulmonol 43:831–835, 2008.)

Bibliography Desai DP, Holinger LD, Gonzalez-Crussi F. Tracheal neoplasms in children. Ann Otol Rhinol Laryngol . 1998;107(9 Pt 1):790–796. Pugnale MJ, Maresh A, Sinha P, et al. Pediatric tracheal tumor masked by a history of travel: case report and literature review. Laryngoscope . 2015;125:1004–1007; 10.1002/lary.24968 .

417.7

Bronchial Tumors Saied Ghadersohi, James W. Schroeder Jr

Keywords Carcinoid tumor pseudotumor Bronchial tumors are rare. In 1 series, carcinoid tumors were the most common, followed by mucoepidermoid and pseudotumors. These patients can present with persistent pneumonia despite adequate treatment. The diagnosis is confirmed at bronchoscopy and biopsy; treatment depends on the histopathology.

Bibliography Al-Qahtani SR, et al. Endobronchial tumors in children: institutional experience and literature review. J Pediatr Surg . 2003;38(5):733–736.

CHAPTER 418

Wheezing, Bronchiolitis, and Bronchitis 418.1

Wheezing in Infants: Bronchiolitis Samantha A. House, Shawn L. Ralston

Keywords Bronchiolitis Wheezing Respiratory Syncytial Virus (RSV)

General Pathophysiology of Wheezing in Infants Wheezing, the production of a musical continuous sound that originates in narrowed airways, is heard on expiration as a result of airway obstruction. Infants are more likely to wheeze than are older children, as a result of differing lung mechanics. Obstruction of airflow is affected by both airway size and compliance of the infant lung. Resistance to airflow through a tube is inversely related to the radius of the tube to the 4th power. In children younger than 5 yr, small-caliber peripheral airways can contribute up to 50% of the total airway

resistance. Marginal additional narrowing, such as that caused by inflammation related to viral infection, is then more likely to result in wheezing. Infant chest wall compliance is also quite high, thus the inward pressure produced in normal expiration subjects the intrathoracic airways to collapse. Differences in tracheal cartilage and airway smooth muscle tone increase the collapsibility of the infant airways in comparison with older children. These mechanisms combine to make the infant more susceptible to airway obstruction, increased resistance, and subsequent wheezing. The mechanical portion of the infant propensity to wheeze resolves with normal growth and muscular development. Although wheezing in infants most frequently results from inflammation due to acute viral infections, there are many potential causes of wheezing (Table 418.1 ). Table 418.1

Differential Diagnosis of Wheezing in Infancy INFECTION Viral Respiratory syncytial virus Human metapneumovirus Parainfluenza Adenovirus Influenza Rhinovirus Bocavirus Coronavirus Enterovirus Other Chlamydia trachomatis Tuberculosis Histoplasmosis Papillomatosis ASTHMA ANATOMIC ABNORMALITIES Central Airway Abnormalities Malacia of the larynx, trachea, and/or bronchi Laryngeal or tracheal web Tracheoesophageal fistula (specifically H-type fistula) Laryngeal cleft (resulting in aspiration) Extrinsic Airway Anomalies Resulting in Airway Compression Vascular ring or sling Mediastinal lymphadenopathy from infection or tumor Mediastinal mass or tumor Esophageal foreign body Intrinsic Airway Anomalies

Airway hemangioma, other tumor Congenital pulmonary airway malformation (cystic adenomatoid malformation) Bronchial or lung cyst Congenital lobar emphysema Aberrant tracheal bronchus Sequestration Congenital heart disease with left-to-right shunt (increased pulmonary edema) Foreign body Immunodeficiency States Immunoglobulin A deficiency B-cell deficiencies AIDS Bronchiectasis MUCOCILIARY CLEARANCE DISORDERS Cystic fibrosis Primary ciliary dyskinesia Bronchiectasis ASPIRATION SYNDROMES Gastroesophageal reflux disease Pharyngeal/swallow dysfunction OTHER Bronchopulmonary dysplasia Eosinophilic granulomatosis with polyangiitis Interstitial lung disease, including bronchiolitis obliterans Heart failure Anaphylaxis Inhalation injury—burns

Acute Bronchiolitis Acute bronchiolitis is a diagnostic term used to describe the clinical picture produced by several different viral lower respiratory tract infections in infants and very young children. The respiratory findings observed in bronchiolitis include tachypnea, wheezing, crackles, and rhonchi which result from inflammation of the small airways (Fig. 418.1 ). Despite its commonality, a universal set of diagnostic criteria for bronchiolitis does not exist, with significant disagreement about the upper age limit for appropriate use of the diagnosis. Some clinicians restrict the term to children younger than 1 yr, and others extend it to the age of 2 yr or beyond.

FIG. 418.1 Typical clinical course and pathophysiology of viral bronchiolitis. (From Florin TA, Plint PC, Zorc JJ: Viral bronchiolitis, Lancet 389:211–224, 2017 [Fig. 1, p. 212]).

The pathophysiology of acute bronchiolitis is characterized by bronchiolar obstruction with edema, mucus, and cellular debris (see Fig. 418.1 ). Resistance in the small air passages is increased during both inspiration and exhalation, but because the radius of an airway is smaller during expiration, the resultant respiratory obstruction leads to expiratory wheezing, air trapping, and lung hyperinflation. If obstruction becomes complete, trapped distal air will be

resorbed and the child will develop atelectasis. Hypoxemia is a consequence of ventilation-perfusion mismatch. With severe obstructive disease hypercapnia can develop. Respiratory syncytial virus (RSV) is responsible for more than 50% of cases of bronchiolitis in most reports. Other agents include human metapneumovirus, rhinovirus, parainfluenza, influenza, bocavirus, and adenovirus. Viral coinfection is reported to impact severity and clinical manifestations, although its significance remains contested. Respiratory viruses can be identified in more than one third of asymptomatic patients younger than the age of 1 yr, calling into question the specificity of current tests for active infection. Although bacterial pneumonia is sometimes confused clinically with bronchiolitis, viral bronchiolitis is rarely followed by bacterial superinfection. Well over 100,000 young children are hospitalized annually in the United States with the diagnosis of bronchiolitis, making it the most common diagnosis resulting in hospitalization for children younger than 1 yr of age in the United States over the past several decades. The increasing rates of hospitalization for bronchiolitis observed from 1980 to 1996 (thought to reflect increased attendance of infants in daycare centers, changes in criteria for hospital admission linked to pulse oximetry use, and/or improved survival of premature infants and other children at risk for severe disease) have not continued. Hospitalization rates have been stable in subsequent years despite introduction and routine use of RSV immunoprophylaxis in high-risk populations. Bronchiolitis is more common in males, those exposed to second-hand tobacco smoke, those who have not been breastfed, and those living in crowded conditions. Risk is also higher for infants with mothers who smoked during pregnancy. Older family members, including older siblings, are a common source of infection; they might experience only minor upper respiratory symptoms (colds) given that bronchiolar edema may be less clinically apparent as airway size increases. Asthma (see Chapter 169 ) is another important cause of wheezing, and the possibility of this diagnosis complicates the treatment of young children with bronchiolitis, although accurate diagnosis of asthma in the very young can be difficult. In prospective, longitudinal population cohort studies of infants, up to half of the cohort experienced a wheezing illness prior to school age, although when followed into adulthood only about 5–8% of patients prove to have asthma. In the largest U.S. cohort, 3 patterns of infant wheezing were proposed: transient early wheezing, comprising about 20% of the cohort, characterized by

lower lung function at birth which improves with growth resulting in resolution of wheezing by age 3; persistent wheezing, comprising about 14% of the cohort, characterized by declining lung function and wheezing before and after age 3; and late-onset wheezing, comprising 15% of the cohort, characterized by relatively stable lung function and wheezing that does not begin until after age 3. The remaining 50% of the population did not suffer a wheezing illness. Following the cohort into adulthood revealed continued declines in the rates of persistent symptoms. Similar patterns are also seen in birth cohort studies in other countries. Multiple studies attempting to predict which infants suffering from early wheezing illnesses will go on to have asthma in later life have failed to achieve discriminant validity. Interestingly, in both U.S. and U.K. prospective cohorts, wheezing with an onset after the first 18-36 mo of life is one of the strongest predictors of eventual asthma in both cohorts. Other proposed risk factors for persistent wheezing include parental history of asthma and allergies, maternal smoking, persistent rhinitis (apart from acute upper respiratory tract infections), allergen sensitization, eczema, and peripheral eosinophilia, although no single factor is strongly discriminative. Despite several randomized trials, there is no evidence that early administration of inhaled corticosteroids to high-risk populations can prevent the development of asthma.

Clinical Manifestations History and Physical Examination The initial history of a wheezing infant should describe the recent event including onset, duration, and associated factors (Table 418.2 ). Birth history includes weeks of gestation, neonatal complications including history of intubation or oxygen requirement, maternal complications, and prenatal smoke exposure. Past medical history includes any comorbid conditions. Family history of cystic fibrosis, immunodeficiencies, asthma in a first-degree relative, or any other recurrent respiratory conditions in children should be obtained. Social history should include any second-hand tobacco or other smoke exposure, daycare exposure, number of siblings, pets, and concerns regarding home environment (e.g., dust mites, construction dust, heating and cooling techniques, mold, cockroaches). The patient's growth chart should be reviewed for signs of failure to thrive.

Table 418.2

Pertinent Medical History in the Wheezing Infant Did the onset of symptoms begin at birth or thereafter? Is the infant a noisy breather, and when is it most prominent? Is the noisy breathing present on inspiration, expiration, or both? Is there a history of cough apart from wheezing? Was there an earlier lower respiratory tract infection? Is there a history of recurrent upper or lower respiratory tract infections? Have there been any emergency department visits, hospitalizations, or intensive care unit admissions for respiratory distress? Is there a history of eczema? Does the infant cough after crying or cough at night? How is the infant growing and developing? Is there associated failure to thrive? Is there a history of electrolyte abnormalities? Are there signs of intestinal malabsorption including frequent, greasy, or oily stools? Is there a maternal history of genital herpes simplex virus infection? What was the gestational age at delivery? Was the patient intubated as a neonate? Does the infant bottle-feed in the bed or the crib, especially in a propped position? Are there any feeding difficulties including choking, gagging, arching, or vomiting with feeds? Is there any new food exposure? Is there a toddler in the home or lapse in supervision in which foreign body aspiration could have occurred? Change in caregivers or chance of nonaccidental trauma?

Acute bronchiolitis is usually preceded by exposure to contacts with a minor respiratory illness within the previous week (see Fig. 418.1 ). The infant first develops signs of upper respiratory tract infection with sneezing and clear rhinorrhea. This may be accompanied by diminished appetite and fever. Gradually, respiratory distress ensues, with paroxysmal cough, dyspnea, and irritability. The infant is often tachypneic, which can interfere with feeding. Apnea may precede lower respiratory signs early in the disease, particularly with very young infants. Term infants at a postconceptual age of 10% or >1,500 cells/µL) in the blood. Evidence of vasculitis on clinical grounds must be present in at least 2 organs. The polyangiitis appears later in the disease process with asthma being the precursor symptom in more than 90% of the cases reported. EGPA affects multiple organs including the skin, heart, gastrointestinal tract, kidneys, and central nervous system (Table 427.12 ). Rhinitis is present in 75% of the patients but is not specific. Symptom complexes of fever, weight loss, fatigue, arthralgia, and myalgia may be seen in approximately two-thirds of patients. Cardiac and renal involvement is insidious in onset and should be screened for. It is the multiple organ involvement that results in the morbidity and mortality of this disease. The typical progression of the disease is in 3 phases: rhinitis and asthma first, tissue eosinophilia second, and, finally, systemic vasculitis. Table 427.12 Eosinophilic Granulomatosis With Polyangiitis VASCULITIC PHENOTYPE Respective frequency ANCA Predominant manifestations

~40% Present (mostly perinuclear-ANCA with antiMPO specificity) Glomerular renal disease Peripheral neuropathy Purpura

EOSINOPHILIC TISSULAR DISEASE PHENOTYPE ~60% Absent Cardiac involvement (eosinophilic myocarditis) Eosinophilic pneumonia

Biopsy-proven vasculitis

Fever

ANCA, Antineutrophil cytoplasmic antibody; MPO , myeloperoxidase. Data from Sablé-Fourtassou R, Cohen P, Mahr A, et al: Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome, Ann Intern Med 2005;143:632–638; and Sinico RA, Di Toma L, Maggiore U, et al: Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome, Arthritis Rheum 2005;52:2926–2935. From Cottin V, Cordier JF: Eosinophilic lung diseases, Immunol Allergy Clin North Am 32(4):557– 586, 2012 (Table 2, p. 569).

The pathogenesis of EGPA is still unknown but several factors are suspected to contribute to the development of the disease. The possible link between leukotriene-receptor antagonists (zafirlukast, montelukast, or pranlukast) is controversial but still considered possible. It is suspected that use of this class of adjunctive medications in severe asthma allows for the reduction in use of corticosteroid leading to the full-blown (unmasking) manifestation of EGPA. Isolated use of leukotriene-receptor antagonists may induce disease, lead to remission with cessation of leukotriene-receptor antagonists, and cause recurrence of EGPA upon reintroduction of this class of medications. Many refrain from use of leukotriene-receptor antagonists when the EGPA syndrome has been diagnosed. Clinical and laboratory findings pinpoint the diagnosis with high specificity (99.7%) and sensitivity (85%) when 4 of 6 criteria are met (asthma, eosinophilia >10%, mononeuropathy or polyneuropathy, nonfixed pulmonary infiltrates, paranasal sinus abnormalities, and biopsy findings of extravascular eosinophil infiltrates). In contrast to GPA, the rhinitis is not destructive and nasal septal perforation does not occur in EGPA. Radiography of the chest by plain radiography or HRCT demonstrates the migratory, peripheral predominant opacities with ground-glass appearance to full consolidation. Bronchiectasis and bronchial wall thickening are reported. Pleural effusion should raise suspicion for the presence of heart failure from cardiomyopathy . Laboratory findings include striking eosinophilia with values generally between 5,000 and 20,000/mm3 at the time of diagnosis. These counts often parallel vasculitis activity. The BAL shows striking eosinophilia with differential counts of >60%. Other organ system levels reflect activity of eosinophils and are not specific for the EGPA diagnosis. ANCAs may be present in the EGPA syndrome. The perinuclear-ANCA targeting myeloperoxidase is specifically found in EGPA in approximately 40%

of the patients; the absence of myeloperoxidase-ANCA does not exclude the diagnosis. Those patients with eosinophilic pneumonia, fever, and cardiac involvement are less likely to have myeloperoxidase-ANCA detected. Those with peripheral neuropathy, renal glomerular disease, and skin purpura usually have detectable myeloperoxidase-ANCAs (see Table 427.12 ). Pulmonary function tests while on bronchodilators and ICS for asthma show an obstructive pattern. The pulmonary obstruction is responsive to oral corticosteroid use but often has mild persistence of obstruction. Treatment of EGPA with systemic oral corticosteroid remains the mainstay of therapy at a starting dose of 1 mg/kg/day for 4 wk. This therapy is often required for up to 12 mo or longer with a steady taper in dosage over that time. EGPA resistant to corticosteroid has responded to cyclophosphamide, IFN-α, cyclosporine, intravenous immunoglobulin, and plasmapheresis. The use of anti– IL-5 (mepolizumab) has been encouraging and may be used as a steroid-sparing agent in the future.

Allergic Bronchopulmonary Aspergillosis ABPA is a complex mixed immunologic hypersensitivity reaction in the lungs and bronchi in response to exposure and colonization of Aspergillus species (usually Aspergillus fumigatus ; see Chapter 264 ). This disease almost exclusively occurs in patients with preexisting asthma and up to 15% of patients with cystic fibrosis (see Chapter 432 ). The quantity of Aspergillus exposure does not correlate with the severity of disease. The clinical pattern of disease (Table 427.13 ) is remarkably similar with a clinical presentation of difficult-to-treat asthma, periods of acute obstructive lung disease with bronchial mucous plugs, elevated total IgE antibody, elevated specific IgE and IgG anti-Aspergillus antibodies, skin prick test reactions to Aspergillus species, precipitating antibody to Aspergillus species, as well as proximal bronchiectasis. Other clinical manifestations include dyspnea, cough, shortness of breath, and peripheral eosinophilia, as well as pulmonary eosinophilia with infiltration of the parenchyma. The use of systemic corticosteroid may lower the total IgE antibody levels such that a diagnosis may be in question when the first tests are performed at that time.

Table 427.13

Criteria for the Diagnosis of Allergic Bronchopulmonary Aspergillosis Allergic bronchopulmonary aspergillosis–central bronchiectasis • Medical history of asthma* • Immediate skin prick test reaction to Aspergillus antigens* • Precipitating (IgG) serum antibodies to Aspergillus fumigatus * • Total IgE concentration > 417 IU/mL (>1,000 ng/mL)* • Central bronchiectasis on chest CT* • Peripheral blood eosinophilia >500/mm3 • Lung infiltrates on chest x-ray or chest HRCT • Elevated specific serum IgE and IgG to A. fumigatus Allergic bronchopulmonary aspergillosis seropositive † • Medical history of asthma † • Immediate skin prick test reaction to A. fumigatus antigens † • Precipitating (IgG) serum antibodies to A. fumigatus † • Total IgE concentration > 417 IU/mL (>1,000 ng/mL) † * The criteria required for diagnosis of ABPA with central bronchiectasis. † The first 4 criteria are required for a diagnosis of seropositive ABPA.

ABPA , Allergic bronchopulmonary aspergillosis; CSD , corticosteroid dependent; HRCT , highresolution computerized tomography.

ABPA should be considered in patients with cystic fibrosis when clinical deterioration occurs without evidence of an identifiable cause. Symptoms heralding such deterioration include increasing cough, wheezing, loss of exercise tolerance, worsening exercise-induced asthma, reduction of pulmonary function, or increased sputum production without another discernible reason. Clinical findings of elevated total IgE antibody, anti-Aspergillus IgE, precipitating antibodies to A. fumigatus , and/or new abnormalities on chest radiography that fail to clear with antibiotics should alert the clinician to the possibility of ABPA. When evaluating a child with asthma symptoms, the clinician must distinguish asthma from ABPA. If the diagnosis is suspected, skin prick test for evidence of IgE-specific antibody directed against A. fumigatus is essential. Intradermal skin testing when the skin prick test is negative, although not routinely performed because of poor specificity, may be performed. The absence of a positive skin prick test and intradermal test to A. fumigatus virtually excludes the diagnosis of ABPA. The prevalence of ABPA in patients with an existing diagnosis of asthma and an abnormal immediate skin prick test response to A. fumigatus has been evaluated. Between 2% and 32% of patients with asthma with concurrent skin

prick test–positive reactions to Aspergillus have evidence of ABPA. It is uncommon for the patient with cystic fibrosis to develop ABPA before the age of 6 yr. When the total IgE antibody in patients with cystic fibrosis exceeds 500 IU/mL (1,200 ng/mL), a strong clinical suspicion of ABPA is necessary. ABPA pathology has characteristic findings of mucoid bronchi impaction, eosinophilic pneumonia, and bronchocentric granulomas in addition to the typical histologic features of asthma. Septated hyphae are often found in the mucus-filled bronchial tree. However, the fungi do not invade the mucosa in this unique disease. Aspergillus may be cultured from sputum in more than 60% of ABPA patients. Interestingly, hyphae may not always be seen on microscopy. Staging of the disease (Table 427.14 ) represents distinct phases of the disease but do not necessarily progress in sequence from stage 1 to stage 5. Staging of ABPA is important for treatment considerations. In many hypersensitivity diseases where IgE antibody contributes to the pathogenesis (e.g., asthma), total IgE is often used for screening for an atopic state but is not a test that helps the clinician with serial measures. In sharp contrast, the measurement of IgE during acute exacerbations, remission, and recurrent ABPA disease is helpful in identifying the activity of disease and may herald the recurrence. During stage 1 disease, the level of IgE antibody is often very high. During stage 2 remission, a fall in the levels may be as much as 35% or more. Recurrence of activity may result in a marked rise of total IgE with a doubling of the baseline level seen during remission. During the use of glucocorticoid therapy, monthly or bimonthly levels of IgE are followed serially to assist the clinician in tapering therapy. Because exacerbations of ABPA are asymptomatic to the patient in approximately 25% of the recurrences, serial IgE accompanied by chest radiography are helpful to the clinician to guide therapy. Table 427.14

Staging of Allergic Bronchopulmonary Aspergillosis Staging of allergic bronchopulmonary aspergillosis Stage 1 Acute Upper and middle lobe infiltration Stage 2 Remission No infiltrate off steroids >6 mo Stage 3 Exacerbation Upper and middle lobe infiltration Stage 4 CSD asthma Minimal infiltrate Stage 5 End stage Fibrosis and/or bullae

CSD , Corticosteroid dependent.

High IgE Normal to high IgE High IgE Normal to high IgE Normal

Radiography Plain chest X-ray shows evidence of infiltrates especially in the upper lobes and the classic findings of bronchiectasis (Fig. 427.7 ). The use of HRCT demonstrates central bronchiectasis in the central regions of the lung (Fig. 427.8 ). HRCT may add value, for the patient with a positive skin prick test and normal chest radiograph, to detecting characteristic abnormalities of ABPA.

FIG. 427.7 Transitory opacities (white arrows) and lobar collapse (black arrow) in patient with allergic bronchopulmonary aspergillosis. (From Douglass JA, Sandrini A, Holgate ST, O'Hehir RE: Allergic bronchopulmonary aspergillosis and hypersensitivity pneumonitis. In Adkinson AF, editor: Middleton's allergy principles and practice , Philadelphia, 2014, Elsevier, Fig. 61.2.)

FIG. 427.8 A, Central bronchiectasis in patient with ABPA (arrows). B, Central bronchiectasis in the upper lobes (arrows). (From Douglass JA, Sandrini A, Holgate ST, O'Hehir RE: Allergic bronchopulmonary aspergillosis and hypersensitivity pneumonitis. In Adkinson AF, editor: Middleton's allergy principles and practice , Philadelphia, 2014, Elsevier, Fig. 61.3.)

Treatment The mainstay of therapy for ABPA has been systemic glucocorticoids with adjunct therapy, antifungal medications, and anti-IgE therapy with omalizumab. Exacerbations in stages 1 and 3 are treated for 14 days with 0.5-1 mg/kg of glucocorticoid followed by every-other-day usage and tapering over 3 mo or as long as 6 mo. Stage 2 remission phase and stage 5 where fibrosis has occurred do not require glucocorticoid therapy. Stage 4 denotes a state where glucocorticoid weaning has not been successful and continued long-term therapy is required. Antifungal therapy with a 16-wk course of itraconazole improves the response rate during exacerbations allowing the reduction of glucocorticoid dosage by 50% and resulting in a reduction of total serum IgE of 25% or more. The proposed mechanisms of action have been to either reduce the antigen load driving the immune response or possibly raising the corticosteroid serum levels by slowing the metabolism of the steroid. This latter mechanism would be true for prednisone, which is methylated in the liver, but not for methylprednisolone, which does not require methylation. The adult dosage recommendation for itraconazole is 200 mg 3 times per day for 3 days followed by 200 mg twice daily for the remainder of the 16 wk. Children should receive 5 mg/kg/day in a single dose. If the proper calculated

dose exceeds 200 mg, then the total dose should be divided equally and given twice daily. Serum levels of itraconazole are necessary to ensure proper absorption of the drug is occurring from the capsule form. The liquid form is more readily absorbed and has achieved substantially higher levels. The use of proton pump inhibitors and histamine 2 antagonists may reduce absorption by blocking acid production. Voriconazole has been used as a substitute antifungal medication. Proper dosing has been established for invasive Aspergillus disease, but not for ABPA. Typical dosage regimen in children of 7 mg/kg/day may cause hepatotoxicity so liver function must be monitored. Omalizumab, an anti-IgE humanized monoclonal antibody, has been used in case series of patients with cystic fibrosis and ABPA as well as a small cohort of adults without cystic fibrosis but with ABPA. Both case series demonstrated significant reductions in asthma exacerbations, ABPA exacerbations, and glucocorticoid usage. The dose prescribed has been 300-375 mg every 2 wk by subcutaneous injection.

Hypereosinophilic Syndrome See Chapter 155 . The HES is a descriptive name of a group of disorders that are characterized by the persistent overproduction of eosinophils accompanied by eosinophil infiltration in multiple organs with end-organ damage from mediator release. The term HES should only be used when there is eosinophilia with end-organ damage from the eosinophils and not from another cause. The discovery of underlying genetic, biochemical, or neoplastic reasons for HES has led to the classification of primary, secondary, and idiopathic HES (Table 427.15 ). Specific syndromes such as EGPA have eosinophilia but the contribution of eosinophils to the organ damage is incompletely understood. Table 427.15 Hypereosinophilic Syndrome Variants Myeloproliferative Lymphocytic Overlap Familial

Nonclonal Clonal–F1P1L1/PDGFRA-positive chronic eosinophilic leukemia Nonclonal T cells Clonal T-cell expansion with T-cell activation Organ restricted Family history of eosinophilia without known cause

Associated Undefined

Eosinophilia in chronic disease like inflammatory bowel disease or EGPA (Churg-Strauss syndrome) Asymptomatic Cyclic angioedema with eosinophilia (Gleich syndrome) Symptomatic without myeloproliferation or lymphocytic form

EGPA , Eosinophilic granulomatosis with polyangiitis; PDGFRA , platelet-derived growth factor receptor-α.

Some variants of HES have genetic mutations in tyrosine kinase receptor platelet-derived growth factor receptor-α (PDGFRA ); males are almost exclusively affected. Otherwise, HES appears to be distributed equally among females and males. Hypereosinophilia is defined as an absolute eosinophil number in the blood that exceeds 1.5 × 109 eosinophils on 2 separate occasions separated by at least 1 mo. Tissues are abnormal when more than 20% of nucleated cells in the bone marrow are of eosinophil origin, a pathologist determines the presence of eosinophilia, or the presence of extensive eosinophilic granule proteins are determined on biopsy to be deposited in large quantities. These disorders can be subclassified into primary (neoplastic), secondary (reactive), and idiopathic (Fig. 427.9 ).

FIG. 427.9 A revised classification of hypereosinophilic syndrome (HES) . Changes from the previous classification are indicated in red. Dashed arrows identify HES forms in some patients that have T-cell–driven disease. Classification of myeloproliferative forms has been simplified, and patients with HES and eosinophil hematopoietin-producing T cells in the absence of a T-cell clone are included in the lymphocytic forms of HES.

CSS, Churg-Strauss syndrome; IBD, inflammatory bowel disease. (From Simon H, Rothenberg ME, Bochner BS, et al: Refining the definition of hypereosinophilic syndrome, J Allergy Clin Immunol 126:45–49, 2010, Fig. 1.)

Clinical manifestations of the HES include organ involvement of the heart (5%), gastrointestinal (14%), skin (37%), and pulmonary (25–63%). The HES is complicated by thrombosis and/or neurologic disease in many patients, although the exact prevalence of this problem is incompletely categorized. Peripheral neuropathy, encephalopathy, transverse sinus thrombosis, or cerebral emboli are the most common neurologic complications. The exact mechanism of the manifestations is unclear especially in major artery thrombosis such as the femoral artery. The most frequent pulmonary symptoms include cough and dyspnea. Many patients have obstructive lung disease with clinical wheezing. Evidence of pulmonary fibrosis and pulmonary emboli are seen with regularity. Because biopsy shows eosinophilic infiltrates similar to other pulmonary eosinophilic diseases of the lung, it is the constellation of other organ involvement or thromboembolic phenomena and other organs that must lead the clinician to a high index of suspicion for the HES. Laboratory evaluation should include evaluation of liver enzymes, kidney function tests, creatine kinase, and troponin. The extent of cardiac involvement should be evaluated by electrocardiogram and echocardiogram. Some unique biomarkers may be tested when evaluating the myeloproliferative and Tlymphocyte HES diagnoses. Vitamin B12 and serum tryptase may be elevated, especially the latter, when the myeloproliferative disease is accompanied by mastocytosis. These 2 biomarkers are most frequently elevated when the mutation is present or fusion in the FIP1L1/PDGFRA sites. Because of the extensive pulmonary disease that is seen in the HES, pulmonary function tests should be performed at diagnosis when possible to include spirometry and lung volumes. Dead space ventilation may be significantly elevated in the patients with pulmonary emboli. Pulse oximetry may be very helpful in the evaluation as well. Chest radiography and CT are very helpful in the evaluation. Spiral chest CT should also be performed when pulmonary emboli are being considered. In 1 series of patients, nearly half of the patients with HES had evidence of pulmonary abnormalities including ground-glass appearing infiltrates, pulmonary emboli, mediastinal lymphadenopathy, and/or pleural effusion.

Treatment of HES depends on the type of variant (myeloproliferative, lymphocytic forms, undefined, associated with systemic diseases such as EGPA, or familial). Rarely, some patients present with marked eosinophilia, where the total count exceeds 100,000 cells/µL, and vascular insufficiency symptoms. Prednisone at 15 mg/kg is indicated to acutely reduce the eosinophil count after diagnostic tests are performed and when safe. If the patient is unstable, the glucocorticoid should be administered to prevent progression of symptoms. Other acute therapies aimed at reduction of eosinophil counts include vincristine, imatinib mesylate, or even leukophoresis. When eosinophil counts are not as dramatically elevated, therapy begins with glucocorticoids at 1 mg/kg for patients who do not have the FIP1L1/PDGFRA mutation. Patients with this mutation are resistant to glucocorticoids and initial treatment should begin with imatinib, a tyrosine kinase inhibitor. Because this genetic test is often not readily available, surrogate markers for the presence of this mutation are vitamin B12 levels > 2,000 pg/mL or serum tryptase >11.5 ng/mL. It denotes the presence of resistant disease that should initially be treated with imatinib. The goal of therapy is to reduce and maintain eosinophil counts below 1.5 × 109 at the lowest dose of prednisone possible to reduce or avoid corticosteroid side effects. If corticosteroid doses cannot be lowered below 10 mg/day, then imatinib can be added as combination therapy in order to spare the dose of steroid. Caution must be used in the presence of cardiac disease as introduction of imatinib has precipitated left ventricular failure. Additional or alternative adjunct therapies that have shown promise include hydroxyurea, interferon α, anti–IL-5 monoclonal antibody therapy, and a monoclonal antibody directed against CD52. Failure of the above modalities may signal a need for hematopoietic stem cell transplantation. This therapy has been successful in some patients.

Bibliography Brackel CLH, Ropers FG, Vermaas-Fricot SFN, et al. Acute eosinophilic pneumonia after recent start of smoking. Lancet . 2015;385:1150. Cottin V, Cordier JF. Eosinophilic lung diseases. Immunol Allergy Clin North Am . 2012;32(4):557–586. Erasmus JJ, McAdams HP, Rossi SE. High-resolution CT of

drug-induced lung disease. Radiol Clin North Am . 2002;40:61. Gibson PG. Allergic bronchopulmonary aspergillosis. Semin Respir Crit Care Med . 2006;27:185. Simon H, Rothenberg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol . 2010;126:45. Uchiyama H, Suda T, Nakamura Y, et al. Alterations in smoking habits are associated with acute eosinophilic pneumonia. Chest . 2008;133:1174.

427.5

Interstitial Lung Disease Kevin J. Kelly, Timothy J. Vece

Keywords ILD anti-GBM disease DSM NEHI ILD in children is caused by a large group of rare, heterogeneous, familial, or sporadic diseases that involve the pulmonary parenchyma and cause significant impairment of gas exchange (Tables 427.16 and 427.17 ). While there are some shared diseases, ILD in children is often different than ILD in adults, especially notable for the absence of idiopathic pulmonary fibrosis in children. Despite wide variations in cause, these disorders are classified together because of the

similar clinical, physiologic, radiographic, and pathologic processes involving disruption of alveolar interstitium and airways. Prevalence estimates vary widely with a range of 0.13-16.2 cases/100,000 children, likely due to the lack of standardization of diseases included in the definition of ILD in children. The pathophysiology is believed to be more complex than that of adult disease because pulmonary injury occurs during the process of lung growth and differentiation. In ILD, the initial injury causes damage to the alveolar epithelium and capillary endothelium. Abnormal healing of injured tissue may be more prominent than inflammation in the initial steps of the development of chronic ILD. Genetic causes of ILD are becoming increasingly important, especially disorders of surfactant metabolism (DSM) and immune dysregulatory disorders. Table 427.16

The Pediatric Interstitial Lung Diseases in Children Under 2 Yr of Age AGE-RELATED INTERSTITIAL LUNG DISEASES IN INFANCY AND EARLY CHILDHOOD Diffuse developmental disorders Acinar dysplasia Congenital alveolar dysplasia Alveolar capillary dysplasia with misalignment of pulmonary veins (some due to FOXF1 mutation) Growth abnormalities reflecting deficient alveolarization Pulmonary hypoplasia Chronic neonatal lung disease Chromosomal disorders Congenital heart disease Neuroendocrine cell hyperplasia of infancy Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonia) Surfactant dysfunction disorders (pulmonary alveolar proteinosis) Surfactant protein–B mutation Surfactant protein–C mutation ABCA3 mutation Granulocyte-macrophage colony-stimulating factor receptor (CSF2RA ) mutation NKX2.1 (transcription factor for SP-B, SPC, ABCA3) INTERSTITIAL LUNG DISEASE DISORDERS WITH KNOWN ASSOCIATIONS Infectious/postinfectious processes Adenovirus viruses Influenza viruses Chlamydia pneumoniae Mycoplasma pneumoniae Environmental agents Hypersensitivity pneumonitis Toxic inhalation Aspiration syndromes PULMONARY DISEASES ASSOCIATED WITH PRIMARY AND SECONDARY IMMUNE

DEFICIENCY Opportunistic infections Granulomatous lymphocytic interstitial lung disease associated with common variable immunodeficiency syndrome Lymphoid intestinal pneumonia (HIV infection) Therapeutic interventions: chemotherapy, radiation, transplantation, and rejection IDIOPATHIC INTERSTITIAL LUNG DISEASES Usual interstitial pneumonitis Desquamative interstitial pneumonitis Lymphocytic interstitial pneumonitis and related disorders Nonspecific interstitial pneumonitis (cellular/fibrotic) Eosinophilic pneumonia Bronchiolitis obliterans syndrome Pulmonary hemosiderosis and acute idiopathic pulmonary hemorrhage of infancy Pulmonary alveolar proteinosis Pulmonary vascular disorders Pulmonary lymphatic disorders Pulmonary microlithiasis Persistent tachypnea of infancy Brain-thyroid-lung syndrome SYSTEMIC DISORDERS WITH PULMONARY MANIFESTATIONS Anti-GBM disease Gaucher disease and other storage diseases Malignant infiltrates Hemophagocytic lymphohistiocytosis Langerhans cell histiocytosis Sarcoidosis Systemic sclerosis Polymyositis/dermatomyositis Systemic lupus erythematosus Rheumatoid arthritis Lymphangioleiomyomatosis Pulmonary hemangiomatosis Neurocutaneous syndromes Hermansky-Pudlak syndrome

Modified from Deutsch GH, Young LR, Deterding RR, et al: diffuse lung disease in young children: application of a novel classification scheme, Am J Respir Crit Care Med 176:1120–1128, 2007.

Table 427.17

The Pediatric Interstitial Lung Diseases in Children Over 2 Yr of Age DISORDERS OF THE IMMUNOCOMPETENT HOST Disorders of Infancy • Growth abnormalities • NEHI • Disorders of surfactant metabolism Systemic Disease

• Immune mediated disorders • Connective tissue disease related lung disease • Pulmonary hemorrhage syndromes • Storage diseases • Sarcoidosis DISORDERS OF THE IMMUNOCOMPROMISED HOST • Opportunistic infections • Related to treatment • Chemotherapy • Radiation • Drug hypersensitivity • Related to transplantation • Rejection • GVHD • PTLD • Lymphoid Infiltrates

GVHD , Graft-versus-host disease; NEHI , neuroendocrine cell hyperplasia of infancy; PTLD , post-transplant lymphoproliferative disease. Modified from Fan LL, Dishop MK, Galambos C, et al: Diffuse lung disease in biopsied children 2 to 18 years of age. Application of the chILD Classification Scheme, Ann Am Thorac Soc 2015;12(10):1498–1505.

Classification and Pathology Through the work of both the children's ILD research network in the United States and the children's ILD-European Union group in Europe, consensus on a classification scheme has been reached. The classification is broken down by age with 2 yr of age serving as a cut-off, and by histologic pattern. The classification scheme was first applied to biopsies from children under 2 and was extended to children over 2 yr of age (see Tables 427.16 and 427.17 ). Growth disorders such as alveolar simplification, unique diseases of infants such as neuroendocrine cell hyperplasia of infancy (NEHI ), and DSM were common in children under 2. In contrast, disorders of the immunocompromised host such as ILD related to immune deficiency, and disorders of systemic diseases such as the collagen vascular disorders, were much more common in older children.

Neuroendocrine Cell Hyperplasia of Infancy See Chapter 427.6 .

Disorders of Surfactant Metabolism

One of the more important groups of disorders in pediatric ILD is the DSM (Table 427.18 ). These disorders likely account for previously unknown cases of neonatal respiratory distress in full-term infants. Surfactant protein B deficiency, caused by mutations in the surfactant protein B gene, is a cause of severe neonatal respiratory distress. Chest CT often has a pattern of diffuse groundglass opacities with septal thickening. Histopathology reveals alveolar proteinosis with interstitial widening, and electron microscopy shows disorganized lamellar bodies. Most children die within the first 2 mo of life without a lung transplant. Surfactant protein C deficiency can cause disease in older infants, children, or adults. Chest CT can show diffuse ground-glass opacities with septal thickening early in the disease or significant fibrosis and honeycombing in more advanced disease. Histopathologic findings vary with age, with alveolar proteinosis and interstitial widening seen in young children, and fibrosis seen in older children and adults. Electron microscopy reveals normal lamellar bodies. ABCA3 mutations cause variable lung disease in children with some having severe disease similar to surfactant protein B deficiency, while other children have less severe disease similar to surfactant protein C. Chest CT most often shows diffuse ground-glass opacities with septal thickening early in the disease (Fig. 427.10 ). Histopathology depends on the age of the child similar to surfactant protein C, however, electron microscopy shows characteristic changes in the lamellar bodies with an eccentric electron dense body without the characteristic concentric circles—the so-called fried egg appearance. DSM due to mutations in the gene NKX2.1 has also been described. NKX2.1 encodes for thyroid transcription factor 1 (TTF-1), which is a major regulator or surfactant protein transcription. Mutations in NKX2.1 cause variable disease in the lungs, brain, and thyroid (see Table 427.18 ). Lung disease is variable and can present similar to surfactant protein B deficiency, or as recurrent pulmonary infections. Finally, mutations in the alpha and beta subunits of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor cause failure of response to GM-CSF by the pulmonary alveolar macrophages. This leads to an inability to recycle surfactant with subsequent accumulation of proteinaceous material and pulmonary alveolar proteinosis. Table 427.18 Clinical Features, Age, and Onset of Surfactant Protein Dysfunction Syndromes (SPDS)

SPDS SFTPB ABCA3

SFTPC

NKX2.1

CLINICAL FEATURES Neonatal ▸ Respiratory distress Neonatal ▸ Respiratory distress Infancy ▸ Cough ▸ Tachypnoea, hypoxemia ▸ Failure to thrive Childhood ▸ Wheeze, crackles ▸ Exercise intolerance ▸ Dyspnea ▸ Retractions, crackles, digital clubbing ▸ Low body weight Neonatal ▸ Respiratory distress Childhood ▸ Cough ▸ Tachypnoea, hypoxemia Respiratory ▸ Neonatal respiratory distress ▸ Recurrent infections ▸ Chronic interstitial lung disease Neurological ▸ Chorea ▸ Ataxia ▸ Developmental delay ▸ Hypotonia Hypothyroidism

AGE AND ONSET Neonate, acute Neonate, acute Infancy and childhood, subacute Late childhood and adulthood, chronic

Neonate, acute (infrequent) Infancy and childhood, subacute Late childhood and adulthood, chronic

Any age Acute or chronic

ABCA3 , ATP binding cassette number A3. From Gupta A, Zheng SL: Genetic disorders of surfactant protein dysfunction: when to consider and how to investigate, Arch Dis Child 102:84–90, 2017 (Table 2, p. 86).

FIG. 427.10 Chest CT from a 2 yr old with a disorder of surfactant metabolism from mutations in ABCA3. Note the ground-glass opacities (white arrow) and septal thickening (white circle) and early cyst formation (black arrow) . (Courtesy R. Paul Guillerman, MD.)

Interstitial Lung Disease Due to Systemic Disease ILD due to systemic disease is more common in older children with diffuse lung disease. The most common lung disease seen on biopsy is nonspecific interstitial pneumonia, however, other patterns are seen depending on the underlying disorder, such as lymphocytic interstitial pneumonia in Sjögren syndrome or cryptogenic organizing pneumonia in dermatomyositis. CT scans depend on the underlying ILD with nonspecific interstitial pneumonia having areas of groundglass opacities and septal thickening in the early cellular phase of the disease (Fig. 427.11 ), progressing to diffuse fibrosis with traction bronchiectasis and peripheral cysts in the later fibrotic stage of the disease. The exact mechanism for disease is unknown but likely is due to auto-antibodies to respiratory tissue.

FIG. 427.11 Chest CT from a 11 yr old patient with systemic sclerosis and cellular nonspecific interstitial pneumonia. Note the areas of ground-glass opacities in the periphery (white arrow) . (Courtesy R. Paul Guillerman, MD.)

Pulmonary vasculitis, either due to GPA, microscopic polyangiitis, idiopathic pulmonary capillaritis, or anti-glomerular basement membrane syndrome (formerly Goodpasture disease) is another common manifestation of systemic diseases. Disease is likely due to auto-antibody stimulation of lymphocytes with resultant inflammation of pulmonary endothelium causing interstitial changes and pulmonary hemorrhage. Histopathology reveals diffuse alveolar hemorrhage, interstitial widening, and with the exception of anti-glomerular basement membrane disease, neutrophilic inflammation of the pulmonary vasculature. Genetic causes of immune dysregulation may also be responsible for ILD in children. Mutations in both STAT3b and LRBA have been shown to cause lymphocytic interstitial pneumonia and lymphoproliferative disease. Mutations in COPA , a protein involved in ER to Golgi transport, cause familial pulmonary hemorrhage and/or ILD. Persistent pulmonary symptoms can occur after respiratory infections caused by adenoviruses, influenza viruses, Chlamydia pneumoniae , and Mycoplasma pneumoniae . The resultant pulmonary disease is called bronchiolitis obliterans and is characterized by obstructive lung disease and obliteration or constriction of the bronchioles on lung biopsy. There is a characteristic appearance on HRCT with mosaicism, vascular attenuation, and central bronchiectasis, which if present, can obviate the need for lung biopsy (Fig. 427.12 ). Aspiration is a frequent cause of chronic lung disease in childhood and can mimic ILD.

Children with developmental delay or neuromuscular weakness are at an increased risk for aspiration of food, saliva, or foreign matter, secondary to swallowing dysfunction and/or gastroesophageal reflux (GER). An undiagnosed tracheoesophageal fistula can also result in pulmonary complications related to aspiration of gastric contents and interstitial pneumonia.

FIG. 427.12 Chest CT from an 11 yr old patient with bronchiolitis obliterans after Stevens-Johnson syndrome. A, Volumetric scan at full inspiration shows central bronchiectasis (arrow) and mosaic attenuation. B, Highresolution image taken in exhalation better highlights the mosaic attenuation, as well as vascular attenuation (circle) .

Children experiencing an exaggerated immunologic response to organic dust,

molds, or bird antigens may demonstrate hypersensitivity pneumonitis. Children with malignancies may have ILD related to the primary malignancy, an opportunistic infection, or chemotherapy or radiation treatment.

Clinical Manifestations A detailed history is needed to assess the severity of symptoms and the possibility of an underlying systemic disease in a patient with suspected ILD as well as any family history of lung disease. Identification of precipitating factors, such as exposure to molds or birds and a severe lower respiratory infection, is important in establishing the diagnosis and instituting avoidance measures. Most patients develop hypoxia and hypercarbia, usually a late and ominous complication. Symptoms are usually insidious and occur in a continuous, not episodic, pattern. Tachypnea, crackles on auscultation, and retractions are noted on physical examination in children with ILD, but chest physical examination findings can be normal. Wheezing and fever are uncommon findings in pediatric ILD. Cyanosis accompanied by a prominent P2 heart sound is indicative of severe disease with the development of secondary pulmonary hypertension. Anemia or hemoptysis suggests a pulmonary vascular disease or pulmonary hemosiderosis. Rashes or joint complaints are consistent with an underlying connective tissue disease.

Diagnosis Radiography Chest radiographic abnormalities can be classified as interstitial, reticular, nodular, reticulonodular, or honeycombed. The chest radiographic appearance may also be normal despite significant clinical impairment and may correlate poorly with the extent of disease. HRCT of the chest better defines the extent and distribution of disease and can provide specific information for selection of a biopsy site. Volume-controlled full-inspiratory and end-expiratory protocols used during HRCT can provide more information. These protocols may show air trapping, ground-glass patterns, mosaic patterns of attenuation, hyperinflation, bronchiectasis, cysts, and/or nodular opacities. Serial HRCT scans have been beneficial in monitoring disease progression and severity.

Pulmonary Function Tests Pulmonary function tests are important in defining the degree of pulmonary dysfunction and in following the response to treatment. In ILD, pulmonary function abnormalities demonstrate a restrictive ventilatory deficit with decreased lung volumes and reduced lung compliance. The functional residual capacity is often reduced but is usually less affected than vital capacity and total lung capacity (TLC). The residual volume (RV) is usually maintained; therefore, ratios of functional residual capacity:TLC and RV:TLC are increased. Diffusion capacity of the lung is often reduced. Exercise testing may detect pulmonary dysfunction, even in the early stage of ILD with a decline in oxygen saturation.

Bronchoalveolar Lavage BAL may provide helpful information regarding secondary infection, bleeding, and aspiration and allows cytology and molecular analyses. Evaluation of cell counts, differential, and lymphocyte markers may be helpful in determining the presence of hypersensitivity pneumonitis or sarcoid. Although BAL does not usually determine the exact diagnosis, it can be diagnostic for disorders such as pulmonary alveolar proteinosis.

Lung Biopsy Lung biopsy for histopathology by conventional thoracotomy or video-assisted thoracoscopy is usually the final step and is often necessary for a diagnosis , except in NEHI and bronchiolitis obliterans. Biopsy yields a diagnosis in greater than 80% of patients. Due to the small size of biopsies obtained and low diagnostic yield, transbronchial biopsies are not recommended for the evaluation of ILD in children. Genetic testing for surfactant dysfunction mutational analysis is available. Evaluation for possible systemic disease may also be necessary.

Treatment Supportive care of patients with ILD is essential and includes supplemental oxygen for hypoxia and adequate nutrition for growth failure. Antimicrobial treatment may be necessary for secondary infections. Some children may receive symptomatic relief from the use of bronchodilators. Antiinflammatory treatment

with corticosteroids remains the initial treatment of choice. Controlled trials in children are lacking, however, and the clinical responses reported in case studies are variable. The usual dose of prednisone is 1-2 mg/kg/24 hr or 10-30 mg/kg of IV methylprednisolone given either weekly or for 3 consecutive days per month. Treatment length varies but is often initially given for 3-6 mo with tapering of dosage dictated by clinical response. Alternative, but not adequately evaluated, agents include hydroxychloroquine, azathioprine, cyclophosphamide, cyclosporine, methotrexate, and intravenous immunoglobulin. Investigational approaches involve specific agents directed against the action of cytokines, growth factors, or oxidants. Lung transplantation for progressive or end-stage ILD is used and outcomes are similar to other end-stage lung diseases in children such as cystic fibrosis. Appropriate treatment for underlying systemic disease is indicated. Preventive measures include avoidance of all inhalation irritants, such as tobacco smoke and, when appropriate, molds and bird antigens. Supervised pulmonary rehabilitation programs may be helpful.

Genetic Counseling A high incidence of ILD in some families suggests a genetic predisposition to either development of the disease or severity of the disorder. Genetic counseling may be beneficial if a positive familial history is obtained.

Prognosis The overall mortality of ILD is variable and depends on specific diagnosis. Some children recover spontaneously without treatment, but other children steadily progress to death. Pulmonary hypertension, failure to thrive, and severe fibrosis are considered poor prognostic indicators.

Anti-Glomerular Basement Membrane Disease (Anti-GBM Disease) Anti-glomerular basement membrane disease, (anti-GBM disease ) formerly known as Goodpasture disease, is the prototypical immunologic mediated ILD (see Chapter 538.4 ). Because of the concurrent presentation of renal and pulmonary disease, the differential diagnosis focuses on distinguishing anti-

GBM disease from GPA, microscopic polyangiitis, Henoch-Schönlein purpura, and idiopathic pulmonary hemorrhage syndromes.

Pathophysiology Immunology Factors The development of anti-GBM antibodies directly correlates with the development of pulmonary and renal disease. Removal of such antibodies by plasmapheresis results in improvement of the disease process in some patients but not in all. The anti-GBM antibodies are IgG1 and IgG4 complement-binding subclasses of IgG which activate complement. Complement fragments signal the recruitment of neutrophils and macrophage in both the lung and kidney basement membranes resulting in damage and capillaritis.

Genetic Factors Genetics appears to contribute strongly to the development of this disease with the presence of major histocompatibility complex class II alleles DR15, DR4, DRB1*1501, DRB1*04, and DRB1*03 predisposing to disease.

Environmental Factors Exposure to smoke appears to be a strong factor in the development anti-GBM disease. Whether smoking alters the ultrastructure of the basement membrane or exogenous particles or noxious substances in smoke alter the type IV collagen is unknown. Smokers are more likely to develop pulmonary hemorrhage than nonsmokers who have anti-GBM disease. Other injuries to the alveoli from infection, hydrocarbon inhalation, or cocaine inhalation have been reported as associated events prior to development of anti-GBM disease.

Clinical Manifestations The majority of patients present with many days or weeks of cough, dyspnea, fatigue, and sometimes hemoptysis. Young children tend to swallow small amounts of blood from hemoptysis and may present with vomiting blood. Occasionally, the hemoptysis is large and resultant anemia is a consequence of large quantities of blood loss. Renal compromise is found with abnormal renal function tests. Younger patients tend to present with both the pulmonary and

renal syndrome concurrently. Adults are less likely to develop pulmonary disease.

Laboratory Serologic detection of anti-GBM antibodies is positive in more than 90% of patients with anti-GBM disease. A complete blood count will show anemia that is normocytic and normochromic as seen in chronic inflammatory disease. Urinalysis may reveal hematuria and proteinuria, while blood tests demonstrate renal compromise with elevated blood urea nitrogen and creatinine. Studies for pANCA (antimyeloperoxidase ANCA) should also be performed and are positive in approximately 25–30% of patients concurrently with antiGBM antibodies. Clinical disease may be more difficult to treat, and the presence of these antibodies may herald a more severe form of disease.

Chest Radiography Chest radiography in anti-GBM disease will often show widely scattered patches of pulmonary infiltrates. If these infiltrates are in the periphery of the lung, they may be difficult to distinguish from the eosinophilic lung diseases. Interstitial patterns of thickening may be found as well. HRCT is usually not performed in this disease as the constellation of pulmonary hemorrhage, renal compromise, and positive serologic tests with anti-GBM antibodies detected often preclude the need for this test.

Pulmonary Function Testing Pulmonary spirometry often reveals a restrictive defect with reduction in FVC and FEV1 . DLCO is a valuable test when pulmonary hemorrhage is a strong consideration. The intent of this test is to measure the ability of the lung to transfer inhaled gas to the red blood cell in the pulmonary capillary bed. This takes advantage of the hemoglobin's high affinity to bind carbon monoxide. It was once thought that reduction of DLCO was a measure of reduced surface area of the alveoli. Current data suggests that it directly correlates with the volume of blood in the pulmonary capillary bed. In pulmonary hemorrhage syndromes, blood in the alveoli plus the blood in the capillary bed increase the DLCO significantly and should alert the clinician to the possibility of pulmonary

hemorrhage.

Bronchoscopy and Bronchoalveolar Lavage Pulmonary abnormalities can often be best assessed by a bronchoscopy with BAL. The visual presence of blood on inspection as well as BAL will be obvious. Infections must be ruled out in many cases, and this technique adds significant value. BAL cell count will show hemosiderin-laden macrophages that have engulfed and broken down the red blood cells, leaving iron in these cells.

Lung Biopsy Lung biopsy in patients with active disease reveals capillaritis from neutrophils, hemosiderin-laden macrophages, type II pneumocyte hyperplasia, and interstitial thickening at the level of the alveolus. Staining for IgG and complement is found by immunofluorescence along the basement membrane in a linear pattern. This antibody deposition pattern led to the investigation of endogenous antigens in the basement membrane.

Treatment More than half of patients with anti-GBM disease who forego treatment die within 2 yr from either respiratory failure, renal failure, or both. After a diagnosis is made, therapy with corticosteroids (e.g., prednisone, 1 mg/kg/day) coupled with oral cyclophosphamide (2.5 mg/kg/day) is begun. The addition of daily plasmapheresis for 2 wk may accelerate improvement. Cyclophosphamide may be discontinued after 2-3 mo. Steroids are often weaned over a 6-9 mo period. Survival is affected by the need for ongoing dialysis. Patients who do not require persistent dialysis have a survival rate at 1 yr of 80% or more.

Bibliography American thoracic society/European respiratory society international multidisciplinary consensus society: classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med . 2002;165:277–304.

Brody AS. Imaging consideration: interstitial lung disease in children. Radiol Clin North Am . 2005;43:391–403. Clement A, Eber E. Interstitial lung diseases in infants and children. Eur Respir J . 2008;31:658–666. Dempsey OJ, Kerr KM, Remmen H, et al. How to investigate a patient with suspected interstitial lung disease. BMJ . 2010;340:1294–1299. Deterding R. Evaluating infants and children with interstitial lung disease. Semin Respir Crit Care Med . 2007;28:333– 341. Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med . 2007;176:1120–1128. Dishop MK. Paediatric interstitial lung disease: classification and definitions. Paediatr Respir Rev . 2011;12:230–237. Doan ML, Guillerman RP, Dishop MK, et al. Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax . 2008;63:366–373. Eldridge WB, Zhang Q, Faro A, et al. Outcomes of lung transplantation for infants and children with genetic disorders of surfactant metabolism. J Pediatr . 2017;184:157–164. Fan LL, Dishop MK, Galambos C, et al. Diffuse lung disease in biopsied children 2 to 18 years of age. Application of the chILD classification scheme. Ann Am Thorac Soc . 2015;12(10):1498–1505. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet . 2012;380:689–698. Griese M. Pulmonary alveolar proteinosis: a comprehensive clinical perspective. Pediatrics . 2017;140(2):e20170610. Griese M, Lorenz E, Hengst M, et al. Surfactant proteins in pediatric interstitial lung disease. Pediatr Res . 2016;79(1):34–41.

Gupta A, Zheng SL. Genetic disorders of surfactant protein dysfunction: when to consider and how to investigate. Arch Dis Child . 2017;102:84–90. Hamvas A, Cole FS, Nogee LM. Genetic disorders of surfactant proteins. Neonatology . 2007;91:311–317. Hepping N, Griese M, Lohse P, et al. Successful treatment of neonatal respiratory failure caused by a novel surfactant protein C p.Cys121gly mutation with hydroxychloroquine. J Perinatol . 2013;33:492–494. Huaringa AJ, Francis WH. Pulmonary alveolar proteinosis: a case report and world literature review. Respirol Case Rep . 2016;4(6):e00201. Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5b promoter polymorphism and interstitial lung abnormalities. N Engl J Med . 2013;368:2192–2200. Kuo CS, Desai TJ. Cellular mechanisms of alveolar pathology in childhood interstitial lung diseases: current insights from mouse genetics. Curr Opin Pediatr . 2015;27:3410347. Kuo CS, Young LR. Interstitial lung disease in children. Curr Opin Pediatr . 2014;26:320–327. Langston C, Dishop MK. Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatr Dev Pathol . 2009;9:173–180. Lazor R, Bigay-Gamé L, Cottin V, et al. Alveolar hemorrhage in anti-basement membrane antibody disease: a series of 28 cases. Medicine (Baltimore) . 2007;86:181. Levy JB, Hammad T, Coulthart A, et al. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int . 1535;66:2004. López-Andreu JA, Hidalgo-Santos A, Fuentes-Castelló MA, et al. Delayed presentation and prolonged survival of a child with surfactant protein B deficiency. J Pediatr . 2017;190:268–270.

Pedchenko V, Bondar O, Fogo AB, et al. Molecular architecture of the goodpasture autoantigen in anti-GBM nephritis. N Engl J Med . 2010;363:343. Rabach I, Poli F, Zennaro F, et al. Is treatment with hydroxychloroquine effective in surfactant protein C deficiency? Arch Bronconeumol . 2013;49(5):213–215. Soares JJ, Deutsch GH, Moore PE, et al. Childhood interstitial lung diseases: an 18-year retrospective analysis. Pediatrics . 2013;132:684–691. Spagnolo P, Bush A. Interstitial lung disease in children younger than 2 years. Pediatrics . 2016;137(6):e20152725. Vece TJ, Fan LL. Diagnosis and management of diffuse lung disease in children. Paediatr Respir Rev . 2011;12(4):238– 242.

427.6

Neuroendocrine Cell Hyperplasia of Infancy W. Adam Gower

Keywords Neuroendocrine cell hyperplasia of infancy NEHI neuroendocrine cell (NEC) neuroendocrine bodies (NEB) diffuse lung disease (DLD)

interstitial lung disease (ILD)

Background/Summary Neuroendocrine cell hyperplasia of Infancy (NEHI) (previously called persistent tachypnea of infancy) is an idiopathic form of diffuse lung disease that typically presents within the 1st yr of life with persistent tachypnea, retractions, hypoxemia, crackles, failure to thrive, and characteristic findings on chest imaging studies and lung histopathology. Pulmonary function studies typically demonstrate an obstructive picture with air trapping. There are no effective specific therapies for NEHI, and the usual approach is supportive care. The natural course is typically one of gradual improvement of symptoms, although exacerbations may occur throughout childhood. The long-term consequences of this disorder are not entirely known.

Epidemiology The prevalence of NEHI is not known, but it is generally regarded to be a rare lung disease. Children with NEHI have accounted for around 10% of children who had lung biopsies in previous multicenter case series. There does not appear to be a clear racial or gender predisposition, and no other maternal or patientlevel risk factors have been identified. Cases of NEHI have been reported in the literature from North and South America, Europe, Asia, and Australia.

Pathophysiology The primary clue to the pathophysiology of NEHI is increased numbers of airway neuroendocrine cells (NEC) in the airways of affected children. These cells are normally found in the airways, where they exist as innervated clusters known as NEB and secrete factors such as bombesin and serotonin (5-HT). They are thought to be involved in local oxygen sensing and may transmit neuroendocrine signals to other cells. Increases in NECs are seen in other respiratory disorders of childhood, usually with other additional findings. It is unclear whether their presence in increased numbers in NEHI causes the clinical picture, or is the result of abnormal pulmonary physiology secondary to some other primary factor. Increased numbers of NECs seem to be associated with

increased small airways obstruction. Although most cases appear to be sporadic, familial NEHI has been described, suggesting a possible inherited mechanism and/or shared environmental influences. The association of NEHI with heterozygosity for a variant in the gene Nkx2.1 , which encodes the protein TTF-1, has been described in one kindred. Variants in this gene are also known to cause a wide spectrum of disorders, including more severe forms of diffuse lung disease (see Chapter 427.5 ).

Clinical Presentation The symptoms of NEHI characteristically appear during infancy, although the diagnosis may be delayed until after the 1st yr of life. The typical presentation includes persistent tachypnea, hypoxemia, retractions, and poor weight gain in an otherwise healthy infant. The exam usually reveals crackles or clear lung sounds, while cough and wheezing are uncommon. Typically, affected infants do not have a history of premature delivery. Echocardiograms usually show absence of structural heart disease or pulmonary hypertension.

Diagnosis The diagnosis of NEHI requires that other more common causes of the presenting symptoms are ruled out. Although children with NEHI may have GER and/or swallowing dysfunction, this is not thought to be sufficient to cause all of the findings, and may be secondary to tachypnea and increased work of breathing. Plain chest films may show hyperinflation. When biopsy material from the lung is stained with bombesin, increased numbers of positive-staining cells are noted in the airways. In general, biopsies from children with NEHI are remarkably void of fibrosis, inflammation, or signs of airway or parenchymal injury (Fig. 427.13 ).

FIG. 427.13 Neuroendocrine cell hyperplasia of infancy. (A) A small airway showing only minimal chronic inflammation on routine staining but (B) staining for bombesin shows increased numbers of neuroendocrine cells within the surface epithelium. (From Corrin B, Nicholson AG: Pathology of the lungs , ed 3, Churchill Livingstone, 2011. Fig. 2.19.)

Although the pattern of NEC hyperplasia seen in histopathology has classically been the gold standard for diagnosis of NEHI, high-resolution chest computed tomography (CT) has a high specificity, such that biopsy may be avoided in most cases. The classic pattern seen on chest CT is ground-glass opacities in the lingula, right middle lobe, and perihilar regions, with air trapping on expiratory images. The lungs otherwise appear normal (Fig. 427.14 ). Some designate a diagnosis made clinically without biopsy as NEHI syndrome and reserve the term NEHI for a diagnosis made by biopsy. If a patient with clinically diagnosed NEHI syndrome has a more severe clinical course than expected, biopsy may be helpful to rule out other pathology.

FIG. 427.14 2 yr old boy with neuroendocrine cell hyperplasia of infancy. CT shows well-defined areas of ground-glass opacity seen centrally and in the right middle lobe and lingula. (From Brody AS: Imaging considerations: interstitial lung disease in children, Radiol Clin North Amer 43:391–403, 2005. Fig. 4.)

The diagnosis of NEHI may be supported by an obstructive pattern that does not reverse with bronchodilators, on either infant pulmonary function testing (iPFT) or standard spirometry. Static lung volumes may show air trapping with increased RV relative to the TLC. BAL findings are notable for lack of inflammatory markers, as compared to other pulmonary diseases of infancy. Genetic testing may be useful to rule out DSM and other causes of infant diffuse lung disease. Targeted testing for variants in Nkx2.1 can be considered, but as this association has been found in only one kindred thus far, the predictive value of such testing is limited.

Natural Course and Treatment As the symptoms of NEHI typically improve and eventually largely resolve over the first few years of life, the standard approach to treatment of NEHI is supportive. The time frame for clinical improvement in NEHI is variable, and symptoms with rest may improve while those on exertion or with sleep persist. Until this occurs, affected children may require supplemental oxygen to maintain normal saturations, sometimes only with sleep or illnesses, but often at all times. The degree of obstruction on iPFTs may be somewhat predictive of degree of desaturation and obstruction in the future. Because they may expend more energy to breathe, children with NEHI may

have difficulty gaining weight, and often require supplemental nutrition. This is often delivered by gastrostomy tube. Management of GER when present may be helpful. When the disease improves, the need for supplemental oxygen and/or nutritional support typically decreases. Inhaled or systemic corticosteroids are generally not thought to be helpful in treating the primary manifestations of NEHI. Children with NEHI, whose symptoms have shown improvement, may experience exacerbations later in childhood. These episodes are associated with increased air trapping. Although the symptoms of NEHI typically resolve during childhood, limited data suggest that some symptoms may persist into the adult years. This may manifest as exercise intolerance, or an asthma-like picture. Obstruction with air trapping may be seen on PFT and persistent abnormalities may be identified on chest imaging. No cases of respiratory failure, need for lung transplantation, or death associated with NEHI have been reported. Diffuse idiopathic neuroendocrine epithelial cell hyperplasia may be a related disorder but is seen predominantly in adult females who have diffuse pulmonary nodules and fixed obstruction or obstructive/restrictive lung disease on pulmonary function testing.

Bibliography Brody AS, Guillerman RP, Hay TC, et al. Neuroendocrine cell hyperplasia of infancy: diagnosis with high-resolution CT. AJR Am J Roentgenol . 2010;194:238–244. Cutz E. Hyperplasia of pulmonary neuroendocrine cells in infancy and childhood. Semin Diagn Pathol . 2015;32:420– 437. Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med . 2007;176:1120–1128. Houin PR, Deterding RR, Young LR. Exacerbations in neuroendocrine cell hyperplasia of infancy are characterized by increased air trapping. Pediatr Pulmonol . 2016;51:E9– E12.

Kerby GS, Wagner BD, Popler J, et al. Abnormal infant pulmonary function in young children with neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol . 2013;48:1008–1015. Langston C, Dishop MK. Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatr Dev Pathol . 2009;12:421–437. Lukkarinen H, Pelkonen A, Lohi J, et al. Neuroendocrine cell hyperplasia of infancy: a prospective follow-up of nine children. Arch Dis Child . 2013;98:141–144. Nevel RJ, Garnett ET, Worrell JA, et al. Persistent lung disease in adults with NKX2.1 mutation and familial neuroendocrine cell hyperplasia of infancy. Ann Am Thorac Soc . 2016;13:1299–1304. Popler J, Wagner BD, Tarro HL, et al. Bronchoalveolar lavage fluid cytokine profiles in neuroendocrine cell hyperplasia of infancy and follicular bronchiolitis. Orphanet J Rare Dis . 2013;8:175. Young LR, Brody AS, Inge TH, et al. Neuroendocrine cell distribution and frequency distinguish neuroendocrine cell hyperplasia of infancy from other pulmonary disorders. Chest . 2011;139:1060–1071.

427.7

Fibrotic Lung Disease Deborah R. Liptzin, Jason P. Weinman, Robin R. Deterding

Keywords Fibrosis pulmonary function oxygen nonspecific interstitial pneumonia Pulmonary fibrosis is scarring in the lung parenchyma (as opposed to bronchiectasis which is scarring of the airways). Idiopathic pulmonary fibrosis is a common form of fibrotic lung disease in adults. This presents with usual interstitial pneumonia (a pathologic finding with patchy interstitial fibrosis, fibroblastic foci, and honeycomb change) (see Chapter 427.5 ). Additional adult fibrotic lung diseases include sarcoidosis, silicosis, coal workers pneumoconiosis and hypersensitivity pneumonitis (e.g., farmer's lung). In children, fibrotic lung disease is rare, and idiopathic pulmonary fibrosis has not been described. The differential diagnosis of fibrotic lung disease includes surfactant dysfunction mutations (Chapter 423 ), radiation-induced fibrosis, bronchiolitis obliterans (Chapter 422.1 ), nonspecific interstitial pneumonia (connective tissue disorders) (Chapter 427), hypersensitivity pneumonitis (Chapter 427.1 ), and aspiration (Chapter 425 ) (Tables 427.19 –427.21 ). Table 427.19

Diseases Associated With Pulmonary Fibrosis • Idiopathic pulmonary fibrosis / nonspecific interstitial pneumonia • Familial pulmonary fibrosis / familial interstitial pneumonia • Hypersensitivity pneumonitis (many agents) • Cryptogenic organizing pneumonia • Adverse reaction to therapy (drugs, radiation) • Pleuroparenchymal fibroelastosis • Hermansky–Pudlak syndrome • Sarcoidosis • Eosinophilic pneumonia (primary or parasitic) • Langerhans cell histiocytosis • Dyskeratosis congenita • Tuberous sclerosis • Neurofibromatosis • Erdheim–Chester disease • Gaucher disease • Niemann–Pick disease • Familial hypocalciuric hypercalcemia

• Lysinuric protein intolerance • IgG4 mediated immune disorder • Myelodysplastic syndrome • Progressive systemic sclerosis • Other connective tissue diseases (SLE, dermatomyositis) • Granulomatosis with polyangiitis • Eosinophilic granulomatosis with polyangiitis

Table 427.20

Pediatric Fibrotic Lung Diseases DISEASES

CT FINDINGS

Surfactant dysfunction

Early: Diffuse ground glass, septal thickening (crazy paving) Chronic: See NSIP

Aspiration

Acute: Consolidation and centrilobular (tree in bud) nodules with a dependent distribution. Chronic: possible UIP with honeycombing

Radiation fibrosis

Architectural distortion, volume loss, traction bronchiectasis. Often with geometric distribution related to radiation field Bronchopulmonary Hyperlucent regions, dysplasia architectural distortion (linear and subpleural triangular opacities)

PATHOLOGY FINDINGS Variable: fibrosis, honeycomb cysts at end stage, NSIP, CPI, few globules of pulmonary alveolar proteinosis, foamy macrophages and cholesterol clefts (endogenous lipoid pneumonia) Airway-centered lesions/bronchiolitis, food particles with or without granulomas, foamy macrophages (endogenous lipoid pneumonia), organizing pneumonia Pleural, septal, and paraseptal fibrosis; reactive atypia of alveolar epithelium and endothelium

Alveolar simplification and enlargement. Patchy hyperinflation. Interstitial fibrosis, with or without interlobular septal fibrosis. Interstitial lymphocytic inflammation and fibrosis with homogenous distribution

ADDITIONAL TREATMENT EVALUATION Genetic testing Hydroxychloroquine, azithromycin, highdose intravenous steroids. Genetic counseling

Video fluoroscopic swallow evaluation

Stop aspiration through thickening feeds, gastric feeds, cleft repair

Supportive care. Consider inhaled corticosteroids

Nonspecific Basilar predominant interstitial findings of groundpneumonia (NSIP) glass opacities (often with subpleural sparing), reticulation, architectural distortion, and traction bronchiectasis Hypersensitivity Patchy and often Airway-centered small non- Lymphocytosis Remove trigger, pneumonitis parahilar reticulation, caseating granulomas, in intravenous steroids (chronic) ground glass, multinucleated giant cells, bronchoalveolar

centrilobular nodules. Honeycombing (rare)

lymphocytic bronchiolitis and peribronchiolitis, airway fibrosis, organizing pneumonia Autoimmune See NSIP. NSIP. Lymphoid connective tissue Honeycombing (rare) hyperplasia. Fibrosis and disorders (collagen cystic change. Pleuritis and vascular disease) pleural fibrosis (variable). Chronic vasculopathy (variable). Airway fibrosis (variable). Drug reactions Peripheral Variable: organizing predominant pneumonia, NSIP, UIP, consolidation or DAD, pulmonary ground glass. Reverse hemorrhage, eosinophilic halo sign. See NSIP. pneumonia Honeycombing (rare) Infection Acute: Consolidation Acute: Neutrophilic and centrilobular (tree alveolitis (bacterial) or in bud) nodules. lymphocytic bronchiolitis Appearance and (viral). Chronic: Variable distribution varies airway fibrosis with type of infection. (constrictive/obliterative Chronic: May bronchiolitis) and progress to IPF/UIP interstitial fibrosis. with honeycombing Immunodeficiency Bronchiectasis, Follicular bronchiolitis or consolidation, diffuse lymphoid centrilobular nodules hyperplasia. NSIP. LIP. GLILD

lavage, precipitins to specific antigen

Usual interstitial pneumonia (UIP)

Genetic testing

Honeycombing, reticulation, traction bronchiectasis, ground glass (less prominent than NSIP)

Fibroblast foci. Interstitial, septal, and pleural fibrosis with heterogenous distribution. Minimal to absent inflammation.

Serologic studies

Disease-specific immune modulation

Drug avoidance

Antimicrobials

Immunologic and genetic testing

Treat underlying immunodeficiency

Table 427.21 Genes Associated With Familial* or Idiopathic Pulmonary Fibrosis GENE IL1RN IL8 FAM13A TLR3 TERT HLADRB1 DSP OBFC1 MUC5B

GENE FUNCTION Inhibitor of pro-inflammatory effect of IL-1alpha and IL-1beta Pro-inflammatory cytokine Signal transduction Pathogen recognition and activation of innate immunity Enzyme in telomerase complex maintaining telomere length Major histocompatibility complex—immune system Tightly links adjacent cells Stimulates the activity of DNA polymerase-alpha-primase Influence on rheological properties of airway mucus, mucociliary transport, and airway defense

MUC2 TOLLIP

Mucin production Regulator of innate immune responses mediated by toll-like receptor and the transforming growth factor β signaling pathway ATP11A Phospholipid translocation MDGA2 Cell–cell interaction MAPT Promotes microtubule assembly and stability SPPL2C Protein cleavage DPP9 Cell–cell adhesion TGFB1 Set of peptides that controls proliferation, differentiation, and other functions in many cell types SFTPC † Component of surfactant fluid SFTPA2 † To modulate innate and adaptive immunity ABCA3 † Transport of lipids across plasma membrane TERC † Template in telomerase complex DKC1 † Stabilization of the template in telomerase complex TINF2 † Telomere maintenance RTELI † DNA helicase PARN † mRNA stability * Also called familial interstitial pneumonia. † Rarer variant.

Adapted from Kaur A, Mathai SK, Schwartz DA: Genetics in idiopathic pulmonary fibrosis pathogenesis, prognosis, and treatment. Frontiers Med 4:154, 2017. Tables 1 and 2.

Clinical Presentation Patients with pulmonary fibrosis will typically present with nonspecific respiratory symptoms such as cough, crackles, wheezes, prolonged expiratory phase, exercise intolerance, and hypoxemia, especially at nighttime. Symptom onset can be insidious or rapid.

Evaluation Pulmonary function tests typically show restriction and reduced diffusion capacity. Air trapping can also be seen. Patients may desaturate with exercise challenges or 6-min walks. There are a variety of findings on computed tomography scan that suggest pulmonary fibrosis. These include reticular opacities, architectural distortion, traction bronchiectasis, and honeycomb cysts. A common late finding in several etiologies of fibrotic lung disease in children is nonspecific interstitial pneumonia: subpleural sparing, ground-glass opacities, reticular change, and bronchiectasis. Typical CT findings in pediatric patients with nonspecific

interstitial pneumonia include basilar predominant ground-glass opacities, reticulation, mild cystic change, and bronchiectasis (Fig. 427.15 ).

FIG. 427.15 Chest CT demonstrates typical CT findings in a pediatric patient with nonspecific interstitial pneumonia including basilarpredominant ground-glass opacities (blue arrows), reticulation (yellow arrows), mild cystic change (green arrows) and bronchiectasis (orange arrow).

In certain disease processes such as surfactant dysfunction mutations (positive genetic testing) or bronchiolitis obliterans (decline in lung function and typical computed tomography scan), biopsy is not necessary for diagnosis. In the absence of a definitive diagnosis, a thoracoscopic wedge biopsy is necessary for diagnosis and to guide treatment. Transthoracic biopsies in pediatrics are of limited utility because the small instruments typically obtain inadequate tissue specimens; transthoracic biopsies in pediatrics are limited to monitoring postlung transplantation and for diagnosis of sarcoidosis. Pathologic findings in pulmonary fibrosis are variable, depending on duration and etiology of disease (see Table 427.20 ), but typically include a component of interstitial inflammation, interstitial expansion by dense collagen, and lobular remodeling (parenchymal architectural distortion and honeycomb cysts). Interlobular septal fibrosis, pleural fibrosis, and chronic pulmonary arteriopathy are common associated findings. Rare dense globules of pulmonary alveolar proteinosis material may indicate a genetic disorder of surfactant metabolism. Reactive lymphoid follicles suggest an immunologic process, such as autoimmune disease

or immunodeficiency. Organizing pneumonia (polypoid aggregates of fibroblasts, Masson bodies ) is a common feature in hypersensitivity pneumonitis and autoimmune diseases. The usual interstitial pneumonia pattern is signaled by fibroblast foci arising within a background of dense interstitial fibrosis and is a rare pattern of disease in children. Connective tissue stains, such as Masson trichrome, Elastic Verhoff von Giesen, and Movat pentachrome, aid in determining the severity and distribution of collagen deposition.

Treatment Treatment varies based on disease process (see Tables 427.19 –427.21 ). Due to the nature of rare disease, treatment regimens are largely based on expert opinion as controlled clinical trials are challenging to perform. Antifibrotic agents approved in adults with idiopathic pulmonary fibrosis (pirfenidone and nintedanib) are not approved for use in children. Patients with fibrotic lung disease should be closely followed by pediatric pulmonary specialists for disease and comorbidity monitoring. Monitoring may include evaluation of pulmonary function (spirometry, lung volumes, and diffusion capacity), functional evaluation of exercise (6-min walk), and screening for comorbidities such as pulmonary hypertension, aspiration, and sleep disordered breathing. Treatment is disease specific but should also include nutritional support secondary to increased metabolic demands. Respiratory support varies depending on each patient's needs, from no support to oxygen via nasal cannula while asleep only, oxygen via nasal cannula all the time, or with ventilation (noninvasive or invasive). Comorbidities should be treated appropriately. Genetic counseling and recurrence risk should be provided with genetic forms of fibrotic lung disease. Patients should be counseled about preventing further lung damage from air pollution, smoking (cigarette, electronic cigarettes, hookah, water pipe, marijuana, etc.), and secondhand smoke exposure.

Outcomes Outcomes vary depending on the underlying disease process.

Bibliography Fan Leland L, et al. Diffuse lung disease in biopsied children 2 to 18 years of age. Application of the child classification scheme. Ann Am Thorac Soc . 2015;12(10):1498–1505. Hansell DM, Bankier AA, MacMahon H, et al. Fleischner society: glossary of terms for thoracic imaging 1. Radiology . 2008;246(3):697–722. King Jr Talmadge E, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370(22):2083–2092. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med . 2018;378(19):1811–1822. Meyer KC. Pulmonary fibrosis, part 1: epidemiology, pathogenesis, and diagnosis. Expert Rev Respir Med . 2017;11(5):343–359. Richeldi L, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med . 2014;370(22):2071–2082. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet . 2017;389. Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest . 2013;143(3):814–824.

CHAPTER 428

Community-Acquired Pneumonia Matthew S. Kelly, Thomas J. Sandora

Epidemiology Pneumonia, defined as inflammation of the lung parenchyma, is the leading infectious cause of death globally among children younger than 5 yr, accounting for an estimated 920,000 deaths each year (Fig. 428.1 ). Pneumonia mortality is closely linked to poverty. More than 99% of pneumonia deaths are in low- and middle-income countries, with the highest pneumonia mortality rate occurring in poorly developed countries in Africa and South Asia (Table 428.1 ).

FIG. 428.1 Pneumonia is the leading infectious killer of children worldwide, as shown by this illustration of global distribution of cause-specific infectious mortality among children younger than age 5 yr in 2015. Pneumonia causes one-third of all under-5 deaths from infection. (From World Health Organization and Maternal and Child Epidemiology Estimation Group estimates, 2015.)

Table 428.1

Pneumonia Cases and Mortality Rate in Children Younger Than Age 5 Yr by UNICEF Region, 2015 UNICEF REGIONS West and Central Africa Sub-Saharan Africa Eastern and Southern Africa South Asia Middle East and North Africa East Asia and the Pacific Latin America and the Caribbean Least Developed Countries World

PNEUMONIA CASES IN CHILDREN YOUNGER THAN 5 YR OF AGE 298,000

PNEUMONIA MORTALITY RATE (UNDER5 DEATHS PER 1,000 LIVE BIRTHS) 16.2

490,000

13.7

177,000

10.9

282,000 46,000

7.9 4.1

81,000

2.7

23,000

2.1

363,000

12.0

920,000

6.6

From United Nations Children's Fund: One is too many—ending child deaths from pneumonia and diarrhoea. https://data.unicef.org/resources/one-many-ending-child-deaths-pneumonia-diarrhoea/ . Accessed January 21, 2017.

In the United States, mortality from pneumonia in children declined by 97% between 1939 and 1996. This decline likely resulted from the development of antibiotics and vaccines and the expansion of medical insurance coverage for children. Effective vaccines against measles (see Chapter 273 ) and pertussis (see Chapter 224 ) contributed to the decline in pneumonia-related mortality during the 20th century. Haemophilus influenzae type b (see Chapter 221 ) was also an important cause of bacterial pneumonia in young children but became uncommon following licensure of a conjugate vaccine in 1987. The introduction of pneumococcal conjugate vaccines (PCVs) (see Chapter 209 ) has been an important contributor to the further reductions in pneumonia-related mortality achieved over the past 15 yr.

Etiology Although most cases of pneumonia are caused by microorganisms, noninfectious causes include aspiration (of food or gastric acid, foreign bodies, hydrocarbons, and lipoid substances), hypersensitivity reactions, and drug- or radiation-induced pneumonitis (see Chapter 427 ). The cause of pneumonia in an individual patient

is often difficult to determine because direct sampling of lung tissue is invasive and rarely performed. Bacterial cultures of sputum or upper respiratory tract samples from children typically do not accurately reflect the cause of lower respiratory tract infection. Streptococcus pneumoniae (pneumococcus) is the most common bacterial pathogen in children 3 wk to 4 yr of age, whereas Mycoplasma pneumoniae and Chlamydophila pneumoniae are the most frequent bacterial pathogens in children age 5 yr and older. In addition to pneumococcus, other bacterial causes of pneumonia in previously healthy children in the United States include group A streptococcus (Streptococcus pyogenes ; see Chapter 210 ) and Staphylococcus aureus (see Chapter 208.1 ) (Tables 428.2 , 428.3 , and 428.4 ). S. aureus pneumonia often complicates an illness caused by influenza viruses. Table 428.2

Causes of Infectious Pneumonia BACTERIAL COMMON Streptococcus pneumoniae Group B streptococci Group A streptococci Staphylococcus aureus Mycoplasma pneumoniae * Chlamydophila pneumoniae * Chlamydia trachomatis Mixed anaerobes Gram-negative enterics UNCOMMON Haemophilus influenzae type b Moraxella catarrhalis Neisseria meningitidis Francisella tularensis Nocardia species Chlamydophila psittaci * Yersinia pestis (plague) Legionella species* Coxiella burnetii * (Q fever) VIRAL COMMON Respiratory syncytial virus Parainfluenza types 1-4 Influenza A, B Adenovirus

Consolidation, empyema Neonates Empyema Pneumatoceles, empyema; infants; nosocomial pneumonia Adolescents; summer–fall epidemics Adolescents Infants Aspiration pneumonia Nosocomial pneumonia Unimmunized

Animal, tick, fly contact; bioterrorism Immunocompromised patients Bird contact (especially parakeets) Rat contact; bioterrorism Exposure to contaminated water; nosocomial Animal (goat, sheep, cattle) exposure

Bronchiolitis Croup High fever; winter months Can be severe; often occurs between January and April

Human metapneumovirus UNCOMMON Rhinovirus Enterovirus Herpes simplex Cytomegalovirus Measles Varicella Hantavirus Coronaviruses [severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS)] FUNGAL Histoplasma capsulatum Blastomyces dermatitidis Coccidioides immitis Cryptococcus neoformans and C. gattii Aspergillus species Mucormycosis Pneumocystis jiroveci RICKETTSIAL Rickettsia rickettsiae MYCOBACTERIAL Mycobacterium tuberculosis Mycobacterium avium complex Other non-tuberculous mycobacteria PARASITIC Various parasites (e.g., Ascaris , Strongyloides species)

Similar to respiratory syncytial virus Rhinorrhea Neonates Neonates, immunocompromised persons Infants; immunocompromised persons (particularly HIV-infected infants) Rash, coryza, conjunctivitis Unimmunized; immunocompromised persons Southwestern United States, rodents Asia, Arabian Peninsula

Ohio/Mississippi River valley; bird, bat contact Ohio/Mississippi River valley Southwestern United States, Great Lakes states Bird contact; immunocompromised; Northwestern United States (C. gattii) Immunocompromised persons; nodular lung infection Immunocompromised persons Immunocompromised persons (particularly HIV-infected infants); steroids Tick bite Travel to endemic region; exposure to highrisk persons Immunocompromised (particularly HIVinfected) persons Immunocompromised persons; cystic fibrosis Eosinophilic pneumonia

* Atypical pneumonia syndrome; may have extrapulmonary manifestations, low-grade fever,

patchy diffuse infiltrates, and poor response to β-lactam antibiotics. Adapted from Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis & therapy , ed 2, Philadelphia, 2004, Elsevier, p. 29.

Table 428.3 Pneumonia Etiologies Grouped by Age of the Patient AGE GROUP Neonates (1 cm) with tissue-like echo-texture (circle) and ultrasonographic bronchograms (arrow) ; (D ) small consolidation ( 1 : 64 are also found in the blood of roughly half of patients with M. pneumoniae infections; however, cold agglutinins are nonspecific because other pathogens such as influenza viruses may also cause increases. Serologic evidence, such as antistreptolysin O and anti-DNase B titers, may also be useful in the diagnosis of group A streptococcal pneumonia. Table 428.6

Factors Suggesting Need for Hospitalization of Children

With Pneumonia Age 200 IU/L; or fluid:serum lactic dehydrogenase ratio >0.6. Although systemic acidosis reduces the usefulness of pleural fluid pH measurements, pH < 7.20 suggests an exudate (see Chapter 400 ). Glucose is usually 5 mg/L, elevated neutrophil percentage), 2 major criteria, or 1 major criteria plus 2 minor criteria (change in sputum color, breathlessness, chest pain, crackles/crepitations, wheeze). Antibiotic choice is dictated by the identification

and sensitivity of organisms found on deep throat, sputum (induced or spontaneous), or bronchoalveolar lavage fluid cultures. The most common organisms found in children with bronchiectasis include S. pneumoniae , H. influenzae non–type b, M. catarrhalis , and Mycoplasma pneumoniae . Amoxicillin/clavulanic acid (22.5 mg/kg/dose twice daily) has been particularly successful at treating most pulmonary exacerbations. Viruses (most commonly human rhinovirus) are often found in children with bronchiectasis suffering from an exacerbation. Long-term prophylactic macrolide antibiotics or nebulized antibiotics (e.g., tobramycin, colistin, aztreonam) may be beneficial (reduced exacerbations and hospitalizations, improved lung function) but may also increase antibiotic resistance. Airway hydration (inhaled hypertonic saline or mannitol) also improves quality of life in adults with bronchiectasis. Any underlying disorder (immunodeficiency, aspiration) that may be contributing must be addressed. When localized bronchiectasis becomes more severe or resistant to medical management, segmental or lobar resection may be warranted. Lung transplantation can also be performed in patients with bronchiectasis. A review of randomized trials among children and adult patients with bronchiectasis did not find strong evidence to support the routine use of inhaled corticosteroids, although some studies demonstrate improved quality of life and reduced exacerbations in patients with bronchiectasis treated with inhaled corticosteroids. Although preventative strategies, including immunization against typical respiratory pathogens (influenza, pneumococci), are generally recommended, no studies have been conducted to date to address the efficacy of these recommendations.

Prognosis Children with bronchiectasis often suffer from recurrent pulmonary illnesses, resulting in missed school days, stunted growth, osteopenia, and osteoporosis. The prognosis for patients with bronchiectasis has improved considerably in the past few decades. Earlier recognition or prevention of predisposing conditions, specialist multidisciplinary management, more powerful and broad-spectrum antibiotics, and improved surgical outcomes are likely reasons.

Bibliography

Banjar HH. A review of 151 cases of pediatric noncystic fibrosis bronchiectasis in a tertiary care center. Ann Thorac Med . 2007;2(1):3–8. Bonavita J, Naidich DP. Imaging of bronchiectasis. Clin Chest Med . 2012;33(2):233–248. Brower KS, Del Vecchio MT, Aronoff SC. The etiologies of non-CF bronchiectasis in childhood: a systematic review of 989 subjects. BMC Pediatr . 2014;14:299–306. Gao YH, Guan WJ, Xu G, et al. Macrolide therapy in adults and children with non-CF bronchiectasis: a systematic reviw and meta-analysis. PLoS ONE . 2014;9(3):e90047. Goyal V, Grimwood K, Marchant J, et al. Pediatric bronchiectasis: no longer an orphan disease. Pediatr Pulmonol . 2016;51:450–469. Gudbjartsson T, Gudmundsson G. Middle lobe syndrome: a review of clinicopathological features, diagnosis and treatment. Respiration . 2012;84:80–86. Hnin K, Nguyen C, Crason KV, et al. Prolonged antibiotics for non-cystic fibrosis bronchiectasis in children and adults (review). Cochrane Database of Syst Rev . 2015;8. Hodge G, Upham JW, Change AB, et al. Increased peripheral blood pro-inflammatory/cytotoxic lymphocytes in children with bronchiectasis. PLoS ONE . 2015;10(8):e0133695. Kapur N, Mackay IM, Sloots TP, et al. Respiratory viruses in exacerbation of non-cyrtic fibrosis bronchiectasis in children. Arch Dis Child . 2014;99:749–753. Lee AL, Button BM, Tannenbaum EL. Airway clearance techniques in children and adolescents with chronic suppurative lung disease and bronchiectasis. Front Pediatr . 2017;5:2. Rashid A, Nanjappa S, Greene JN. Infectious causes of right middle lobe syndrome. Cancer Control . 2017;24(1):60–65. Romagnoli V, Priftis KN, de Benedictis FM. Middle lobe

syndrome in children today. Pediatr resp Rev . 2014;15:188– 193. Snijders D, Calgaro S, Bertozzi I, et al. Bronchiectasis in children. Int J Immunopathol Pharmacol . 2013;26(2):529– 534.

CHAPTER 431

Pulmonary Abscess Oren J. Lakser

Lung infection that destroys the lung parenchyma, resulting in cavitations and central necrosis, can result in localized areas composed of thick-walled purulent material, called lung abscesses. Primary lung abscesses occur in previously healthy patients with no underlying medical disorders and are usually solitary. Secondary lung abscesses occur in patients with underlying or predisposing conditions and may be multiple. Lung abscesses are much less common in children (estimated at 0.7 per 100,000 admissions per year) than in adults.

Pathology and Pathogenesis A number of conditions predispose children to the development of pulmonary abscesses, including aspiration, pneumonia, cystic fibrosis (see Chapter 432 ), gastroesophageal reflux (see Chapter 349 ), tracheoesophageal fistula (see Chapter 345 ), immunodeficiencies, postoperative complications of tonsillectomy and adenoidectomy, seizures, a variety of neurologic diseases, and other conditions associated with impaired mucociliary defense. In children, aspiration of infected materials or a foreign body is the predominant source of the organisms causing abscesses. Initially, pneumonitis impairs drainage of fluid or the aspirated material. Inflammatory vascular obstruction occurs, leading to tissue necrosis, liquefaction, and abscess formation. Abscess can also occur as a result of pneumonia and hematogenous seeding from another site. If the aspiration event occurred while the child was recumbent, the right and left upper lobes and apical segment of the right lower lobes are the dependent areas most likely to be affected. In a child who was upright, the posterior segments of the upper lobes were dependent and therefore are most likely to be affected. Primary abscesses are found most often on the right side, whereas

secondary lung abscesses, particularly in immunocompromised patients, have a predilection for the left side. Both anaerobic and aerobic organisms can cause lung abscesses. Common anaerobic bacteria that can cause a pulmonary abscess include Bacteroides spp., Fusobacterium spp., and Peptostreptococcus spp. Abscesses can be caused by aerobic organisms such as Streptococcus spp., Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and very rarely Mycoplasma pneumoniae . Aerobic and anaerobic cultures should be part of the workup for all patients with lung abscess. Occasionally, concomitant viralbacterial infection can be detected. Fungi can also cause lung abscesses, particularly in immunocompromised patients.

Clinical Manifestations The most common symptoms of pulmonary abscess in the pediatric population are fever, cough, and emesis. Other common symptoms include tachypnea, dyspnea, chest pain, sputum production, weight loss, and hemoptysis. Physical examination typically reveals tachypnea, dyspnea, retractions with accessory muscle use, decreased breath sounds, and dullness to percussion in the affected area. Crackles and occasionally a prolonged expiratory phase may be heard on lung examination.

Diagnosis Diagnosis is most commonly made on the basis of chest radiography. Classically, the chest radiograph shows a parenchymal inflammation with a cavity containing an air-fluid level (Fig. 431.1 ). A chest CT scan can provide better anatomic definition of an abscess, including location and size (Fig. 431.2 ).

FIG. 431.1 A and B, Multiloculated lung abscess (arrows) . (From Brook I: Lung abscess and pulmonary infections due to anaerobic bacteria. In Chernick V, Boat TF, Wilmott RW, et al, editors: Kendig's disorders of the respiratory tract in children , ed 7, Philadelphia, 2006, WB Saunders, p. 482.)

FIG. 431.2 Pulmonary abscess in a 2 yr old boy with persistent cough. A, Chest radiograph shows large oval mass in the left upper lobe. B, CT scan demonstrates an abscess with a thick enhancing wall that contains both air and fluid. (From Slovis TL, editor: Caffey's pediatric diagnostic imaging , ed 11, Philadelphia, 2008, Mosby, Fig. 78-3, p. 1297.)

An abscess is usually a thick-walled lesion with a low-density center progressing to an air-fluid level. Abscesses should be distinguished from pneumatoceles, which often complicate severe bacterial pneumonias and are characterized by thin- and smooth-walled, localized air collections with or without air-fluid level (Fig. 431.3 ). Pneumatoceles often resolve spontaneously with the treatment of the specific cause of the pneumonia.

FIG. 431.3 Appearance over a period of 5 days of a large multiloculated pneumonocele in a segment of alveolar consolidation. A, There is a large cavity with 2 air-fluid levels in a segment of alveolar pneumonia in the right upper lobe. B, Five days later, the cavity and most of the pneumonic consolidation have disappeared. (From Silverman FN, Kuhn JP: Essentials of Caffey's pediatric x-ray diagnosis, Chicago, 1990, Year Book, p. 303.)

The determination of the etiologic bacteria in a lung abscess can be very helpful in guiding antibiotic choice. Although Gram stain of sputum can provide an early clue as to the class of bacteria involved, sputum cultures typically yield mixed bacteria and therefore are not always reliable. Attempts to avoid contamination from oral flora include direct lung puncture, percutaneous (aided by CT guidance) or transtracheal aspiration, and bronchoalveolar lavage specimens obtained bronchoscopically. Bronchoscopic aspiration should be avoided because it can be complicated by massive intrabronchial aspiration, and great care should therefore be taken during the procedure. To avoid invasive procedures in previously normal hosts, empiric therapy can be initiated in the absence of culturable material.

Treatment Conservative management is recommended for pulmonary abscess. Most experts advocate a 2- to 3-wk course of parenteral antibiotics for uncomplicated cases, followed by a course of oral antibiotics to complete a total of 4-6 wk. Antibiotic choice should be guided by results of Gram stain and culture but initially should include agents with aerobic and anaerobic coverage. Treatment regimens should include a penicillinase-resistant agent active against S. aureus and anaerobic coverage, typically with clindamycin or ticarcillin/clavulanic acid. If gramnegative bacteria are suspected or isolated, an aminoglycoside should be added. Early CT-guided percutaneous aspiration or drainage has been advocated because it can hasten the recovery and shorten the course of parenteral antibiotic therapy needed. For severely ill patients, patients with larger abscess, or those whose status fails to improve after 7-10 days of appropriate antimicrobial therapy, surgical intervention should be considered. Minimally invasive percutaneous aspiration techniques, often with CT guidance, are the initial and, often, only intervention required. Thorascopic drainage has also been successfully used with minimal complications. In rare complicated cases, thoracotomy with surgical drainage or lobectomy and/or decortication may be necessary. Abscess drainage is reportedly required in ~20% of cases of pulmonary abscess in children.

Prognosis Overall, prognosis for children with primary pulmonary abscesses is excellent. The presence of aerobic organisms may be a negative prognostic indicator, particularly in those with secondary lung abscesses. Most children become asymptomatic within 7-10 days, although the fever can persist for as long as 3 wk. Radiologic abnormalities usually resolve in 1-3 mo but can persist for years.

Bibliography Alsubie H, Fitzgerald DA. Lung abscess in children. J Ped Infect Dis . 2009;4:27–35. Choi MS, Chun JH, Lee KS, et al. Clinical experience of lung abscess in children: 15 year experience at two university

hospitals. Korean J Pediatr . 2015;58(12):476–483. Goyadi P, Srikanth KP, Vaidya PC, et al. Primary lung abscess in early infancy. Indian Pedtr . 2015;52(3):241–242. Hogan MJ, Marshalleck FE, Sidhu MK, et al. Quality improvement guidelines for pediatric abscess and fluid drainage. Pediatr Radiol . 2012;42:1527–1535. Madhani K, McGrath E, Guglani L. A 10-year retrospective review of pediatric lung abscesses from a single center. Ann Thorac Med . 2016;11:191–196. Rahman A, Rman M. Clindamycin in treatment of lung abscess in children. Amer J Drug Delivery Therapeutics . 2014;1(1):1–8. Ruffini E, De Petris L, Candeloni P, et al. Lung abscess in a child secondary to Mycoplasma pneumonia infection. Ped Med Chir (Med Surg Ped) . 2014;36:87–89. Saxena A, Vatkar A, Chaudhary P, et al. Lung abscess in children: current perspective. J Dent and Med Sciences . 2015;14(3):13–14.

CHAPTER 432

Cystic Fibrosis Marie E. Egan, Michael S. Schechter, Judith A. Voynow

Cystic fibrosis (CF) is an inherited multisystem disorder of children and adults; it is the most common life-limiting recessive genetic trait among whites. Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the primary defect, leads to a wide and variable array of presenting manifestations and complications. CF is responsible for most cases of exocrine pancreatic insufficiency in early life and is the major cause of severe chronic lung disease in children. It is also responsible for many cases of hyponatremic salt depletion, nasal polyposis, pansinusitis, rectal prolapse, pancreatitis, cholelithiasis, and nonautoimmune insulin-dependent hyperglycemia. Because CF may manifest as failure to thrive and hepatic dysfunction, including cirrhosis, this disorder enters into the differential diagnosis of many pediatric conditions (Table 432.1 ). Table 432.1

Complications of Cystic Fibrosis RESPIRATORY Bronchiectasis, bronchitis, bronchiolitis, pneumonia Atelectasis Hemoptysis Pneumothorax Nasal polyps Sinusitis Reactive airway disease Mucoid impaction of the bronchi Allergic bronchopulmonary aspergillosis Cor pulmonale Respiratory failure GASTROINTESTINAL Meconium ileus, meconium plug (neonate) Meconium peritonitis (neonate)

Distal intestinal obstruction syndrome (non-neonatal obstruction) Rectal prolapse Intussusception Volvulus Fibrosing colonopathy (strictures) Appendicitis Intestinal atresia Pancreatitis Biliary cirrhosis (portal hypertension: esophageal varices, hypersplenism) Neonatal obstructive jaundice Hepatic steatosis Gastroesophageal reflux Cholelithiasis Inguinal hernia Growth failure (malabsorption) Vitamin deficiency states (vitamins A, K, E, D) Insulin deficiency, symptomatic hyperglycemia, diabetes Malignancy (rare) OTHER Infertility Delayed puberty Edema-hypoproteinemia Dehydration–heat exhaustion Hypertrophic osteoarthropathy-arthritis Clubbing Amyloidosis Diabetes mellitus Aquagenic palmoplantar keratoderma (skin wrinkling)

Adapted from Silverman FN, Kuhn JP: Essentials of Caffey's pediatric x-ray diagnosis, Chicago, 1990, Year Book, p. 649.

Genetics CF occurs most frequently in white populations of northern Europe, North America, and Australia/New Zealand. The prevalence in these populations varies but approximates 1 in 3,500 live births (1 in 9,200 individuals of Hispanic descent and 1 in 15,000 African Americans). Although less frequent in African, Hispanic, Middle Eastern, South Asian, and eastern Asian populations, the disorder does exist in these populations as well (Fig. 432.1 ).

FIG. 432.1 Approximate cystic fibrosis birth prevalence and common mutations for selected countries. Birth prevalence is reported as number of live births per case of cystic fibrosis. Common/important mutations in each region are listed below the prevalence figures. The birth prevalence can vary greatly among ethnic groups in a country. (From O'Sullivan BP, Freedman SD: Cystic fibrosis, Lancet 373:1891–1902, 2009.)

CF is inherited as an autosomal recessive trait. The CF gene codes for the CFTR protein, which is 1,480 amino acids. CFTR is expressed largely in epithelial cells of airways, the gastrointestinal tract (including the pancreas and biliary system), the sweat glands, and the genitourinary system. CFTR is a member of the adenosine triphosphate–binding cassette superfamily of proteins. It functions as a chloride channel and has other regulatory functions that are perturbed variably by the different mutations. More than 1,900 CFTR polymorphisms have been described, many of which are not clearly of clinical significance. Those that are associated with clinical manifestations may be grouped into 6 main classes based upon how they impact upon protein structure and function (Table 432.2 ; Fig. 432.2 ). Mutation class I-III are generally considered to be severe mutations in that they lead to a complete or nearly complete absence of CFTR function, whereas class IV-VI mutations are associated with some residual functional protein. The most prevalent mutation of

CFTR is the deletion of a single phenylalanine residue at amino acid 508 (F508del). This mutation is responsible for the high incidence of CF in northern European populations and is considerably less frequent in other populations, such as those of southern Europe and Israel. Nearly 50% of individuals with CF in the United States Cystic Fibrosis Foundation (CFF) Patient Registry are homozygous for F508del, and approximately 87% carry at least 1 F508del gene. Remaining patients have an extensive array of mutations, none of which has a prevalence of more than several percentage points, except in certain populations; for example, the W1282X mutation occurs in 60% of Ashkenazi Jews with CF. Through the use of probes for 40 of the most common mutations, the genotype of 80–90% of Americans with CF can be ascertained. Genotyping using a discreet panel of mutation probes is quick and less costly than more comprehensive sequencing and is the approach typically used in state newborn screening programs. In remaining patients, sequencing the entire CFTR gene and looking for deletions and duplications are necessary to establish the genotype. As sequencing technologies evolve and costs decrease, sequencing the entire CFTR gene may become mainstream for all patients. Table 432.2

One Proposed Classification of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations CLASS EFFECT ON CFTR

FUNCTIONAL CFTR SAMPLE MUTATIONS PRESENT? No Stop codons (designation in X; e.g., Trp1282X, Gly542X); splicing defects with no protein production (e.g., 711+1G→T, 1717-1G→A) No/substantially Phe508del, Asn1303Lys, Gly85Gly, reduced leu1065Pro, Asp507, Ser549Arg

I

Lack of protein production

II

Defect in protein trafficking with ubiquitination and degradation in endoplasmic reticulum/Golgi body Defective regulation; CFTR not No (nonfunction Gly551Asp, Ser492Phe, Val520Phe, activated by adenosine triphosphate CFTR present in Arg553Gly, Arg560Thr, Arg560Ser or cyclic adenosine monophosphate apical membrane)

III

IV V

Reduced chloride transport through Yes CFTR at the apical membrane Splicing defect with reduced Yes production of CFTR

Ala455Glu, Arg117Cys, Asp1152His, Leu227Arg, Arg334Trp, Arg117His* 3849+10kbC→T, 1811+16kbA→G, IVS8-5T, 2789+5G→A

* Function of Arg117His depends on the length of the polythymidine track on the same

chromosome in intron 8 (IVS8): 5T, 7T, or 9T. There is more normal CFTR function with a longer polythymidine track.

From O'Sullivan BP, Freedman SD: Cystic fibrosis, Lancet 373:1891–1902, 2009.

FIG. 432.2 Classes of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Mutations in the CFTR gene can be divided into 6 classes. Class I mutations result in no protein production. Class II mutations (including the most prevalent, Phe508del) cause retention of a misfolded protein at the endoplasmic reticulum and subsequent degradation in the proteasome. Class III mutations affect channel regulation, impairing channel opening (e.g., Gly551Asp). Class IV mutants show reduced conduction—that is, decreased flow of ions (e.g., Arg117His). Class V mutations cause substantial reduction in mRNA or protein, or both, Class VI mutations cause substantial plasma membrane instability and include Phe508del when rescued by most correctors (rPhe508del). (From Boyle MP, De Boeck K: A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect, Lancet Respir Med 1:158–63, 2013.)

The relationship between CFTR genotype and clinical phenotype is highly complex. CFTR mutation class is strongly associated with pancreatic dysfunction and will usually predict this manifestation in any given patient. Respiratory complications and lung function decline are also correlated with mutation class severity but with greater variation due to the influence of nonCFTR modifier gene polymorphisms and environmental influences on the manifestations of lung disease in any one individual. Studies have identified

specific non-CFTR modifier genes of importance; genome-wide association studies identified a polymorphism on chromosome 11 in the intergenic region between EHF (an epithelial transcription factor) and APIP (an inhibitor of apoptosis) that is associated with lung disease severity and may influence the expression of EHF and APIP, as well as other genes in the region, including PDHX , CD44 , and ELF5 . A region on chromosome 20 may also be found to relate to lung disease severity. This region encompasses several genes (MC3R, CASS4, AURKA) that may play a role in lung host defense involving neutrophil function, apoptosis, and phagocytosis. Genome-wide association studies analysis also identified genetic regions that predispose to risk for liver disease, CF-related diabetes, and meconium ileus. The high-frequency of CFTR mutations has been ascribed to resistance to the morbidity and mortality associated with infectious dysenteries through the ages. Cultured CF intestinal epithelial cells homozygous for the F508del mutation are unresponsive to the secretory effects of cholera toxin. CFTR heterozygous mice experience less mortality when treated with cholera toxin than their unaffected wild-type littermates.

Pathogenesis A number of long-standing observations of CF are of fundamental pathophysiologic importance; they include failure to clear mucous secretions, a paucity of water in mucous secretions, an elevated salt content of sweat and other serous secretions, and chronic infection limited to the respiratory tract. In addition, there is a greater negative potential difference across the respiratory epithelia of patients with CF than across the respiratory epithelia of control subjects. Aberrant electrical properties are also demonstrated for CF sweat gland duct and rectal epithelia. The membranes of CF epithelial cells are unable to secrete chloride or bicarbonate in response to cyclic adenosine monophosphate– mediated signals, and at least in the respiratory epithelial cells, excessive amounts of sodium are absorbed through these membranes. These defects can be traced to a dysfunction of CFTR. CFTR function is highly regulated and energy dependent; it requires both cyclic adenosine monophosphate–stimulated protein kinase A phosphorylation of the regulatory domain and ATP binding and hydrolysis at the nucleotide binding domains. CFTR also interacts with other ion channels, signal transduction proteins, and the cytoskeleton (Fig. 432.3 and see Fig. 432.2 ).

FIG. 432.3 Schematic diagram depicting cystic fibrosis (CF) epithelial channel defects, characterized by impaired chloride secretion, massive sodium absorption, and movement of water through the epithelium, leading to a dehydrated airway surface. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; CFTR, cystic fibrosis transmembrane conductance regulator; ClCa, alternative chloride channel; ENaC, epithelium sodium channel; PKA, protein kinase A. (From Michelson P, Faro A, Ferkol T: Pulmonary disease in cystic fibrosis. In Kendig's Disorders of the Respiratory Tract in Children , ed 9, Philadelphia, 2019, Elsevier, [Fig. 51.1, p. 778].)

Many hypotheses have been postulated to explain how CFTR dysfunction results in the clinical phenotype (Fig. 432.4 ). It is likely that no one hypothesis explains the full spectrum of disease. One model is that airway hydration homeostasis requires both CFTR and P2Y2 -regulated calcium-activated chloride secretion. When extracellular ATP is depleted such as after viral infections, calcium-activated chloride secretion is not activated and the failure of mutant CFTR chloride secretion results in dehydrated airway secretions, increased concentration of mucin solids, and more viscoelastic mucus that is not cleared by normal mucociliary transport. Another mechanism that is supported by both primary human airway studies and investigations in the CF pig is that mutant CFTR causes failure of HCO3 − secretion and a more acidic airway surface liquid, which increases mucous viscoelasticity resulting in poor mucociliary clearance. Mucous secretions are tethered to submucosal gland ducts and are retained and obstruct airways, starting with those of the smallest caliber, the bronchioles. Airflow obstruction at the level of small airways is the earliest observable physiologic abnormality of the respiratory system. CFTR dysfunction in airway smooth muscle has been implicated in tracheal and airway

abnormalities in humans and in animal models of the disease (pig and mice). These data suggest that CFTR expression in this nonepithelial tissue contributes to airway constriction.

FIG. 432.4 Schema of mutant cystic fibrosis transmembrane conductance regulator (CFTR) mechanisms of chronic airway disease. CFTR conducts several anions including chloride, bicarbonate, thiocyanate, and glutathione. The loss of CFTR function impacts critical airway epithelial functions: (1) It increases the risk for dehydration of airway surface liquid (ASL) with loss of chloride efflux and associated increased sodium channel activity. (2) The loss of secreted bicarbonate and/or acidic pH of the ASL increases mucous viscoelasticity resulting in failure of mucociliary transport. (3) Acidic pH in the ASL impairs normal innate immune clearance of bacteria. (4) Loss of thiocyanate impairs lactoperoxidase bacterial killing. (5) Loss of glutathione secretion depletes the antioxidant capacity of the airway resulting in increased inflammation, increased mucous secretion, and increased mucous viscoelasticity. These factors lead to a vicious cycle of infection and inflammation that is progressive.

It is plausible that similar pathophysiologic events take place in the pancreatic

and biliary ducts (and in the vas deferens), leading to desiccation of proteinaceous secretions and obstruction. Because the function of sweat gland duct cells is to absorb rather than secrete chloride, salt is not retrieved from the isotonic primary sweat as it is transported to the skin surface; chloride and sodium levels are consequently elevated. Chronic infection in CF is limited to the airways. One explanation for infection is a sequence of events starting with failure to clear inhaled bacteria promptly and then proceeding to persistent infection and an inflammatory response in airway walls. Another explanation for early infection is the failure of innate immune proteins to kill bacteria in an abnormally acidic airway milieu. In addition, it has been proposed that abnormal CFTR creates a proinflammatory state or amplifies the inflammatory response to initial infections (viral or bacterial). Some investigators have identified primary differences in CF-affected immune cells (including macrophage, neutrophils, lymphocytes, and dendritic cells) and have suggested that these alterations contribute to this proinflammatory state as well as a dysregulated immune response. It appears that inflammatory events occur first in small airways, perhaps because it is more difficult to clear altered secretions and microorganisms from these regions. The agents of airway injury include neutrophil products, such as oxidative radicals and proteases, and immune reaction products. These inflammatory products further aggravate airway obstruction by increasing mucin secretion and altering mucin structure to promote both intramolecular and intermolecular interactions. Excessive inflammatory cell polymers in CF sputum, including DNA, filamentous actin, and glycosaminoglycans, further contribute to abnormal mucous viscoelastic properties and airway obstruction. Chronic bronchiolitis and bronchitis are the initial lung manifestations (see Chapter 418 ), but after months to years, structural changes in airway walls produce bronchiolectasis and bronchiectasis . With advanced lung disease, infection may extend to peribronchial lung parenchyma. A central feature of lung disease in patients with CF is the high prevalence of airway infection with Staphylococcus aureus (see Chapter 208.1 ), Pseudomonas aeruginosa (see Chapter 232.1 ), and Burkholderia cepacia complex (see Chapter 232.2 ), organisms that rarely infect the lungs of other individuals. It has been postulated that the CF airway epithelial cells or surface liquids may provide a favorable environment for harboring these organisms. CF airway epithelium may be compromised in its innate defenses against these organisms, through either acquired or genetic alterations. Antimicrobial activity

is diminished in CF secretions; this diminution may be related to hyperacidic surface liquids or other effects on innate immunity. Another puzzle is the propensity for P. aeruginosa to undergo mucoid transformation in the CF airways. The complex polysaccharide produced by these organisms generates a biofilm that provides a hypoxic environment and thereby protects Pseudomonas against antimicrobial agents. Altered lipid homeostasis has been implicated as a predisposing factor for respiratory tract infection and inflammation. Concentrations of lipoxins— molecules that suppress neutrophilic inflammation—are suppressed in CF airways. There is an imbalance of lipids with increased arachidonic acid and decreased docosahexaenoic acid, which promotes inflammation. There is also an imbalance of ceramide in the CF airway that is proinflammatory. Supporting the idea that altered lipid uptake affects infection and inflammation is the observation that the 10–15% of individuals with CF who retain substantial exocrine pancreatic function have delayed acquisition of P. aeruginosa and slower deterioration of lung function. However, it appears that nutritional factors are contributory only because preservation of pancreatic function does not preclude development of typical lung disease. The variation in progression of lung disease seen in patients with CF is largely influenced by social and physical environment factors, whose impact matches that of CFTR genotype. Exposure to environmental tobacco smoke and outdoor air pollutants, and early acquisition of respiratory virus infections, as well as pathogenic organisms like P. aeruginosa and methicillin-resistant S. aureus, have been implicated as causes of worsening disease. Sex/gender disparities also seem to exist, with females having a poorer prognosis. Although studies have suggested that estrogen may influence disease exacerbations, the gap seems to be narrowing in the past decade. Although most CF care is delivered at specialty centers and is broadly influenced by current clinical guidelines, there is enough variability in treatment approaches to cause large variation in respiratory and nutritional outcomes across the care networks in both North America and Europe. Social determinants of health are associated with significant disparities in outcome; socioeconomic status has been shown to be a strong predictor of mortality, as well as both nutritional status and lung function on both sides of the Atlantic. The specific mechanism of effect is unclear, but evidence suggests a role for socioeconomic status–related differences in health behaviors and disease self-management practices, stress and mental health issues, and environmental tobacco smoke

exposure. Differential access to specialty care and medications is not a major factor in North American children (lack of insurance in some adults is a problem); however, differences in disease outcomes across European countries of varying wealth are quite clear.

Pathology The earliest pathologic lesion in the lung is that of bronchiolitis (mucous plugging and an inflammatory response in the walls of the small airways); with time, mucous accumulation and inflammation extend to the larger airways (bronchitis ) (see Chapter 418.2 ). Goblet cell hyperplasia and submucosal gland hypertrophy become prominent pathologic findings, which is most likely a response to chronic airway infection. Organisms appear to be confined to the endobronchial space; invasive bacterial infection is not characteristic. With longstanding disease, evidence of airway destruction such as bronchiolar obliteration, bronchiolectasis, and bronchiectasis (see Chapter 430 ) becomes prominent. Imaging modalities demonstrate both increased airway wall thickness and luminal cross-sectional area relatively early in lung disease evaluation. Bronchiectatic cysts and emphysematous bullae or subpleural blebs are frequent with advanced lung disease, the upper lobes being most commonly involved. These enlarged air spaces may rupture and cause pneumothorax. Interstitial disease is not a prominent feature, although areas of fibrosis appear eventually. Bronchial arteries are enlarged and tortuous, contributing to a propensity for hemoptysis in bronchiectatic airways. Small pulmonary arteries eventually display medial hypertrophy, which would be expected in secondary pulmonary hypertension. The paranasal sinuses are uniformly filled with secretions containing inflammatory products, and the epithelial lining displays hyperplastic and hypertrophied secretory elements (see Chapter 408 ). Polypoid lesions within the sinuses and erosion of bone have been reported. The nasal mucosa may form large or multiple polyps , usually from a base surrounding the ostia of the maxillary and ethmoidal sinuses. The pancreas is usually small, occasionally cystic, and often difficult to find at postmortem examination. The extent of involvement varies at birth. In infants, the acini and ducts are often distended and filled with eosinophilic material. In 85–90% of patients, the lesion progresses to complete or almost complete disruption of acini and replacement with fibrous tissue and fat. Infrequently, foci

of calcification may be seen on radiographs of the abdomen. The islets of Langerhans contain normal-appearing β cells, although they may begin to show architectural disruption by fibrous tissue in the 2nd decade of life. The intestinal tract shows only minimal changes. Esophageal and duodenal glands are often distended with mucous secretions. Concretions may form in the appendiceal lumen or cecum. Crypts of the appendix and rectum may be dilated and filled with secretions. Focal biliary cirrhosis secondary to blockage of intrahepatic bile ducts is uncommon in early life, although it is responsible for occasional cases of prolonged neonatal jaundice. This lesion becomes much more prevalent and extensive with age and is found in 70% of patients at postmortem examination. This process can proceed to symptomatic multilobular biliary cirrhosis that has a distinctive pattern of large irregular parenchymal nodules and interspersed bands of fibrous tissue. Approximately 30–70% of patients have fatty infiltration of the liver, in some cases despite apparently adequate nutrition. At autopsy, hepatic congestion secondary to cor pulmonale is frequently observed. The gallbladder may be hypoplastic and filled with mucoid material and often contains stones. The epithelial lining often displays extensive mucous metaplasia. Atresia of the cystic duct and stenosis of the distal common bile duct have been observed. Glands of the uterine cervix are distended with mucus, copious amounts of which collect in the cervical canal. In >95% of males, the body and tail of the epididymis, the vas deferens, and the seminal vesicles are obliterated or atretic, resulting in male infertility.

Clinical Manifestations Since the universal adoption of CF newborn screening in the United States and overseas, as well as the evolution of aggressive and proactive treatment approaches, the clinical face of CF is very different from what it was in earlier decades. Diagnosis is typically accomplished before 1 mo of age, prior to any obvious clinical symptoms or signs, and treatment is targeted on immediately correcting nutritional deficiencies and delaying the respiratory complications of the disease. The interaction of mutational heterogeneity and environmental factors leads to highly variable involvement of the lungs, pancreas, and other organs. A summary of the time course of potential development of clinical manifestations is shown in Fig. 432.5 .

FIG. 432.5 Approximate age of onset of clinical manifestations of cystic fibrosis. ABPA, Allergic bronchopulmonary aspergillosis; CBAVD, congenital bilateral absence of the vas deferens; CFRD, cystic fibrosis– related diabetes mellitus; DIOS, distal intestinal obstruction syndrome; HPOA, hypertrophic pulmonary osteoarthritis. (From O'Sullivan BP, Freedman SD: Cystic fibrosis, Lancet 373:1891–1902, 2009.)

Respiratory Tract Infants diagnosed by CF newborn screening are generally asymptomatic from a respiratory standpoint. Nonetheless, the majority are infected with S. aureus , Haemophilus influenza , or even P. aeruginosa within the 1st mo of life, and chest CT scans show characteristic heterogeneous air trapping in of infants by their first birthday, and bronchiectasis is found in more than 10% of 1 yr olds and ∼60% of 5 yr olds. The earliest symptom is usually cough that may begin with a viral respiratory tract infection but then persists unless treated with antibiotics. With treatment, the generally realized goal is for patients to remain asymptomatic throughout childhood, except for the periodic development of cough, chest congestion, sputum production, and/or wheezing that define a pulmonary exacerbation . The rate of progression of lung disease is the chief determinant of morbidity and mortality. As lung disease slowly progresses, chronic cough, sputum production, exercise intolerance, shortness of breath, and failure to thrive are

noted. Cor pulmonale, respiratory failure, and death eventually supervene unless lung transplantation is accomplished; this has become increasingly uncommon in childhood. Infection with certain strains of B. cepacia and other multidrugresistant organisms may be associated with particularly rapid pulmonary deterioration and death. Eventual physical findings include increased anteroposterior diameter of the chest, generalized hyperresonance, scattered or localized coarse crackles, and digital clubbing. Expiratory wheezes may be heard, a manifestation of airway inflammation and edema that may or may not be associated with bronchodilator responsiveness. Cyanosis is a late sign. Common pulmonary complications include atelectasis, hemoptysis, pneumothorax, and cor pulmonale; these usually appear in late adolescence or beyond. Even though the paranasal sinuses are virtually always opacified radiographically, acute sinusitis is infrequent. Nasal obstruction and rhinorrhea are common, caused by inflamed, swollen mucous membranes or, in some cases, nasal polyposis. Nasal polyps are most troublesome between 5 and 20 yr of age.

Intestinal Tract In 15–20% of newborn infants with CF, the ileum is completely obstructed by meconium (meconium ileus ). The frequency is greater among siblings born subsequent to a child with meconium ileus and is particularly striking in monozygotic twins, reflecting a genetic contribution from one or more unknown modifying genes. Abdominal distention, emesis, and failure to pass meconium appear in the first 24-48 hr of life (see Chapters 123.1 and 356.2 ) and often requires surgical intervention. Abdominal radiographs (Fig. 432.6 ) show dilated loops of bowel with air-fluid levels and, frequently, a collection of granular, “ground-glass” material in the lower central abdomen. Rarely, meconium peritonitis results from intrauterine rupture of the bowel wall and can be detected radiographically as the presence of peritoneal or scrotal calcifications.

FIG. 432.6 A and B, Contrast enema study in a newborn infant with abdominal distention and failure to pass meconium. Notice the small diameter of the sigmoid and ascending colon and dilated, air-filled loops of small intestine. Several air-fluid levels in the small bowel are visible on the upright lateral view.

Ileal obstruction with fecal material (distal intestinal obstruction syndrome [DIOS] ) occurs in older children, causing cramping abdominal pain, abdominal distention, and obstruction that can be treated with medical approaches to bowel evacuation. More than 85% of children with CF have exocrine pancreatic insufficiency, causing protein and fat malabsorption. Symptoms, if untreated, include frequent, bulky, greasy stools and failure to gain weight even when food intake appears to be large. Weight gain can be challenging, but attainment of normal growth and development is an expectation of treatment. A protuberant abdomen, decreased muscle mass, poor growth, and delayed maturation are classic and rarely seen physical signs. Excessive flatus may be a problem. Supplementation with fatsoluble vitamin preparations has made deficiencies of vitamin A, E, and K unusual, but vitamin D deficiency continues to be prevalent and, although rickets is rare, osteoporosis is common, especially in older patients and those with more severe lung disease. Class IV-VI mutations are associated with pancreatic sufficiency, but patients with these mutations are prone to pancreatitis when they reach adolescence. Historically a relatively common event, rectal prolapse occurs much less frequently as the result of earlier diagnosis and initiation of pancreatic enzyme replacement therapy.

Biliary Tract Infants may occasionally present with neonatal jaundice suggestive of biliary obstruction. Evidence for liver dysfunction is most often detected in the first 15 yr of life and can be found in up to 30% of individuals. Biliary cirrhosis becomes symptomatic in only 5–7% of patients. Manifestations can include icterus, ascites, hematemesis from esophageal varices, and evidence of hypersplenism. Biliary colic secondary to cholelithiasis may occur in the 2nd decade or later. Liver disease occurs independent of genotype but is associated with meconium ileus and pancreatic insufficiency.

Cystic Fibrosis–Related Diabetes and Pancreatitis Endocrine pancreatic insufficiency tends to develop in the 2nd decade and beyond and is more common in patients with a family history of type II diabetes mellitus. It most commonly begins with postprandial hyperglycemia and may or may not be accompanied by weight loss or flattening weight gain. Fasting hyperglycemia and elevated hemoglobin A1c are later manifestations. Ketoacidosis usually does not occur, but eye, kidney, and other vascular complications have been noted in patients living ≥10 yr after the onset of hyperglycemia. Recurrent, acute pancreatitis occurs occasionally in individuals who have residual exocrine pancreatic function and may be the sole manifestation of homozygotic CFTR mutations.

Genitourinary Tract Virtually all males are azoospermic because of failure of development of wolffian duct structures, but sexual function is generally unimpaired. The female fertility rate is diminished, especially in women who have poor nutrition or advanced lung disease. Pregnancy is generally tolerated well by women with good pulmonary function but may accelerate pulmonary progression in those with advanced lung problems and may lead to glucose intolerance. Urinary incontinence associated with cough occurs in 18–47% of female children and adolescents.

Sweat Glands

Excessive loss of salt in the sweat predisposes young children to salt depletion episodes, especially during episodes of gastroenteritis and during warm weather. These children may present with hypochloremic alkalosis. Hyponatremia is a risk particularly in warm climates. Frequently, parents notice salt frosting of the skin or a salty taste when they kiss the child. A few genotypes are associated with normal sweat chloride values.

Diagnosis and Assessment The diagnosis of CF has been based on a positive quantitative sweat test (Cl− ≥ 60 mEq/L) in conjunction with one or more of the following features: identification of 2 CFTR mutations, typical chronic obstructive pulmonary disease, documented exocrine pancreatic insufficiency, and a positive family history. With newborn screening, diagnosis is often made prior to obvious clinical manifestations such as failure to thrive and chronic cough. Diagnostic criteria have been recommended to include additional testing procedures (Table 432.3 ). Table 432.3 Diagnostic Criteria for Cystic Fibrosis (CF) Presence of typical clinical features (respiratory, gastrointestinal, or genitourinary) or A history of CF in a sibling or A positive newborn screening test plus Laboratory evidence for CFTR (CF transmembrane regulator) dysfunction: Two elevated sweat chloride concentrations obtained on separate days or Identification of two CF mutations or An abnormal nasal potential difference measurement

Sweat Testing

The sweat test, which involves using pilocarpine iontophoresis to collect sweat and performing chemical analysis of its chloride content, is the standard approach to diagnosis of CF. The procedure requires care and accuracy. An electric current is used to carry pilocarpine into the skin of the forearm and locally stimulate the sweat glands. If an adequate amount of sweat is collected, the specimens are analyzed for chloride concentration. Infants with a positive newborn screen for CF should have the sweat chloride testing performed after 36-wk corrected gestational age and at a weight greater than 2 kg and at age greater than 10 days to increase the likelihood of sufficient sweat collection for an accurate study. Positive results should be confirmed; for a negative result, the test should be repeated if suspicion of the diagnosis remains. More than 60 mmol/L of chloride in sweat is diagnostic of CF when one or more other criteria are present. In individuals with a positive newborn screen, a sweat chloride level less than 30 mmol/L indicates that CF is unlikely. Borderline (or intermediate) values of 30-59 mmol/L have been reported in patients of all ages who have CF with atypical involvement and require further testing. Table 432.4 lists the conditions associated with false-negative and falsepositive sweat test results. Table 432.4

Conditions Associated With False-Positive and FalseNegative Sweat Test Results WITH FALSE-POSITIVE RESULTS Eczema (atopic dermatitis) Ectodermal dysplasia Malnutrition/failure to thrive/deprivation Anorexia nervosa Congenital adrenal hyperplasia Adrenal insufficiency Glucose-6-phosphatase deficiency Mauriac syndrome Fucosidosis Familial hypoparathyroidism Hypothyroidism Nephrogenic diabetes insipidus Pseudohypoaldosteronism Klinefelter syndrome Familial cholestasis syndrome Autonomic dysfunction Prostaglandin E infusions Munchausen syndrome by proxy WITH FALSE-NEGATIVE RESULTS

Dilution Malnutrition Edema Insufficient sweat quantity Hyponatremia Cystic fibrosis transmembrane conductance regulator mutations with preserved sweat duct function

DNA Testing Several commercial laboratories test for 30-96 of the most common CFTR mutations. This testing identifies ≥90% of individuals who carry 2 CF mutations. Some children with typical CF manifestations are found to have 1 or no detectable mutations by this methodology. Some laboratories perform comprehensive mutation analysis screening for all the >1,900 identified mutations.

Other Diagnostic Tests The finding of increased potential differences across nasal epithelium (nasal potential difference) that is the increased voltage response to topical amiloride application, followed by the absence of a voltage response to a β-adrenergic agonist, has been used to confirm the diagnosis of CF in patients with equivocal or frankly normal sweat chloride values. This testing is primarily used in research applications and has never undergone extensive validation as a clinical tool.

Pancreatic Function The diagnosis of pancreatic malabsorption can be made by the quantification of elastase-1 activity in a fresh stool sample by an enzyme-linked immunosorbent assay specific for human elastase. The quantification of fat malabsorption with a 72-hr stool collection is rarely necessary in the clinical setting. CF-related diabetes affects approximately 20% of adolescents and 40–50% of adults, and clinical guidelines recommend yearly oral glucose tolerance testing (OGTT) after age 10. OGTT may sometimes be clinically indicated at an earlier age. Spot testing of blood and urine glucose levels and glycosylated hemoglobin levels are not sufficiently sensitive.

Radiology Hyperinflation of lungs occurs early and is often accompanied by nonspecific peribronchial thickening (Fig. 432.7 ). Bronchial thickening and plugging and ring shadows suggesting bronchiectasis usually appear first in the upper lobes. Nodular densities, patchy atelectasis, and confluent infiltrate follow. Hilar lymph nodes may be prominent. With advanced disease, impressive hyperinflation with markedly depressed diaphragms, anterior bowing of the sternum, and a narrow cardiac shadow are noted. Cyst formation, extensive bronchiectasis, dilated pulmonary artery segments, and segmental or lobar atelectasis is often apparent with advanced disease. Most CF centers obtain chest radiographs (posteroanterior [PA] and lateral) at least annually. Standardized scoring of radiologic changes has been used to follow progression of lung disease. CT of the chest can detect heterogeneous hyperinflation and localized thickening of bronchial airway walls, mucous plugging, focal hyperinflation, and early bronchiectasis (Fig. 432.8 ). CT abnormalities are commonly seen at a young age, even in asymptomatic children with normal lung function.

FIG. 432.7 Serial radiographs in a boy show the changing appearance of

cystic fibrosis over 6 yr. A, At 9 yr, frontal radiograph shows minimal peribronchial thickening and hyperaerated lungs indistinguishable from asthma. B, Nineteen mo later, the radiographic picture has worsened considerably. Extensive peribronchial thickening is now noted. Mucoid impaction of the bronchus is seen in the left upper lobe and hilar shadows have become abnormally prominent. C, Ten mo later, further deterioration is obvious. Widespread typical changes of cystic fibrosis (CF) are noted throughout both lungs. D, Follow-up studies show considerable improvement, which suggested that some of the changes evident on C were from superimposed infection. E, One yr later, note the progressive changes of CF—most severe in the upper lobes bilaterally. (From Long FR, Druhan SM, Kuhn JP. Diseases of the bronchi and pulmonary aeration. In Slovis TL, editor: Caffey's pediatric diagnostic imaging , ed 11, Philadelphia, 2008, Mosby, Fig. 73-54.)

FIG. 432.8 CT scans of the chest in cystic fibrosis. A, A 12 yr old boy with moderate lung disease. Airway and parenchymal changes are present throughout both lungs. Multiple areas of bronchiectasis (arrows) and mucous plugging (arrowheads) can be seen. B, A 19 yr old girl has mostly normal lung with 1 area of saccular bronchiectasis in the right upper lobe (arrows) and a focal area of peripheral mucous plugging in the right lower

lobe (arrowhead). Lung density is heterogeneous with areas of normal lung (open arrow) and areas of low attenuation reflecting segmental and subsegmental air trapping (asterisk).

Radiographs of paranasal sinuses reveal panopacification and, often, failure of frontal sinus development. CT provides better resolution of sinus changes if this information is required clinically. Fetal ultrasonography may show pancreatic changes indicative of CF and suggest ileal obstruction with meconium early in the second trimester, but this finding is not predictive of meconium ileus at birth.

Pulmonary Function Infant pulmonary function testing is done routinely for clinical evaluation at a few CF centers but, given its complexity and the need for sedation, for the most part it is reserved for research protocols. Lung clearance index (LCI) measured by multiple breath washout can be done in infants and young children and is a sensitive measure of ventilation inhomogeneity caused by small airways disease. Currently it is primarily used for research, but given its ease and applicability it may be adopted as a standard monitoring tool in the future as CF care centers become more accustomed to its use. Standard pulmonary function studies are usually obtained starting at about 4 yr of age and are routinely done by age 6. Forced expiratory volume in 1 sec (FEV1 ) is the measurement that has been shown to correlate most closely with mortality and shows a gradual decline averaging 2–3% per year throughout childhood. Although a small number of children may already show evidence of airway obstruction by age 6, trends over the past several decades, as reported by the CFF patient registry, show a steady improvement in average FEV1 of the CF population, and as of 2015 ∼75% had normal or near-normal lung function at age 18 yr. Residual volume and functional residual capacity are increased early in the course of lung disease and are the cause of decreasing forced vital capacity (FVC) measurement. Restrictive changes, characterized by declining total lung capacity and vital capacity, correlate with extensive lung injury and fibrosis and are a late finding. Testing at each clinic visit is recommended to evaluate the course of the pulmonary involvement and allow for early intervention when clinically significant decrements are documented—this is probably the most sensitive indicator of a pulmonary exacerbation that should be treated with systemic antibiotics.

Microbiologic Studies H. influenza and S. aureus are the most common organisms recovered in young children (Fig. 432.9 ). Pseudomonas may be acquired early and is eventually an organism of key significance. P. aeruginosa appears to have a special propensity for the CF airway and over time characteristically develops a biofilm associated with a mucoid appearance in the microbiology lab and which correlates with more rapid progression of lung disease. Once P. aeruginosa develops a mucoid phenotype, it is extremely difficult to eradicate from the airway. A wide range of other organisms are frequently recovered, particularly in advanced lung disease; they include a variety of Gram-negative rods including the Burkholderia cepacia complex, which may be associated with a fulminant downhill course (the cepacia syndrome); Stenotrophomonas maltophilia , and Achromobacter xylosoxidans; assorted fungi, especially Aspergillus fumigatus , which is most important due to the relatively common development of allergic bronchopulmonary aspergillosis ; and nontuberculous mycobacterial species, especially Mycobacterium avium complex and Mycobacterium abscessus . Airway cultures are obtained regularly, most typically using oropharyngeal swabs in young children, and then sputum (which may be induced) in older children capable of expectoration. Oropharyngeal swabs typically give a good indication of the lower airway flora, but fiberoptic bronchoscopy may be used to gather lower respiratory tract secretions of infants and young children who do not expectorate if there is a concern for false-negative cultures, especially regarding the presence of P. aeruginosa .

FIG. 432.9 Prevalence of respiratory microorganisms by age cohort. In young patients, early colonization with Haemophilus influenza and Staphylococcus aureus take place. Over time, Pseudomonas aeruginosa is

detected in respiratory cultures and may become chronic. P. aeruginosa may change over time to become mucoidy, and P. aeruginosa is at risk for becoming multidrug resistant (MDR) . Other organisms may infect the CF airway including methicillin-resistant S. aureus (MRSA) , Achromobacter , Burkholderia cepacia complex, and Stenotrophomonas maltophilia . (From the Cystic Fibrosis Foundation Patient Registry 2015. Annual Data Report. ©2016 Cystic Fibrosis Foundation, Bethesda, Maryland.)

The CF airway microbiome consists of a large number of additional organisms, especially anaerobes that are identified through antigen detection but not culture methods. The significance of this finding and its therapeutic implications remain somewhat unclear, but it has long been appreciated that response to antibiotic treatment of pulmonary exacerbations is not always predictable based upon culture and sensitivity of airway cultures.

Newborn Screening Newborn screening for CF is mandated in all 50 states and is the most common way that CF is diagnosed. A variety of newborn screening algorithms are in place to identify infants with CF. Most algorithms use a combination of immunoreactive trypsinogen (IRT) results and limited DNA testing on blood spots; because not all mutations can be found using this approach, babies with an elevated IRT and a single detected mutation are considered a positive screen, and all positive screens are followed by a confirmatory sweat analysis. Depending upon race and ethnicity, about 10–15% of infants with a positive screen based on the finding of only 1 CF mutation will be found to have CF. This screening test is ≈95% sensitive and should result in a median age at diagnosis of less than 1 mo. Newborn diagnoses can prevent early nutritional deficiencies and improve long-term growth and may improve cognitive function. Importantly, good nutritional status (50 percentile weight for length or 50 percentile body mass index) is associated with better lung function at 6 yr of age. An occasional patient may be missed by newborn screening, and those caring for adolescents and adults need to be aware that most of those older patients were not screened at birth and may present at later ages, into late adulthood. Prior to the advent of newborn screening, infants and children commonly presented with malabsorption and failure to thrive, in addition to respiratory symptoms. Most older patients whose diagnosis was missed early in life will have unusual class IV, V, or VI mutations and therefore normal pancreatic function. They will more typically present with chronic productive cough due to

either bronchitis or chronic sinusitis and may have nasal polyps or allergic bronchopulmonary aspergillosis or unexplained bronchiectasis. The most common nonrespiratory manifestations will be congenital bilateral absence of the vas deferens (CBAVD) (in males) or recurrent pancreatitis. It is important to recognize that sweat testing at an adept lab (typically limited to CF Foundation accredited care centers) is the most accurate way to diagnose CF in this group. CFTR mutation testing with standard panels is never as sensitive as sweat testing and will frequently miss the unusual mutations that are seen more commonly in people who present late in this manner. There is a subset of infants with a positive newborn screen for CF who have a nondiagnostic sweat chloride (30-59 mmol/L) and/or 1 or 2 CFTR mutations that is not clearly disease causing. These infants have CFTR -related metabolic syndrome (CRMS) (also called CFTR-related disease) and should be followed in a CF center closely through the 1st yr and then annually to evaluate them for the development of CF symptoms. Indeed, in some (∼10%) patients, the sweat test becomes clearly abnormal over time and they can be diagnosed as having CF. Because CRMS is a condition defined by asymptomatic detection in the context of newborn screening and CF newborn screening has been commonly performed only in the past decade or so, it is not clear whether some children in this group will eventually develop manifestations of CFTR-related disorder, such as CBAVD, chronic sinusitis, recurrent pancreatitis, or even bronchiectasis. An approach to the evaluation of patients with CRMS is seen in Fig. 432.10 .

FIG. 432.10 2015 European Cystic Fibrosis Society recommended process for diagnosis of CFTR-RD. Global diagnostic algorithm for CF and CFTR-RD. A global flow-chart of genetic and functional diagnostic testing in CF and CFTR-RD is presented. CBAVD, congenital bilateral absence of the vas deferens; CF, cystic fibrosis; CF? mutation , mutation of unproven or uncertain clinical significance; CF* , diagnosis of CF or consider this diagnosis; CFTR, cystic fibrosis transmembrane conductance regulator; CFTR-RD , CFTR-related disorders; ICM , intestinal current measurement; NPD , nasal potential difference; ST , sweat test (repeated; false positive should be excluded/sought in a specialized center). (From Bombieri C, Claustres M, De Boeck K, Derichs N, Dodge J, Girodon E, et al. Recommendations for the classification of diseases as CFTR-related disorders, J Cyst Fibros 10(Suppl 2):S86–102, 2011. Fig 1.)

Treatment General Approach to Care Initial efforts after diagnosis should be intensive and should include baseline assessment, initiation of treatment to prevent pulmonary involvement in young infants or reverse it in those diagnosed later, nutritional maintenance or remediation, and education of the patient and parents. Follow-up evaluations are scheduled every 1-3 mo, depending on the age at diagnosis, because many aspects of the condition require careful monitoring. An interval history and physical examination should be obtained at each visit. A sputum sample or, if

that is not available, a lower pharyngeal swab taken during or after a forced cough is obtained for culture and antibiotic susceptibility studies. Because irreversible loss of pulmonary function from low-grade infection can occur gradually and without acute symptoms, emphasis is placed on a thorough pulmonary history and physical exam and routine pulmonary function testing. Table 432.5 lists symptoms and signs that suggest the need for more intensive antibiotic and physical therapy (PT). Protection against exposure to methicillinresistant S. aureus, P. aeruginosa, B. cepacia, and other resistant Gram-negative organisms is essential, including contact isolation procedures and careful attention to cleaning of inhalation therapy equipment. A nurse, physical therapist, respiratory therapist, social worker, and dietitian, as members of the multidisciplinary care team, should evaluate children regularly and contribute to the development of a comprehensive daily care plan. Considerable education and programs to empower families and older children to take responsibility for care are likely to result in the best adherence to daily care programs. Screening patients and caregivers for anxiety and depression annually is expected to identify issues that can interfere with adherence to daily care. Standardization of practice, on the part of both caregivers and families, as well as close monitoring and early intervention for new or increasing symptoms appears to result in the best long-term outcomes. Table 432.5

Symptoms and Signs Associated With Exacerbation of Pulmonary Infection in Patients With Cystic Fibrosis SYMPTOMS Increased frequency and duration of cough Increased sputum production Change in appearance of sputum Increased shortness of breath Decreased exercise tolerance Decreased appetite Feeling of increased congestion in the chest SIGNS Increased respiratory rate Use of accessory muscles for breathing Intercostal retractions Change in results of auscultatory examination of chest Decline in measures of pulmonary function consistent with the presence of obstructive airway disease Fever and leukocytosis Weight loss New infiltrate on chest radiograph

From Ramsey B: Management of pulmonary disease in patients with cystic fibrosis, N Engl J Med 335:179, 1996.

Because secretions of CF patients are not adequately hydrated, attention in early childhood to oral hydration, especially during warm weather or with acute gastroenteritis, may minimize complications associated with impaired mucous clearance. Intravenous therapy for dehydration should be initiated early. The goal of therapy is to maintain a stable condition for prolonged periods. This can be accomplished for most patients by interval evaluation and adjustments of the home treatment program. Some children have episodic acute or low-grade chronic lung infection that progresses. For these patients, intensive inhalation and airway clearance and intravenous antibiotics are indicated. Improvement is most reliably accomplished in a hospital setting; selected patients have demonstrated successful outcomes while completing these treatments at home. Intravenous antibiotics may be required infrequently or as often as every 2-3 mo. The goal of treatment is to return patients to their previous pulmonary and functional status. The basic daily care program varies according to the age of the child, the degree of pulmonary involvement, other system involvement, and the time available for therapy. The major components of this care are pulmonary and nutritional therapies. Because therapy is medication intensive, iatrogenic problems frequently arise. Monitoring for complications is also an important part of management

Pulmonary Therapy The object of pulmonary therapy is to clear secretions from airways and to control infection. When a child is not doing well, every potentially useful aspect of therapy should be reconsidered.

Inhalation Therapy Human recombinant DNase (2.5 mg) enzymatically dissolves extracellular DNA released by neutrophils, a major contributor to the characteristically sticky and viscous CF airway secretions. It is usually given as a single daily aerosol dose, improves pulmonary function, decreases the number of pulmonary exacerbations, and promotes a sense of well-being. Benefit for those with mild, moderate, and severe lung disease has been documented. Improvement is sustained for 12 mo or longer with continuous therapy.

Nebulized hypertonic saline, acting as a hyperosmolar agent, is believed to draw water into the airway and rehydrate mucus and the periciliary fluid layer, resulting in improved mucociliary clearance. Seven percent hypertonic saline nebulized 2-4 times daily increases mucous clearance and reduces pulmonary exacerbation, with only a slight short-term improvement in pulmonary function.

Airway Clearance Therapy Airway clearance treatment begins in infancy with chest percussion (with or without postural drainage) and derives its rationale from the idea that cough clears mucus from large airways, but chest vibrations are required to shear secretions for the airway wall and move secretions from small airways, where expiratory flow rates are low. Chest PT can be particularly useful for patients with CF because they accumulate secretions in small airways first, even before the onset of symptoms. Cessation of chest PT in children with mild to moderate airflow limitation results in deterioration of lung function within 3 wk, and prompt improvement of function occurs when therapy is resumed, but it is less clear which available modality is best. Airway clearance therapy is recommended 2-4 times a day, depending on the severity of lung dysfunction, and usually increased during acute exacerbations. Cough, huffing, or forced expirations are encouraged intermittently throughout the session. Vest-type mechanical percussors (high-frequency chest wall oscillation) are commonly used past infancy due to their convenience, as are a variety of oscillatory positive expiratory pressure devices (such as Acapella and Aerobika) and other controlled breathing techniques (e.g., autogenic drainage ). Routine aerobic exercise appears to slow the rate of decline of pulmonary function, and benefit has also been documented with weight training. No one airway clearance technique can be shown to be superior to any other, so all modes should be considered in the development of an airway clearance prescription. Adherence to daily therapy is important but rarely achieved; therefore airway clearance technique plans are individualized for each patient.

Antibiotic Therapy Antibiotics are the mainstay of therapy designed to control progression of lung infection. The goal is to reduce the intensity of endobronchial infection and to delay progressive lung damage. The usual guidelines for acute chest infections, such as fever, tachypnea, or chest pain, are often absent. Consequently, all

aspects of the patient's history and examination, including anorexia, weight loss, and diminished activity, must be used to guide the frequency and duration of therapy. Antibiotic treatment varies from intermittent short courses of 1 antibiotic to nearly continuous treatment with 1 or more antibiotics. Dosages for some antibiotics are often 2-3 times the amount recommended for minor infections because patients with CF have proportionately more lean body mass and higher clearance rates for many antibiotics than other individuals. In addition, it is difficult to achieve effective drug levels of many antimicrobials in respiratory tract secretions.

Oral Antibiotic Therapy Indications for oral antibiotic therapy in a patient with CF include the presence of respiratory tract symptoms, physical signs, or changes in pulmonary function testing or chest x-ray. Treatment is guided by identification of pathogenic organisms in respiratory tract cultures and in vitro sensitivity testing. Common organisms, including S. aureus (MRSA or MSSA), nontypeable H. influenzae, P. aeruginosa; B. cepacia and other Gram-negative rods, are encountered with increasing frequency. The usual course of therapy is 2 wk, and maximal doses are recommended. Table 432.6 lists useful oral antibiotics. The quinolones are the only broadly effective oral antibiotics for Pseudomonas infection, but resistance against these agents may emerge. Macrolides may reduce the virulence properties of P. aeruginosa, such as biofilm production, and contribute antiinflammatory effects. Long-term therapy with azithromycin 3 times a week improves lung function in patients with chronic P. aeruginosa infection. Table 432.6

Antimicrobial Agents for Cystic Fibrosis Lung Infection

Dicloxacillin Linezolid Cephalexin Clindamycin Amoxicillin-clavulanate Amoxicillin

DOSAGE (mg/kg/24 hr) 25-50 20 50 10-30 25-45 50-100

NO. DOSES/24 hr 4 2 4 3-4 2-3 2-3

Ciprofloxacin

20-30

2-3

Trimethoprim-

8-10*

2-4

ROUTE

ORGANISMS

AGENTS

Oral

Staphylococcus aureus

Haemophilus influenzae Pseudomonas aeruginosa Burkholderia cepacia

Empirical Intravenous S. aureus P. aeruginosa

B. cepacia Aerosol

sulfamethoxazole Azithromycin Erythromycin Nafcillin Vancomycin Tobramycin Amikacin Ticarcillin Piperacillin Ticarcillin-clavulanate Piperacillin-tazobactam Meropenem Imipenem-cilastatin Ceftazidime Aztreonam Chloramphenicol Meropenem Tobramycin (inhaled) Aztreonam (inhaled)

10, day 1; 5, days 2-5 30-50 100-200 40 8-12 15-30 400 300-400 400 † 240-400 ‡ 60-120 45-100 150 150-200 50-100 60-120 300 § 75

1 3-4 4-6 3-4 1-3 2-3 4 4 4 3 3 3-4 3 4 4 3 2 3

* Quantity of trimethoprim. † Quantity of ticarcillin. ‡

Quantity of piperacillin.

§ In mg per dose.

Aerosolized Antibiotic Therapy Aerosolized antibiotics are often used as part of daily therapy when the airways are infected with P. aeruginosa . Aerosolized tobramycin inhalation solution or powder, or aztreonam inhalation solution used as a suppressive therapy (on 1 mo, off 1 mo), may reduce symptoms, improve pulmonary function, and decrease the occurrence of pulmonary exacerbations. Although these therapies are sometimes used in acute pulmonary exacerbations, the evidence to support this application is limited. Another important indication for aerosolized antibiotic therapy is to eradicate P. aeruginosa in the airways after initial detection. Early infection may be cleared for mo to several yr in this way, although eventual reinfection is common. Other antibiotics have been used via inhalation, including liposomal amikacin and levofloxacin for P. aeruginosa , and there was no inferiority of efficacy compared with inhaled tobramycin.

Intravenous Antibiotic Therapy

For the patient who has not responded to oral antibiotics and intensive home measures with return of signs, symptoms, and FEV1 to baseline, intravenous antibiotic therapy is indicated. This therapy is usually initiated in the hospital but is sometimes completed on an ambulatory basis if the likelihood of complete adherence to the therapeutic regimen is good. The ideal duration of treatment is unknown; although many patients show improvement within 7 days, many CF physicians believe that it is usually advisable to extend the period of treatment to at least 14 days. Permanent intravenous access can be provided for long-term or frequent courses of therapy in the hospital or at home. Thrombophilia screening should be considered before the use of totally implantable intravenous devices or for recurring problems with venous catheters. Table 432.6 lists commonly used intravenous antibiotics. In general, treatment of Pseudomonas infection is thought to require 2-drug therapy. A 3rd agent may be given for optimal coverage of S. aureus or other organisms. Aminoglycosides are usually effective when given every 24 hr to minimize toxicity and optimize convenience. Some CF physicians use peak and trough levels to guide dosing, but most clinical pharmacists recommend measuring levels at other times, commonly 2 and 12 hr, to use pharmacokinetic calculations to guide dosing. Changes in therapy should be guided by lack of improvement more than by culture results; sensitivities do not always predict response to therapy, and this may be due to the presence of other organisms that are not detected by culture methods. If patients do not show improvement, complications such as right heart failure, asthma, or infection with viruses, A. fumigatus (especially ABPA) (see Chapter 237 ), nontuberculous mycobacteria (see Chapters 217 and 399 ), or other unusual organisms should be considered. B. cepacia complex and acinetobacter are Gram-negative rods that may be particularly refractory to antimicrobial therapy. Infection control in both the outpatient and inpatient medical setting is critically important to prevent nosocomial spread of resistant bacterial organisms between patients.

Bronchodilator Therapy Reversible airway obstruction occurs in many children with CF, sometimes in conjunction with frank asthma or allergic bronchopulmonary aspergillosis. Reversible obstruction is conventionally defined as improvement of ≥12% in FEV1 or FVC after inhalation of a bronchodilator. In many patients with CF, these may improve by only 5–10% (physiologic response), but subjects may

report subjective benefit.

Antiinflammatory Agents Corticosteroids are useful for the treatment of allergic bronchopulmonary aspergillosis and severe asthma occasionally encountered in children with CF. Prolonged systemic corticosteroid treatment of CF lung disease reduces the decline in lung function modestly but causes predictably prohibitive side effects. Inhaled corticosteroids have theoretical appeal, but there are contradictory and weak data regarding efficacy unless the patient has clinically diagnosable asthma. Ibuprofen, given chronically in high doses adjusted to achieve a peak serum concentration of 50-100 µg/mL, is associated with a slowing of disease progression, particularly in younger patients with mild lung disease. However, there are concerns regarding side effects of nonsteroidal antiinflammatory drugs, so this therapy has not gained broad acceptance. Macrolide antibiotics have an antiinflammatory effect, and 3 days/wk azithromycin has been shown to reduce the likelihood of development of pulmonary exacerbations, especially in patients with chronic Pseudomonas airway infection, so this is a commonly used therapy.

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapies A major breakthrough in CF therapy is ivacaftor, a small molecule potentiator of the CFTR mutation, G551D (present in ∼5% of patients). Ivacaftor activates the CFTR-G551D mutant protein, a class III CFTR mutation that results in protein localized to the plasma membrane but loss of chloride channel function (Fig. 432.11 ). Ivacaftor therapy resulted in improvement in FEV1 by an average of 10.6%, decreased the frequency of pulmonary exacerbations by 55%, decreased sweat chloride by an average of 48 mEq/L, and increased weight gain by an average of 2.7 kg. Ivacaftor is approved for patients older than 2 yr of age with class III and class IV mutations.

FIG. 432.11 Cystic fibrosis transmembrane conductance regulator (CFTR) pharmacologic modulators have different modes of action. A, Read-through compounds which include aminoglycoside antibiotics (e.g., gentamicin, tobramycin) act by suppressing premature termination codons (PTCs), thus permitting translation to continue to the normal termination of the transcript and thus increasing the total amount of complete CFTR being produced in the cell. B, Correctors (e.g., VX-809 also known as lumacaftor; VX-661) potentially promote folding of mutant CFTR protein, allowing it to escape ER degradation and reach the cell surface, thus increasing the number of channels present at the plasma membrane. C, Stabilizers include compounds (e.g., hepatocyte growth factor) that enhance CFTR retention/anchoring at the cell surface, thus also contributing to increase the number of channels present at the cell surface. D, Potentiators (e.g., VX-770 also known as ivacaftor) activate CFTR, that is, increase the open probability (Po ) of the channel by regulating its gating and possibly also the conductance. (From Bell SC, De Boeck K, Amaral MD: New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls, Pharmacol Therapeu 145:19–34, 2015 [Fig. 4, p. 26].)

The combination of ivacaftor with lumacaftor, a corrector that stabilizes misfolded F508del and enables trafficking of the mutant molecule to the apical cell membrane where it is potentiated by ivacaftor, is available for patients older than 6 yr of age who are homozygous for the F508del mutation (see Fig. 432.11 ). This medication is associated with smaller increments in pulmonary and nutritional outcomes but is an important proof-of-concept treatment. Tezacaftor and ivacaftor is another combination indicated for patients ≥ 12 yr with 1 or 2 Phe508del alleles. This combination improves predicted FEV1 and overall well-being (Table 432.7 ). VX-445 combined with tezacaftor-ivacaftor adds another CFTR correction agent; the triple combination improves predicted FEV1 and reduces sweat chloride levels. Table 432.7

Cystic Fibrosis Transmembrane Regulator Modulators for Cystic Fibrosis

DRUG Ivacaftor

FDA-APPROVED INDICATION ≥ 12 mo with a responsive mutation 1

Lumacaftor/ivacaftor ≥ 2 yr, F508del-homozygous

Tezacaftor/ivacaftor

≥ 12 yr, F508del-homozygous or F508del-heterozygous with another responsive mutation 1

FORMULATIONS USUAL DOSAGE 150 mg tabs; 50, 75 mg ≥ 6 years: 150 mg q12 granule packets 2 hr 3 100/125, 200/125 mg tabs; 6-11 yr: 200/250 100/125, 150/188 mg mg q12 hr granule packets 2 ≥ 12 yr: 400/250 mg q12 hr 4 100/150 mg tabs co≥ 12 yr: 100/150 mg packaged with ivacaftor tab qAM, then 150 mg 150 mg tabs ivacaftor qPM

1 Responsive mutations are those in which chloride transport is expected to increase to at least

10% of untreated normal over baseline with drug therapy, based on clinical or in vitro data. 2 The granules should be mixed with 5 mL of room-temperature or cold soft food or liquid and

consumed within 1 hr. 3 In patients 12 mo to 6 yr old, the recommended dosage is 50 mg every 12 hr for those weighing

3 cm compared to asymptomatic side Unilateral pitting edema Collateral superficial veins Previously documented deep vein thrombosis Alternative diagnosis at least as likely as deep vein thrombosis WELLS' SCORE FOR PULMONARY EMBOLISM † , ‡ Alternative diagnosis less likely than pulmonary embolism Clinical signs and symptoms of deep vein thrombosis Heart rate >100 beats/min Previous deep vein thrombosis or pulmonary embolism Immobilization or surgery within the past 4 wk Active cancer Hemoptysis REVISED GENEVA SCORE FOR PULMONARY EMBOLISM § , || Heart rate ≥95 beats/min Heart rate 75–94 beats/min Pain on lower-limb deep venous palpation and unilateral edema

+1 +1 +1 +1 +1 +1 +1 +1 +1 −2

NA NA NA NA NA NA NA NA NA NA

+3 +3 +1⋅5 +1⋅5 +1⋅5 +1 +1

+1 +1 +1 +1 +1 +1 +1

+5 +3 +4

+2 +1 +1

Unilateral lower-limb pain Previous deep vein thrombosis or pulmonary embolism Active cancer Hemoptysis Surgery or fracture within the past 4 wk Age >65 yr

+3 +3 +2 +2 +2 +1

+1 +1 +1 +1 +1 +1

*

Classification for original Wells' score for deep vein thrombosis: deep vein thrombosis unlikely if score ≤2; deep vein thrombosis likely if score >2. †

Classification for original Wells' score for pulmonary embolism: pulmonary embolism unlikely if score ≤4; pulmonary embolism likely if score >4. ‡

Classification for simplified Wells' score for pulmonary embolism: pulmonary embolism unlikely if score ≤1; pulmonary embolism likely if score >1. § Classification for original revised Geneva score for pulmonary embolism: non-high probability of

pulmonary embolism if score ≤10; high probability of pulmonary embolism if score >10. || Classification for simplified revised Geneva score for pulmonary embolism: non-high probability

of pulmonary embolism if score ≤4; high probability of pulmonary embolism if score >4. From Di Nisio M, van Es N, Büller HR: Deep vein thrombosis and pulmonary embolism, Lancet 388:3060–3069, 2016 (Table 1, p. 3062).

Epidemiology A retrospective cohort study was performed with patients younger than 18 yr of age, discharged from 35 to 40 children's hospitals across the United States from 2001 to 2007. During this time, a dramatic increase was noted in the incidence of VTE; the annual rate of VTE increased by 70% from 34 to 58 cases per 10,000 hospital admissions. Although this increased incidence was noted in all age groups, a bimodal distribution of patient ages was found, consistent with prior studies; infants younger than 1 yr of age and adolescents made up the majority of admissions with VTE, but neonates continue to be at greatest risk. The peak incidence for VTE in childhood appears to occur in the 1st mo of life. It is in this neonatal period that thromboembolic events are more problematic, likely as a result of an imbalance between procoagulant factors and fibrinolysis. The yearly incidence of venous events was estimated at 5.3/10,000 hospital admissions in children and 24/10,000 in the neonatal intensive care. Pediatric autopsy reviews have estimated the incidence of thromboembolic disease in children as between 1% and 4%, although not all were clinically significant. Thromboembolic pulmonary disease is often unrecognized, and antemortem studies may underestimate the true incidence. Pediatric deaths from

isolated pulmonary emboli are rare. Most thromboemboli are related to central venous catheters. The source of the emboli may be lower or upper extremity veins as well as the pelvis and right heart. In adults, the most common location for DVT is the lower leg. However, one of the largest pediatric VTE/PE registries found two-thirds of DVTs occurring in the upper extremity.

Pathophysiology Favorable conditions for thrombus formation include injury to the vessel endothelium, hemostasis, and hypercoagulability. In the case of PE, a thrombus is dislodged from a vein, travels through the right atrium, and lodges within the pulmonary arteries. In children, emboli that obstruct 90% of congenital chest wall anomalies. There is a positive family history in one-third of cases.

Clinical Manifestations The deformity is present at or shortly after birth in one-third of cases but is usually not associated with any symptoms at that time. In time, fatigue, chest pain, palpitations, recurrent respiratory infections, wheezing, stridor, and cough may be present. Decreased exercise tolerance is one of the most common symptoms. Because of the cosmetic nature of this deformity, children may experience significant psychologic stress. Physical examination may reveal sternal depression, protracted shoulders, kyphoscoliosis, dorsal lordosis, inferior rib flares, rib cage rigidity, forward head tilt, scapular winging, and loss of vertebral contours (Fig. 445.1 ). Patients exhibit paroxysmal sternal motion and a shift of point of maximal impulse to the left. Innocent systolic murmurs may be heard.

FIG. 445.1 Pectus excavatum in a 15 yr old male. Note the presence of protracted shoulders, inferior rib flares, and sternal depression.

Laboratory Findings Lateral chest radiograms demonstrate the sternal depression. The Haller index on chest CT (maximal internal transverse diameter of the chest divided by the minimal anteroposterior diameter at the same level) in comparison with age- and gender-appropriate normative values have been used historically to help determine the extent of the anatomic abnormality. However, the correlation of the Haller index with the physiologic compromise or associated systems appears suboptimal. Use of 3D chest optical imaging or “surface scan” is gaining popularity in the evaluation. An electrocardiogram may show a right-axis deviation or Wolff-Parkinson-White syndrome (see Chapter 463 ); an echocardiogram may demonstrate mitral valve prolapse (see Chapter 455.3 ) and ventricular compression. Results of static pulmonary function tests may be normal but commonly show an obstructive defect in the lower airways and, less commonly, a restrictive defect as the result of abnormal chest wall mechanics. Exercise testing may demonstrate either normal tolerance or limitations from underlying cardiopulmonary dysfunction that are associated with the severity of the defect. Pulmonary limitations such as ventilatory limitations and associated flow volume loop abnormalities are commonly seen in younger children and adolescents, whereas additional cardiac limitations secondary to stroke volume impairments are more commonly seen in older adolescents and young adults.

Treatment

Treatment is based on the severity of the deformity and the extent of physiologic compromise as defined by physical examination and physiologic assessment of cardiopulmonary function (lung function and exercise tolerance assessment). Therapeutic options include careful observation, use of physical therapy to address musculoskeletal compromise, corrective surgery, cosmetic surgery, and noninvasive thorascopic techniques. For patients with significant physiologic compromise, surgical correction may improve the cosmetic deformity and may help minimize progression or even improve the cardiopulmonary compromise. The 2 main surgical interventions are the Ravitch and Nuss procedures. Superiority of one approach has not been established. The extent of the anatomic defect including the degree of asymmetry may help determine the appropriate surgical approach. While surgical repair may result in improved exercise tolerance for some individuals, usually observed at submaximal exercise intensities, many patients do not show improvement in either respiratory or cardiac function. Normalization of lung perfusion scans and maximal voluntary ventilation have also been observed after surgery. Utilization of a magnetic brace with gradual remodeling (Magnetic Mini Mover procedure) of the pectus deformity is under clinical investigation. The use of surgically placed silicone implants for cosmetic appearance has also been utilized with high patient satisfaction. For selected patients, the use of a more noninvasive approach (i.e., cup suction) has been gaining popularity. Regardless of the treatment approach, addressing the secondary musculoskeletal findings is commonly employed before and after any intervention.

Bibliography Borowitz D, Cerny F, Zallen G, et al. Pulmonary function and exercise response in patients with pectus excavatum after Nuss repair. J Pediatr Surg . 2003;38:544–547. Brigato RR, Campos JR, Jatene FB, et al. Pectus excavatum: evaluation of Nuss technique by objective methods. Interact Cardiovasc Thorac Surg . 2008;7:1084–1088. Chavoin J, Grolleau J, Moreno B, et al. Correction of pectus excavatum by custom-made silicone implants: contribution of computer-aided design reconstruction. A 20-year experience

and 401 cases. Plast Reconst Surg . 2016;137:860e. Daunt SW, Cohen JH, Miller SF. Age-related normal ranges for the Haller index in children. Pediatr Radiol . 2004;34:326– 330. Haller JA Jr, Loughlin GM. Cardiorespiratory function is significantly improved following corrective surgery for severe pectus excavatum: proposed treatment guidelines. J Cardiovasc Surg (Torino) . 2000;41:125–130. Harrison MR, Gonzales KD, Bratton BJ, et al. Magnetic minimover procedure for pectus excavatum III: safety and efficacy in a Food and Drug Administration sponsored clinical trial. J Pediatr Surg . 2012;47:154–159. Koumbourlis AC. Pectus deformities and their impact on pulmonary physiology. Pediatr Respir Rev . 2015;16:18–24. Lopez M, Patoir A, Costes F, et al. Preliminary study of efficacy of cup suction in the correction typical pectus excavatum. J Pediatr Surgery . 2016;51:183–187. Malek MH, Fonkalsrud EW, Cooper CB. Ventilatory and cardiovascular responses to exercise in patients with pectus excavatum. Chest . 2003;124:870–882. Nuss D, Kelly RE Jr. Minimally invasive surgical correction of chest wall deformities in children (Nuss procedure). Adv Pediatr . 2008;55:395–410. Ohno K, Morotomi Y, Nakahira M, et al. Indications for surgical repair of funnel chest based on indices of chest wall deformity and psychologic state. Surg Today . 2003;33:662– 665. Rowland T, Moriarty K, Banever G. Effect of pectus excavatum deformity on cardiorespiratory fitness in adolescent boys. Arch Pediatr Adolesc Med . 2005;159:1069–1073. Swanson JW, Avansino JR, Phillips GS, et al. Correlating Haller Index and cardiopulmonary disease in pectus excavatum. Am J Surg . 2012;203:660–664.

445.2

Pectus Carinatum and Sternal Clefts Steven R. Boas

Keywords pectus carinatum sternal clefts

Pectus Carinatum Etiology and Epidemiology Pectus carinatum is a sternal deformity accounting for 5–15% of congenital chest wall anomalies. Anterior displacements of the mid and lower sternum and adjacent costal cartilages are the most common types. They are most commonly associated with protrusion of the upper sternum; depression of the lower sternum occurs in only 15% of patients. Asymmetry of the sternum is common, and localized depression of the lower anterolateral chest is also often observed. Males are affected 4 times more often than females. There is a high familial occurrence and a common association of mild to moderate scoliosis. Mitral valve disease and coarctation of the aorta are associated with this anomaly. Three types of anatomic deformity occur (upper, lower, and lateral pectus carinatum), with corresponding physiologic changes and treatment algorithms.

Clinical Manifestations In early childhood, symptoms appear minimal. School-age children and adolescents commonly complain of dyspnea with mild exertion, decreased endurance with exercise, and exercise-induced wheezing. The incidence of increased respiratory infections and use of asthma medication is higher than in

nonaffected individuals. On physical examination, a marked increase in the anteroposterior chest diameter is seen, with resultant reduction in chest excursion and expansion (Fig. 445.2 ). Spirometry has demonstrated both restrictive and obstructive patterns, although the majority of individuals have normal values. Increases in residual volume are often present and result in tachypnea and diaphragmatic respirations. Exercise testing shows variable results. Chest radiographs show an increased anteroposterior diameter of the chest wall, emphysematous-appearing lungs, and a narrow cardiac shadow. The pectus severity score (width of chest divided by distance between sternum and spine; analogous to the Haller index) is reduced.

FIG. 445.2 Pectus carinatum in a 13 yr old male. Note the central sternal prominence.

Treatment For symptomatic patients with pectus carinatum, minimally invasive surgical correction procedures may result in improvement of the clinical symptoms.

Many surgeons prefer to use bracing techniques as a first-line treatment. Although surgery is performed for some individuals who are symptomatic, it is often performed for cosmetic and psychological reasons.

Sternal Clefts Sternal clefts are rare congenital malformations that result from the failure of the fusion of the sternum during the 8th wk of gestation. No familial predisposition has been described. Sternal clefts occur in less than 1% of all chest wall deformities. Sternal clefts are classified as partial or complete. Partial sternal clefts are more common and may involve the superior sternum in association with other lesions, such as vascular dysplasias and supraumbilical raphe, or the inferior sternal clefts, which are often associated with other midline defects (pentalogy of Cantrell). Complete sternal clefts with complete failure of sternal fusion are rare. These disorders may also occur in isolation. The paradoxic movement of thoracic organs with respiration may alter pulmonary mechanics. Rarely, respiratory infections and even significant compromise result. Surgery is required early in life, before fixation and immobility occur.

Bibliography Abramson H, D'Agostino J, Wuscovi S. A 5-year experience with a minimally invasive technique for pectus carinatum repair. J Pediatr Surg . 2009;44:118–123. Coelho Mde S, Guimarães Pde S. Pectus carinatum. J Bras Pneumol . 2007;33:463–474. Emil S, Sevigny M, Mopntpetit K, et al. Success and duration of dynamic bracing for pectus carinatum: a four-year prospective study. J Pediatr Surg . 2017;52:124–129. Engum SA. Embryology, sternal clefts, ectopic cordis, and Cantrell's pentalogy. Semin Pediatr Surg . 2008;17:154–160. Fonkalsrud EW, Anselmo DM. Less extensive techniques for repair of pectus carinatum: the undertreated chest deformity. J Am Coll Surg . 2004;198:898–905. Goretsky MJ, Kelly RE, Croitoru D, et al. Chest wall anomalies:

pectus excavatum and pectus carinatum. Adolesc Med Clin . 2004;15:455–471. Ohye RG, Rutherford JA, Bove EL. Congenital sternal clefts. Pediatr Cardiol . 2002;23:472–473. Williams AM, Crabbe DC. Pectus deformities of the anterior chest wall. Paediatr Respir Rev . 2003;4:237–242.

445.3

Asphyxiating Thoracic Dystrophy (Thoracic-Pelvic-Phalangeal Dystrophy) Steven R. Boas

Keywords asphyxiating thoracic dystrophy Jeune syndrome

Etiology A multisystem autosomal recessive disorder, asphyxiating thoracic dystrophy results in a constricted and narrow rib cage. Also known as Jeune syndrome , the disorder is associated with characteristic skeletal abnormalities as well as variable involvement of other systems, including renal, hepatic, neurologic, pancreatic, and retinal abnormalities (see Chapter 720 ).

Clinical Manifestations Most patients with this disorder die shortly after birth from respiratory failure, although less-aggressive forms have been reported in older children. For those who survive the neonatal period, progressive respiratory failure often ensues, owing to impaired lung growth, recurrent pneumonia, and atelectasis originating from the rigid chest wall.

Diagnosis Physical examination reveals a narrowed thorax that, at birth, is much smaller than the head circumference. The ribs are horizontal, and the child has short extremities. Chest radiographs demonstrate a bell-shaped chest cage with short, horizontal, flaring ribs and high clavicles.

Treatment No specific treatment exists, although thoracoplasty to enlarge the chest wall and long-term mechanical ventilation has been tried. Rib-expanding (vertical expandable prosthetic titanium rib/[VEPTR]) procedures have resulted in improved survival (Fig. 445.3 ).

FIG. 445.3 A, Seven month old with Jeune syndrome preoperatively. B, 18 mo post-VEPTR insertion. (From Mayer OH: Chest wall hypoplasia—

principles and treatment. Pediatr Respir Rev 16:30–34, 2015, Fig. 3, p. 34.)

Prognosis For some children with asphyxiating thoracic dystrophy, improvement in the bony abnormalities occurs with age. However, children younger than age 1 yr often succumb to respiratory infection and failure. Progressive renal disease often occurs with older children. Use of vaccines for influenza and other respiratory pathogens is warranted, as is aggressive use of antibiotics for respiratory infections.

Bibliography Davis JT, Long FR, Adler BH, et al. Lateral thoracic expansion for Jeune syndrome: evidence of rib healing and new bone formation. Ann Thorac Surg . 2004;77:445–448. Kajantic E, Anderson S, Kaitila I. Familial asphyxiating thoracic dysplasia: clinical variability and impact of improved neonatal intensive care. J Pediatr . 2001;139:130–133. Keppler-Noreuil KM, Adam MP, Welch J, et al. Clinical insights gained from eight new cases and review of reported cases with Jeune syndrome (asphyxiating thoracic dystrophy). Am J Med Genet . 2001;155A:1021–1032. Phillips JD, van Aalst JA. Jeune's syndrome (asphyxiating thoracic dystrophy): congenital and acquired. Semin Pediatr Surg . 2008;17:167–172. Sharoni E, Erez E, Chorev G, et al. Chest reconstruction in asphyxiating thoracic dystrophy. J Pediatr Surg . 1998;33:1578–1581. Wiebicke W, Pasterkamp H. Long-term continuous positive pressure in a child with asphyxiating thoracic dystrophy. Pediatr Pulmonol . 1988;4:54–58.

445.4

Achondroplasia Steven R. Boas

Keyword achondroplasia

Etiology Achondroplasia is the most common condition characterized by disproportionate short stature (see Chapter 716 ). This condition is inherited as an autosomal dominant disorder that results in disordered growth. Much has been learned about this disorder, including its genetic origins (95% of cases caused by mutations in the gene coding for fibroblast growth factor receptor type 3) and how to minimize its serious complications.

Clinical Manifestations Restrictive pulmonary disease, affecting 90 mm Hg, and may decline to normal levels after the infants awaken. This problem becomes most apparent when multiple attempts at extubation fail in an intubated neonate, who appears well with ventilatory support but develops respiratory failure after removal of the support. However, more severely affected infants hypoventilate awake and asleep; thus, the previously described difference in PaCO2 between states may not be apparent. Often, the respiratory rate is higher in rapid eye movement (REM) sleep than in non-REM sleep in individuals with CCHS, and in general, respiratory rates are higher in infants and children with CCHS than peers with intact control of breathing. LO-CCHS should be suspected in infants, children, and adults who have

unexplained centrally mediated hypoventilation and/or seizures or cyanosis, especially subsequent to the use of anesthetic agents and/or sedation, acute respiratory illness or recurrent severe respiratory illness with difficulty weaning from ventilator support (and failed extubations), and potentially obstructive sleep apnea (OSA) unresponsive to traditional intervention. These individuals may have other evidence of chronic hypoventilation, including pulmonary hypertension, polycythemia, elevated bicarbonate concentration, difficulty concentrating, and mild unexplained neurocognitive impairment. A heightened level of suspicion has led to increasing numbers of older children and adults diagnosed with LO-CCHS receiving proper treatment. This later presentation reflects the variable penetrance of a subset of PHOX2B mutations and potential role of an environmental cofactor. In addition to treatment for the alveolar hypoventilation, children with CCHS require comprehensive physiologic evaluation during sleep and wakefulness, including activities of daily living such as eating, as their hypoxemia and hypercarbia from insufficient artificial ventilation may go unnoticed. It is necessary to provide coordinated care to optimally manage associated, multisystem abnormalities such as Hirschsprung disease, tumors of neural crest origin, and symptoms of physiologic ANSD including cardiac asystole, among other findings (details provided in American Thoracic Society 2010 Statement on CCHS).

Differential Diagnosis Testing should be performed to rule out primary neuromuscular, lung, and cardiac disease as well as an identifiable brainstem lesion that could account for the full constellation of symptoms characteristic of CCHS. The availability of clinical PHOX2B genetic testing allows for early and definitive diagnosis of CCHS (Table 446.3 ). Because individual features of CCHS mimics many treatable and/or genetic diseases, the following disorders should also be considered: altered airway or intrathoracic anatomy (diagnosis made with bronchoscopy and chest CT), diaphragm dysfunction (diagnosis made with diaphragm fluoroscopy), a structural hindbrain or brainstem abnormality (diagnosis made with MRI of the brain and brainstem), Möbius syndrome (diagnosis made with MRI of the brain and brainstem and neurologic examination), and specific metabolic diseases, such as Leigh syndrome, pyruvate dehydrogenase deficiency, and discrete carnitine deficiency. However, profound

hypercarbia without respiratory distress during sleep will quickly lead the clinician to consider the diagnosis of CCHS or LO-CCHS. Table 446.3

Differential Diagnoses of Congenital Central Hypoventilation Syndrome METABOLIC Mitochondrial defects, e.g., Leigh disease Pyruvate dehydrogenase deficiency Hypothyroidism NEUROLOGIC Structural central nervous system abnormalities, e.g., Arnold Chiari malformation, Moebius syndrome Vascular injury, e.g., central nervous system (CNS) hemorrhage, infarct Trauma Tumor PULMONARY Primary lung disease Respiratory muscle weakness, e.g., diaphragm paralysis, congenital myopathy GENETIC Prader Willi syndrome Familial dysautonomia SEDATIVE DRUGS OTHER Rapid-onset obesity, hypothalamic dysregulation hypoventilation, autonomic dysregulation (ROHHAD)

Modified from Healy F, Marcus CL: Congenital central hypoventilation syndrome in children, Pediatr Respir Rev 12:253–263, 2011 (Table 1, p. 258).

Management Supported Ventilation—Diaphragm Pacing Depending on the severity of the hypoventilation, the individual with CCHS can have various options for artificial ventilation: positive pressure ventilation (noninvasive via mask or via tracheostomy) or negative pressure ventilation (pneumosuit, chest cuirass, or diaphragm pacing). Chronic mechanical ventilation is addressed in Chapters 446.1 and 446.4 . Diaphragm pacing offers another mode of supported ventilation, involving bilateral surgical implantation of electrodes beneath the phrenic nerves, with connecting wires to subcutaneously implanted receivers. The external transmitter, which is much smaller and lighter in weight than a ventilator, sends a signal to flat donut-shaped antennae that are placed on the skin over the subcutaneously implanted

receivers. A signal travels from the external transmitter to the phrenic nerve to stimulate contraction of the diaphragm. A tracheostomy is typically required, because the pacers induce a negative pressure on inspiration as a result of the contraction of the diaphragm being unopposed by pharyngeal dilatation, resulting in airway obstruction with paced breaths. Individuals with CCHS who are ventilator-dependent for 24 hr a day are ideal candidates for diaphragm pacing to provide increased ambulatory freedom (without the ventilator tether) while they are awake; however, they still require mechanical ventilator support while they are asleep. This balance between awake pacing and asleep mechanical ventilation allows for a rest from phrenic nerve stimulation at night. In addition, a growing number of children and adults who require artificial ventilatory support only during sleep are now using diaphragm pacing. This is likely because of the introduction of thoracoscopic diaphragm pacer implantation and shortened postoperative recovery time. However, in the absence of a tracheostomy, diaphragm pacing during sleep may cause airway obstruction at varied levels of the airway depending on the specific patient. The potential for these obstructions needs to be carefully considered before diaphragm pacer implantation, and definitely before tracheal decannulation.

Monitoring in the Home Home monitoring for individuals with CCHS and LO-CCHS is distinctly different from and more conservative than that for other children requiring longterm ventilation, because CCHS individuals lack innate ventilatory and arousal responses to hypoxemia and hypercarbia. In the event of physiologic compromise, other children will show clinical signs of respiratory distress. By contrast, for children and adults with CCHS and LO-CCHS, the only means of determining adequate ventilation and oxygenation is with objective measures from a pulse oximeter, end-tidal CO2 monitor, and close supervision of these values by a highly trained registered nurse (RN) in the home and at school. While awake, patients with CCHS themselves are unable to sense or adequately respond to a respiratory challenge that may occur with ensuing respiratory illness, increased exertion, or even the simple activity of eating. At a minimum, it is essential that individuals with CCHS have continuous monitoring with pulse oximetry and end-tidal CO2 with RN supervision during all sleep time, but ideally 24 hr/day. These recommendations apply to all CCHS and LO-CCHS patients regardless of the nature of their artificial ventilatory support, but

especially those with diaphragm pacers as they have no intrinsic alarms in the diaphragm pacer device.

Noninvasive Equipment Supplemental oxygen with positive pressure support can be administered by nasal cannulae. The nasal cannula system has the ability to deliver heated, supersaturated, high-flow gases. There are a number of mechanical devices available for the delivery of bi-level ventilation via an actual ventilator, but this is suitable only for children with milder hypoventilation during sleep only. Longterm use of mask ventilation in small children may result in mid-face dysplasia or pressure wounds.

Positive Pressure Ventilators Ideally, a ventilator intended for home use is lightweight and small, quiet so it does not interfere with activities of daily living or sleep, is able to entrain room air, preferably has continuous flow, and has a wide range of settings (particularly for pressure support, pressure, volume, and rate) that allows ventilatory support from infancy to adulthood. Battery power for the ventilator, both internal and external, should be sufficient to permit unrestricted portability in the home and community. The equipment must also be impervious to electromagnetic interference and must be relatively easy to understand and troubleshoot. A variety of ventilators that are approved for home use are available, and familiarity with these devices is necessary to choose the best option for the individual child. Children who are chronically ventilated via positive pressure ventilation will require surgical placement of a tracheostomy tube. The tracheostomy tube provides stable access to the airway, a standardized interface for attaching the ventilator circuit to the patient, and the ability to easily remove airway secretions or deliver inhaled medications. Pediatric tracheostomy tubes typically have a single lumen and may have an inflatable cuff. Tracheostomy tubes with/without cuff inflation should be sized to control the air leak around the tube and promote adequate gas exchange, yet allow enough space around the tube to facilitate vocalization and prevent tracheal irritation and erosion from the tube. When a tracheostomy tube is surgically placed, a slit opening is made in the trachea between the cartilaginous rings. Stay sutures are attached to the margins of the incision to facilitate emergent tube replacement prior to healing of the

stoma tract. The tracheostomy tube is often electively changed by ENT about 1 wk after initial placement, and the child is subsequently cleared for tracheostomy tube changes by the nursing staff. The child's caregivers, usually parents or family members and home nursing staff, are instructed in all aspects of tracheostomy care: stoma care, elective and emergent tracheostomy change, proper securing of the tracheostomy tube, suctioning of secretions, and recognition of tube obstruction or decannulation. The child's caregivers have to demonstrate competency with all the tasks, and with cardiopulmonary resuscitation, prior to home discharge.

Optimizing Neurocognitive Performance Impaired oxygen delivery to the brain, whether acute or chronic, can have detrimental effects on neurocognitive development. The ATS statement recommends positive pressure ventilation via tracheostomy in the first several years of life to ensure optimal oxygenation and ventilation. The method of choice in later years will depend on a variety of factors including severity of disease, patient age, level of patient and family cooperation, and availability and quality of home health care, among other factors. The level of oxygen stability obtained with each varies. Thus, the method of respiratory assistance, especially in infancy and early childhood, is likely to play a factor in neurocognitive outcome. Past literature has indicated deficiencies of mental abilities in school-age children with CCHS. Even in preschool years, children with CCHS demonstrate reduced neurocognitive performance. In these cases, PHOX2B genotype is clearly associated with both mental and motor outcomes. This association is also found with CCHS-related features such as severe cyanotic breath holding spells, sinus pauses, seizures, and severity of hypoventilation. It is unclear if this association is intrinsic to the specific mutation, the phenotypes associated with the mutation, or most likely both. Despite observed delays, 29% of preschool subjects had mid-average mental development scores, and 13% performed above that level. These findings suggest the potential for excellent neurocognitive outcome. This potential appears greatest in individuals with a 20/25 genotype (Bayley mental scores over the population mean of 100). However, a 2015 report identified remarkably low IQs in a cohort of 19 Japanese children with the 20/25 genotype, with 42% of these cases reported as having displayed cognitive impairment. Many of these 20/25 genotype Japanese patients were diagnosed

after the 1st mo of life and some were managed with minimal support including home oxygen only, despite clear recommendations against such support. These contrasting results indicating disparity within the same genotype emphasizes need for early recognition and conservative management to insure optimized neurocognitive outcome. Recognizing this, neurodevelopmental monitoring would be most beneficial beginning in early infancy. Efforts are underway to evaluate and characterize the CCHS phenotype longitudinally through the International CCHS Registry (https://clinicaltrials.gov/show/NCT03088020 ) (Northwestern University). Delineating markers of disease progression and understanding the clinical manifestations of CCHS with advancing age will provide more accurate guidelines to healthcare providers, allowing physicians, families, and patients to better anticipate healthcare needs of affected individuals.

Bibliography Bachetti T, Parodi S, Di Duca M, et al. Low amounts of PHOX2B expanded alleles in asymptomatic parents suggest unsuspected recurrence risk in congenital central hypoventilation syndrome. J Mol Med . 2011;89(5):505–513. Basu SM, Bchir MB, Chung FF, et al. Anesthetic considerations for patients with congenital central hypoventilation syndrome: a systematic review of the literature. Anesth Analg . 2017;124:169–178. Carroll MS, Patwari PP, Kenny AS, et al. Residual chemosensory response to exogenous ventilatory challenges in paired-like homeobox 2b mutation-confirmed congenital central hypoventilation syndrome. J Appl Physiol . 2014;116:439–450 [PMID] 24381123. Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, et al. Congenital central hypoventilation syndrome (CCHS): neurocognition already reduced in preschool-age children. Chest . 2016;149(3):809–815. Chin AC, Shaul DB, Patwari PP, et al. Diaphragmatic pacing in

infants and children with congenital central hypoventilation syndrome (CCHS). Kheirandish-Gozal L, Gozal D. Sleep disordered breathing in children: a clinical guide . Springer Press: New York, NY; 2012:553–573; 10.1007/978-1-60761725-729 [2012]. Gronli JO, Santucci BA, Leurgans SE, et al. Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol . 2008;43:77–86. Healy F, Marcus CL. Congenital central hypoventilation syndrome in children. Pediatr Respir Rev . 2011;12:253–263. Jennings LJ, Yu M, Rand CM, et al. Variable human phenotype associated with novel deletions of the PHOX2B gene. Pediatr Pulmonol . 2012;47(2):153–161 [PMID] 21830319. Jennings LJ, Yu M, Zhou L, et al. Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers. Diagn Mol Pathol . 2010;19(4):224–231. Kinney HC. Structural abnormalities in the brainstem and cerebellum in congenital central hypoventilation syndrome. Pediatr Res . 2008;64:226–227. Kumar R, Lee K, Macey P, et al. Mammillary body and fornix injury in congenital central hypoventilation syndrome. Pediatr Res . 2009;66:429–434. Kumar R, Macey PM, Woo MA, et al. Diffusion tensor imaging demonstrates brainstem and cerebellar abnormalities in congenital central hypoventilation syndrome. Pediatr Res . 2008;64:275–280. Lijubić K, Fister I Jr, Fister I. Congenital central hypoventilation syndrome: a comprehensive review and future challenges. J Respir Med . 2014;1–8 http://dx.doi.org/10.1155/2014/856149 [Article ID]. Marazita ML, Maher BS, Cooper ME, et al. Genetic segregation analysis of autonomic nervous system dysfunction in families

of probands with congenital central hypoventilation syndrome. Am J Med Genet . 2001;100:229–236. Moreira TS, Takakura AC, Czeisler C, Otero JJ. Respiratory and autonomic dysfunction in congenital central hypoventilation syndrome. J Neurophysiol . 2016;116:742– 752. Nobuta H, Cilio MR, Danhaive O, et al. Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome. Acta Neuropathol . 2015;130(2):171–183. Rand CM, Yu M, Jennings LJ, et al. Germline mosaicism of PHOX2B mutation accounts for familial recurrence of congenital central hypoventilation syndrome (CCHS). Am J Med Genet A . 2012;158A(9):2297–2301 [PMID] 22821709. Straus C, Trang H, Becquemin MH, et al. Chemosensitivity recovery in Ondine's curse syndrome under treatment with desogestrel. Respir Physiol Neurobiol . 2010;171(2):171–174. Todd ES, Weinberg SM, Berry-Kravis EM, et al. Facial phenotype in children and young adults with PHOX2B determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology. Pediatr Res . 2006;59:39–45. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An official ATS clinical policy statement. Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med . 2010;181:626– 644. Weese-Mayer DE, Marazita ML, Berry-Kravis EM. Congenital central hypoventilation syndrome. Pagon RA, Bird TC, Dolan CR, et al. GeneReviews . University of Washington: Seattle; 1993 www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? book=gene&part=ondine . Weese-Mayer DE, Patwari PP, Rand CM, et al. Congenital central hypoventilation syndrome (CCHS) and PHOX2B

mutations. Robertson D, Biaggioni I, Burnstock G, et al. Primer on the autonomic nervous system . Academic Press: Oxford, UK; 2012:445–450. Weese-Mayer DE, Rand CM, Berry-Kravis EM, et al. Congenital central hypoventilation syndrome from past to future: model of translational and transitional autonomic medicine. Pediatr Pulmonol . 2009;44:521–535. Weese-Mayer DE, Rand CM, Zhou A, et al. Congenital central hypoventilation syndrome (CCHS): a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life. Pediatr Res . 2017;81(1–2):192–201 [PMID] 27673423 [50th anniversary success stories]Weese-Mayer DE, Silvestri JM, Huffman AD, et al: Case/control family study of ANS dysfunction in idiopathic congenital central hypoventilation syndrome, Am J Med Genet 100:237–245, 2001].

446.3

Other Conditions Affecting Respiration Zehava L. Noah, Cynthia Etzler Budek

Myelomeningocele With Arnold-Chiari Type II Malformation Arnold-Chiari type II malformation (see Chapter 609 ) is associated with myelomeningocele, hydrocephalus, and herniation of the cerebellar tonsils,

caudal brainstem, and the 4th ventricle through the foramen magnum. Sleepdisordered breathing, including OSA and hypoventilation, has been reported. Direct pressure on the respiratory centers or brainstem nuclei or increased intracranial pressure because of the hydrocephalus may be responsible. Vocal cord paralysis, apnea, hypoventilation, and bradyarrhythmias have also been reported. Patients with Arnold-Chiari type II malformation have blunted responses to hypercapnia, and, to a lesser degree, hypoxia.

Management An acute change in the ventilatory state of a patient with this malformation requires immediate evaluation. Consideration must be given to posterior fossa decompression and/or treatment of the hydrocephalus. If this treatment is unsuccessful in resolving central hypoventilation or apnea, tracheostomy and LMV should be considered.

Rapid-Onset Obesity, Hypothalamic Dysfunction, and Autonomic Dysregulation See Chapter 60.1 .

Obesity Hypoventilation Syndrome As its name implies, obesity hypoventilation syndrome is a syndrome of central hypoventilation during wakefulness in obese patients with sleep-disordered breathing. Although it was initially described mainly in adult obese patients, obese children have also demonstrated the syndrome. Sleep-disordered breathing is a combination of OSA, hypopnea, and/or sleep hypoventilation syndrome. Patients are hypercapnic with cognitive impairment, morning headache, and hypersomnolence during the day. Chronic hypoxemia may lead to pulmonary hypertension and cor pulmonale. Obesity is associated with reduced respiratory system compliance, increased airway resistance, reduced functional residual capacity, and increased work of breathing. Affected patients are unable to increase their respiratory drive in

response to hypercapnia. Leptin may have a role in this syndrome. The sleepdisordered breathing leads to compensatory metabolic alkalosis. Because of the long half-life of bicarbonate, its elevation causes compensatory respiratory acidosis during wakefulness with elevated PaCO2 .

Management The use of CPAP during sleep may be sufficient for many patients. Patients with hypoxemia may require BiPAP and supplemental oxygen. Tracheostomy may be considered for patients who do not tolerate mask ventilation.

Acquired Alveolar Hypoventilation Traumatic, ischemic, and inflammatory injuries to the brainstem, brainstem infarction, brain tumors, bulbar polio, and viral paraneoplastic encephalitis may also result in central hypoventilation.

Obstructive Sleep Apnea Epidemiology Habitual snoring during sleep is extremely common during childhood. As many as 27% of children who snore are affected by OSA . The current obesity epidemic has affected the epidemiology of this condition. Peak prevalence is at 2-8 yr of age. The ratio between habitual snoring and OSA is 4:1 to 6:1.

Pathophysiology OSA occurs when the luminal cross-sectional area of the upper airway is significantly reduced during inspiration. With increased airway resistance and reduced activation of pharyngeal dilators, negative pressure leads to upper airway collapse. The site of upper airway closure in children with OSA is at the level of tonsils and adenoids. The size of tonsils and adenoids increases throughout childhood up to 12 yr of age. Environmental irritants such as cigarette smoke or allergic rhinitis may accelerate the process. Reports suggest that early viral infections may affect adenotonsillar proliferation.

Clinical Presentation Snoring during sleep, behavioral disturbances, learning difficulties, excessive daytime sleepiness, metabolic issues, and cardiovascular morbidity may alert the parent or physician to the presence of OSA. Diagnosis is made with the help of airway radiograms and a polysomnogram.

Treatment When adenotonsillar hypertrophy is suspected, a consultation with an ear, nose, and throat specialist for adenoidectomy and/or tonsillectomy may be indicated. For patients who are not candidates for surgical intervention or persist with OSA despite adenoidectomy and/or tonsillectomy, CPAP or BiPAP during sleep may alleviate the obstruction (see Chapter 31 ).

Spinal Cord Injury Epidemiology There are an estimated 11,000 new spinal cord injuries (SCIs) annually in the United States, with more than 50% resulting in quadriplegia. SCI is relatively rare in pediatric patients, with an incidence of 1–13% of all SCI patients. The incidence in infancy and early childhood is similar for boys and girls. The preponderance of SCI in adolescents is in males. Motor vehicle accidents, falls, sports injuries, and assaults are the main causes. SCI usually leads to lifelong disability.

Pathophysiology Children with SCI have a disproportionately higher involvement of the upper cervical spine, high frequency of SCI without radiographic abnormality, delayed onset of neurologic deficits, and higher proportion of complete injury. Thus, there is a high likelihood in pediatric SCI of quadriplegia with intercostal muscle and/or diaphragmatic paralysis leading to respiratory failure.

Management Immobilization and stabilization of the spine must be accomplished

simultaneously with initial patient resuscitation. Children with high SCI typically require lifelong ventilation, so the decision to place a tracheostomy for chronic ventilatory support is usually made early in their course of treatment. Depending on the child's age and general condition, diaphragmatic pacing may be considered. Often patients with diaphragmatic pacing need tracheostomy placement if there is dyscoordination between pacing and glottal opening. Muscle spasms occur frequently in the SCI patient and are treated with muscle relaxants. Occasionally the muscle spasms involve the chest and present a serious impediment to ventilation. Continuous intrathecal infusion of muscle relaxant via an implanted subcutaneous pump may be indicated (see Chapter 83 ).

Metabolic Disease Mucopolysaccharidoses See Chapter 107 . Mucopolysaccharidoses are a group of progressive hereditary disorders that lack the lysosomal enzymes that degrade glycosaminoglycans. Incompletely catabolized mucopolysaccharides accumulate in connective tissue throughout the body. The inheritance is autosomal recessive except for Hunt syndrome, which is X-linked. The diagnosis is suggested by the presence of glycosaminuria and is confirmed by a lysosomal enzyme assay. I-cell disease mucolipidosis type II is an inherited lysosomal disorder with accumulation of mucolipids. Phenotypically, it is similar to mucopolysaccharidoses, but the age of onset is earlier and there is no mucopolysacchariduria. Mucopolysaccharide deposits are frequently found in the head and neck and cause airway obstruction. Typically, the affected child has a coarse face and large tongue. Significant deposits are found in the adenoids, tonsils, and cartilage. Airway radiograms and a polysomnogram may help define the severity of the upper airway obstruction. Treatment options have included enzyme replacement therapy and stem cell transplantation with limited success. Adenoidectomy and/or tonsillectomy may be indicated but surgery alone seldom solves the problem of airway obstruction. Noninvasive CPAP or BiPAP, or tracheostomy with ventilatory support may be helpful.

Dysplasias Campomelic dysplasia (see Chapter 718 ) and thanatophoric dysplasia (see Chapter 716 ) affect rib cage size, shape, and compliance, leading to respiratory failure. Most patients with these disorders do not survive beyond early infancy. Tracheostomy and ventilation may prolong life.

Glycogenosis Type II See Chapter 105.1 . Glycogenosis type II is an autosomal recessive disorder. Clinical manifestations include cardiomyopathy and generalized muscle weakness. Cardiac issues may include heart failure and arrhythmias. Muscle weakness leads to respiratory insufficiency and sleep-disordered breathing. Treatment includes emerging therapies such as enzyme replacement therapy, chaperone molecules, and gene therapy. Supportive therapy may consist of either noninvasive ventilation, or tracheostomy and mechanical ventilation. Cardiac medications, protein-rich nutrition, and judicious physical therapy are additional measures that can be utilized.

Severe Tracheomalacia and/or Bronchomalacia (Airway Malacia) Conditions associated with airway malacia include tracheoesophageal fistula, innominate artery compression, and pulmonary artery sling after surgical repair (see Chapter 416 ). Patients with tracheobronchomalacia present with cough, lower airway obstruction, and wheezing. Diagnosis is made via bronchoscopy, preferably with the patient breathing spontaneously in order to evaluate dynamic airway function. Positive end-expiratory pressure titration during the bronchoscopy helps identify the ideal airway pressure required to maintain airway patency and prevent tracheobronchial collapse.

Neuropathy of Severe Illness Children recuperating from severe illness in the intensive care unit often have neuromuscular weakness from suboptimal nutrition. This neuromuscular weakness can be devastating when coupled with the catabolic effects of severe

illness and the residual effects of sedatives, analgesics, and muscle relaxants, particularly if corticosteroids were administered. Children with neuromuscular compromise have limited ability to increase ventilation and usually do so by increasing respiratory rate. Because of weakness, costal and sternal retractions may not be observed. Children with severe neuromyopathy may respond to increased respiratory load by becoming apneic. A look of panic, a change in vital signs such as significant tachycardia or bradycardia, and cyanosis may be the only signs of impending respiratory failure.

Mitochondrial Diseases See Chapter 106 . Mitochondria are primarily responsible for the production of adenosine triphosphate. Mitochondrial diseases are a heterogeneous group of diseases in which adenosine triphosphate production is disrupted. Mitochondrial diseases are increasingly recognized and diagnosed in the pediatric population. Organs with high-energy requirements such as the neurons, and skeletal and cardiac muscles are particularly vulnerable. Although myopathy is the most frequently recognized presentation of mitochondrial disease, it is often part of a multisystem disease process. Neurologic complications include progressive proximal myopathy, kyphoscoliosis, dyskinesia, dystonia and spasticity, stroke, epilepsy, and visual and hearing impairment. Nonneurologic manifestations include cardiomyopathy, gastrointestinal dysmotility, gastroesophageal reflux, delayed gastric emptying, and pseudoobstruction. Respiratory complications of mitochondrial disease are multi-factorial. Muscle weakness, kyphoscoliosis, muscle spasms, and movement disorders may result in a restrictive pattern, and respiratory compromise. Additionally, dyscoordinated swallow and reflux may result in aspiration. In some mitochondrial diseases such as Leigh syndrome (see Chapter 106 ), central hypoventilation is an integral part of the disease. Supportive care for these patients may include noninvasive or invasive ventilation, tracheostomy placement, diuretics, appropriate nutrition, and dietary supplements.

446.4

Long-Term Mechanical Ventilation Robert J. Graham

Keywords chronic respiratory failure home ventilation decision-making tracheostomy noninvasive ventilation weaning chronic disease complex care See also Chapter 734.1 .

Goals and Decision-Making The decision to implement LMV has many challenges stemming from a diversity of underlying pathophysiology, uncertain disease trajectories, the development of new condition-specific therapies, personal experiences, and values held by providers, patients, parents, and the broader community, variability in resources, and lack of standards. While optimizing gas exchange (i.e., oxygenation and CO2 removal) remains a primary objective, it represents a tool for the comprehensive care of children with complex needs (see Chapters 446.1 and 734.1 ). LMV has a role within the spectrum of palliative care. It is used proactively to attenuate cumulative morbidities (respiratory and cardiac) associated with progressive neuromuscular conditions, such as Duchenne muscular dystrophy. LMV is also used reactively when acute illness (e.g., acute respiratory distress syndrome) does not resolve. In infants with premature lung disease or complex

airway anomalies, LMV may be implemented as a temporary measure, as these conditions may resolve with maturity or surgical interventions. LMV can also represent a bridge to lung transplant for those with intrinsic pulmonary or pulmonary vascular disease. LMV has become a destination therapy to optimize symptom management and prolong life in complex conditions. Etiology of the respiratory insufficiency includes, but is not limited to, congenital anomalies (e.g., complex cardiac conditions, central nervous system disorders, interruptions in aerodigestive morphogenesis, and skeletal dysplasias), acquired central neurological injuries from perinatal, infectious, traumatic, and hypoxic-ischemic events, metabolic disorders, or progressive neuromuscular conditions. Progress in other areas of medicine, such as gene-targeted therapy in spinal muscular atrophy and myotubular myopathy, may alter the LMV decision-making landscape as families foresee the prospect of improvement.

Noninvasive and Transtracheal Supports The essential modalities for LMV include negative pressure, noninvasive positive pressure ventilation (NIPPV with either continuous or biphasic support provided through an occlusive mask interface), or transtracheal positive pressure. Considerations for a given patient should include, but are not limited to, anatomic factors, physiologic goals, long-term care goals, comfort, tolerability/compliance, and safety (mobility/portability, monitoring, device availability and back-up, training capacity). Negative pressure devices, such as the cuirass ventilator, do not require any interface with the face or trachea and are more natural from a mechanical perspective. NIPPV can address dynamic upper airway obstruction as well as augment respiratory mechanics and gas-exchange. This modality may, however, have limitations if upper airway obstruction is severe or fixed or the need for oxygen supplementation is high. Masks, prongs, and pillows of varying sizes are available for nasal, oral, combination, and full interface, including those for infants. Mouthpiece interface has also been demonstrated to be effective and feasible. The choice of continuous positive airway pressure (CPAP) versus biphasic positive airway pressure (BiPAP) is dependent upon the underlying pathophysiology. Conceptually, CPAP can overcome a dynamic upper airway obstruction and allow for spontaneous ventilation, while BiPAP is more versatile in compensating for upper airway obstruction and supporting lung recruitment and gas-exchange. In practice, CPAP is limited to management of mild OSA.

While NIPPV can be maintained 24 hr/day, efficacy of ventilation, difficult airway considerations (i.e., Can the child be intubated?), developmental needs, implications for midface hypoplasia, and secretion clearance are among factors that impact the decision to pursue tracheostomy placement and invasive LMV. Transtracheal LMV provides the most secure and effective respiratory support. Fixed and dynamic upper airway obstruction are bypassed with tracheostomy tube placement. Secretions are more readily cleared from the lower airway. Positive pressure and oxygen delivery via a tracheostomy tube more consistently address primary impairments in gas exchange (within limits) as well as mechanical disadvantages from neuromuscular insufficiency and restrictive disease. When possible, placement of a tracheostomy tube in a child should be coordinated at an institution with pediatric expertise, because the short-term morbidities and, potentially, mortality are not insignificant. Individuals using NIPPV are at risk for pressure ulcerations on the face as well as on the scalp. Proper fit of the interface must be assured since a tighter fit is not necessarily commensurate with better support. Alternating masks on a regular basis may alleviate pressure on a given site. Additional non-adhesive dressings can also be used to facilitate mask seal and minimize skin breakdown. For those with a tracheostomy tube in place, care of tracheostomy ties and regular assessment of the stoma is required. Moisture-wicking dressings can attenuate risk of maceration, but their use should be balanced against the value of exposure to air for drying. Stomal assessment should include evaluation for granulation, fissures, and traction created by additional torque from ventilator tubing, which should be maintained midline and without weight displacement on the tracheostomy tube itself. Any areas of integument interruption are potential niduses for infection and of great concern for immunocompromised hosts.

Augmented Secretion Clearance (See Chapter 446.1 ).

Aerodigestive and Communication Considerations Assessment of swallowing and speaking capacity should be part of an assessment for LMV and may help guide the modality. In general,

implementation of noninvasive or transtracheal supports will not further impair either of these functions. Rather, the underlying condition is the primary determinant. This consideration is most notable in patients with neurologic injury or neuromuscular conditions. Decision-making around placement of a transabdominal gastric or gastrojejunal enteral feeding tube, if not already in place, should coincide with decisions around LMV. Nasogastric tubes, it should be appreciated, may impair NIPPV mask seal as well as cause laryngeal irritation in the long-term. Use of NIPPV must be approached cautiously in those with impaired swallowing as positive pressure will increase the risk of macro- and microaspiration. Individuals using NIPPV can eat and drink while on support with risk versus benefit determination and quality of life. Aerophagia on NIPPV is also problematic, regardless of bulbar function and swallowing capacity; abdominal distention is uncomfortable, contributes to satiety as well as vomiting risk, and further impairs respiratory mechanics with decreased functional residual capacity and increased inspiratory workload. If a gastrostomy is present, active evacuation of swallowed air and use of passive venting tubes can be helpful. Children with swallowing capacity can continue to eat and drink by mouth with a tracheostomy tube in place on LMV. The presence of a cuffed tracheostomy tube does not prevent aspiration if swallowing is impaired. Speaking may be facilitated by LMV, as settings can be increased or a speaking valve utilized to increased airflow across the vocal cords. Regardless, multidisciplinary care with a speech language pathologist, feeding specialist, and augmented communication services can be helpful for many children and their families utilizing LMV. Conditioned aversions to oral stimulation can be challenging for infants but developmental gains should not be impeded by LMV.

Gas-Exchange Goals and Ventilator Strategies Pressure- or volume-regulated modes, spontaneous or controlled settings, and mixed modes are all feasible for NIPPV and transtracheal supports with new devices. The appropriate support should coincide with oxygenation and ventilation goals on a case-by-case basis. Consideration, however, should be given to the site of care and contingencies for presentation to acute cure during

intercurrent illness or emergency. Providers should assess limitations in oxygen supplementation outside of the hospital; measured or estimated delivered fractional inspired oxygen (FIO 2 ) will inform families and providers of capacity when adding oxygen in liters/minute flow to the ventilator circuit; dilution can have a dramatic effect and achieving FIO 2 > 0.60 may be difficult when oxygen is added to a home ventilator circuit. Safety allowances should also account for the duration of portable oxygen provision, which is based upon liter flow and tank/reservoir volume. Monitoring of CO2 in the homecare setting is not usual, although portable end-tidal CO2 devices are available. Conditions such as congenital central hypoventilation syndrome warrant vigilance, and parameters for implementation, or titration, of mechanical ventilation should be discussed with families. Recognition that significant and indolent hypercapnia can precede hypoxia is necessary, and long-term effects on cerebral and pulmonary vasculature should be considered. In the absence of direct CO2 monitoring, periodic measurement of serum bicarbonate may be helpful to assess for renal compensation for altered CO2 clearance; interpretation, however, may be altered in the presence of diuretic therapy, metabolic disease, or ketogenic diets.

Cardiopulmonary Interactions Closely linked to the gas-exchange goals are considerations for cardiopulmonary interactions. While there are subtle implications for systemic venous return of any form of positive pressure ventilation, LMV can be used to decrease transmural myocardial load as well as optimize right ventricular afterload through lung recruitment and pulmonary vascular reactivity. The prolonged survival of young males with Duchenne muscular dystrophy is in part due to consistent respiratory support to optimize lung health as well as attenuate myocardial dysfunction. Primary or secondary pulmonary hypertension, whether overt or indolent, requires consideration of oxygenation and ventilation goals. Echocardiograms are not required for all patients with LMV, but this modality may be helpful to guide management in cohorts with congenital heart lesions, cardiomyopathies, severe obstructive pulmonary disease, significant central dysregulation, and on a case-by-case basis. When considering gas-change goals and cardiopulmonary interactions, providers must also consider daytime and nocturnal differences. Neuromuscular-

derived hypoventilation is more prominent at night as is upper airway obstructive disease; the latter is more important for those using noninvasive LMV. Daytime support provision must account for increased oxygen consumption and demand based upon variable activity as well as stressors, including environmental temperature. Providers and families must factor in mobility, behavioral tolerance, and quality of life.

Chest Wall/Thoracic Configuration Positive pressure through LMV in early childhood for children with neuromuscular conditions and/or restrictive lung disease is also used to improve thoracic compliance and configuration. Lung inflation can be used to attenuate the impact of thoracic asphyxiation as well as progressive parasol chest deformation in diaphragm-dependent conditions, such spinal muscular atrophy. This use has implications for atelectasis and secretion inspissation, associated pulmonary vasoconstriction, and cumulative restrictive or asymmetric pulmonary mechanics.

Nutrition and Weight Gain See Chapter 446.1 .

Developmental Considerations Decisions regarding the LMV modality, noninvasive or transtracheal, requires consideration of development as well. Beyond safety factors, tolerance of interventions, availability of appropriate sized interfaces, and portability, there remains substantial subjectivity with respect to perspective on the implication for social interactions (i.e., devices covering the face versus a device in the neck). While there are no published series, long-term or near-continuous NIV also has implications for midface hypoplasia and potentially compounds upper airway obstructive symptoms, as is evident by images of BiPAP faces . Swallowing and speech capacity primarily reflect the child's underlying condition rather than the LMV.

Projected Interventions and Needs Trajectory and management of the underlying disease as well as symptom management are primary drivers in determining the need and duration of LMV. Stakeholders should also consider future interventions, specifically surgical procedures. LMV, noninvasive or transtracheal, can be utilized to optimize perioperative standing and facilitate recovery and provision of opiate-based analgesia that could alter respiratory drive. The maintenance of a tracheostomy tube in anticipation of sequential surgeries (e.g., spinal instrumentation, craniofacial and airway reconstruction, or serial cardiac interventions) may be required for practical reasons, but also minimizes the need for repeated intubation.

Monitoring Conceptually, monitoring is used to detect early physiologic changes and determine adequacy of LMV to minimize cumulative morbidities and risk of mortality. Recommendations for monitoring children and young adults on LMV vary based upon underlying vulnerability, care setting, and activity (e.g., home, long-term care facility, school, or in transport via car), and adjuvant supports (e.g., home nursing or personal care assistant). Pulse oximetry can be used intermittently or on a continuous basis with oxygen and heart rate parameters determined on a case-by-case basis. Internal ventilator alarm settings, for both NIV and transtracheal ventilators, are utilized to monitor high- and low-pressure parameters and minute ventilation. Stakeholders must acknowledge, however, that internal alarms may be insufficient in the setting of a large mask or peritracheal leak or in the event of a device malfunction. There are also pragmatic considerations of signal-to-noise when determining monitoring parameters; recurrent false alarms will desensitize providers and may disturb a child's sleep; conversely, wide alarm parameters circumvent early warning systems with significant consequences.

Transitioning From Acute Care to Rehabilitation or Community Setting Disposition of children and young adults with LMV will vary based upon their

relative stability, local support services, and goals of care. A proactive, comprehensive care model is required to assure safe and effective provision. The impact of care needs on the child and family are inextricably linked.

Routine Health Maintenance Airway Evaluation There is no standard for regular airway assessment for children with LMV, specifically those with transtracheal support, but annual evaluation should represent the minimum. Office-based transtracheal tube endoscopy can facilitate assessment of tube upsizing for linear growth, presence of granulation tissue, airway inflammation, and general mucosal integrity. Formal diagnostic laryngoscopy and bronchoscopy under general anesthesia is required to assess for suprastomal and laryngeal level pathology as well as the rare, acquired trachea-esophageal fistulae. Of note, independent of routine evaluation, recurrent or unexpected tracheal bleeding may warrant evaluation for a trachea-vascular fistula via CT angiogram and bronchoscopy.

Bacterial Colonization Chronic respiratory failure lends itself to airway bacterial colonization due to alterations in secretion clearance, aerodigestive interactions, the presence of artificial airways with the development of biofilms, and other factors. Hydrophilic and Gram-negative bacteria (e.g., Pseudomonas, Serratia, and Stenotrophomonas ) are not uncommon. There is no standard of care for determining pathogenicity versus colonization. Use of systemic or inhaled antibacterial agents to decrease colonization load, frequency of tracheostomy tube exchanges to reduce biofilm accumulation, utility of viral screening, and threshold for treatment of an acute lower airway process or tracheitis is provider and case dependent. Providers should appreciate that recurrent empiric antibacterial treatment may select for resistant bacterial strains and has implications for enteric bacterial colonization.

Dental Care Routine daily and office-based dental care should follow standard

recommendations for all children. Extrapolation from the acute care setting and general population would suggest that oropharyngeal care and minimization of bacterial overgrowth would impact the risk of superimposed respiratory illness in LMV and long-term cardiovascular outcomes, respectively. Special consideration with respect to aspiration risk, developmental tolerance, and prophylaxis and procedural sedation for intervention may require engagement of specialty providers.

Immunizations There are no immunizations specifically indicated for individuals receiving LMV. Routine provision is recommended, including seasonal vaccinations for viral pathogens.

Radiography, Laboratory Evaluation, Polysomnography, and Pulmonary Function Testing There are no recommendations for routine chest radiography, standard or crosssectional, in the context of LMV. The cumulative radiation exposure would need to be considered. Gas exchange adequacy can often be assessed noninvasively. Venous, capillary, or arterial puncture for determining resting and long-term oxygenation and ventilation status may be of limited utility and validity, as intercurrent illness, technique with tourniquet, and associated agitation will alter results. Condition-specific (e.g., muscular dystrophy, polysomnography, spirometry, or pulmonary function) testing recommendations have been established. Regular assessment may also be helpful when gauging disease trajectory, LMV titration, safety parameters, and weaning potential.

Long-Term Mechanical Ventilation Weaning and Tracheal Decannulation Reassessment of the role of LMV should be part of routine and family-centered care. Determination should include, but is not limited to, the factors described above with open discussion of goals of care, developmental appropriateness, physiologic and anatomic consideration, growth implications, and contingencies.

As there are no definitive conditioning regimens or LMV weaning strategies, providers can determine the value of time off versus decreased level of supports as well as pragmatic considerations for the child and family. Continuity of care, however, holds implicit value. Monitoring provision may need to be increased during weaning. If tracheal decannulation is required, a formal diagnostic laryngoscopy and bronchoscopy should be considered to rule out granulation (supra and infrastomal) as well as dynamic airway collapse that may prohibit immediate tracheostomy tube removal. If positive pressure or oxygen supplementation will still be required after decannulation, determination of the child's tolerance of NIV or other interventions (e.g., cough assist) should be determined in advance. Desensitization may be required. Ultimately, LMV has an increasing role in the support of children and young adults with chronic respiratory failure. Transition from pediatric to adult services should be anticipated as this population ages. Additional research is required to inform all stakeholders regarding daily management decisions as well as healthcare resource utilization and long-term patient-centered outcomes.

Bibliography Amaddeo A, Moreau J, Frapin A, et al. Long term continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) in children: initiation criteria in real life. Pediatr Pulmonol . 2016;51(9):968–974. Bach JR, Chiou M, Saporito LR, Esquinas AM. Evidence-based medicine analysis of mechanical Insufflation-exsufflation devices. Respir Care . 2017;62(5):643. Bach JR, Martinez D. Duchenne muscular dystrophy: continuous noninvasive ventilatory support prolongs survival. Respir Care . 2011;56(6):744–750. Bidiwala A, Volpe L, Halaby C, et al. A comparison of high frequency chest wall oscillation and intrapulmonary percussive ventilation for airway clearance in pediatric patients with tracheostomy. Postgrad Med . 2017;129(2):276–282. Chatwin M, Tan HL, Bush A, et al. Long term non-invasive

ventilation in children: impact on survival and transition to adult care. PLoS ONE . 2015;10(5):e0125839. Cristea AI, Carroll AE, Davis SD, et al. Outcomes of children with severe bronchopulmonary dysplasia who were ventilator dependent at home. Pediatrics . 2013;132(3):e727–e734. Fauroux B, Quijano-Roy S, Desguerre I, Khirani S. The value of respiratory muscle testing in children with neuromuscular disease. Chest . 2015;147(2):552–559. Fine-Goulden MR, Ray S, Brierley J. Decision making in longterm ventilation for children. Lancet Respir Med . 2015;3(10):745–746. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantileonset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet . 2016;388(10063):3017–3026. Hull J, Aniapravan R, Chan E, et al. British thoracic society guideline for respiratory management of children with neuromuscular weakness. Thorax . 2012;67(Suppl 1):i1–i40. Katz SL, Barrowman N, Monsour A, et al. Long-term effects of lung volume recruitment on maximal inspiratory capacity and vital capacity in duchenne muscular dystrophy. Ann Am Thorac Soc . 2016;13(2):217–222. Khirani S, Ramirez A, Delord V, et al. Evaluation of ventilators for mouthpiece ventilation in neuromuscular disease. Respir Care . 2014;59(9):1329–1337. Lacombe M, Del Amo Castrillo L, Bore A, et al. Comparison of three cough-augmentation techniques in neuromuscular patients: mechanical insufflation combined with manually assisted cough, insufflation-exsufflation alone and insufflation-exsufflation combined with manually assisted cough. Respiration . 2014;88(3):215–222. Liptzin DR, Connell EA, Marable J, et al. Weaning nocturnal ventilation and decannulation in a pediatric ventilator care

program. Pediatr Pulmonol . 2016;51(8):825–829. MacIntyre EJ, Asadi L, McKim DA, Bagshaw SM. Clinical outcomes associated with home mechanical ventilation: a systematic review. Can Respir J . 2016;2016:6547180. Mack DL, Poulard K, Goddard MA, et al. Systemic AAV8Mediated gene therapy drives Whole-body correction of myotubular myopathy in dogs. Mol Ther . 2017;25(4):839– 854. Martinez EE, Smallwood CD, Bechard LJ, et al. Metabolic assessment and individualized nutrition in children dependent on mechanical ventilation at home. J Pediatr . 2015;166(2):350–357. Mellies U, Goebel C. Optimum insufflation capacity and peak cough flow in neuromuscular disorders. Ann Am Thorac Soc . 2014;11(10):1560–1568. Prickett KK, Sobol SE. Inpatient observation for elective decannulation of pediatric patients with tracheostomy. JAMA Otolaryngol Head Neck Surg . 2015;141(2):120–125. Simonds AK, Hare A. New modalities for non-invasive ventilation. Clin Med (Lond) . 2013;13(Suppl 6):s41–s45. Sterni LM, Collaco JM, Baker CD, et al. An official American thoracic society clinical practice guideline: pediatric chronic home invasive ventilation. Am J Respir Crit Care Med . 2016;193(8):e16–e35. Wilfond BS. Tracheostomies and assisted ventilation in children with profound disabilities: navigating family and professional values. Pediatrics . 2014;133(Suppl 1):S44–S49.

PA R T X I X

The Cardiovascular System OUTLINE Section 1 Developmental Biology of the Cardiovascular System Section 2 Evaluation of the Cardiovascular System and the Child with A Heart Murmur Section 3 Congenital Heart Disease Section 4 Cardiac Arrhythmias Section 5 Acquired Heart Disease Section 6 Diseases of the Myocardium and Pericardium Section 7 Cardiac Therapeutics Section 8 Diseases of the Peripheral Vascular System

SECTION 1

Developmental Biology of the Cardiovascular System OUTLINE Chapter 447 Cardiac Development Chapter 448 The Fetal to Neonatal Circulatory Transition

CHAPTER 447

Cardiac Development Daniel Bernstein

Knowledge of the cellular and molecular mechanisms of cardiac development is necessary for understanding congenital heart defects and will be even more important in developing strategies for prevention, whether cell or molecular therapies or fetal cardiac interventional procedures. Cardiac defects have traditionally been grouped by common morphologic patterns: for example, abnormalities of the outflow tracts (conotruncal lesions such as tetralogy of Fallot and truncus arteriosus) and abnormalities of atrioventricular septation (primum atrial septal defect, complete atrioventricular canal defect). These morphologic categories may be revised or eventually supplanted by new categories as our understanding of the genetic basis of congenital heart disease progresses.

447.1

Early Cardiac Morphogenesis Daniel Bernstein

In the early presomite embryo, the first identifiable cardiac progenitor cell clusters are arranged in the anterior lateral plate mesoderm on both sides of the embryo's central axis; these clusters form paired cardiac tubes by 18 days of gestation. The cardiac progenitor zone is shaped by a balanced gradient of

positive and negative signals arising from the tissues surrounding the cardiac mesodermal cells, with signals from the surrounding ventral/lateral tissues promoting cardiogenesis through signaling molecules such as BMP (bone morphogenetic protein) and FGF8 (fibroblast growth factor 8), and signals from dorsal/medial structures such as members of the Wnt/β-catenin pathway inhibiting cardiogenesis. Cardiogenic signals activate the expression of cardiacspecific transcription factors (e.g., Tbx, GATA, Nkx2.5) to activate cardiac gene expression. The paired tubes fuse in the midline on the ventral surface of the embryo to form the primitive heart tube by 22 days. This straight heart tube is composed of an outer myocardial layer, an inner endocardium, and a middle layer of extracellular matrix (ECM) known as the cardiac jelly . There are 2 distinct cell lineages: the first heart field (regulated mainly by Nkx2.5) provides precursor cells for the left ventricle; the second heart field (regulated mainly by Isl1) provides precursors for the atria and right ventricle. Premyocardial cells, including epicardial cells and cells derived from the neural crest, continue their migration into the region of the heart tube. Regulation of this early phase of cardiac morphogenesis is controlled in part by the interaction of specific signaling molecules or ligands, usually expressed by one cell type, with specific receptors, usually expressed by another cell type. Positional information is conveyed to the developing cardiac mesoderm by factors such as retinoids (isoforms of vitamin A), which bind to specific nuclear receptors and regulate gene transcription. Migration of epithelial cells into the developing heart tube is directed by ECM proteins (e.g., fibronectin) that interact with cell surface receptors (the integrins ). The clinical importance of these signaling pathways is revealed by the spectrum of cardiac teratogenic effects caused by the retinoidlike drug isotretinoin. As early as 20-22 days, before cardiac looping, the embryonic heart begins to contract and exhibit phases of the cardiac cycle that are surprisingly similar to those in the mature heart. Morphologists initially identified segments of the heart tube that were believed to correspond to structures in the mature heart (Fig. 447.1 ): the sinus venosus and atrium (right and left atria), the primitive ventricle (left ventricle), the bulbus cordis (right ventricle), and the truncus arteriosus (aorta and pulmonary artery). However, this model is oversimplified. Only the trabecular (most heavily muscularized) portions of the left ventricular myocardium are present in the early cardiac tube; the cells that will become the inlet portion of the left ventricle migrate into the cardiac tube at a later stage (after looping is initiated). Even later to appear are the primordial cells that give

rise to the great arteries (truncus arteriosus), including cells derived from the neural crest, which are not present until after cardiac looping is complete. Chamber-specific transcription factors participate in the differentiation of atria from ventricles and in the right and left ventricles. The basic helix-loop-helix (bHLH ) transcription factor dHAND is expressed in the developing right ventricle; disruption of this gene or of other transcriptional factors such as myocyte enhancer factors 2C (MEF2C) in mice leads to hypoplasia of the right ventricle. Other genetic markers of second heart field (early right ventricle) cells include Irx4, Tbx20, Isl1, TnT, MLC2v, and Tbx1. The transcription factor eHAND is expressed in the developing left ventricle and conotruncus and is also critical to their development. Other genetic markers of first heart field (early left ventricle) cells include Tbx5, Ncx2.5, TnT, MLC2V, and HCN4.

FIG. 447.1 Timeline of cardiac morphogenesis. (From Larsen WJ: Essentials of human embryology, New York, 1998, Churchill Livingstone.)

Recent research has focused on how regulation of developmentally coordinated groups of genes is achieved. One mechanism is through the

expression of small, noncoding RNAs known as micro RNAs, each of which regulates the expression of multiple target genes. Another is through modifications in chromatin , the DNA scaffolding that acts as a controller of gene expression. Chromatin remodeling mediated by factors such as Brg1, Chd7, histone demethylases, and methyltransferases is associated with cardiac developmental defects.

447.2

Cardiac Looping Daniel Bernstein

At approximately 22-24 days, the heart tube begins to bend ventrally and toward the right (see Fig. 447.1 ). The heart is the first organ to escape from the bilateral symmetry of the early embryo. An asymmetric signaling program that also affects the position of the lungs, liver, spleen, and gastrointestinal tract determines the direction of cardiac looping. During gastrulation, before organ formation begins, asymmetric expression of sonic hedgehog (SHH) and nodal (a member of the TGF-β family) are directed in the lateral mesoderm. These directionality signals set up a concentration gradient between the right and left sides of the embryo in the expression of critical signaling molecules. This asymmetric signaling is then amplified and propagated through the transcription factor Pitx2, which is expressed on the left side of the early heart tube, lefty1 and LR dynein. Interestingly, mice in which the LR dynein gene has been inactivated display random left-right (L-R) orientation of the heart and abdominal viscera, with 50% of their hearts looping to the right and 50% looping to the left. Other potential mechanisms of cardiac looping include differential growth rates for myocytes on the convex vs the concave surface of the curve, differential rates of programmed cell death (apoptosis), and mechanical forces generated within myocardial cells at the inner and outer edges of the bending heart tube through their actin cytoskeleton. Looping brings the future left ventricle leftward and in continuity with the

sinus venosus (future left and right atria), whereas the future right ventricle is shifted rightward and in continuity with the truncus arteriosus (future aorta and pulmonary artery). This pattern of development explains the relatively common occurrence of the cardiac anomalies double-outlet right ventricle and doubleinlet left ventricle and the extreme rarity of double-outlet left ventricle and double-inlet right ventricle (see Chapter 457.5 ). When cardiac looping is abnormal (situs inversus , heterotaxia ), the incidence of serious cardiac malformations is high, and there are usually associated abnormalities in the L-R patterning of the lungs and abdominal viscera, including absence of the spleen (asplenia ) or multiple small spleens (polysplenia ).

447.3

Cardiac Septation Daniel Bernstein

When looping is complete, the external appearance of the heart is similar to that of a mature heart; internally, the structure resembles a single tube, although it now has several bulges resulting in the appearance of primitive chambers. The common atrium (comprising both right and left atria) is connected to the primitive ventricle (future left ventricle) via the atrioventricular canal. The primitive ventricle is connected to the bulbus cordis (future right ventricle) via the bulboventricular foramen . The distal portion of the bulbus cordis is connected to the truncus arteriosus via an outlet segment (the conus ). The heart tube now consists of several layers of myocardium and a single layer of endocardium separated by cardiac jelly (acellular ECM secreted by myocardium). Septation of the heart begins at approximately day 26 with the ingrowth of large tissue masses, the endocardial cushions , at both the atrioventricular and conotruncal junctions (see Fig. 447.1 ). These cushions consist of protrusions of ECM (cardiac jelly), which, in addition to their role in development, also serve a physiologic function as primitive heart valves. Endocardial cells dedifferentiate and migrate into the cardiac jelly in the region

of the endocardial cushions, eventually becoming mesenchymal cells (endothelial-mesenchymal transformation) that will form part of the atrioventricular valves. The endocardium, secondary heart field, and neural crest all contribute to the formation of the valve leaflets. Besides direct contribution to valve tissue, these progenitor cells also interact with each other and with other cells in the heart to orchestrate cardiac valve development. Complete septation of the atrioventricular canal occurs with fusion of the endocardial cushions. Most of the atrioventricular valve tissue is derived from the ventricular myocardium in a process involving undermining of the ventricular walls. Because this process occurs asymmetrically, the tricuspid valve annulus sits closer to the apex of the heart than the mitral valve annulus. Physical separation of these 2 valves produces the atrioventricular septum, the absence of which is the primary common defect in patients with atrioventricular canal defects (see Chapter 453.5 ). If the process of undermining is incomplete, the right atrioventricular valve may not separate normally from the ventricular myocardium, a possible cause of Ebstein anomaly (see Chapter 457.7 ). Septation of the atria begins at around 30 days with growth of the septum primum downward toward the endocardial cushions (see Fig. 447.1 ). The orifice that remains is the ostium primum. The endocardial cushions then fuse and, together with the completed septum primum, divide the atrioventricular canal into right and left segments. A second opening appears in the posterior portion of the septum primum, the ostium secundum, and it allows a portion of the fetal venous return to the right atrium to pass across to the left atrium. Finally, the septum secundum grows downward, just to the right of the septum primum. Together with a flap of the septum primum, the ostium secundum forms the foramen ovale , through which fetal blood passes from the inferior vena cava to the left atrium (see Chapter 448 ). Septation of the ventricles begins at about embryonic day 25 with protrusions of endocardium in both the inlet (primitive ventricle) and outlet (bulbus cordis) segments of the heart. The inlet protrusions fuse into the bulboventricular septum and extend posteriorly toward the inferior endocardial cushion, where they give rise to the inlet and trabecular portions of the interventricular septum. Ventricular septal defects can occur in any portion of the developing interventricular septum (see Chapter 453.6 ). The outlet or conotruncal septum develops from ridges of cardiac jelly, similar to the atrioventricular cushions. These ridges fuse to form a spiral septum that brings the future pulmonary artery

into communication with the anterior and rightward right ventricle and the future aorta into communication with the posterior and leftward left ventricle. Differences in cell growth of the outlet septum lead to lengthening of the segment of smooth muscle beneath the pulmonary valve (conus), a process that separates the tricuspid and pulmonary valves. In contrast, disappearance of the segment beneath the aortic valve leads to fibrous continuity of the mitral and aortic valves. Within the lumen of distal outflow tract, local tissue swellings (truncal cushions ) arise and are later populated by mesenchymal cells originating from the neural crest, participating in the formation of the semilunar (pulmonary and aortic) valves. Defects in these processes are responsible for conotruncal and aortic arch defects (truncus arteriosus, tetralogy of Fallot, pulmonary atresia, double-outlet right ventricle, interrupted aortic arch), a group of cardiac anomalies often associated with deletions of the DiGeorge critical region of chromosome 22q11 (see Chapters 450 and 451 ). The transcription factor Tbx1 has been implicated as a candidate gene, which may be responsible for DiGeorge syndrome. Several genes have been implicated in valve formation, including PTPN11 , which encodes the tyrosine phosphatase Shp-2, and when present in a mutated form, is one of the genes responsible for Noonan syndrome , associated with pulmonary valve stenosis, and NOTCH1 , a regulator of cell differentiation associated with aortic valve disease.

447.4

Aortic Arch Development Daniel Bernstein

The aortic arch, head and neck vessels, proximal pulmonary arteries, and ductus arteriosus develop from the aortic sac, arterial arches, and dorsal aortae. When the straight heart tube develops, the distal outflow portion bifurcates into the right and left 1st aortic arches, which join the paired dorsal aortae (Fig. 447.2 ). The dorsal aortae will fuse to form the descending aorta. The proximal aorta from the aortic valve to the left carotid artery arises from the aortic sac. The 1st

and 2nd arches largely regress by about 22 days, with the 1st aortic arch giving rise to the maxillary artery and the 2nd to the stapedial and hyoid arteries. The 3rd arches participate in the formation of the innominate artery and the common and internal carotid arteries. The right 4th arch gives rise to the innominate and right subclavian arteries, and the left 4th arch participates in formation of the segment of the aortic arch between the left carotid artery and the ductus arteriosus. The 5th arch does not persist as a major structure in the mature circulation. The 6th arches join the more distal pulmonary arteries, with the right 6th arch giving rise to a portion of the proximal right pulmonary artery and the left 6th arch to the ductus arteriosus. The aortic arch between the ductus arteriosus and left subclavian artery is derived from the left-sided dorsal aorta, whereas the aortic arch distal to the left subclavian artery is derived from the fused right and left dorsal aortae. Abnormalities in development of the paired aortic arches are responsible for right aortic arch , double aortic arch , and vascular rings (see Chapter 459.1 ).

FIG. 447.2 Schematic drawings illustrating the changes that result during transformation of the truncus arteriosus, aortic sac, aortic arches, and dorsal aortae into the adult arterial pattern. The vessels that are not shaded or colored are not derived from these structures. A, Aortic arches at 6 wk; by this stage the 1st 2 pairs of aortic arches have largely disappeared. B, Aortic arches at 7 wk; the parts of the dorsal aortae and aortic arches that normally disappear are indicated by broken lines . C, Arterial vessels of 6 mo old infant. (From Moore KL, Persaud TVN, Torchia M: The developing human, Philadelphia, 2007, Elsevier.)

447.5

Cardiac Differentiation Daniel Bernstein

The process by which the totipotential cells of the early embryo become committed to specific cell lineages is termed differentiation . Precardiac mesodermal cells differentiate into mature cardiac muscle cells with an appropriate complement of cardiac-specific contractile elements, regulatory proteins, receptors, and ion channels. Expression of the contractile protein myosin occurs at an early stage of cardiac development, even before fusion of the bilateral heart primordia. Differentiation in these early mesodermal cells is regulated by signals from the anterior endoderm, a process known as induction . Several putative early signaling molecules include fibroblast growth factor, activin, and insulin. Signaling molecules interact with receptors on the cell surface; these receptors activate second messengers, which in turn activate specific nuclear transcription factors (GATA-4, MEF2, Nkx, bHLH, and retinoic acid receptor family) that induce the expression of specific gene products to regulate cardiac differentiation. Some of the primary disorders of cardiac muscle, the cardiomyopathies, may be related to defects in some of these signaling molecules (see Chapter 466 ). Developmental processes are chamber specific. Early in development, ventricular myocytes express both ventricular and atrial isoforms of several proteins, such as atrial natriuretic peptide (ANP) and myosin light chain (MLC). Mature ventricular myocytes do not express ANP and express only a ventricularspecific MLC 2v isoform, whereas mature atrial myocytes express ANP and an atrial-specific MLC 2a isoform. Heart failure (see Chapter 469 ), volume overload (Chapters 453 and 455 ), and pressure overload hypertrophy (Chapter 454 ) are associated with a recapitulation of fetal cell phenotypes in which mature myocytes reexpress fetal proteins. Because different isoforms have

different contractile behavior (fast vs slow activation, high vs low adenosine triphosphatase activity), expression of different isoforms may have important functional consequences.

447.6

Developmental Changes in Cardiac Function Daniel Bernstein

During development, the composition of the myocardium undergoes profound changes that result in an increase in the number and size of myocytes. During prenatal life, this process involves myocyte division (hyperplasia ), whereas after the 1st few postnatal weeks, subsequent cardiac growth occurs mostly by an increase in myocyte size (hypertrophy ). The myocytes themselves change shape from round to cylindrical, the proportion of myofibrils (which contain the contractile apparatus) increases, and the myofibrils become more regular in their orientation. The plasma membrane (known as the sarcolemma in myocytes) is the location of the ion channels and transmembrane receptors that regulate the exchange of chemical information from the cell surface to the cell interior. Ion fluxes through these channels control the processes of depolarization and repolarization. Developmental changes have been described for the sodium-potassium pump, the sodium-hydrogen exchanger, and voltage-dependent calcium channels. As the myocyte matures, extensions of the sarcolemma develop toward the interior of the cell (the t-tubule system), which dramatically increases its surface area and enhances rapid activation of the myocyte. Regulation of the membrane's αand β-adrenergic receptors with development enhances the ability of the sympathetic nervous system to control cardiac function as the heart matures. The sarcoplasmic reticulum (SR), a series of tubules surrounding the myofibrils, controls the intracellular calcium concentration. A series of pumps

regulate calcium release to the myofibrils for initiation of contraction (ryanodine-sensitive calcium channel) and calcium uptake for initiation of relaxation (adenosine triphosphate–dependent SR calcium pump). This SR calcium transport system is less well developed in immature hearts, which thus increasingly depend on transport of calcium from outside the cell for contraction. In a mature heart the majority of the calcium to activate contraction comes from the SR. This developmental phenomenon may explain the sensitivity of the infant heart to sarcolemmal calcium channel blockers such as verapamil, which can result in a marked depression in contractility (see Chapter 462 ). The major contractile proteins (myosin, actin, tropomyosin, and troponin) are organized into the functional unit of cardiac contraction, the sarcomere . Each has several isoforms that are expressed differentially by location (atrium vs ventricle) and by developmental stage (embryo, fetus, newborn, adult). Changes in myocardial structure and myocyte biochemistry result in easily quantifiable differences in cardiac function with development. Fetal cardiac function is less responsive to changes in both preload (filling volume) and afterload (systemic resistance). The most effective means of increasing ventricular function in a fetus is through increasing the heart rate. After birth and with further maturation, preload and afterload play an increasing role in regulating cardiac function. The rate of cardiac relaxation is also developmentally regulated. The decreased ability of the immature SR calcium pump to remove calcium from the contractile apparatus is manifested as a decreased ability of the fetal heart to enhance relaxation in response to sympathetic stimulation.

Bibliography Boettger T, Braun T. A new level of complexity: the role of microRNAs in cardiovascular development. Circ Res . 2012;110:1000–1013. Breckpot J, Thienpont B, Peeters H, et al. Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects. J Pediatr . 2010;156:810–817. Bruneau BG. The developmental genetics of congenital heart disease. Nature . 2008;451:943–948. Chang C-P, Bruneau BG. Epigenetics and cardiovascular

development. Annu Rev Physiol . 2012;74:41–68. Epstein JA. Cardiac development and implication for heart disease. N Engl J Med . 2010;363:1638–1646. Fahed AC, Gelb BD, Seidman JG, et al. Genetics of congenital heart disease: the glass half empty. Circ Res . 2013;112:707– 720. Ieda M, Fu J-D, Delgado-Olguin P, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell . 2010;142:375–386. Layman WS, Hurd EA, Martin DM. Chromodomain proteins in development: lessons from CHARGE syndrome. Clin Genet . 2010;78:11–20. Lin CJ, Lin CY, Chen CH, et al. Partitioning the heart: mechanisms of cardiac septation and valve development. Development . 2012;139:3277–3299. Olson EN. Gene regulatory networks in the evolution and development of the heart. Science . 2006;313:1922–1927. Paige SL, Plonowska K, Xu A, Wu SM. Molecular regulation of cardiomyocyte differentiation. Circ Res . 2015;116(2):341– 353. Peral SC, Bernstein D, Nelson TJ. Regenerative medicine: from stem cell biology to clinical trials for pediatric heart failure. Prog Pediatr Cardiol . 2017;43:87–89. Srivastava D. Genetic regulation of cardiogenesis and congenital heart disease. Annu Rev Pathol . 2006;1:199–213. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell . 2006;126:1037–1048. Van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol . 2011;58:2241–2247.

CHAPTER 448

The Fetal to Neonatal Circulatory Transition 448.1

The Fetal Circulation Daniel Bernstein

Keywords ductus venosus foramen ovale ductus arteriosus total fetal cardiac output hypoplastic left heart syndrome patent ductus arteriosus The human fetal circulation and its adjustments after birth are similar to those of other large mammals, although rates of maturation differ. In the fetal circulation, the right and left ventricles exist in a parallel circuit, as opposed to the series circuit of a newborn or adult (Fig. 448.1A ). In the fetus, the placenta provides for gas and metabolite exchange. Because the lungs do not provide gas exchange, the pulmonary vessels are vasoconstricted, diverting blood away from the pulmonary circulation. Three cardiovascular structures unique to the fetus are important for maintaining this parallel circulation: the ductus venosus,

foramen ovale, and ductus arteriosus.

FIG. 448.1 A, The human circulation before birth (partly after Dawes). Red indicates more highly oxygenated blood, and arrows indicate the direction of flow. More highly oxygenated blood from the placenta passes through the foramen ovale from the right to the left atrium, thus bypassing the lungs. B, Percentages of combined ventricular output that return to the fetal heart, that are ejected by each ventricle, and that flow through the main vascular channels. Figures are those obtained from studies of lategestation fetal lambs. Ao, Aorta; DA, ductus arteriosus; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava. (From Rudolph AM: Congenital diseases of the heart, Chicago, 1974, Year Book.)

The placenta is not as efficient an oxygen-exchange organ as the lungs, so that umbilical venous partial pressure of oxygen (PO 2 ), the highest O2 level provided to the fetus, is only 30-35 mm Hg. Approximately 50% of the umbilical venous blood enters the hepatic circulation, whereas the rest bypasses the liver and joins the inferior vena cava (IVC) via the ductus venosus, where it partially mixes with poorly oxygenated IVC blood derived from the lower part of the fetal body. This combined lower body plus umbilical venous blood flow (PO 2 of 26-28 mm

Hg) enters the right atrium and is preferentially directed by a flap of tissue at the right atrium–IVC junction, the eustachian valve, across the foramen ovale to the left atrium (see Fig. 448.1B ). This is the major source of left ventricular (LV) blood flow, because pulmonary venous return is minimal. LV blood is then ejected into the ascending aorta, where it supplies predominantly the fetal upper body and brain. Fetal superior vena cava (SVC) blood, which is considerably less oxygenated (PO 2 of 12-14 mm Hg) than IVC blood, enters the right atrium and preferentially flows across the tricuspid valve, rather than the foramen ovale, into the right ventricle. From the right ventricle, the blood is ejected into the pulmonary artery. Because the pulmonary arterial circulation is vasoconstricted, only approximately 5% of right ventricular (RV) outflow enters the lungs. The major portion of this blood bypasses the lungs and flows right-to-left through the ductus arteriosus into the descending aorta to perfuse the lower part of the fetal body, including providing flow to the placenta via the 2 umbilical arteries. Thus the upper part of the fetal body (including the coronary and cerebral arteries and those to the upper extremities) is perfused exclusively from the left ventricle with blood that has a slightly higher PO 2 than the blood perfusing the lower part of the fetal body, which is derived mostly from the right ventricle. Only a small volume of blood from the ascending aorta (10% of fetal cardiac output) flows all the way around the aortic arch (aortic isthmus) to the descending aorta. The total fetal cardiac output —the combined output of both the left and right ventricles—is approximately 450 mL/kg/min. Approximately 65% of descending aortic blood flow returns to the placenta; the remaining 35% perfuses the fetal organs and tissues. In the sheep fetus, where most of these circulatory pathways were studied, RV output is approximately twice LV output. In the human fetus, which has a larger percentage of blood flow going to the brain, RV output is probably closer to 1.3 times LV flow. Thus, during fetal life the right ventricle is not only pumping against systemic blood pressure, but also performing a slightly greater volume of work than the left ventricle. Thus the RV wall is as thick as the LV wall during fetal and immediate neonatal life, explaining the unique features of the neonatal electrocardiogram (showing what would be called right ventricular hypertrophy in an adult). Blood flow is believed to be an important determinant of growth of fetal cardiac chambers, valves, and blood vessels. Thus, in the presence of a narrowing (stenosis) of an upstream structure such as the mitral valve, flow downstream into the left ventricle is limited and LV growth may be

compromised, which may be a cause of hypoplastic left heart syndrome (HLHS; see Chapter 458.10 ). Similarly, stenosis of a downstream structure such as the aortic valve can disrupt flow into the left ventricle and also potentially lead to HLHS. Fetal cardiac interventional treatments, currently experimental, are aimed at opening stenotic aortic valves in mid-gestation fetuses and allowing more normal LV growth. However, the outcome of these procedures does not enhance LV growth in all patients, suggesting that in many cases of HLHS there is a separate defect in the LV cardiomyocytes themselves (i.e., cell-autonomous defect).

448.2

The Transitional Circulation Daniel Bernstein

At birth, mechanical expansion of the lungs and an increase in arterial PO 2 result in a rapid decrease in pulmonary vascular resistance (PVR). Concomitantly, removal of the low-resistance placental circulation leads to an increase in systemic vascular resistance (SVR). The output from the right ventricle now flows entirely into the pulmonary circulation, and because PVR becomes lower than SVR, the shunt through the ductus arteriosus reverses and becomes left to right. Over several days the high arterial PO 2 constricts and eventually closes the ductus arteriosus, which eventually becomes the ligamentum arteriosum. The increased volume of pulmonary blood flow returning to the left atrium from the lungs increases left atrial volume and pressure sufficiently to close the flap of the foramen ovale functionally, although the foramen may remain patent, on probing, for several years. Removal of the placenta from the circulation also results in closure of the ductus venosus. The left ventricle is now coupled to the high-resistance systemic circulation, and its wall thickness and mass begin to increase. In contrast, the right ventricle is now coupled to the low-resistance pulmonary circulation, and

its wall thickness and mass decrease. The left ventricle, which in the fetus pumped blood only to the upper part of the body and brain, must now deliver the entire systemic cardiac output (approximately 350 mL/kg/min), an almost 200% increase in output. This marked increase in LV performance is achieved through a combination of hormonal and metabolic signals, including an increase in the level of circulating catecholamines and in the density of myocardial β-adrenergic receptors, through which catecholamines have their effect. When superimposed on these dramatic physiologic changes, congenital structural cardiac defects often impede this smooth transition and greatly increase the burden on the newborn myocardium. In addition, because the ductus arteriosus and foramen ovale do not close completely at birth, they may remain patent in certain congenital cardiac lesions. Patency of these fetal pathways may either provide a lifesaving pathway for blood to bypass a congenital defect (patent ductus in pulmonary atresia or coarctation of aorta , foramen ovale in transposition of great vessels ) or present an additional stress to the circulation (patent ductus arteriosus in premature infant, pathway for right-to-left shunting in infant with pulmonary hypertension). Therapeutic agents may either maintain these fetal pathways (e.g., prostaglandin E1 ) or hasten their closure (e.g., indomethacin ). This pharmacology explains why indomethacin and similar drugs are contraindicated during the third trimester.

448.3

The Neonatal Circulation Daniel Bernstein

At birth, the fetal circulation must immediately adapt to extrauterine life as gas exchange is transferred from the placenta to the lungs (see Chapter 122.1 ). Some of these changes are virtually instantaneous with the first breath, whereas others develop over hours or weeks. With the onset of breathing and lung ventilation, pulmonary vascular resistance is greatly decreased as a consequence

of both active (i.e., PO 2 related) and passive (i.e., mechanical related) pulmonary vasodilation. In a normal neonate, closure of the ductus arteriosus and the fall in PVR decreases pulmonary arterial and RV pressures. The largest decline in PVR from the high fetal levels to the lower “adult” levels in the human infant at sea level usually occurs within 2-3 days, but may be prolonged for ≥7 days after birth. Over the next several weeks of life, PVR decreases even further, secondary to a remodeling of the pulmonary vasculature, including thinning of the vascular smooth muscle and recruitment of new vessels. This decrease in PVR significantly influences the timing of the clinical appearance of many congenital heart lesions dependent on the relative levels of SVR and PVR. The left-to-right shunt through a large ventricular septal defect (VSD) may be minimal in the 1st week after birth, when PVR is still high. As PVR decreases in the next 1 or 2 wk, the volume of the left-to-right shunt through the VSD increases and eventually leads to symptoms of heart failure within the 1st or 2nd mo of postnatal life. Significant differences between the neonatal circulation and that of older infants: (1) right-to-left or left-to-right shunting may persist across the patent foramen ovale; (2) in the presence of cardiopulmonary disease, continued patency of the ductus arteriosus may allow left-to-right, right-to-left, or bidirectional shunting; (3) the neonatal pulmonary vasculature constricts more vigorously in response to hypoxemia, hypercapnia, and acidosis; (4) the wall thickness and muscle mass of the neonatal left and right ventricles are almost equal; and (5) newborn infants at rest have relatively high oxygen consumption, which is associated with relatively high cardiac output. The newborn cardiac output (350 mL/kg/min) falls in the 1st 2 mo of life to approximately 150 mL/kg/min and then more gradually to the normal adult cardiac output of 75 mL/kg/min. Although fetal hemoglobin is beneficial to delivery of oxygen in the low-PO 2 fetal circulation, the high percentage of fetal hemoglobin present in the newborn may actually interfere with delivery of oxygen to tissues in the high– systemic PO 2 neonatal circulation (see Chapter 122.1 ). The foramen ovale is usually functionally closed by the 3rd mo of life, although it is possible to pass a probe through the overlapping flaps in a large percentage of children and in 15–25% of adults. Functional closure of the ductus arteriosus is usually complete by 10-15 hr of postnatal age in a normal neonate, although the ductus may remain patent much longer in the presence of congenital heart disease, especially when associated with cyanosis. In premature newborn infants, an evanescent systolic murmur with late accentuation or a

continuous murmur may be audible, and in the context of respiratory distress syndrome, the presence of a patent ductus arteriosus should be suspected (see Chapter 122.5 ). The normal ductus arteriosus differs morphologically from the adjoining aorta and pulmonary artery in that the ductus has a significant amount of circularly arranged smooth muscle in its medial layer. During fetal life, patency of the ductus arteriosus appears to be maintained by the combined relaxant effects of low oxygen tension and endogenously produced prostaglandins, specifically prostaglandin E2 . In a full-term neonate, oxygen is the most important factor controlling ductal closure. When the PO 2 of the blood passing through the ductus reaches about 50 mm Hg, the ductal wall begins to constrict. The effects of oxygen on ductal smooth muscle may be direct or mediated by its effects on prostaglandin synthesis. Gestational age also appears to play an important role; the ductus of a premature infant is less responsive to oxygen, even though its musculature is developed.

448.4

Persistent Pulmonary Hypertension of the Neonate (Persistence of Fetal Circulatory Pathways) See Chapter 122.9 .

Bibliography Barker DJ. The origins of the developmental origins theory. J Intern Med . 2007;261:412–417. Donofrio MT, Levy RJ, Schuette JJ, et al. Specialized delivery room planning for fetuses with critical congenital heart disease. Am J Cardiol . 2013;111:737–747.

Freud LR, McElhinney DB, Marshall AC, et al. Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients. Circulation . 2014;130(8):638–645. Friedberg MK, Silverman NH, Moon-Grady AJ, et al. Prenatal detection of congenital heart disease. J Pediatr . 2009;155(1):26–31. Gluckman PD, Hanson MA, Pinal C. The developmental origins of adult disease. Matern Child Nutr . 2005;1:130–141. Ionescu-Ittu R, Marelli AJ, Mackie AS, et al. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. BMJ . 2009;338:b1673. Ozanne SE, Fernandez-Twinn D, Hales CN. Fetal growth and adult diseases. Semin Perinatol . 2004;28:81–87. Ravi P, Mills L, Fruitman D, et al. Population trends in prenatal detection of transposition of great arteries: impact of obstetrical screening ultrasound guidelines. Ultrasound Obstet Gynecol . 2018;51:659–664. Rudolph AM. Aortopulmonary transposition in the fetus: speculation on pathophysiology and therapy. Pediatr Res . 2007;61:375–380. Rudolph AM. Congenital diseases of the heart: clinicalphysiological considerations . ed 3. Wiley-Blackwell: New York; 2009. Szwast A, Rychik J. Prenatal diagnosis of hypoplastic left heart syndrome: can we optimize outcomes? J Am Soc Echocardiogr . 2013;26(9):1080–1083. Trines J, Hornberger LK. Evolution of heart disease in utero. Pediatr Cardiol . 2004;25:287–298.

SECTION 2

Evaluation of the Cardiovascular System and the Child with A Heart Murmur OUTLINE Chapter 449 History and Physical Examination in Cardiac Evaluation Chapter 450 Laboratory Cardiac Evaluation

CHAPTER 449

History and Physical Examination in Cardiac Evaluation Daniel Bernstein

The importance of the history and physical examination cannot be overemphasized in the evaluation of infants and children with suspected cardiovascular disorders. One of the most common reasons for cardiac evaluation in young children is the heart murmur; innocent or functional murmurs may be heard in up to 30% of patients at some time during childhood. Functional murmurs are usually accentuated by fever and first noticed during a visit for an intercurrent illness. Thus the general pediatrician must be able to distinguish those murmurs that are functional from those that are potentially pathologic and refer patients with pathologic-sounding murmurs or murmurs of uncertain nature for evaluation by a pediatric cardiologist. Although several attempts have been made to develop computerized systems for distinguishing innocent from pathologic murmurs, the accuracy of these systems is still wanting, and there is no substitute for a careful examination by the clinician. Patients may require further laboratory evaluation and eventual treatment, or the family may be reassured that no significant problem exists. Although the ready availability of echocardiography may entice the clinician to skip these preliminary steps, an initial evaluation by a skilled cardiologist is preferred for several reasons: (1) a cardiac examination allows the cardiologist to guide the echocardiographic evaluation toward confirming or eliminating specific diagnoses, thereby increasing its accuracy; (2) because most childhood murmurs are innocent, evaluation by a pediatric cardiologist can eliminate unnecessary and expensive laboratory tests; and (3) the cardiologist's knowledge and experience are important in reassuring the patient's family and preventing unnecessary restrictions on healthy physical activity. An experienced pediatric cardiologist can differentiate an innocent murmur from serious congenital heart

disease by history and physical examination alone with high sensitivity and specificity.

History The evaluation begins with a comprehensive cardiac history, as diagnosis of a functional murmur can only be made in the absence of any concerning symptoms, signs, or family history. A comprehensive cardiac history starts with details of the perinatal period, including the presence of cyanosis, respiratory distress, or prematurity. Maternal complications such as gestational diabetes, teratogenic medications, systemic lupus erythematosus, or substance abuse can be associated with cardiac problems. If cardiac symptoms began during infancy, the timing of the initial symptoms should be noted to provide important clues about the specific cardiac condition. Many of the symptoms of heart failure in infants and children are age specific. In infants, feeding difficulties are common. Inquiry should be made about the frequency of feeding and either the volume of each feeding or the time spent on each breast. An infant with heart failure often takes less volume per feeding and becomes dyspneic or diaphoretic while sucking. After falling asleep exhausted, the baby, inadequately fed, will awaken for the next feeding after a brief time. This cycle continues around the clock and must be carefully differentiated from colic or other feeding disorders. Additional symptoms and signs include those of respiratory distress: rapid breathing, nasal flaring, cyanosis, and chest retractions. In older children, heart failure may be manifested as exercise intolerance, difficulty keeping up with peers during sports or the need for a nap after coming home from school, poor growth, or chronic abdominal complaints. Eliciting a history of fatigue in an older child requires questions about age-specific activities, including stair climbing, walking, bicycle riding, physical education class, and competitive sports; information should be obtained regarding more severe manifestations such as orthopnea and nocturnal dyspnea. Parents often overlook their baby's cyanosis at rest; it may be mistaken for a normal individual variation in color. Cyanosis during crying or exercise, however, is more often noted as abnormal by observant parents. Many infants and toddlers turn “blue around the lips” when crying vigorously or during breath-holding spells; this condition must be carefully differentiated from cyanotic heart disease by inquiring about inciting factors, the length of episodes, and whether the tongue and mucous membranes also appear cyanotic.

Newborns often have cyanosis of their extremities (acrocyanosis ) when undressed and cold; this response to cold must be carefully differentiated from true cyanosis, where the mucous membranes are also blue. Chest pain is an unusual manifestation of cardiac disease in pediatric patients, although it is a frequent cause for referral to a pediatric cardiologist, especially in adolescents. Nonetheless, a careful history, physical examination, and, if indicated, laboratory or imaging tests will assist in identifying the cause of chest pain (Table 449.1 ). For patients with some forms of repaired congenital heart disease (CHD) or those with a history of Kawasaki disease (see Chapter 471.1 ), chest pain should be evaluated carefully for a coronary etiology.

Table 449.1

Differential Diagnosis of Chest Pain in Pediatric Patients Musculoskeletal (Common) Trauma (accidental, abuse) Exercise, overuse injury (strain, bursitis) Costochondritis (Tietze syndrome) Herpes zoster (cutaneous or without rash) Pleurodynia Fibrositis Slipping rib Rib fracture Precordial catch Sickle cell anemia vasoocclusive crisis Osteomyelitis (rare) Primary or metastatic tumor (rare) Fibromyalgia Nerve entrapment

Pulmonary (Common) Pneumonia Pleurisy

Asthma Chronic cough Pneumothorax Infarction (sickle cell anemia) Foreign body Embolism (rare) Pulmonary hypertension (rare) Tumor (rare) Bronchiectasis

Gastrointestinal (Less Common) Esophagitis (gastroesophageal reflux, infectious, pill) Esophageal foreign body Esophageal spasm Cholecystitis Subdiaphragmatic abscess Perihepatitis (Fitz-Hugh-Curtis syndrome) Peptic ulcer disease Pancreatitis Splenic rupture

Cardiac (Less Common) Pericarditis Postpericardiotomy syndrome Endocarditis Myocarditis Cardiomyopathy Mitral valve prolapse Aortic or subaortic stenosis Arrhythmias (supraventricular, ventricular, tachycardias) Marfan syndrome (dissecting aortic aneurysm) Kawasaki disease Cocaine, sympathomimetic ingestion Ischemia (familial hypercholesterolemia, anomalous coronary artery)

Takotsubo cardiomyopathy (primary or secondary)

Idiopathic (Common) Anxiety, hyperventilation Panic disorder

Other (Less Common) Spinal cord or nerve root compression Breast-related pathologic condition (mastalgia) Castleman disease (lymph node neoplasm) Cardiac disease may be a manifestation of a known congenital malformation syndrome with typical physical findings (Table 449.2 ) or a manifestation of a generalized disorder affecting the heart and other organ systems (Table 449.3 ). Extracardiac malformations may be noted in 20–45% of infants with CHD. Between 5% and 10% of patients have a known chromosomal abnormality; the importance of genetic evaluation will increase as our knowledge of specific gene defects linked to CHD increases (Fig. 449.1 ). Table 449.2

Congenital Malformation Syndromes Associated With Congenital Heart Disease SYNDROME CHROMOSOMAL DISORDERS Trisomy 21 (Down syndrome) Trisomy 21p (cat-eye syndrome) Trisomy 18 Trisomy 13 Trisomy 9 XXXXY Penta X Triploidy XO (Turner syndrome) Fragile X Duplication 3q2

FEATURES Endocardial cushion defect, VSD, ASD Miscellaneous, total anomalous pulmonary venous return VSD, ASD, PDA, TOF, coarctation of aorta, bicuspid aortic or pulmonary valve VSD, ASD, PDA, coarctation of aorta, bicuspid aortic or pulmonary valve Miscellaneous, VSD PDA, ASD PDA, VSD VSD, ASD, PDA Bicuspid aortic valve, coarctation of aorta Mitral valve prolapse, aortic root dilatation Miscellaneous

Deletion 4p Deletion 9p Deletion 5p (cri du chat syndrome) Deletion 10q Deletion 13q Deletion 18q Deletion 1p36 Deletion/duplication 1q21.1 Deletion 17q11 (William syndrome) Deletion 11q 24-25 (Jacobsen syndrome) SYNDROME COMPLEXES CHARGE association (c oloboma, h eart, a tresia choanae, r etardation, g enital, and e ar anomalies) DiGeorge sequence, CATCH 22 (c ardiac defects, a bnormal facies, t hymic aplasia, c left palate, h ypocalcemia, and deletion 22q11) Alagille syndrome (arteriohepatic dysplasia) VATER association (v ertebral, a nal, t racheoe sophageal, r adial, and r enal anomalies) FAVS (f acioa uriculov ertebral s pectrum) CHILD (c ongenital h emidysplasia with i chthyosiform erythroderma, l imb d efects) Mulibrey nanism (muscle, liver, brain, eye) Asplenia syndrome

Polysplenia syndrome

PHACE syndrome (p osterior brain fossa anomalies, facial h emangiomas, a rterial anomalies, c ardiac anomalies and aortic coarctation, e ye anomalies) TERATOGENIC AGENTS Congenital rubella Fetal hydantoin syndrome Fetal alcohol syndrome Fetal valproate effects Maternal phenylketonuria Retinoic acid embryopathy OTHERS Apert syndrome Autosomal dominant polycystic kidney disease Carpenter syndrome Conradi syndrome Crouzon disease Cutis laxa De Lange syndrome Ellis–van Creveld syndrome

VSD, PDA, aortic stenosis Miscellaneous VSD, PDA, ASD, TOF VSD, TOF, conotruncal lesions* VSD VSD ASD, VSD, PDA, TOF, cardiomyopathy ASD, VSD, PS Supravalvar AS, branch PS VSD, left sided lesions VSD, ASD, PDA, TOF, endocardial cushion defect

Aortic arch anomalies, conotruncal anomalies

Peripheral pulmonic stenosis, PS, TOF VSD, TOF, ASD, PDA TOF, VSD Miscellaneous Pericardial thickening, constrictive pericarditis Complex cyanotic heart lesions with decreased pulmonary blood flow, transposition of great arteries, anomalous pulmonary venous return, dextrocardia, single ventricle, single atrioventricular valve Acyanotic lesions with increased pulmonary blood flow, azygos continuation of inferior vena cava, partial anomalous pulmonary venous return, dextrocardia, single ventricle, common atrioventricular valve VSD, PDA, coarctation of aorta, arterial aneurysms

PDA, peripheral pulmonic stenosis VSD, ASD, coarctation of aorta, PDA ASD, VSD Coarctation of aorta, hypoplastic left side of heart, aortic stenosis, pulmonary atresia, VSD VSD, ASD, PDA, coarctation of aorta Conotruncal anomalies VSD Mitral valve prolapse PDA VSD, PDA PDA, coarctation of aorta Pulmonary hypertension, pulmonic stenosis VSD Single atrium, VSD

Holt-Oram syndrome Infant of diabetic mother Kartagener syndrome Meckel-Gruber syndrome Noonan syndrome Pallister-Hall syndrome Primary ciliary dyskinesia Rubinstein-Taybi syndrome Scimitar syndrome Smith-Lemli-Opitz syndrome TAR syndrome (thrombocytopenia and absent radius) Treacher Collins syndrome

ASD, VSD, 1st-degree heart block Hypertrophic cardiomyopathy, VSD, conotruncal anomalies Dextrocardia ASD, VSD Pulmonic stenosis, ASD, cardiomyopathy Endocardial cushion defect Heterotaxia disorders VSD Hypoplasia of right lung, anomalous pulmonary venous return to inferior vena cava VSD, PDA ASD, TOF VSD, ASD, PDA

* Conotruncal includes TOF, pulmonary atresia, truncus arteriosus, and transposition of great

arteries. ASD, Atrial septal defect; AV, aortic valve; PDA, patent ductus arteriosus; PS, pulmonary stenosis; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Table 449.3

Cardiac Manifestations of Systemic Diseases SYSTEMIC DISEASE CARDIAC COMPLICATIONS INFLAMMATORY DISORDERS Sepsis Hypotension, myocardial dysfunction, pericardial effusion, pulmonary hypertension Juvenile idiopathic arthritis Pericarditis, rarely myocarditis Systemic lupus erythematosus Pericarditis, Libman-Sacks endocarditis, coronary arteritis, coronary atherosclerosis (with steroids), congenital heart block Scleroderma Pulmonary hypertension, myocardial fibrosis, cardiomyopathy Dermatomyositis Cardiomyopathy, arrhythmias, heart block Kawasaki disease Coronary artery aneurysm and thrombosis, myocardial infarction, myocarditis, valvular insufficiency Sarcoidosis Granuloma, fibrosis, amyloidosis, biventricular hypertrophy, arrhythmias Lyme disease Arrhythmias, myocarditis Löffler hypereosinophilic syndrome Endomyocardial disease INBORN ERRORS OF METABOLISM Refsum disease Arrhythmia, sudden death Hunter or Hurler syndrome Valvular insufficiency, heart failure, hypertension Fabry disease Mitral insufficiency, coronary artery disease with myocardial infarction Glycogen storage disease IIa Short P-R interval, cardiomegaly, heart failure, arrhythmias (Pompe disease) Carnitine deficiency Heart failure, cardiomyopathy Gaucher disease Pericarditis Homocystinuria Coronary thrombosis Alkaptonuria Atherosclerosis, valvular disease Morquio-Ullrich syndrome Aortic incompetence Scheie syndrome Aortic incompetence

CONNECTIVE TISSUE DISORDERS Arterial calcification of infancy Calcinosis of coronary arteries, aorta, heart failure, hypertension Marfan syndrome Aortic and mitral insufficiency, dissecting aortic aneurysm, mitral valve prolapse Congenital contractural Mitral insufficiency or prolapse arachnodactyly Ehlers-Danlos syndrome Mitral valve prolapse, dilatated aortic root Osteogenesis imperfecta Aortic incompetence Pseudoxanthoma elasticum Peripheral arterial disease NEUROMUSCULAR DISORDERS Friedreich ataxia Cardiomyopathy Duchenne dystrophy Cardiomyopathy, heart failure Tuberous sclerosis Cardiac rhabdomyoma Familial deafness Occasionally arrhythmia, sudden death Neurofibromatosis Pulmonic stenosis, pheochromocytoma, coarctation of aorta Riley-Day syndrome Episodic hypertension, postural hypotension Von Hippel–Lindau disease Hemangiomas, pheochromocytomas ENDOCRINE-METABOLIC DISORDERS Graves' disease Tachycardia, arrhythmias, heart failure Hypothyroidism Bradycardia, pericardial effusion, cardiomyopathy, low-voltage electrocardiogram Pheochromocytoma Hypertension, myocardial ischemia, myocardial fibrosis, cardiomyopathy Carcinoid Right-sided endocardial fibrosis HEMATOLOGIC DISORDERS Sickle cell anemia High-output heart failure, cardiomyopathy, pulmonary hypertension Thalassemia major High-output heart failure, hemochromatosis Hemochromatosis (1st or 2nd Cardiomyopathy degree) OTHERS Appetite suppressants (fenfluramine Cardiac valvulopathy, pulmonary hypertension and dexfenfluramine) Cockayne syndrome Atherosclerosis Familial dwarfism and nevi Cardiomyopathy Jervell and Lange-Nielsen Prolonged Q-T interval, sudden death syndrome Kearns-Sayre syndrome Heart block LEOPARD syndrome (lentiginosis) Pulmonic stenosis, prolonged Q-T interval Progeria Accelerated atherosclerosis Osler-Weber-Rendu disease Arteriovenous fistula (lung, liver, mucous membrane) Romano-Ward syndrome Prolonged Q-T interval, sudden death Weill-Marchesani syndrome Patent ductus arteriosus Werner syndrome Vascular sclerosis, cardiomyopathy

LEOPARD, Multiple l entigines, e lectrocardiographic conduction abnormalities, o cular hypertelorism, p ulmonary stenosis, a bnormal genitals, r etardation of growth, sensorineural d eafness.

FIG. 449.1 Genetics screening algorithm for congenital heart disease (CHD) patients. FISH, Fluorescence in situ hybridization; WES, whole exome sequencing. (From Simmons MA, Brueckner M: The genetics of congenital heart disease… understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician, Curr Opin Pediatr 29:520–528, 2017, Fig 2, p 526.)

A careful family history may also reveal early (at age 200 beats/min in neonates, 150 beats/min in infants, or 120 beats/min in older children), bradycardia, or an irregular heartbeat other than sinus arrhythmia requires investigation to exclude pathologic arrhythmias (see Chapter 462 ). Sinus arrhythmia can usually be distinguished by the rhythmic nature of the heart rate variations, occurring in concert with the respiratory cycle, and with a P wave before every QRS complex. Table 449.4

Pulse Rates at Rest

LOWER LIMITS OF NORMAL (beats/min) Newborn 70 1–11 mo 80 2 yr 80 4 yr 80 6 yr 75 8 yr 70 10 yr 70 GIRLS BOYS 12 yr 70 65 14 yr 65 60 16 yr 60 55 18 yr 55 50 AGE

AVERAGE (beats/min) 125 120 110 100 100 90 90 GIRLS BOYS 90 85 85 80 80 75 75 70

UPPER LIMITS OF NORMAL (beats/min) 190 160 130 120 115 110 110 GIRLS BOYS 110 105 105 100 100 95 95 90

Careful evaluation of the character of the pulses is an important early step in the physical diagnosis of CHD. A wide pulse pressure with bounding pulses may suggest an aortic runoff lesion such as patent ductus arteriosus (PDA), aortic insufficiency, an arteriovenous communication, or increased cardiac output secondary to anemia, anxiety, or conditions associated with increased catecholamine or thyroid hormone secretion. The presence of diminished pulses in all extremities is associated with pericardial tamponade, left ventricular outflow obstruction, or cardiomyopathy. The radial and femoral pulses should always be palpated simultaneously. Normally, the femoral pulse should be appreciated immediately before the radial pulse. In infants with coarctation of the aorta, the femoral pulses may be decreased. However, in older children with coarctation of the aorta, blood flow to the descending aorta may channel through collateral vessels and results in the femoral pulse being palpable but delayed until after the radial pulse (radial-femoral delay). Blood pressure (BP) should be measured in the legs as well as in the arms to be certain that coarctation of the aorta is not overlooked. Palpation of the femoral or dorsalis pedis pulse, or both, is not reliable alone to exclude coarctation. In older children, a mercury sphygmomanometer with a cuff that covers approximately two thirds of the upper part of the arm or leg may be used for BP measurement. A cuff that is too small results in falsely high readings, whereas a cuff that is too large records slightly decreased BP. Pediatric clinical facilities should be equipped with 3, 5, 7, 12, and 18 cm cuffs to accommodate the large spectrum of pediatric patient sizes. The first Korotkoff sounds indicate systolic pressure. As cuff pressure is slowly decreased, the sounds usually become muffled before they disappear. Diastolic pressure may be recorded when the sounds become muffled (preferred) or when they disappear altogether; the

former is usually slightly higher and the latter slightly lower than true diastolic pressure. For lower-extremity BP determination, the stethoscope is placed over the popliteal artery. Typically, the BP recorded in the legs with the cuff technique is approximately 10 mm Hg higher than that in the arms. In infants, BP can be determined by auscultation, palpation, or an oscillometric (Dinamap) device that, when properly used, provides accurate measurements in infants as well as older children. Blood pressure varies with the age of the child and is closely related to height and weight. Significant increases occur during adolescence, and many temporary variations take place before the more stable levels of adult life are attained. Exercise, excitement, coughing, crying, and struggling may raise the systolic BP of infants and children as much as 40-50 mm Hg greater than their usual levels. Variability in BP in children of approximately the same age and body build should be expected, and serial measurements should always be obtained when evaluating a patient with hypertension (Figs. 449.2 and 449.3 ).

FIG. 449.2 Age-specific percentiles of blood pressure (BP) measurements: birth to 13 yr. A, Boys from birth to 12 mo of age. B, Girls from birth to 12 mo of age. C, Boys 1-13 yr of age. D, Girls 1-13 yr of age. Korotkoff phase IV (K4) used for diastolic BP. Dias, Diastolic; Ht, height; Perc, percentile; Sys, systolic; Wt, weight. (From Report of the Second Task Force on Blood Pressure Control in Children—1987. National Heart, Lung, and Blood Institute, Bethesda, MD, Pediatrics 79:1–25, 1987. Copyright 1987 by the

American Academy of Pediatrics.)

FIG. 449.3 Age-specific percentiles of blood pressure (BP) measurements: age 13-18 yr. A, Boys 13-18 yr of age. B, Girls 13-18 yr of age. Korotkoff phase V (K5) used for diastolic BP. Dias, Diastolic; Ht, height; Perc, percentile; Sys, systolic; Wt, weight. (From Report of the Second Task Force on Blood Pressure Control in Children—1987, National Heart, Lung, and Blood Institute, Bethesda, MD, Pediatrics 79:1–25, 1987. Copyright 1987 by the American Academy of Pediatrics.)

Although of little use in infants, in cooperative older children, inspection of the jugular venous pulse wave provides information about central venous and right atrial pressure. The neck veins should be inspected with the patient sitting at a 90-degree angle. The external jugular vein should not be visible above the clavicles unless central venous pressure is elevated. Increased venous pressure transmitted to the internal jugular vein may appear as venous pulsations without visible distention; such pulsation is not seen in normal children reclining at an angle of 45 degrees. Because the great veins are in direct communication with the right atrium, changes in pressure and the volume of this chamber are also transmitted to the veins. The one exception occurs in superior vena cava obstruction, in which venous pulsatility is lost.

Cardiac Examination The heart should be examined in a systematic manner, starting with inspection and palpation. Any abnormalities on inspection and/or palpation strongly suggest a pathologic rather than a functional etiology of any heart murmur. A precordial bulge to the left of the sternum with increased precordial activity suggests cardiac enlargement; such bulges can often best be appreciated by having the child lay supine with the examiner looking up from the child's feet. A substernal thrust indicates the presence of right ventricular enlargement, whereas an apical heave is noted with left ventricular enlargement. A hyperdynamic precordium suggests a volume load such as that found with a large left-to-right shunt, although it may be normal in a thin patient. An overly silent precordium with a barely detectable apical impulse suggests pericardial effusion or severe cardiomyopathy, but may be normal in an obese patient. The relationship of the apical impulse to the midclavicular line is also helpful in the estimation of cardiac size: the apical impulse moves laterally and inferiorly with enlargement of the left ventricle. Right-sided apical impulses signify dextrocardia, tension pneumothorax, or left-sided thoracic spaceoccupying lesions (e.g., diaphragmatic hernia). Thrills are the palpable equivalent of murmurs and correlate with the area of maximal auscultatory intensity of the murmur. It is important to palpate the suprasternal notch and neck for aortic bruits, which may indicate the presence of aortic stenosis or, when faint, pulmonary stenosis. Right lower sternal border and apical systolic thrills are characteristic of ventricular septal defect (VSD) and mitral insufficiency, respectively. Diastolic thrills are occasionally palpable in the presence of atrioventricular valve stenosis. The timing and localization of thrills should be carefully noted. Auscultation is an art that improves with practice. The diaphragm of the stethoscope is placed firmly on the chest for high-pitched sounds; a lightly placed bell is optimal for low-pitched sounds. The physician should initially concentrate on the characteristics of the individual heart sounds and their variation with respirations and later concentrate on murmurs. In some congenital heart diseases, such as atrial septal defect (ASD), the murmur is very nonspecific and sounds identical to many functional murmurs, and it is the abnormality of the second heart sound that points to a pathologic condition. The patient should be supine, lying quietly, and breathing normally. The first heart sound (S1 ) is best heard at the apex, whereas the second heart sound (S2 ) should be

evaluated at the upper left and right sternal borders. S1 is caused by closure of the atrioventricular valves (mitral and tricuspid). S2 is caused by closure of the semilunar valves (aortic and pulmonary) (Fig. 449.4 ). During inspiration, the decrease in intrathoracic pressure results in increased filling of the right side of the heart, which leads to an increased right ventricular ejection time and thus delayed closure of the pulmonary valve; consequently, splitting of the second heart sound increases during inspiration and decreases during expiration.

FIG. 449.4 Idealized diagram of the temporal events of a cardiac cycle.

Often, S2 seems to be single during expiration. The presence of a normally split S2 is strong evidence against the diagnosis of ASD, defects associated with pulmonary arterial hypertension, severe pulmonary valve stenosis, aortic and pulmonary atresia, and truncus arteriosus. Wide S2 splitting is noted in ASD, pulmonary stenosis, Ebstein anomaly, total anomalous pulmonary venous return, and right bundle branch block. An accentuated pulmonic component of S2 with narrow splitting is a sign of pulmonary hypertension. A single S2 occurs in pulmonary or aortic atresia or severe stenosis, truncus arteriosus, and, often, transposition of the great arteries. A third heart sound (S3 ) is best heard with the bell at the apex in middiastole. A fourth heart sound (S4 ) occurring in conjunction with atrial contraction may be heard just before the S1 in late diastole. S3 may be normal in an adolescent with a relatively slow heart rate, but in a patient with the clinical signs of heart failure and tachycardia, S3 may be heard as a gallop rhythm and may merge with an S4 , a finding known as a summation gallop . A gallop rhythm is attributed to poor compliance of the ventricle, and exaggeration of the normal S3 is associated with ventricular filling. Ejection clicks , which are heard in early systole, are usually caused by a mildly to moderately stenotic aortic or pulmonary valve or to a dilated ascending aorta or pulmonary artery. They are heard so close to S1 that they may be mistaken for a split S1 . Aortic ejection clicks are best heard at the left middle to right upper sternal border and are constant in intensity. They occur in conditions where the aortic valve is stenotic or the aorta is dilated (e.g., tetralogy of Fallot, truncus arteriosus). Pulmonary ejection clicks, which are associated with mild to moderate pulmonary stenosis, are best heard at the left middle to upper sternal border and vary with respirations, often disappearing with inspiration. Split first heart sounds are usually heard best at the lower left sternal border. A midsystolic click heard at the apex, often preceding a late systolic murmur, suggests mitral valve prolapse. Murmurs should be described according to their intensity, pitch, timing (systolic or diastolic), variation in intensity, time to peak intensity, area of maximal intensity, and radiation to other areas. Auscultation for murmurs should be carried out across the upper precordium, down the left or right sternal border, and out to the apex and left axilla. Auscultation should also always be performed

in the right axilla and over both sides of the back. Systolic murmurs are classified as ejection, pansystolic, or late systolic according to the timing of the murmur in relation to S1 and S2 . The intensity of systolic murmurs is graded from I to VI: I , barely audible; II , medium intensity; III , loud but no thrill; IV , loud with a thrill; V , very loud but still requiring positioning of the stethoscope at least partly on the chest; and VI , so loud that the murmur can be heard with the stethoscope off the chest. In patients who have undergone prior heart surgery, a murmur of grade IV or greater may be heard in the absence of a thrill. Systolic ejection murmurs start a short time after a well-heard S1 , increase in intensity, peak, and then decrease in intensity; they usually end before S2 . In patients with severe pulmonary stenosis, however, the murmur may extend beyond the first component of S2 , thus obscuring it. Pansystolic or holosystolic murmurs begin almost simultaneously with S1 and continue throughout systole, on occasion becoming gradually decrescendo. It is helpful to remember that after closure of the atrioventricular valves (S1 ), a brief period occurs during which ventricular pressure increases but the semilunar valves remain closed (isovolumic contraction; see Fig. 449.3 ). Thus, pansystolic murmurs (heard during both isovolumic contraction and the ejection phases of systole) cannot be caused by flow across the semilunar valves because these valves are closed during isovolumic contraction. Pansystolic murmurs must therefore be related to blood exiting the contracting ventricle via either an abnormal opening (VSD) or atrioventricular (mitral or tricuspid) valve insufficiency. Systolic ejection murmurs usually imply increased flow or stenosis across one of the ventricular outflow tracts (aortic or pulmonic). In infants with rapid heart rates, it is often difficult to distinguish between ejection and pansystolic murmurs. If a clear and distinct S1 can be appreciated, the murmur is most likely ejection in nature. A continuous murmur is a systolic murmur that continues or “spills” into diastole and indicates continuous flow, such as in the presence of a PDA or other aortopulmonary communication. This murmur should be differentiated from a to-and-fro murmur , where the systolic component of the murmur ends at or before S2 , and the diastolic murmur begins after semilunar valve closure (aortic or pulmonary stenosis combined with insufficiency). A late systolic murmur begins well beyond S1 and continues until the end of systole. Such murmurs may be heard after a midsystolic click in patients with mitral valve prolapse and insufficiency. Several types of diastolic murmurs (graded I-IV) can be identified. A

decrescendo diastolic murmur is a blowing murmur along the left sternal border that begins with S2 and diminishes toward mid-diastole. When highpitched, this murmur is associated with aortic valve insufficiency or pulmonary insufficiency related to pulmonary hypertension. When low-pitched, this murmur is associated with pulmonary valve insufficiency in the absence of pulmonary hypertension. A low-pitched decrescendo diastolic murmur is typically noted after surgical repair of the pulmonary outflow tract in defects such as tetralogy of Fallot or in patients with absent pulmonary valves. A rumbling mid-diastolic murmur at the left middle and lower sternal border may be caused by increased blood flow across the tricuspid valve, such as occurs with ASD or, less often, because of actual stenosis of this valve. When this murmur is heard at the apex, it is caused by increased flow across the mitral valve, such as occurs with large left-to-right shunts at the ventricular level (VSDs), at the great vessel level (PDA, aortopulmonary shunts), or with increased flow because of mitral insufficiency. When an apical diastolic rumbling murmur is longer and is accentuated at the end of diastole (presystolic), it usually indicates anatomic mitral valve stenosis. The absence of a precordial murmur does not rule out significant congenital or acquired heart disease. Congenital heart defects, some of which are ductal dependent, may not demonstrate a murmur if the ductus arteriosus closes. These lesions include pulmonary or tricuspid valve atresia and transposition of the great arteries. Murmurs may seem insignificant in patients with severe aortic stenosis, ASDs, anomalous pulmonary venous return, atrioventricular septal defects, coarctation of the aorta, or anomalous insertion of a coronary artery. Careful attention to other components of the physical examination (growth failure, cyanosis, peripheral pulses, precordial impulse, heart sounds) increases the index of suspicion of congenital heart defects in these patients. In contrast, loud murmurs may be present in the absence of structural heart disease, for example, in patients with a large noncardiac arteriovenous malformation, myocarditis, severe anemia, or hypertension. Many murmurs are not associated with significant hemodynamic abnormalities. These murmurs are referred to as functional, normal, insignificant, or innocent (the preferred term). During routine random auscultation, >30% of children may have an innocent murmur at some time in their lives; this percentage increases when auscultation is done under nonbasal circumstances (high cardiac output because of fever, infection, anxiety). The most common innocent murmur is a medium-pitched, vibratory or “musical,”

relatively short systolic ejection murmur, which is heard best along the left lower and midsternal border and has no significant radiation to the apex, base, or back. It is heard most frequently in children between 3 and 7 yr of age. The intensity of the murmur often changes with respiration and position and may be attenuated in the sitting or prone position. Innocent pulmonic murmurs are also common in children and adolescents and originate from normal turbulence during ejection into the pulmonary artery. These are higher-pitched, blowing, brief, early systolic murmurs of grades I-II in intensity and are best detected in the 2nd left parasternal space with the patient in the supine position. Features suggestive of heart disease include murmurs that are pansystolic, grade III or higher, harsh, located at the left upper sternal border, and associated with an early or midsystolic click or an abnormal S2 . A venous hum is another example of a common innocent murmur heard during childhood. Such hums are produced by turbulence of blood in the jugular venous system; they have no pathologic significance and may be heard in the neck or anterior portion of the upper part of the chest. A venous hum consists of a soft humming sound heard in both systole and diastole; it can be exaggerated or made to disappear by varying the position of the head, or it can be decreased by lightly compressing the jugular venous system in the neck. These simple maneuvers are sufficient to differentiate a venous hum from the murmurs produced by organic cardiovascular disease, particularly a PDA. The lack of significance of an innocent murmur should be discussed with the child's parents. It is important to offer complete reassurance because lingering doubts about the importance of a cardiac murmur may have profound effects on child-rearing practices, most often in the form of overprotectiveness. An underlying fear that a cardiac abnormality is present may negatively affect a child's self-image and subtly influence personality development. The physician should explain that an innocent murmur is simply a “noise” and does not indicate the presence of a significant cardiac defect. When asked, “Will it go away?” the best response is to state that because the murmur has no clinical significance, it does not matter whether it “goes away.” Parents should be warned that the intensity of the murmur might increase during febrile illnesses, a time when, typically, another physician examines the child. With growth, however, innocent murmurs are less well heard and often disappear completely. At times, additional studies may be indicated to rule out a congenital heart defect. However, “routine” electrocardiographic, chest radiographic, and echocardiographic examinations should be avoided in well children with an

innocent murmur.

Bibliography Biancaniello T. Innocent murmurs. Circulation . 2005;111:e20– e22. Blue GM, Kirk EP, Giannoulatou E, et al. Targeted nextgeneration sequencing identifies pathogenic variants in familial congenital heart disease. J Am Coll Cardiol . 2014;64(23):2458–2506. Camm CF, Sunderland N, Camm AJ. A quality assessment of cardiac auscultation material on Youtube. Clin Cardiol . 2013;36:77–81. Chang RKR, Gurvitz M, Rodriguez S. Missed diagnosis of critical congenital heart disease. Arch Pediatr Adolesc Med . 2008;162:969–974. Chizner MA. Cardiac auscultation: rediscovering the lost art. Curr Probl Cardiol . 2008;33:326–408. Danduran MJ, Sheridan DC, Frommelt PC. Chest pain: characteristics of children/adolescents. Pediatr Cardiol . 2008;29:775–781. Kang S, Doroshow R, McConnaughey J, Shekhar R. Automated identification of innocent still's murmur in children. IEEE Trans Biomed Eng . 2017;64(6):1326–1334. Kumar K, Thompson WR. Evaluation of cardiac auscultation skills in pediatric residents. Clin Pediatr (Phila) . 2013;52:66–73. Mackie AS, Jutras LC, Dancea AB, et al. Can cardiologists distinguish innocent from pathologic murmurs in neonates? J Pediatr . 2009;154:50–54. Pelech AN. The physiology of cardiac auscultation. Pediatr Clin North Am . 2004;51:1515–1535. Rosner B, Prineas RJ, Loggie MH, et al. Blood pressure

nomograms for children and adolescents, by height, sex, and age, in the United States. J Pediatr . 1993;123:871–886. Simmons MA, Brueckner M. The genetics of congenital heart disease… understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician. Curr Opin Pediatr . 2017;29:520–528. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics . 2007;119:237–246.

CHAPTER 450

Laboratory Cardiac Evaluation 450.1

Radiologic Cardiac Assessment Daniel Bernstein

Keywords cardiothoracic ratio ventricular hypertrophy bundle branch block polycythemia echocardiography TTE TEE exercise ECG E/A ratio fractional shortening cardiac balloon angioplasty catheterization transcatheter valve implantation Despite the widespread easy access to advanced imaging techniques, such as echocardiography, computed tomography (CT) scan, and magnetic resonance

imaging (MRI), the chest x-ray film (radiograph, roentgenogram) remains a highly valuable diagnostic tool and is often the first imaging study performed in a child suspected of having a cardiac defect. It can provide information about cardiac size and shape, pulmonary blood flow (vascularity), pulmonary edema, and associated lung and thoracic anomalies that may be associated with congenital syndromes (e.g., skeletal dysplasias, extra or deficient number of ribs, abnormal vertebrae, previous cardiac surgery). Combined with a careful physical examination, the chest radiograph can help the clinician to establish a diagnosis of congenital heart disease (CHD), as opposed to pulmonary disease, and to narrow the differential diagnosis to specific categories of CHD (e.g., left-to-right shunt lesions vs obstructive lesions). The most frequently used measurement of cardiac size is the maximal width of the cardiac shadow in a posteroanterior (PA) chest film taken mid-inspiration. A vertical line is drawn down the middle of the sternal shadow, and perpendicular lines are drawn from the sternal line to the extreme right and left borders of the heart; the sum of the lengths of these lines is the maximal cardiac width . The maximal chest width is obtained by drawing a horizontal line between the right and left inner borders of the rib cage at the level of the top of the right diaphragm. When the maximal cardiac width is more than half the maximal chest width (cardiothoracic ratio >50%), the heart is usually enlarged. Cardiac size should be evaluated only when the film is taken during inspiration with the patient in an upright position. A diagnosis of “cardiac enlargement” on expiratory or prone films is a common cause of unnecessary referrals and laboratory studies. The cardiothoracic ratio is a less useful index of cardiac enlargement in infants than in older children because the horizontal position of the heart may increase the ratio to >50% in the absence of true enlargement. Furthermore, the thymus may overlap not only the base of the heart but also virtually the entire mediastinum, thus obscuring the true cardiac silhouette. A lateral chest radiograph may be helpful in infants as well as in older children with pectus excavatum or other conditions that result in a narrow anteroposterior (AP) chest dimension. The heart may appear small in the lateral view and suggest that the apparent enlargement in the PA projection was caused by either the thymic image (anterior mediastinum only) or flattening of the cardiac chambers as a result of a structural chest abnormality. In the PA view the left border of the cardiac shadow consists of 3 convex shadows produced, from above downward, by the aortic knob, the main and left

pulmonary arteries, and the left ventricle (Fig. 450.1 ). In cases of moderate to marked left atrial enlargement, the atrium may project between the pulmonary artery and the left ventricle. The right ventricular outflow tract (RVOT) does not contribute to the shadows formed by the left border of the heart. The aortic knob is not as easily seen in infants and children as in adults. The side of the aortic arch (left or right) can often be inferred as being opposite the side of the midline from which the air-filled trachea is visualized. This observation is important because a right-sided aortic arch is often present in cyanotic CHD, particularly in tetralogy of Fallot. Three structures contribute to the right border of the cardiac silhouette. In the view from above, they are the superior vena cava, the ascending aorta, and the right atrium.

FIG. 450.1 Idealized diagrams showing normal position of the cardiac chambers and great blood vessels. IVC, Inferior vena cava; LA, left atrium; LPA, left pulmonary artery; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RPA, right pulmonary artery; RV, right ventricle; SVC, superior vena cava. (Adapted and redrawn from Dotter CT, Steinberg I: Angiocardiographic interpretation, Radiology 153:513, 1949.)

Enlargement of cardiac chambers or major arteries and veins results in

prominence of the areas in which these structures are normally outlined on the chest radiograph. In contrast, the electrocardiogram is a more sensitive and accurate index of ventricular hypertrophy , which is a thickening of the ventricular wall and may or may not be associated with dilation of the affected cardiac chamber. The chest radiograph is also an important tool for assessing the degree of pulmonary vascularity. Pulmonary overcirculation is usually associated with left-to-right shunt lesions, whereas pulmonary undercirculation is associated with obstruction of the RVOT. The esophagus is closely related to the great vessels, and a barium esophagogram can help delineate these structures in the initial evaluation of suspected vascular rings, although this has largely been supplanted by CT. Echocardiographic examination best defines the morphologic features of intracardiac chambers, cardiac valves, and intracardiac shunts. CT is used as an adjunct to echo to evaluate extracardiac vascular morphology. MRI is used most often to provide a more quantitative assessment of ventricular volumes, cardiac function, and shunt and regurgitant fractions than is possible with echo.

450.2

Electrocardiography Daniel Bernstein

Developmental Changes The marked changes that occur in cardiac physiology and chamber dominance during the perinatal transition (see Chapter 448 ) are reflected in the evolution of the electrocardiogram (ECG) during the neonatal period. Because vascular resistance in the pulmonary and systemic circulations is nearly equal in a term fetus, the intrauterine work of the heart results in an equal mass of both the right and left ventricles. After birth, systemic vascular resistance (SVR) rises when the placental circulation is eliminated, and pulmonary vascular resistance (PVR)

falls when the lungs expand. These changes are reflected in the ECG as the right ventricular (RV) wall begins to thin. The ECG demonstrates these anatomic and hemodynamic features principally by changes in QRS and T-wave morphologic features. Typically, pediatric ECGs include several additional leads rarely used in adults, such as V3 R and V4 R, which are mirror images of leads V3 and V4 and are important in the evaluation of right ventricular hypertrophy (RVH). On occasion, lead V1 is inappropriately positioned too far leftward to reflect RV forces accurately. This problem is present particularly in premature infants, in whom the electrocardiographic electrode gel may produce contact among all the precordial leads. An additional lead used in children is V7 , located more laterally than V6 and useful for assessing left-sided forces. During the 1st postnatal days of life, right axis deviation, large R waves, and upright T waves in the right precordial leads (V3 R or V4 R and V1 ) are the norm (Fig. 450.2 ). As PVR decreases in the 1st few days after birth, the right precordial T waves become negative. In the great majority of cases, this change occurs within the 1st 48 hr of postnatal life. Upright T waves that persist in leads V3 R, V4 R, or V1 beyond 1 wk of life are an abnormal finding indicating RVH or RV strain, even in the absence of QRS voltage criteria. The T wave in V1 should never be positive before 6 yr of age and may remain negative into adolescence or early adulthood. This finding represents one of the most important yet subtle differences between pediatric and adult ECGs and is a common source of error when adult cardiologists interpret pediatric ECGs.

FIG. 450.2 Electrocardiogram in a normal neonate 2.5 mm), narrow, and spiked P waves are indicative of right atrial enlargement and are seen in congenital pulmonary stenosis, Ebstein anomaly of the tricuspid valve, tricuspid atresia, and sometimes cor pulmonale. These abnormal waves are most obvious in leads II, V3 R, and V1 (Fig. 450.8A ). Similar waves are sometimes seen in thyrotoxicosis. Broad P waves, commonly bifid and sometimes biphasic , are indicative of left atrial enlargement (Fig. 450.8B ). They are seen in some patients with large left-to-right shunts (ventricular septal defect [VSD], patent ductus arteriosus) and with severe mitral stenosis or mitral regurgitation. Left atrial enlargement, however, is one of the most common false-positive readings generated by computerized ECG machines. Flat P waves may be encountered in patients with hyperkalemia.

FIG. 450.8 Atrial enlargement. A, Peaked narrow P waves characteristic of right atrial enlargement. B, Wide, bifid M-shaped P waves typical of left atrial enlargement.

QRS Complex Right Ventricular Hypertrophy For the most accurate assessment of ventricular hypertrophy, pediatric ECGs should include the right precordial lead V3 R or V4 R, or both. The diagnosis of RVH depends on demonstration of the following changes (see Fig. 450.6 ): (1) a qR pattern in the RV surface leads; (2) a positive T wave in leads V3 R-V4 R and V1 -V3 between ages 6 days and 6 yr; (3) a monophasic R wave in V3 R, V4 R, or V1 ; (4) an rsR′ pattern in the right precordial leads with the 2nd R wave taller than the 1st; (5) age-corrected increased voltage of the R wave in leads V3 R-V4 R or the S wave in leads V6 -V7 , or both; (6) marked right axis deviation (>120 degrees in patients beyond the newborn period); and (7) complete reversal of the normal adult precordial RS pattern. At least 2 of these changes should be present to support a diagnosis of RVH. Abnormal ventricular loading can be characterized as either systolic (as a result of RVOT obstruction, as in pulmonic stenosis) or diastolic (as a result of increased volume load, as in atrial septal defect [ASD]). These 2 types of abnormal loads result in distinct electrocardiographic patterns. The systolic overload pattern is characterized by tall, pure R waves in the right precordial leads. In older children the T waves in these leads are initially upright and later become inverted. In infants and children 65%), patients with cyanotic CHD are at risk for the development of vascular thromboses, especially of cerebral veins. Dehydration increases the risk of thrombosis, and thus adequate fluid intake must be maintained during hot

weather or intercurrent gastrointestinal illnesses. Diuretics should be used with caution in these patients and may need to be decreased if fluid intake is a concern. Polycythemic infants with concomitant iron deficiency are at even greater risk for cerebrovascular accidents, probably because of the decreased deformability of microcytic red blood cells. Iron therapy may reduce this risk somewhat, but surgical treatment of the cardiac anomaly is the best therapy. Severely cyanotic patients should have periodic determinations of hemoglobin and hematocrit. Increasing polycythemia, often associated with headache, fatigue, dyspnea, or a combination of these conditions, is one indication for palliative or corrective surgical intervention. In cyanotic patients with inoperable conditions, partial exchange transfusion may be required to treat symptomatic (most often headache or chest pain) individuals whose hematocrit has risen to the 65–70% level. This procedure is not without risk, especially in patients with an extreme elevation in PVR. Because these patients do not tolerate wide fluctuations in circulating blood volume, blood should be replaced with freshfrozen plasma or albumin.

450.4

Echocardiography Daniel Bernstein

Transthoracic echocardiography (TTE) has replaced invasive studies such as cardiac catheterization for the diagnosis of most forms of CHD. The echocardiographic examination can be used to evaluate cardiac structures in congenital heart lesions using two-dimensional (2D) and three-dimensional (3D) imaging, estimate intracardiac pressures and gradients across stenotic valves and vessels using echo-Doppler and color flow Doppler, quantitate cardiac contractile function (both systolic and diastolic), determine the direction of flow across a defect, examine the integrity of the coronary arteries, and detect the presence of vegetations from endocarditis, as well as the presence of pericardial fluid, cardiac tumors, and chamber thrombi.

Echocardiography may also be used to assist in the performance of interventional procedures, including pericardiocentesis, balloon atrial septostomy (see Chapter 458.2 ), ASD or VSD closure, transcatheter valve implantation, and endocardial biopsy. Transesophageal echocardiography (TEE) is used routinely to monitor ventricular function in patients during surgical procedures and can provide an immediate assessment of the results of surgical repair of congenital heart lesions. A complete TTE examination usually entails a combination of M-mode and 2D and 3D imaging, as well as pulsed, continuous, and color Doppler flow studies. Doppler tissue imaging provides a more quantitative assessment of ventricular systolic and diastolic function.

M-Mode Echocardiography M-mode echocardiography displays a one-dimensional slice of cardiac structure varying over time (Fig. 450.14 ). It is used mostly for the measurement of cardiac dimensions (wall thickness and chamber size) and cardiac function (fractional shortening, wall thickening). M-mode echocardiography is also useful for assessing the motion of intracardiac structures (opening and closing of valves, movement of free walls and septa) and the anatomy of valves (Fig. 450.15 ). The most frequently used index of cardiac function in children is percent fractional shortening (%FS), which contrasts to adults, where ejection fraction is the most common functional measurement. %FS is calculated as (LVED − LVES)/LVED, where LVED is left ventricular dimension at enddiastole and LVES is left ventricular dimension at end-systole. Normal fractional shortening is approximately 28–42%. Other M-mode indices of cardiac function include the mean velocity of fiber shortening (mean VCF ), systolic time intervals (LVPEP = LV preejection period, LVET = LV ejection time), and isovolemic contraction time. M-mode measurements are highly susceptible to errors because of differences in wall motion between different segments of the heart (more frequently seen in adults with ischemic heart disease, but which can be seen in children with congenital and acquired heart disease, especially after surgical repair).

FIG. 450.14 M-mode echocardiogram. A, Diagram of a sagittal section of a heart showing the structures traversed by the echo beam as it is moved superiorly to positions (1), (2), and (3). AMC, Anterior mitral cusp; APM, anterior papillary muscle; Dec. aorta, descending aorta; LA, left atrium; LV, left ventricle; PMC, posterior mitral cusp; PPM, posterior papillary muscle; RV, right ventricle. B, Echocardiogram from transducer position (1); this view is the best one for measuring cardiac dimensions and fractional shortening. Fractional shortening is calculated as (LVED − LVES)/LVED. CW, Chest wall; Ds, LV dimension in systole; LVED, LV dimension at end-diastole (Dd); RVED, RV dimension at end-diastole.

FIG. 450.15 M-mode echocardiograms. The small figure at the top of each panel shows the 2D parasternal short axis echo image from which the M-modes are derived. The cursor can be seen midway through the image, indicating the one-dimensional line through which the M-mode is being sampled. A, M-mode echocardiogram of a normal mitral valve. Arrow shows the opening of the anterior leaflet in early diastole (see ECG tracing above for reference). B, M-mode echocardiogram of a normal aortic valve. The opening and closing of the aortic leaflets in systole are outlined by the 2 arrows . Ao, Aorta; IVS, interventricular septum; LV, left ventricle; RV, right ventricle.

Two-Dimensional Echocardiography Two-dimensional echocardiography provides a real-time image of cardiac structures. With 2D echocardiography, the contracting heart is imaged in real time using several standard views, including parasternal long axis (Fig. 450.16 ), parasternal short axis (Fig. 450.17 ), apical 4 chamber (Fig. 450.18 ), subcostal (Fig. 450.19 ), and suprasternal (Fig. 450.20 ), each of which emphasizes specific structures. Two-dimensional echocardiography has replaced cardiac angiography for the preoperative diagnosis and follow-up of the vast majority of congenital heart lesions. However, when information from the cardiac examination or other studies is not consistent with the echocardiogram (e.g., size of left-to-right shunt), cardiac catheterization remains an important tool to confirm the anatomic diagnosis and evaluate the degree of physiologic derangement. MRI is also a valuable adjunct to provide a better quantification of ventricular size and function.

FIG. 450.16 Normal parasternal long axis echocardiographic window. The transducer is angulated slightly posteriorly, imaging the left-sided cardiac structures. If the transducer were to be angulated more anteriorly, the right ventricular structures would be imaged. The mitral valve leaflets can be seen in partially open position in early diastole (arrows). The closed aortic valve leaflets can be seen just below the label Ao (aorta). LA, Left atrium; LV, left ventricle; RV, right ventricle.

FIG. 450.17 Normal parasternal short axis echocardiographic windows. A, With the transducer angled superiorly and rightward, the aortic valve (AV) is imaged, surrounded by both inflow and outflow portions of the right ventricle (RV). LPA, Left pulmonary artery; MPA, main pulmonary artery; PV, pulmonary valve; RA, right atrium; RPA, right pulmonary artery; TV, tricuspid valve. B, With the transducer angled inferiorly and leftward, the left ventricular chamber is imaged along with crosssectional view of the mitral valve (arrows). LV, Left ventricle; RV, right ventricle.

FIG. 450.18 Normal apical 4-chamber echocardiographic window showing all 4 cardiac chambers and both atrioventricular valves opened in diastole. LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

FIG. 450.19 Normal subcostal echocardiographic window showing the left ventricular outflow tract. The right-sided structures are not fully imaged in this view. Ao, Ascending aorta; LV, left ventricle; RA, right atrium; RV, right ventricle; SVC, superior vena cava.

FIG. 450.20 A, Normal suprasternal echocardiographic window showing the aortic arch and its major branches. AsAo, Ascending aorta; BrA, brachiocephalic artery; DescAo, descending aorta; LCA, left carotid artery; LSCA, left subclavian artery. B, Normal high parasternal window showing color Doppler imaging of normal pulmonary venous return to the left atrium (LA) of both right (RLPV) and left (LLPV) lower pulmonary veins.

Doppler Echocardiography Doppler echocardiography displays blood flow in cardiac chambers and vascular channels based on the change in frequency imparted to a sound wave by the movement of erythrocytes. In pulsed Doppler and continuous wave Doppler, the speed and direction of blood flow in the line of the echo beam change the transducer's reference frequency. This frequency change can be translated into volumetric flow (L/min) data for estimating systemic or pulmonary blood flow and into pressure (mm Hg) data for estimating gradients across the semilunar or

atrioventricular valves or across septal defects or vascular communications such as shunts. Color Doppler permits highly accurate assessment of the presence and direction of intracardiac shunts and allows identification of small or multiple left-to-right or right-to-left shunts (Fig. 450.21 ). The severity of valvular insufficiency can be evaluated qualitatively with both pulsed and color Doppler (Fig. 450.22 ). Alterations in venous Doppler flow patterns can be used to detect abnormalities of systemic and pulmonary veins, and alterations of atrioventricular valve Doppler flow patterns can be used to assess ventricular diastolic functional abnormalities, particularly the E/A ratio , the ratio of peak velocity flow in diastole (i.e., the ratio of the early-diastole E wave to the peak velocity flow in late diastole caused by atrial [A] contraction wave).

FIG. 450.21 Color and pulsed Doppler evaluation of pulmonary arterial flow. A, Color Doppler evaluation of a parasternal short axis view showing normal flow through the pulmonary valve to the main and branch pulmonary arteries. The color of the Doppler flow is blue, indicating that the flow is moving away from the transducer (which is located at the top of the figure, at the apex of the triangular ultrasound window). Note that the color assigned to the Doppler signal does not indicate the oxygen saturation of

the blood. AO, Aorta; LPA, left pulmonary artery; MPA, main pulmonary artery; RPA, right pulmonary artery. B, Pulsed wave Doppler flow pattern through the pulmonary valve showing a low velocity of flow (90% of patients with trisomy 18, 50% of patients with trisomy 21, and 40% of those with Turner syndrome. Other genetic factors may have a role in CHD; for example, certain types of VSDs (supracristal) are more common in Asian children. The risk of CHD increases if a first-degree relative (parent or sibling) is affected. A growing list of congenital heart lesions has been associated with specific chromosomal abnormalities, and several have even been linked to specific gene defects. Fluorescence in situ hybridization (FISH) analysis allows clinicians rapid screening of suspected cases once a specific chromosomal abnormality has been identified, although clinical laboratory tests for specific gene defects are still uncommon. Chromosome microarray tools, including array comparative genome hybridization and single nucleotide polymorphism (SNP) arrays have identified previously unknown copy number variations (microdeletions or microduplications) or single nucleotide variants in many patients with CHD and suspicion of a congenital anomaly syndrome. These variants are submicroscopic and thus not visible on routine chromosome analysis. Comparative genome hybridization has in many cases replaced routine karyotyping in the clinical workup of newborns with CHD. A well-characterized genetic cause of CHD is the deletion of a large region (1.5-3 Mb) of chromosome 22q11.2, known as the DiGeorge critical region . At least 30 genes have been mapped to the deleted region; Tbx1, a transcription factor involved in early outflow tract development, is one gene that has been implicated as a possible cause of DiGeorge syndrome. The estimated prevalence of 22q11.2 deletions is 1 in 4,000 live births. Cardiac lesions associated with 22q11.2 deletions are most often seen in association with either the DiGeorge

syndrome or the Shprintzen (velocardiofacial) syndrome. The acronym CATCH 22 has been used to summarize the major components of these syndromes: cardiac defects, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia. The specific cardiac anomalies are conotruncal defects (tetralogy of Fallot, truncus arteriosus, double-outlet right ventricle, subarterial VSD) and branchial arch defects (coarctation of the aorta, interrupted aortic arch, right aortic arch). Congenital airway anomalies such as tracheomalacia and bronchomalacia are sometimes present. Although the risk of recurrence is extremely low in the absence of a parental 22q11.2 deletion, it is 50% if 1 parent carries the deletion. More than 90% of patients with the clinical features of DiGeorge syndrome have a deletion at 22q11.2. A 2nd genetic locus on the short arm of chromosome 10 (10p13p14) has also been identified, the deletion of which shares some, but not all, phenotypic characteristics with the 22q11.2 deletion; patients with del(10p) have an increased incidence of sensorineural hearing loss. Other structural heart lesions associated with specific chromosomal abnormalities include familial secundum atrial septal defect (ASD) associated with heart block (the transcription factor Nkx2.5 on chromosome 5q35), familial ASD without heart block (the transcription factor GATA4), Alagille syndrome (Jagged1 on chromosome 20p12), and Williams syndrome (elastin on chromosome 7q11). Of interest, patients with VSDs and atrioventricular septal defects have been found to have multiple Nkx2.5 mutations in cells isolated from diseased heart tissues, but not from normal heart tissues or from circulating lymphocytes, indicating a potential role for somatic mutations leading to mosaicism in the pathogenesis of congenital heart defects. Tables 451.2 and 451.3 are a compilation of known genetic causes of CHD. Table 451.2

Genetics of Congenital Heart Disease: Defects Associated With Syndromes CARDIOVASCULAR DISEASE

CHROMOSOMAL LOCATION

DiGeorge syndrome, 22q11.2, 11p13p14 velocardiofacial syndrome Familial ASD with heart 5q35 block Familial ASD without 8p22-23

NKX2.5

COMMON CARDIAC DEFECTS TOF, IAA, TA, VSD ASD, heart block

GATA4

ASD

GENE(S) IMPLICATED* TBX1

heart block Alagille syndrome (bile duct hypoplasia, rightsided cardiac lesions)

20p12, 1p12

JAGGED1, NOTCH2

Holt-Oram syndrome (limb defects, ASD) Trisomy 21 (Down syndrome) Isolated familial AV septal defect (without trisomy 21) Familial TAPVR Noonan syndrome (PS, ASD, hypertrophic cardiomyopathy) Ellis–van Creveld syndrome (polydactyly, ASD) Char syndrome (craniofacial, limb defects, PDA) Williams-Beuren syndrome (supravalvular AS, branch PS, hypercalcemia) Marfan syndrome (connective tissue weakness, aortic root dilation) Familial laterality abnormalities

12q24

TBX5

Peripheral pulmonary hypoplasia, PS, TOF ASD, VSD, PDA

21q22

Not known

AVSD

1p31-p21, 3p25

CRELD1

AVSD

4p13-q12 12q24, 12p1.21, 2p212, 3p25.2, 7q34, 15q22.31, 11p15.5, 1p13.2, 10q25.2, 11q23.3,17q11.2 4p16

Not known PTPN11, KRAS, SOS1, SOS2, RAF1, BRAF, MEK1, HRAS, NRAS, SHOC2, CBL, NF1 EVC, EVC2

TAPVR PS, ASD, VSD, PDA, cardiomyopathy ASD, common atrium

6p12-21.1

TFAP2B

PDA

7q11.23

ELN (Elastin)

Supravalvular AS, peripheral PS

15q21

Fibrillin

Aortic aneurysm, mitral valve disease

Xq24-2q7, 1q42, 9p13-21

ZIC3, DNAI1

Turner syndrome

X

Not known

Trisomy 13 (Patau syndrome)

13

Not known

Trisomy 18 (Edwards syndrome)

18

Not known

Cri du chat syndrome

5p15.2

CTNND2

Cat-eye syndrome Jacobsen Costello

22q11 11q23 11p15.5

Not known JAM3 HRAS

CHARGE Kabuki syndrome

8p12, 7q21.11 12q13.12

CHD7, SEMA3E MLL2

Situs inversus, complex congenital heart disease Coarctation of the aorta, aortic stenosis ASD, VSD, PDA, valve abnormalities ASD, VSD, PDA, valve abnormalities ASD, VSD, PDA, TOF TAPVR, TOF HLHS PS, hypertrophic cardiomyopathy, arrhythmias ASD, VSD, TOF ASD, VSD, TOF, coarctation, TGA

Carney syndrome

2p16

PRKAR1A

Atrial and ventricular myxomas

*

In many cases, mutation of a single gene has been closely linked to a specific cardiovascular disease, for example, by finding a high incidence of mutations or deletions of that gene in a large group of patients. These findings are often confirmed by studies in mice in which deletion or alteration of the gene induces a similar cardiac phenotype to the human disease. In others, mutation of a gene may increase the risk of cardiovascular disease, but with decreased penetrance, suggesting that modifier genes or environmental factors play a role. Finally, in some cases, gene mutations have only been identified in a small number of pedigrees, and confirmation awaits screening of larger numbers of patients. AS, aortic stenosis; ASD, atrial septal defect; AV, atrioventricular; AVSD, atrioventricular septal defect; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; PDA, patent ductus arteriosus; PS, pulmonic stenosis; TA, truncus arteriosus; TAPVR, total anomalous pulmonary venous return; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Table 451.3

Genetics of Isolated Congenital Heart Disease (Nonsyndromic) GENE PROTEIN ENCODED CARDIAC DEFECTS IMPLICATED* GENES ENCODING TRANSCRIPTION FACTORS ANKRD1 Ankyrin repeat domain TAPVR CITED2 cAMP responsive element-binding ASD, VSD protein FOG2/ZFPM2 Friend of GATA TOF GATA6 GATA6 transcription factor ASD, VSD, TOF, PS, AVSD, PDA HAND2 Helix-loop-helix transcription factor TOF IRX4 Iroquois homeobox 4 VSD MED13L Mediator complex subunit 13-like TGA NKX2-5/NKX2.5 Homeobox containing transcription factor ASD, VSD, TOF, HLHS, CoA, TGA, IAA TBX20 T-Box 20 transcription factor ASD, VSD, mitral stenosis ZIC3 Zinc finger transcription factor TGA, PS, TAPVR, HLHS, ASD, VSD GENES ENCODING RECEPTORS AND SIGNALING MOLECULES ACVR1/ALK2 BMP receptor AVSD ACVR2B Activin receptor PS, DORV, TGA ALDH1A2 Retinaldehyde dehydrogenase TOF CFC1/CRYPTIC Cryptic protein TOF, TGA, AVSD, ASD, VSD, IAA, DORV CRELD1 Epidermal growth factor–related proteins ASD; AVSD FOXH1 Forkhead activin signal transducer TOF, TGA GDF1 Growth differentiation factor-1 TOF, TGA, DORV, heterotaxy GJA1 Connexin 43 ASD, HLHS, TAPVR LEFTY2 Left-right determination factor TGA, AVSD, IAA, CoA

NODAL Nodal homolog (TGF-β superfamily) NOTCH1 NOTCH1 (Ligand of JAG1) PDGFRA Platelet-derived growth factor receptor α SMAD6 MAD-related protein TAB2 TGF-β–activated kinase TDGF1 Teratocarcinoma-derived growth factor 1 VEGF Vascular endothelial growth factor GENES ENCODING STRUCTURAL PROTEINS ACTC α Cardiac actin MYH11 Myosin heavy chain 11 MYH6 α-Myosin heavy chain MYH7 β-Myosin heavy chain

TGA, PA, TOF, DORV, TAPVR, AVSD Bicuspid aortic valve, AS, CoA, HLHS TAPVR Bicuspid aortic valve, CoA, AS Outflow tract defects TOF, VSD CoA, outflow tract defects ASD PDA, aortic aneurysm ASD, TA, AS, TGA Ebstein anomaly, ASD

* In many cases, mutation of a single gene has been closely linked to a specific cardiovascular

disease, for example, by finding a high incidence of mutations or deletions of that gene in a large group of patients. These findings are often confirmed by studies in mice in which deletion or alteration of the gene induces a similar cardiac phenotype to the human disease. In others, mutation of a gene may increase the risk of cardiovascular disease, but with decreased penetrance, suggesting that modifier genes or environmental factors play a role. Finally, in some cases, gene mutations have only been identified in a small number of pedigrees, and confirmation awaits screening of larger numbers of patients. AS, Aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; cAMP, cyclic adenosine monophosphate; CoA, coarctation of the aorta; DORV, double-outlet right ventricle; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; PA, pulmonary artery; PDA, patent ductus arteriosus; PS, pulmonic stenosis; TA, truncus arteriosus; TAPVR, total anomalous pulmonary venous return; TGA, transposition of the great arteries; TGF, transforming growth factor; TOF, tetralogy of Fallot; VSD, ventricular septal defect. Partially adapted from Fahed AC, Gelb BD, Seidman JG, Seidman CE: Genetics of congenital heart disease: the glass half empty. Circ Res 112:707–720, 2013.

The most progress in identifying the genetic origin of cardiovascular disease has been made in the genetic cardiomyopathies , and in particular, hypertrophic cardiomyopathy. Mutations in about a dozen genes have been implicated, most of which encode protein components of the cardiac sarcomere, either components of the thick filaments (myosin) or associated regulatory subunits, although mutations in mitochondrial genes are increasingly recognized and play a larger role in those presenting with hypertrophic cardiomyopathy as young infants than in older children and adults. Mutations of the cardiac βmyosin heavy-chain gene MYH7 (chromosome 14q1) and the myosin-binding protein C gene (chromosome 11q11) are the most common (see Table 451.4 ), with less common mutations including the cardiac troponin T and I genes, αtropomyosin, regulatory and essential myosin light chains, titin, and the αmyosin heavy chain. Several hundred mutations have been identified in these genes, and some patients (up to 15% in one study) may carry mutations in more than one gene. Routine clinical laboratory tests are now available for most of

these mutations, however, not all mutations causing hypertrophic cardiomyopathy have been identified, so a negative test does not eliminate a genetic cause. Table 451.4

Genetics of Cardiomyopathies CARDIOMYOPATHY Hypertrophic cardiomyopathy

CHROMOSOMAL LOCATION 14q1 15q2 1q31 19p13.2-19q13.2 11p13-q13 12q23 13p21 2q31 3p25 Mitochondrial DNA Mitochondrial DNA 7q36.1

Hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome Other Genetic Diseases Causing Cardiac Hypertrophy Familial amyloid disease 18q12.1 Noonan syndrome 12q24.1, 2p22.1, 3p25, 12p12.1 Fabry disease Danon disease Hereditary hemochromatosis Pompe disease Dilated cardiomyopathy X-linked Autosomal recessive

GENE β-Myosin heavy chain α-Tropomyosin Troponin T Troponin I Myosin-binding protein C Cardiac slow myosin regulatory light chain Ventricular slow myosin essential light chain Titin Caveolin-3 tRNA-glycine tRNA-isoleucine AMP-activated protein kinase

Xq22 Xq24 6p21.3 17q25

Transthyretin (TTR) Protein tyrosine phosphatase 11 (PTPN11), son of sevenless homolog 1 (SOS1), RAF1 protooncogene, GTPase KRAS α-Galactoside A (GLA) Lysosomal-associated membrane protein 2 (LAMP2) Hereditary hemochromatosis protein (HFE) Acid α-glucosidase (GAA)

Xp21 Xp28 19p13.2-19q13.2

Dystrophin Tafazzin Troponin I

Autosomal dominant : Genes encoding multiple proteins have been identified, including cardiac actin; desmin; δ-sarcoglycan; β-myosin heavy chain; cardiac troponin C and T; α-tropomyosin; titin; metavinculin; myosin-binding protein C; muscle LIM protein; α-actinin-2; phospholamban; Cypher/LIM binding domain 3; α-myosin heavy chain; SUR2A (regulatory subunit of KATP channel); and lamin A/C. Isolated noncompaction of the left ventricle : Autosomal dominant, autosomal recessive, Xlinked, and mitochondrial inheritance patterns have been reported. Genes that have been implicated include those for α-dystrobrevin, Cypher/ZASP, lamin A/C, Tafazzin, MIB1, and LIM domain-binding protein 3 (LDB3). Partially adapted from Dunn KE, Caleshu C, Cirino AL, et al: A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management, Circ

Cardiovasc Genet 6:118–131, 2013.

Progress has also been made in identifying the genetic basis of dilated cardiomyopathy, which is familial in 20–50% of cases. Autosomal dominant inheritance is most often encountered, and similar to hypertrophic cardiomyopathy, multiple genes have been identified (see Table 451.2 ). Xlinked inheritance accounts for 5–10% of cases of familial dilated cardiomyopathy. Mutations in the dystrophin gene (chromosome Xp21) are the most common in this group, causing Duchene or Becker muscular dystrophy . Mutations in the gene encoding tafazzin are associated with Barth syndrome and some cases of isolated noncompaction of the left ventricle (LVNC). Autosomal recessive inheritance is associated with a mutation in cardiac troponin I. Mitochondrial myopathies may be caused by mutations of enzymes of the electron transport chain encoded by nuclear DNA (in which inheritance will follow mendelian genetic patterns) or enzymes of fatty acid oxidation encoded by mitochondrial DNA (which is inherited solely from the mother). Table 451.4 is a compilation of the most common genetic causes of cardiomyopathy. The genetic basis of heritable arrhythmias , most notably the long QT syndromes , has been linked to mutations of genes coding for subunits of cardiac potassium and sodium channels (see Table 451.2 ). Other heritable arrhythmias include arrhythmogenic right ventricular dysplasia , familial atrial fibrillation, familial complete heart block, and Brugada syndrome . Table 451.5 is a compilation of the most common genetic causes of arrhythmias. Table 451.5

Genetics of Arrhythmias ARRHYTHMIA Complete heart block Long QT syndrome LQT1 (autosomal dominant) LQT2 (autosomal dominant) LQT3 (autosomal dominant) LQT4 (autosomal dominant) LQT5 (autosomal dominant) LQT6 Jervell and Lange-Nielsen syndrome (autosomal recessive, congenital deafness)

CHROMOSOMAL GENE(S) IMPLICATED LOCATION 19q13 Not known 11p15.5 7q35 3p21 4q25-27 21q22-q22 21q22.1 11p15.5

KVLQT1 (K+ channel) HERG (K+ channel) SCN5A (Na+ channel) Not known KCNE1 (K+ channel) KCNE2 (K+ channel) KVLQT1 (K+ channel)

LQT8-13 Unknown Private mutations (rare) Arrhythmogenic right ventricular dysplasia (ARVD): 11 genes are now associated with ARVD (ARVD1 through ARVD11 ) usually with autosomal dominant inheritance, but with variable penetrance. These genes include TGF β3 (transforming growth factor β), RYR2 (ryanodine receptor), LAMR1 (laminin receptor-1), PTPLA (protein tyrosine phosphatase), DSP (desmoplakin), PKP2 (plakophilin-2), DSG2 (desmoglein), and DSC2 (desmocollin). Familial atrial fibrillation (autosomal dominant) 10q22-q24, 6q14-16 Not known 11p15.5 KVLQT1 (K+ channel) 11p15.5 KCNQ1 (K+ channel) 21q22 KCNE2 (K+ channel) 17q23.1-q24.2 KCNJ2 (K+ channel) 7q35-q36 KCNH2 (K+ channel) Brugada syndrome (right bundle branch block, ST segment 3p21-p24 SCN5A (Na+ channel) elevation, unexpected sudden death) 3p22-p24 GPD-1L (glycerol-3phosphate dehydrogenase) Catecholaminergic polymorphic ventricular tachycardia — RYR2 (autosomal dominant) — CASQ2 (autosomal recessive)

Of all cases of congenital heart disease, 2–4% are associated with known environmental or adverse maternal conditions and teratogenic influences, including maternal diabetes mellitus, maternal phenylketonuria, or systemic lupus erythematosus; congenital rubella syndrome; and maternal ingestion of drugs (lithium, ethanol, warfarin, thalidomide, antimetabolites, vitamin A derivatives, anticonvulsant agents) (see Table 449.2 ). Associated noncardiac malformations noted in identifiable syndromes may be seen in as many as 25% of patients with CHD. Gender differences in the occurrence of specific cardiac lesions have been identified. Transposition of the great arteries and left-sided obstructive lesions are slightly more common in boys (65%), whereas ASD, VSD, PDA, and pulmonic stenosis are more common in girls. No racial differences in the occurrence of congenital heart lesions as a whole have been noted; for specific lesions such as transposition of the great arteries, a higher occurrence is seen in white infants.

Next-Generation Genome Sequencing and Congenital Heart Disease The US National Institutes of Health (NIH) launched the Pediatric Cardiac Genomics Consortium (PCGC) in 2009 with the aim of performing genome sequencing on 10,000 children with CHD and both parents (known as a trio ), to identify de novo gene variants associated with congenital heart defects. In one study, in >300 trios, de novo mutations in several hundred genes were found to

contribute to 10% of cases of severe CHD. Another major PCGC study found that the incidence of de novo gene variants was 10-fold higher (20% vs 2%) in patients with CHD and neurodevelopmental defects than in those with CHD alone, linking CHD with neurodevelopmental disorders at the genetic level. The identification of a candidate de novo mutation is far from proof of its role in causing CHD, which must be verified in animal models or by identifying multiple additional patients with a similar genotype-phenotype connection. The relationship between a specific gene variant and CHD is further complicated by the tremendous genotype-phenotype variability; a single mutation may lead to a wide variety of heart defects or sometimes to none at all.

Genetic Counseling Parents who have a child with CHD require counseling regarding the probability of a cardiac malformation occurring in subsequent children (see Chapter 94.1 ). Except for syndromes caused by mutation of a single gene, most CHD is still relegated to a multifactorial inheritance pattern, which should result in a low risk of recurrence. As more genetic etiologies are identified, these risks will need constant updating. The incidence of CHD in the normal population is 0.8%, increasing to 2–6% for a 2nd pregnancy after the birth of a child with CHD or if a parent is affected. This recurrence risk is highly dependent on the type of lesion in the 1st child. When 2 first-degree relatives have CHD, the risk for a subsequent child may reach 20–30%. When a 2nd child is found to have CHD, it will tend to be of a similar class as the lesion in their first-degree relative (conotruncal lesions, left- or right-sided obstructive lesions, atrioventricular septation defects). The degree of severity may vary, as may the presence of associated defects. Careful echocardiographic screening of first-degree relatives will often uncover mild forms of CHD that were clinically silent. The incidence of bicuspid aortic valve is more than double (5% vs 2% in the general population) in the relatives of children with left ventricular outflow obstructions (aortic stenosis, coarctation of the aorta, HLHS). Consultation with a knowledgeable genetic counselor is the most reliable way of providing the family with up-to-date information regarding the risk of recurrence. Fetal echocardiography improves the rate of detection of congenital heart lesions in high-risk patients (see Chapter 450.4 ). This type of ultrasound is much more comprehensive than the screening ultrasound performed by an obstetrician and is usually performed and interpreted by a pediatric cardiologist

specializing in fetal echocardiography. The resolution and accuracy of fetal echocardiography are excellent, but not perfect; families should be counseled that a normal fetal echocardiogram does not guarantee the absence of CHD. Congenital heart lesions may evolve in the course of the pregnancy; moderate aortic stenosis with a normal-sized left ventricle at 18 wk of gestation may evolve into aortic atresia with a hypoplastic left ventricle by 34 wk because of decreased flow through the atria, ventricle, and aorta in the latter half of gestation. This progression has prompted initial clinical trials of interventional treatment, such as fetal aortic balloon valvuloplasty, for the prevention of HLHS (see Chapter 450.7 ). The major factor in determining whether a woman with congenital heart disease, either unoperated or operated, will be able to carry a fetus to term is the mother's cardiovascular status. In the presence of a mild congenital heart defect or after successful repair of a more complex lesion, normal childbearing is likely. In a woman with palliated CHD or with poor cardiac function, however, the increased hemodynamic burden imposed by pregnancy may result in a significantly increased risk to both the mother and fetus and these pregnancies should be managed by an experienced high risk obstetrician/perinatologist in conjunction with a cardiologist with expertise in adult CHD (see Chapter 461.1 ).

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disease. N Engl J Med . 2010;363:1638–1646. Fahed AC, Gelb BD, Seidman JG, et al. Genetics of congenital heart disease: the glass half empty. Circ Res . 2013;112:707– 720. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail . 2009;15:83–97. Homsy J, Zaidi S, Shen Y, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science . 2015;350(6265):1262–1266. Leatherby L, Berul CI. Genetics of congenital heart disease: is the glass now half-full? Circ Cardiovasc Genet . 2017;10:e001746. Miller A, Riehle-Colarusso T, Alverson CJ, et al. Congenital heart defects and major structural noncardiac anomalies, Atlanta, 1968 to 2005. J Pediatr . 2011;159:70–78. Oster ME, Riehle-Colarusso T, Alverson CJ, et al. Associations between maternal fever and influenza and congenital heart defects. J Pediatr . 2011;158:990–995. Srivastava D. Genetic regulation of cardiogenesis and congenital heart disease. Annu Rev Pathol . 2006;1:199–213. Patel A, Costello JM, Backer CL, et al. Prevalence of noncardiac and genetic abnormalities in neonates undergoing cardiac operations: analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. Ann Thorac Surg . 2016;102:1607–1614. Priest J, Mohammed N, Schultz K, et al. De novo and rare variants at multiple loci support the oligogenic origins of atrioventricular septal heart defects. PLoS Genet . 2016;12(4):e1005963. Rollins CK, Newburger JW, Roberts AE. Genetic contribution to neurodevelopmental outcomes in congenital heart disease: are some patients pre-determined to have developmental

delay? Curr Opin Pediatr . 2017;29(5):529–533. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell . 2006;126:1037–1048. Syrmou A, Tzetis M, Fryssira H, et al. Array comparative genomic hybridization as a clinical diagnostic tool in syndromic and nonsyndromic congenital heart disease. Pediatr Res . 2013;73:772–776. Yuan S, Zaidi S, Brueckner M. Congenital heart disease: emerging themes linking genetics and development. Curr Opin Genet Dev . 2013;23:352–359.

CHAPTER 452

Evaluation and Screening of the Infant or Child With Congenital Heart Disease Daniel Bernstein

The initial evaluation for suspected congenital heart disease (CHD) involves a systematic approach with 3 major components. First, congenital cardiac defects can be divided into 2 major groups based on the presence or absence of cyanosis , which can be determined by physical examination aided by pulse oximetry. Second, these 2 groups can usually be further subdivided based on whether the chest radiograph shows evidence of increased, normal, or decreased pulmonary vascular markings. Third, the electrocardiogram (ECG) can be used to determine whether right, left, or biventricular hypertrophy exists. The character of the heart sounds and the presence and character of any murmurs further narrow the differential diagnosis. The final diagnosis is then confirmed by echocardiography, cardiac CT or MRI and/or cardiac catheterization. Multiple studies demonstrate the benefit of routine pulse oximetry screening for all newborns to detect unsuspected critical cyanotic CHD; lesions include hypoplastic left heart syndrome, pulmonary atresia, tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries, tricuspid atresia, truncus arteriosus, neonatal coarctation of the aorta, and aortic arch hypoplasia/atresia. Many of these lesions are ductal dependent, and if the ductus arteriosus closes, severe cardiac decompensation will ensue. In addition, pulse oximetry may also detect respiratory disorders and primary pulmonary hypertension. Such screening has been endorsed by the American Academy of Pediatrics, American Heart Association, American College of Cardiology, and the March of Dimes, and recommended, although not mandated, in the United States by the Department of Health and Human Services. Screening is performed

between 24 and 48 hr of life and before discharge in asymptomatic newborns. A pulse oximetry saturation of 90–94% in the right hand or either foot requires urgent echocardiography. A pulse oximetry saturation 3% between the right hand and either foot is considered a positive test and should be repeated in an hour; if positive again, it should be repeated in another hour. If it remains positive, echocardiography is indicated. In addition, a careful reexamination of the pulses and blood pressure in the upper and lower extremity as well as cardiac auscultation are indicated in children with an initial positive screen.

Acyanotic Congenital Heart Lesions Acyanotic congenital heart lesions can be classified according to the predominant physiologic load that they place on the heart. Although many congenital heart lesions induce >1 physiologic disturbance, it is helpful to focus on the primary load abnormality for purposes of classification. The most common lesions are those that produce a volume load , and the most common of these are the left-to-right shunt lesions. Atrioventricular (AV) valve regurgitation and dilated cardiomyopathies are other causes of increased volume load. The 2nd major class of lesions causes an increase in pressure load , most often secondary to ventricular outflow obstruction (pulmonic or aortic valve stenosis) or narrowing of a great vessel (branch pulmonary artery stenosis or coarctation of the aorta). The chest radiograph and ECG are useful tools for differentiating between these major classes of volume- and pressure-overload lesions.

Lesions Resulting in Increased Volume Load The most common lesions resulting in increased volume load are those that cause left-to-right shunting (see Chapter 453 ): atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defects (previously known as AV canal or endocardial cushion defects), and patent ductus arteriosus. The pathophysiologic common denominator in this group is the presence of a communication between the systemic and pulmonary sides of the circulation, which results in shunting of fully oxygenated blood back into the lungs for a 2nd passage. This shunt can be quantitated by calculating the ratio of pulmonary-to-systemic blood flow (Qp:Qs). Thus a 3 : 1 shunt implies 3 times the normal pulmonary blood flow, which is a moderately large shunt likely to

cause symptoms of heart failure. The direction and magnitude of the shunt across such a communication depend on the size of the defect, the relative pulmonary and systemic pressure and vascular resistance, and the compliances of the 2 chambers connected by the defect. These factors are dynamic and may change dramatically with age; intracardiac defects may grow smaller with time; pulmonary vascular resistance (PVR), which is high in the immediate newborn period, decreases to normal adult levels by several weeks of life; and chronic exposure of the pulmonary circulation to high pressure and blood flow results in a gradual increase in PVR (Eisenmenger physiology ; see Chapter 460.2 ). Thus, a lesion such as a large VSD may be associated with little shunting and few symptoms during the initial 1-2 wk of life. When PVR declines over the next 2-4 wk, the volume of the leftto-right shunt increases, and symptoms begin to appear. The increased volume of blood in the lungs decreases pulmonary compliance and increases the work of breathing. Fluid leaks into the interstitial space and alveoli and causes pulmonary edema. The infant develops the symptoms we refer to as heart failure , such as tachypnea, tachycardia, sweating, chest retractions, nasal flaring, and wheezing. For children with large left-to-right shunts, however, the term heart failure is a misnomer; total left ventricular output is not decreased but is actually several times greater than normal, although much of this output is ineffective because it returns back to the lungs. To maintain this high level of left ventricular output, heart rate and stroke volume are increased, in part mediated by the Frank-Starling relation as the increased ventricular volume stretches the cardiac sarcomeres, and in part mediated by an increase in sympathetic nervous system activity. The increase in catecholamine release, combined with the increased work of breathing, results in an elevation in total body oxygen consumption (due to increased β-receptor stimulation), often beyond the oxygen transport ability of the circulation. Sympathetic activation leads to peripheral vasoconstriction (due to increased αreceptor stimulation) and to the additional symptoms of sweating and irritability, and the imbalance between oxygen supply and demand leads to failure to thrive. Remodeling of the heart occurs, with predominantly chamber dilation caused by the increased volume load and a lesser degree of hypertrophy. If left untreated, the PVR eventually begins to rise, and by several years of age, the shunt volume will decrease and symptoms will improve. If still uncorrected, the shunt will eventually reverse to right-to-left as the PVR rises (see Chapter 460.2 ). Additional lesions that impose a volume load on the heart include the

regurgitant lesions (see Chapter 455 ) and the dilated cardiomyopathies (see Chapter 466.1 ). Regurgitation through the AV valves is most frequently encountered in patients with partial or complete AV septal defects (AV canal or endocardial cushion defects). In these lesions, the combination of a left-to-right shunt with AV valve regurgitation increases the volume load on the heart and often leads to more severe symptoms. Isolated regurgitation through the tricuspid valve is seen in Ebstein anomaly (see Chapter 457.7 ). Regurgitation involving one of the semilunar (aortic or pulmonary) valves also results in a volume load but is often also associated with some degree of stenosis, leading to a combined pressure and volume load. Aortic regurgitation may be encountered in patients with a VSD directly under the aortic valve (supracristal VSD), leading to 2 sources of volume load on the left ventricle. In contrast to left-to-right shunts, in which intrinsic cardiac muscle function is generally either normal or increased, heart muscle function can be decreased in the cardiomyopathies. Cardiomyopathies may affect systolic contractility or diastolic relaxation, or both. Decreased cardiac function results in increased atrial and ventricular filling pressure, and pulmonary edema occurs secondary to increased capillary pressure. Poor cardiac output leads to decreased end-organ blood flow, sympathetic activation, and the symptoms of poor perfusion and decreased urine output. The major causes of cardiomyopathy in infants and children include viral myocarditis, metabolic disorders, and gene mutations in sarcomeric and other cardiac structural and functional genes (see Chapter 466 ).

Lesions Resulting in Increased Pressure Load The pathophysiologic common denominator of lesions resulting in increased pressure load is an obstruction to normal blood flow . The most frequent are obstructions to ventricular outflow : valvular pulmonic stenosis, valvular aortic stenosis, and coarctation of the aorta (see Chapter 454 ). Less common are obstructions to ventricular inflow : tricuspid or mitral stenosis, cor triatriatum, and obstruction of the pulmonary veins. Ventricular outflow obstruction can occur at the valve, below the valve (double-chambered right ventricle, subaortic membrane), or above it (branch pulmonary stenosis or supravalvular aortic stenosis). Unless the obstruction is severe, cardiac output will be maintained and the clinical symptoms of heart failure will be either subtle or absent. The heart compensates for the increased afterload by increasing wall thickness (hypertrophy), but in later stages the affected chamber develops fibrosis and will

begin to dilate and can progress to ventricular failure. The clinical picture is different when obstruction to outflow is severe, which is usually encountered in the immediate newborn period. The infant may become critically ill within several hours of birth. Severe pulmonic stenosis in the newborn period (called critical pulmonic stenosis ) results in signs of rightsided heart failure (hepatomegaly, peripheral edema) as well as cyanosis from right-to-left shunting across the foramen ovale. Severe aortic stenosis in the newborn period (critical aortic stenosis ) is characterized by signs of left-sided heart failure (pulmonary edema, poor perfusion) and often combined with rightsided failure (hepatomegaly, peripheral edema), and it may progress rapidly to total circulatory collapse. In older children, severe pulmonic stenosis leads to symptoms of right-sided heart failure, but usually not to cyanosis unless a pathway persists for right-to-left shunting (e.g., patency of foramen ovale). Coarctation of the aorta in older children and adolescents is usually manifested as upper body hypertension and diminished pulses in the lower extremities. In the immediate newborn period, presentation of coarctation can range from decreased pulses in the lower extremities to total circulatory collapse, depending on the severity of the narrowing. However, the clinical presentation of coarctation may be delayed because of the normally patent ductus arteriosus in the 1st few days of life. In these patients, even as the ductus begins to close, the open aortic end serves as a conduit for blood flow to partially bypass the obstruction; in more severe coarctations, blood leaving the right ventricle traverses the ductus to directly supply the descending aorta (as it did in the fetus). These infants then become symptomatic, often dramatically, when the ductus finally closes, usually within the 1st few wk of life.

Cyanotic Congenital Heart Lesions The cyanotic group of congenital heart lesions can also be further divided according to pathophysiology: where pulmonary blood flow is decreased, usually from an obstruction to right ventricular outflow (tetralogy of Fallot, tetralogy with pulmonary atresia, or pulmonary atresia with an intact septum), or an obstruction to right ventricular inflow (tricuspid atresia), or total anomalous pulmonary venous return (TAPVR) with obstruction; or where pulmonary blood flow is increased and where oxygenated and deoxygenated blood are mixing (transposition of the great arteries, single ventricle, truncus arteriosus, TAPVR without obstruction). The chest radiograph is a valuable tool

for initial differentiation between these 2 categories.

Cyanotic Lesions With Decreased Pulmonary Blood Flow For cyanosis to occur, these lesions must include both an obstruction to pulmonary blood flow (at the tricuspid valve or pulmonary valve level) and a pathway by which systemic venous blood can shunt from right to left and enter the systemic circulation (via a patent foramen ovale, ASD, or VSD). Common lesions in this group include tricuspid atresia, tetralogy of Fallot, tetralogy of Fallot with pulmonary atresia, pulmonary atresia with intact septum, and various forms of single ventricle with pulmonary stenosis or atresia (see Chapter 457 ). In these lesions, the degree of cyanosis depends on the degree of obstruction to pulmonary blood flow. If the obstruction is mild, cyanosis may be absent at rest. These patients may have hypercyanotic (“tet”) spells during conditions of stress. In contrast, if the obstruction is severe, pulmonary blood flow may be totally dependent on patency of the ductus arteriosus. When the ductus closes in the 1st few days of life, the neonate experiences profound hypoxemia.

Cyanotic Lesions With Increased Pulmonary Blood Flow This group of lesions is not associated with obstruction to pulmonary blood flow. Cyanosis is caused by either abnormal ventricular-arterial connections or total mixing of systemic venous (deoxygenated) and pulmonary venous (oxygenated) blood within the heart (see Chapter 458 ). Transposition of the great arteries (or vessels ) is the most common of the former group of lesions. In this condition the aorta arises from the right ventricle, and the pulmonary artery arises from the left ventricle. Systemic venous blood returning to the right atrium is pumped directly back to the body, and oxygenated blood returning from the lungs to the left atrium is pumped back into the lungs. The persistence of fetal pathways (foramen ovale and ductus arteriosus) allows for some degree of mixing in the immediate newborn period, keeping the systemic saturation from falling precipitously when the ductus begins to close; these infants can become extremely cyanotic. Total mixing lesions include cardiac defects with a common atrium or ventricle, TAPVR, and truncus arteriosus (see Chapter 458 ). In this group,

deoxygenated systemic venous blood and oxygenated pulmonary venous blood mix completely in the heart and, as a result, the oxygen saturation is equal in the pulmonary artery and aorta. If pulmonary blood flow is not obstructed, these infants have a combination of cyanosis and pulmonary overcirculation leading to heart failure. In contrast, if pulmonary stenosis is present, these infants may have cyanosis alone, similar to patients with tetralogy of Fallot.

Bibliography Bouma BJ, Mulder BJ. Changing landscape of congenital heart disease. Circ Res . 2017;120(6):908–922. Bradshaw EA, Martin GR. Screening for critical congenital heart disease: advancing detection in the newborn. Curr Opin Pediatr . 2012;24:603–608. Brooks PA, Penny DJ. Management of the sick neonate with suspected heart disease. Early Hum Dev . 2008;84:155–159. Centers for Disease Control and Prevention. Newborn screening for critical congenital heart disease: potential roles of birth defects surveillance programs—United States, 2010–1011. MMWR . 2012;61:849–852. Ewer AK, Martin GR. Newborn pulse oximetry screening: which algorithm is best? Pediatrics . 2016;138(5):e20161206. Frank LH, Bradshaw E, Beekman R, et al. Critical congenital heart disease screening using pulse oximetry. J Pediatr . 2013;162:445–453. Hu XJ, Ma XJ, Zhao QM, et al. Pulse oximetry and auscultation for congenital heart disease detection. Pediatrics . 2017;140(4):e20171154. Johnson BA, Ades A. Delivery room and early postnatal management of neonates who have prenatally diagnosed congenital heart disease. Clin Perinatol . 2005;32:921–946. Lister G, Moreau G, Moss M, et al. Effects of alterations of oxygen transport on the neonate. Semin Perinatol . 1984;8:8192–8204.

Lister G, Pitt BR. Cardiopulmonary interactions in the infant with congenital heart disease. Clin Chest Med . 1983;4:219– 232. Manzoni P, Martin GR, Luna MS, et al. Pulse oximetry screening for critical congenital heart defects: a European consensus statement. Lancet . 2017;1:88–90. Martin GR, Beekman RH III, Bradshaw Mikula E, et al. Implementing recommended screening for critical congenital heart disease. Pediatrics . 2013;132:e185–e192. Martin J, Shekerdemian LS. The monitoring of venous saturations of oxygen in children with congenitally malformed hearts. Cardiol Young . 2009;19:34–39. Rudolph AM. Congenital diseases of the heart: clinicalphysiological considerations . ed 3. Wiley-Blackwell: New York; 2009. Schena F, Picciolli I, Agosti M, et al. Perfusion index and pulse oximetry screening for congenital heart defects. J Pediatr . 2017;183:74–79. Thangaratinam S, Brown K, Zamora J, et al. Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and metaanalysis. Lancet . 2012;379:2459–2464. Triedman JK, Newburger JW. Trends in congenital heart disease: the next decade. Circulation . 2016;133(25):2716– 2733.

CHAPTER 453

Acyanotic Congenital Heart Disease Left-to-Right Shunt Lesions 453.1

Atrial Septal Defect Daniel Bernstein

Atrial septal defects (ASDs ) can occur in any portion of the atrial septum —secundum , primum , or sinus venosus —depending on which embryonic septal structure has failed to develop normally (Fig. 453.1 ) (see Chapter 447 ). Less often, the atrial septum may be almost absent, with the creation of a functional single atrium. Isolated secundum ASDs account for approximately 7% of congenital heart defects. The majority of cases of ASD are sporadic; autosomal dominant inheritance does occur as part of the Holt-Oram syndrome (hypoplastic or absent thumbs, radii, triphalangism, phocomelia, first-degree heart block, ASD) or in families with both secundum ASD and heart block (see Table 451.2 ).

FIG. 453.1 Atrial septal defects (ASDs). A, Schematic diagram outlining the different types of interatrial shunting that can be encountered. Note that only the central defect is suitable for device closure. B, Left panel, Subcostal right anterior oblique view of a secundum ASD (asterisk) that is suitable for device closure. Right panel, Specimen as seen in a similar view, outlining the landmarks of the defect. C, Left image, Transesophageal echocardiogram with color flow before device closure. Right image, Taken following release of an Amplatzer device. D, Montage of echocardiographic interatrial communications that are not secundum ASDs (asterisks) and therefore not suitable for device closure. Top left image, Coronary sinus defect caused by unroofing; top right image, superior sinus venosus defect; bottom left image, inferior sinus venosus defect; bottom right image, ASD in the setting of an atrioventricular septal defect. AO, Aorta; CS, coronary sinus; Eus, eustachian; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; RA, right atrium; SVC, superior vena cava; Tric, tricuspid. (From Webb GD, Smallhorn JF, Therrien J, Redington AN: Congenital heart disease in the adult and pediatric patient. In Braunwald's heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018, Elsevier, Fig 75.17, p 1536.)

An isolated valve-incompetent patent foramen ovale (PFO) is a common echocardiographic finding during infancy. It is usually of no hemodynamic significance and is not considered an ASD; a PFO may play an important role if other structural heart defects are present. If another cardiac anomaly is causing increased right atrial pressure (pulmonary stenosis or atresia, tricuspid valve abnormalities, right ventricular dysfunction), venous blood may shunt across the PFO into the left atrium with resultant cyanosis. Because of the anatomic structure of the PFO, left-to-right shunting is unusual outside the immediate newborn period. In the presence of a large volume load or a hypertensive left atrium (e.g., secondary to mitral stenosis), the foramen ovale may be sufficiently dilated to result in a significant atrial left-to-right shunt. A valve-competent but probe-patent (able to be pushed opened with a catheter) PFO may be present in 15–30% of adults. An isolated PFO does not require surgical treatment, although it may be a risk for paradoxical (right to left) systemic embolization. Device closure of these defects is one treatment option considered in adults with a history of thromboembolic stroke.

Bibliography

Beda RD, Gill EA Jr. Patent foramen ovale: does it play a role in the pathophysiology of migraine headache? Cardiol Clin . 2005;23:91–96. Benson DW, Silberbach GM, Kavanaugh-McHugh A, et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest . 1999;104:1567–1573. Kharouf R, Luxenberg DM, Khalid O, et al. Atrial septal defect: spectrum of care. Pediatr Cardiol . 2008;29:271–280. Masura J, Gavora P, Podnar T. Long-term outcome of transcatheter secundum-type atrial septal defect closure using Amplatzer septal occluders. J Am Coll Cardiol . 2005;45:505–507. Messé SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med . 2013;368:1152–1153. Radzik D, Davignon A, van Doesburg N, et al. Predictive factors for spontaneous closure of atrial septal defects diagnosed in the first 3 months of life. J Am Coll Cardiol . 1993;22:851–853. Riggs T, Sharp SE, Batton D, et al. Spontaneous closure of atrial septal defects in premature vs full term neonates. Pediatr Cardiol . 2000;21:129–134. Saito T, Ohta K, Nakayama Y, et al. Natural history of mediumsized atrial septal defect in pediatric cases. J Cardiol . 2012;60:248–251. Steimle JD, Moskowitz IP. TBX5: a key regulator of heart development. Curr Top Dev Biol . 2017;122:195–221. Xu YJ, Qiu XB, Yuan F, et al. Prevalence and spectrum of NKX2.5 mutations in patients with congenital atrial septal defect and atrioventricular block. Mol Med Rep . 2017;15(4):2247–2254. Yew G, Wilson NJ. Transcatheter atrial septal defect closure with the Amplatzer septal occluder: five-year follow-up.

Catheter Cardiovasc Interv . 2005;64:193–196.

453.2

Ostium Secundum Defect Daniel Bernstein

An ostium secundum defect in the region of the fossa ovalis is the most common form of ASD and is associated with structurally normal atrioventricular (AV) valves (see Fig. 453.1 ). Mitral valve prolapse has been described in association with this defect but is rarely an important clinical consideration. Secundum ASDs may be single or multiple (fenestrated atrial septum), and openings ≥2 cm in diameter are common in symptomatic older children. Large defects may extend inferiorly toward the inferior vena cava (IVC) and ostium of the coronary sinus, superiorly toward the superior vena cava (SVC), or posteriorly. Females outnumber males 3 : 1 in incidence. Partial anomalous pulmonary venous return (PAPVR), usually of the right upper pulmonary vein, may be an associated lesion.

Pathophysiology The degree of left-to-right shunting depends on the size of the defect, the relative compliance of the right and left ventricles, and the relative vascular resistance in the pulmonary and systemic circulations. In large defects, a considerable shunt of oxygenated blood flows from the left to the right atrium (Fig. 453.2 ). This blood is added to the usual venous return to the right atrium and is pumped by the right ventricle to the lungs. With large defects, the ratio of pulmonary-tosystemic blood flow (Qp:Qs) is usually between 2 : 1 and 4 : 1. The paucity of symptoms in infants with ASDs is related to the structure of the right ventricle in early life, when its muscular wall is thick and less compliant, thus limiting the left-to-right shunt. As the infant becomes older and pulmonary vascular

resistance (PVR) drops, the right ventricular (RV) wall becomes thinner, and the left-to-right shunt across the ASD increases. The increased blood flow through the right side of the heart results in enlargement of the right atrium and ventricle and dilation of the pulmonary artery. The left atrium may also be enlarged as the increased pulmonary blood flow returns to the left atrium, but the left ventricle and aorta are normal in size. Despite the large pulmonary blood flow, pulmonary arterial pressure is usually initially normal because of the absence of a highpressure communication between the pulmonary and systemic circulations. PVR remains low throughout childhood, although it may begin to increase in adulthood and may eventually result in reversal of the shunt and clinical cyanosis.

FIG. 453.2 Physiology of atrial septal defect (ASD). Circled numbers represent oxygen saturation (SO 2 ) values. The numbers next to the arrows represent volumes of blood flow (in L/min/m2 ). This illustration shows a hypothetical patient with a pulmonary-tosystemic blood flow ratio (Qp:Qs) of 2 : 1. Desaturated blood enters the right atrium from the vena cava at a volume of 3 L/min/m2 and mixes with an additional 3 L of fully saturated blood shunting left to right across the ASD; the result is an increase in SO 2 in the right atrium. Six liters of blood flows through the tricuspid valve and causes a middiastolic flow rumble. SO 2 may be slightly higher in the right ventricle because of incomplete mixing at the atrial level. The full 6 L flows across the right ventricular outflow tract and causes a systolic ejection flow murmur. Six liters returns to the left atrium, with 3 L shunting left to right across the defect and 3 L crossing the mitral valve to be ejected by the left ventricle into the ascending aorta (normal cardiac output).

Clinical Manifestations A child with an ostium secundum ASD is most often asymptomatic; the lesion is often discovered inadvertently during physical examination. Even an extremely large secundum ASD rarely produces clinically evident heart failure in childhood. On closer evaluation, however, younger children may show subtle failure to thrive, and older children may have varying degrees of exercise intolerance. Often, the degree of limitation may go unnoticed by the family until after repair, when the child's growth or activity level greatly increases (e.g., “I never knew she could run so fast”). The physical findings of an ASD are usually characteristic but fairly subtle and require careful examination of the heart, with special attention to the heart sounds. Examination of the chest may reveal a mild left precordial bulge. An RV systolic lift may be palpable at the left sternal border. Sometimes a pulmonic ejection click can be heard. In most patients with an ASD, the characteristic finding is that the second heart sound (S2 ) is widely split and fixed in its splitting during all phases of respiration. Normally, the duration of RV ejection varies with respiration, with inspiration increasing RV volume and delaying closure of the pulmonary valve, widening the S2 split. With an ASD, RV diastolic volume is constantly increased, and ejection time is prolonged throughout all phases of respiration. A systolic ejection murmur is heard; it is usually no greater than a grade 3/6, medium pitched, without harsh qualities, seldom accompanied by a thrill, and best heard at the left middle and upper sternal border. It is produced by the increased flow across the RV outflow tract into the pulmonary artery. Flow across the ASD between the 2 low-pressure atria does not cause an audible murmur. A short, rumbling mid-diastolic murmur produced by the increased volume of blood flow across the tricuspid valve is often audible at the lower left sternal border. This finding, which may be subtle and is heard best with the bell of the stethoscope, usually indicates a Qp:Qs ratio of at least 2 : 1.

Diagnosis The chest radiograph shows varying degrees of enlargement of the right ventricle and atrium, depending on the size of the shunt. The pulmonary artery is enlarged, and pulmonary vascularity is increased. These signs vary and may not

be conspicuous in mild cases. Cardiac enlargement is often best appreciated on the lateral view because the right ventricle protrudes anteriorly as its volume increases. The electrocardiogram (ECG) shows RV volume overload: the QRS axis may be normal or exhibit right axis deviation, and a minor RV conduction delay (rsR′ pattern in the right precordial leads) may be present. Right ventricular hypertrophy would be unusual in the absence of pulmonary hypertension or other lesions (e.g., valvar pulmonic stenosis). The echocardiogram shows findings characteristic of RV volume overload, including an increased RV end-diastolic dimension and flattening and abnormal motion of the ventricular septum (see Fig. 453.1 ). A normal septum moves posteriorly during systole and anteriorly during diastole (synchronous with the left ventricular contractions). With RV overload and normal PVR, septal motion is either flattened or reversed—that is, anterior movement in systole. The location and size of the ASD are readily appreciated by two-dimensional (2D) scanning, with a characteristic brightening of the echo image seen at the edge of the defect caused by the increased reflectivity of ultrasound at the tissue-blood interface (T-artifact). The shunt is confirmed by pulsed and color flow Doppler. The normal entry of all pulmonary veins into the left atrium should be confirmed. Patients with the classic features of a hemodynamically significant ASD on physical examination and chest radiography, in whom echocardiographic identification of an isolated secundum ASD is made, need not undergo diagnostic catheterization before repair, with the exception of an older patient, in whom PVR may be a concern. If pulmonary vascular disease is suspected, cardiac catheterization confirms the presence of the defect and allows measurement of the shunt ratio and pulmonary pressure and resistance. If catheterization is performed, usually at the time of device closure (see Treatment ), the oxygen content of blood from the right atrium will be much higher than that from the SVC. This feature is not specifically diagnostic because it may occur with PAPVR to the right atrium, with a ventricular septal defect (VSD) in the presence of tricuspid insufficiency, with AV septal defects associated with left ventricular–to–right atrial shunts, and with aorta–to–right atrial communications (ruptured sinus of Valsalva aneurysm). Pressure in the right side of the heart is usually normal, but small to moderate pressure gradients (95th percentile for age. It is important to determine the BP in each arm; a BP higher in the right than the left arm suggests involvement of the left subclavian artery in the area of coarctation. Occasionally, the right subclavian may arise anomalously from below the area of coarctation and result in a left arm BP that is higher than the right. With exercise, a more prominent rise in systemic BP occurs, and the upper-to-lower extremity pressure gradient will increase. The precordial impulse and heart sounds are usually normal; the presence of a systolic ejection click or thrill in the suprasternal notch suggests a bicuspid aortic valve (present in 70% of cases). A short systolic murmur is often heard along the left sternal border at the 3rd and 4th intercostal spaces. The murmur is well transmitted to the left infrascapular area and occasionally to the neck. Often, the typical murmur of mild aortic stenosis can be heard in the 3rd right intercostal space. Occasionally, more significant degrees of obstruction are noted across the aortic valve. The presence of a low-pitched mid-diastolic murmur at the apex suggests mitral valve stenosis. In older patients with well-developed collateral blood flow, systolic or continuous murmurs may be heard over the left and right sides of the chest laterally and posteriorly. In these patients, a palpable thrill can occasionally be appreciated in the intercostal spaces on the back. Neonates or infants with more severe coarctation, usually including some degree of transverse arch hypoplasia, initially have signs of lower-body hypoperfusion, acidosis, and severe heart failure. These signs may be delayed days or weeks until after closure of the ductus arteriosus. If detected before ductal closure, patients may exhibit differential cyanosis, best demonstrated by simultaneous oximetry of the upper and lower extremities. On physical

examination the heart is large, and a systolic murmur is heard along the left sternal border with a loud S2 .

Diagnosis Findings on x-ray examination depend on the age of the patient and on the effects of hypertension and the collateral circulation. Cardiac enlargement and pulmonary congestion are noted in infants with severe coarctation. During childhood, the findings are not striking until after the 1st decade, when the heart tends to be mildly or moderately enlarged because of LV prominence. The enlarged left subclavian artery typically produces a prominent shadow in the left superior mediastinum. Notching of the inferior border of the ribs from pressure erosion by enlarged collateral vessels is common by late childhood. In most patients the descending aorta has an area of poststenotic dilation. The ECG is usually normal in young children but reveals evidence of LV hypertrophy in older patients. Neonates and young infants display right or biventricular hypertrophy. The segment of coarctation can generally be visualized by 2D echocardiography (Fig. 454.8 ); associated anomalies of the mitral and aortic valve can also be demonstrated. The descending aorta is hypopulsatile. Color Doppler is useful for demonstrating the specific site of the obstruction. Pulsed and continuous wave Doppler studies determine the pressure gradient directly at the area of coarctation; in the presence of a PDA, however, the severity of the narrowing may be underestimated. CT and MRI are valuable noninvasive tools for evaluation of coarctation when the echocardiogram is equivocal. Cardiac catheterization with selective left ventriculography and aortography is useful in occasional patients with additional anomalies and as a means of visualizing collateral blood flow. In cases that are well defined by echocardiography, CT, or MRI, diagnostic catheterization is not usually required before surgery.

FIG. 454.8 Echocardiogram demonstrating coarctation of the aorta with hypoplastic transverse arch. A, Suprasternal notch 2D echocardiogram showing marked narrowing beginning just distal to the brachiocephalic artery. B, Color Doppler demonstrates turbulent flow in the juxtaductal area (arrow). AscAo, Ascending aorta; BR, brachiocephalic artery; LCA, left carotid artery; LSCA, left subclavian artery.

Treatment In neonates with severe coarctation of the aorta, closure of the ductus often results in hypoperfusion, acidosis, and rapid deterioration. These patients should be given an infusion of prostaglandin E1 to reopen the ductus and reestablish adequate lower-extremity blood flow. Once a diagnosis has been confirmed and the patient stabilized, surgical repair should be performed. Older infants with heart failure but good perfusion should be managed with anticongestive measures to improve their clinical status before surgical intervention. There is usually no reason to delay surgical repair waiting for patient growth; successful repairs have been performed in small premature infants.

Older children with significant coarctation of the aorta should be treated relatively soon after diagnosis. Delay is unwarranted, especially after the 2nd decade of life, when the operation may be less successful because of decreased LV function and degenerative changes in the aortic wall. Nevertheless, if cardiac reserve is sufficient, satisfactory repair is possible well into mid-adult life. The procedure of choice for isolated juxtaductal coarctation of the aorta is controversial. Surgery remains the treatment of choice at most centers, and several surgical techniques are used. The area of coarctation can be excised and a primary reanastomosis performed. Most often, the transverse aorta is splayed open and an “extended end-to-end” anastomosis performed to increase the effective cross-sectional area of the repair. The subclavian flap procedure, which involves division of the left subclavian artery and its incorporation into the wall of the repaired coarctation, has fallen out of favor because of a higher degree of residual stenosis. Some centers favor a patch aortoplasty, in which the area of coarctation is enlarged with a roof of prosthetic material. The use of primary angioplasty for native coarctation remains controversial because of concern over subsequent recoarctation, aortic dissection, and aneurysm development. The use of primary stent placement is under evaluation and is most useful in conditions where surgical intervention may be associated with increased risk in patients with severe LV dysfunction. In adolescents and adults, primary stenting after angioplasty has been successful for native coarctation and restenosis (Fig. 454.9 ). In older children, a 2nd, larger stent may be needed later to accommodate aortic growth.

FIG. 454.9 Coarctation of the aorta. A, CT angiogram of coarcation. B, 3D reconstruction. Angiograms of the coarctation before (C) and after (D) stenting (arrows). AO, Aorta. (Adapted from Webb GD, Smallhorn JF, Therrien J, Redington AN: Congenital heart disease in the adult and pediatric patient. In Braunwald's heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018, Elsevier, Fig 75.41, p 1561.)

After surgery, a striking increase in the amplitude of pulsations in the lower extremities is noted. In the immediate postoperative course, “rebound” hypertension can occur and requires medical management. This exaggerated acute hypertension gradually subsides, and in most patients, antihypertensive medications can be discontinued. Residual murmurs are common and may result from associated cardiac anomalies, a residual flow disturbance across the repaired area, or collateral blood flow. Rare operative problems include spinal cord injury from aortic cross-clamping (if the collaterals are poorly developed), chylothorax, diaphragm injury, and laryngeal nerve injury. If a left subclavian flap approach is used, the radial pulse and BP in the left arm are diminished or absent.

Postcoarctectomy Syndrome Postoperative mesenteric arteritis may be associated with acute hypertension and abdominal pain in the immediate postoperative period. The pain varies in severity and may occur in conjunction with anorexia, nausea, vomiting, leukocytosis, intestinal hemorrhage, bowel necrosis, and small bowel obstruction. Relief is usually obtained with antihypertensive drugs (e.g., nitroprusside, esmolol, captopril) and intestinal decompression; surgical exploration is rarely required for bowel obstruction or infarction.

Prognosis Although restenosis in older patients after coarctectomy is rare, a significant number of infants operated on before 1 yr of age require revision later in childhood. All patients should be monitored carefully for the development of recoarctation and an aortic anastomotic aneurysm. Should recoarctation occur, balloon angioplasty is the procedure of choice. In these patients, scar tissue from previous surgery may make reoperation more difficult yet makes balloon angioplasty safer because of the lower incidence of aneurysm formation. Relief of obstruction with this technique is usually excellent. Intravascular stents are typically used, especially in adolescents and young adults, with generally excellent results. Repair of coarctation in the 2nd decade of life or beyond may be associated with a higher incidence of premature cardiovascular disease, even in the absence of residual cardiac abnormalities. Early onset of adult chronic hypertension may occur, even in patients with adequately resected coarctation. Abnormalities of the aortic valve are present in most patients. Bicuspid aortic valves are common but do not generally produce clinical signs unless the stenosis is significant. The association of a PDA and coarctation of the aorta is also common. VSDs and ASDs may be suspected by signs of a left-to-right shunt; they are exacerbated by the increased resistance to flow through the left side of the heart. Mitral valve abnormalities are also occasionally seen, as is subvalvular aortic stenosis. Severe neurologic damage or even death may rarely occur from associated cerebrovascular disease. Subarachnoid or intracerebral hemorrhage may result from rupture of congenital aneurysms in the circle of Willis, rupture of other vessels with defective elastic and medial tissue, or rupture of normal vessels;

these accidents are secondary to hypertension. Children with PHACE syndrome (posterior brain fossa anomalies, facial hemangiomas, arterial anomalies, cardiac anomalies and aortic coarctation, eye anomalies syndrome) may have strokes (see Table 449.2 ). Abnormalities of the subclavian arteries may include involvement of the left subclavian artery in the area of coarctation, stenosis of the orifice of the left subclavian artery, and anomalous origin of the right subclavian artery. Untreated, the great majority of older patients with coarctation of the aorta would succumb between ages 20 and 40 yr; some live well into middle life without serious disability. The common serious complications are related to systemic hypertension, which may result in premature coronary artery disease, heart failure, hypertensive encephalopathy, or intracranial hemorrhage. Heart failure may be worsened by associated anomalies. Infective endocarditis or endarteritis is a significant complication in adults. Aneurysms of the descending aorta or the enlarged collateral vessels may develop.

Bibliography Beaton AZ, Nguyen T, Lai WW, et al. Relation of coarctation of the aorta to the occurrence of ascending aortic dilation in children and young adults with bicuspid aortic valves. Am J Cardiol . 2009;103:266–270. Dijkema EJ, Leiner T, Grotenhuis HB. Diagnosis, imaging and clinical management of aortic coarctation. Heart . 2017;103:1148–1155. Egan M, Holzer RJ. Comparing balloon angioplasty, stenting and surgery in the treatment of aortic coarctation. Expert Rev Cardiovasc Ther . 2009;7:1401–1412. Fernandes JF, Goubergrits L, Brüning J, et al. CARDIOPROOF Consortium. Beyond pressure gradients: the effects of intervention on heart power in aortic coarctation. PLoS ONE . 2017;12(1):e0168487. Hall DJ, Wallis GA, Co-Vu JG, et al. Coarctation of the aorta in late adolescence. J Pediatr . 2013;162:646. Karamlou T, Bernasconi A, Jaeggi E, et al. Factors associated

with arch reintervention and growth of the aortic arch after coarctation repair in neonates weighing less than 2.5 kg. J Thorac Cardiovasc Surg . 2009;137:1163–1167. Metry DW, Dowd CF, Barkovich J, et al. The many faces of PHACE syndrome. J Pediatr . 2001;139:117–123. O'Sullivan JJ, Derrick G, Darnell R. Prevalence of hypertension in children after early repair of coarctation of the aorta: a cohort study using casual and 24-hour blood pressure measurement. Heart . 2002;88:163–166. Roeleveld PP, Zwijsen EG. Treatment strategies for paradoxical hypertension following surgical correction of coarctation of the aorta in children. World J Pediatr Congenit Heart Surg . 2017;8(3):321–331. Saxena A. Recurrent coarctation: interventional techniques and results. World J Pediatr Congenit Heart Surg . 2015;6(2):257–265. Senzaki H, Iwamoto Y, Ishido H, et al. Ventricular-vascular stiffening in patients with repaired coarctation of aorta: integrated pathophysiology of hypertension. Circulation . 2008;118(Suppl 14):S191–S198. Shone JD, Sellers RD, Anderson RC, et al. The developmental complex of “parachute mitral valve,” supravalvar ring of left atrium, subaortic stenosis, and coarctation of the aorta. Am J Cardiol . 1963;11:714–725. Vigneswaran TV, Sinha MD, Valverde I, et al. Hypertension in coarctation of the aorta: challenges in diagnosis in children. Pediatr Cardiol . 2017; 10.1007/s00246-017-1739-x . Vijayalakshmi K, Griffiths A, Hasan A, et al. Late hazards after repair of coarctation of the aorta. BMJ . 2008;336:772–773. Zussman ME, Hirsch R, Herbert C, Stapleton GE. Transcatheter intervention for coarctation of the aorta. Cardiol Young . 2016;26(8):1563–1567.

454.7

Coarctation With Ventricular Septal Defect Daniel Bernstein

Coarctation in the presence of a VSD results in both increased preload and afterload on the left ventricle, and patients with this combination of defects will be recognized either at birth or in the 1st mo of life and often have intractable cardiac failure. The magnitude of the left-to-right shunt through a VSD depends on the ratio of pulmonary to systemic vascular resistance. In the presence of coarctation, resistance to systemic outflow is enhanced by the obstruction, and the volume of the shunt is greatly increased. The clinical picture is that of a seriously ill infant with tachypnea, failure to thrive, and typical findings of heart failure. Often, the BP difference between the upper and lower extremities is not very marked because cardiac output may be low. Medical management should be used to stabilize the patient initially, but should not be used to delay corrective surgery inordinately. In most cases, coarctation is the major anomaly causing the severe symptoms, and resection of the coarcted segment results in striking improvement. Many centers routinely repair both the VSD and coarctation at the same operation through a midline sternotomy using cardiopulmonary bypass. Some centers repair the coarctation through a left lateral thoracotomy and, at the same time, place a pulmonary artery band to decrease the ventricular-level shunt. This may be performed when a complicated VSD is present (multiple VSDs, apical muscular VSD), to avoid open heart surgery during infancy for these complex ventricular septal abnormalities.

454.8

Coarctation With Other Cardiac Anomalies and Interrupted Aortic Arch Daniel Bernstein

Coarctation often occurs in infancy in association with other major cardiovascular anomalies, including hypoplastic left heart, severe mitral or aortic valve disease, transposition of the great arteries, and variations of double-outlet or single ventricle. The clinical manifestations depend on the effects of the associated malformations, as well as on the coarctation itself. Coarctation of the aorta associated with severe mitral and aortic valve disease may have to be treated within the context of the hypoplastic left heart syndrome (see Chapter 458.10 ), even if the LV chamber is not severely hypoplastic. Such patients usually have a long segment of narrow, transverse aortic arch in addition to an isolated coarctation at the site of the ductus arteriosus. Coarctation of the aorta with transposition of the great arteries or single ventricle may be repaired alone or in combination with other corrective or palliative measures. Complete interruption of the aortic arch is the most severe form of coarctation and is usually associated with other intracardiac pathology. Interruption may occur at any level, although it is most often seen between the left subclavian artery and the insertion of the ductus arteriosus (type A ), followed in frequency by those between the left subclavian and left carotid arteries (type B ), or between the left carotid and brachiocephalic arteries (type C ). In newborns with an interrupted aortic arch, the ductus arteriosus provides the sole source of blood flow to the descending aorta, and differential oxygen saturations between the right arm (normal saturation) and the legs (decreased saturation) is noted. When the ductus begins to close, severe congestive heart failure, lower-extremity hypoperfusion, anuria, and shock usually develop. Patients with an interrupted aortic arch can be supported with prostaglandin E1 to keep the ductus patent before surgical repair. As one of the conotruncal

malformations, an interrupted aortic arch, especially type B, can be associated with DiGeorge syndrome (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia). Cytogenetic analysis using fluorescence in situ hybridization demonstrates deletion of a segment of chromosome 22q11, known as the DiGeorge critical region .

454.9

Congenital Mitral Stenosis Daniel Bernstein

Congenital mitral stenosis is a rare anomaly that can be isolated or associated with other defects, the most common being subvalvar and valvar aortic stenosis and coarctation of the aorta (Shone complex ). The mitral valve may be funnel shaped, with thickened leaflets and chordae tendineae that are shortened and deformed. Other mitral valve anomalies associated with stenosis include parachute mitral valve, caused by a single papillary muscle, and double-orifice mitral valve. If the stenosis is moderate to severe, symptoms usually appear within the 1st 2 yr of life. These infants have failure to thrive and various degrees of dyspnea and pallor. In some patients, wheezing may be a dominant symptom, and a misdiagnosis of bronchiolitis or reactive airway disease may have been made. Heart enlargement because of dilation and hypertrophy of the right ventricle and left atrium is common. Most patients have rumbling apical diastolic murmurs, but the auscultatory findings may be relatively obscure. S2 is loud and split. An opening snap of the mitral valve may be present. The ECG reveals RVH and may show bifid or spiked P waves indicative of left atrial enlargement. Radiographs usually show left atrial and RV enlargement and pulmonary congestion in a perihilar or venous pattern. The echocardiogram is characteristic and shows thickened mitral valve leaflets, a significant reduction of the mitral valve orifice, abnormal papillary muscle structure (or a single papillary muscle), and an enlarged left atrium with a normal or small left ventricle. A double orifice

may also be visualized. Doppler studies demonstrate a mean pressure gradient across the mitral orifice. Associated anomalies such as aortic stenosis and coarctation can be evaluated. Cardiac catheterization is usually performed to confirm the transmitral pressure gradient before surgery. An increase in RV, pulmonary artery, and pulmonary capillary wedge pressure can be noted. Angiocardiography shows delayed emptying of the left atrium and the small mitral orifice. The results of surgical treatment depend on the anatomy of the valve, but if the mitral orifice is significantly hypoplastic, reduction of the gradient may be difficult. In some patients, a mitral valve prosthesis is required, and if the valve orifice is too small, the prosthesis may be placed in the supramitral position. However, whatever prosthesis is used, it must be replaced serially as the child grows. These patients must be managed by anticoagulation with warfarin, and complications of excessive and insufficient anticoagulation are fairly common in infancy. Transcatheter balloon valvuloplasty has been used as a palliative procedure with disappointing results, except in the situation of rheumatic mitral stenosis. Recent experience using the Melody stent-valve in selected patients in the mitral position are encouraging.

Bibliography Chandrashekhar Y, Westaby S, Narula J. Mitral stenosis. Lancet . 2009;374:1271–1283. Del Nido PJ, Baird C. Congenital mitral valve stenosis: anatomic variants and surgical reconstruction. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu . 2012;15:69–74. Delmo Walter EM, Javier M, Hetzer R. Repair of parachute and hammock valve in infants and children: early and late outcomes. Semin Thorac Cardiovasc Surg . 2016;28(2):448– 459. Freud LR, Marx GR, Marshall AC, et al. Assessment of the Melody valve in the mitral position in young children by echocardiography. J Thorac Cardiovasc Surg . 2017;153(1):153–160.e1. Marino BS, Kruge LE, Cho CJ, et al. Parachute mitral valve:

morphologic descriptors, associated lesions, and outcomes after biventricular repair. J Thorac Cardiovasc Surg . 2009;137:385–393. Selamet Tierney ES, Pigula FA, et al. Mitral valve replacement in infants and children 5 years of age or younger: evolution in practice and outcome over three decades with a focus on supra-annular prosthesis implantation. J Thorac Cardiovasc Surg . 2008;136:954–961. Silverman NH. Echocardiography of congenital mitral valve disorders: echocardiographic-morphological comparisons. Cardiol Young . 2014;24(6):1030–1048. Toscano A, Pasquini L, Iacobelli R, et al. Congenital supravalvar mitral ring: an underestimated anomaly. J Thorac Cardiovasc Surg . 2009;137:538–542.

454.10

Pulmonary Venous Hypertension Daniel Bernstein

A variety of lesions may give rise to chronic pulmonary venous hypertension, which when extreme may result in pulmonary arterial hypertension and rightsided heart failure. These lesions include congenital mitral stenosis , mitral insufficiency , total anomalous pulmonary venous return with obstruction , left atrial myxomas , cor triatriatum , individual pulmonary vein stenosis , and supravalvular mitral rings . Early symptoms can be confused with chronic pulmonary disease such as asthma because of a lack of specific cardiac findings on physical examination. Subtle signs of pulmonary hypertension may be present. The ECG shows RVH with spiked P waves. Radiographic studies reveal cardiac enlargement and prominence of the pulmonary veins in the hilar region,

the right ventricle and atrium, and the main pulmonary artery; the left atrium is normal in size or only slightly enlarged. The echocardiogram may demonstrate left atrial myxoma, cor triatriatum, stenosis of 1 or more pulmonary veins, or a mitral valve abnormality, especially supravalvar mitral ring. Cardiac catheterization excludes the presence of a shunt and demonstrates pulmonary hypertension with elevated pulmonary arterial wedge pressure. Left atrial pressure is normal if the lesion is at the level of the pulmonary veins, but it is elevated if the lesion is at the level of the mitral valve. Selective pulmonary arteriography usually delineates the anatomic lesion. Cor triatriatum, left atrial myxoma, and supravalvular mitral rings can all be successfully managed surgically. The differential diagnosis includes pulmonary venoocclusive disease , an idiopathic process that produces obstructive lesions in 1 or more pulmonary veins. The cause is uncertain, and disease that begins in 1 vein can spread to others. Although it is usually encountered in patients after repair of obstructed total anomalous pulmonary venous return (see Chapter 458.7 ), it can occur in the absence of congenital heart disease. The patient initially presents with leftsided heart failure on the basis of congested lungs with apparent pulmonary edema. Dyspnea, fatigue, and pleural effusions are common. Left atrial pressure is normal, but pulmonary arterial wedge pressure is usually elevated. A normal wedge pressure may be encountered if collaterals have formed or the wedge recording is performed in an uninvolved segment. Angiographically, the pulmonary veins return normally to the left atrium, but one or more pulmonary veins are narrowed, either focally or diffusely. Studies using lung biopsy have demonstrated pulmonary venous and, occasionally, arterial involvement. Pulmonary veins and venules demonstrate fibrous narrowing or occlusion, and pulmonary artery thrombi may be present. Attempts at surgical repair, balloon dilation, and transcatheter stenting have not significantly improved the generally poor prognosis of these patients. Clinical trials of antiproliferative chemotherapy are currently in progress. Combined heart-lung transplantation is often the only alternative therapeutic option (see Chapter 470.2 ).

CHAPTER 455

Acyanotic Congenital Heart Disease Regurgitant Lesions 455.1

Pulmonary Valvular Insufficiency and Congenital Absence of the Pulmonary Valve Daniel Bernstein

Keywords pulmonary valvular insufficiency congenital absence of pulmonary valve mitral valve prolapse mitral insufficiency atrioventricular septal defect tricuspid regurgitation Ebstein anomaly Pulmonary valvular insufficiency most often accompanies other cardiovascular diseases or may be secondary to severe pulmonary hypertension .

Incompetence of the valve is an expected result after surgery for right ventricular outflow tract (RVOT) obstruction, including pulmonary valvotomy in patients with valvular pulmonic stenosis or valvotomy with infundibular resection in patients with tetralogy of Fallot . Isolated congenital insufficiency of the pulmonary valve is rare. These patients are usually asymptomatic because the insufficiency is generally mild. The prominent physical sign is a decrescendo diastolic murmur at the upper and mid-left sternal border, which has a lower pitch than the murmur of aortic insufficiency because of the lower pressure involved. Radiographs of the chest show prominence of the main pulmonary artery and, if the insufficiency is severe, right ventricular (RV) enlargement. The electrocardiogram (ECG) is normal or shows an rSR′ pattern in the right precordial leads (V1 , V2 ) and minimal RV hypertrophy. Pulsed and color Doppler studies demonstrate retrograde flow from the pulmonary artery to the right ventricle during diastole. Cardiac magnetic resonance angiography (MRA) is the best method for quantifying both RV volume and the regurgitant fraction, as well as RV systolic function (ejection fraction). Isolated pulmonary valvular insufficiency is generally well tolerated and does not require surgical treatment. When pulmonary insufficiency is severe, especially if significant tricuspid insufficiency has begun to develop, replacement with a homograft valve or transcatheter stent valve may become necessary to preserve RV function. Congenital absence of the pulmonary valve is usually associated with a ventricular septal defect (VSD), often in the context of tetralogy of Fallot (see Chapter 457.1 ). In many of these neonates, the pulmonary arteries become widely dilated and compress the bronchi, with subsequent recurrent episodes of wheezing, pulmonary collapse, and pneumonitis. The presence and degree of cyanosis are variable. Florid pulmonary valvular incompetence may not be well tolerated, and death may occur from a combination of bronchial compression, hypoxemia, and heart failure. Correction involves plication of the massively dilated pulmonary arteries, closure of the VSD, and placement of a homograft across the RVOT.

Bibliography Chelliah A, Berger JT, Blask A, et al. Clinical utility of fetal magnetic resonance imaging in tetralogy of Fallot with absent

pulmonary valve. Circulation . 2013;127:757–759. Donofrio MT, Levy RJ, Schuette JJ, et al. Specialized delivery room planning for fetuses with critical congenital heart disease. Am J Cardiol . 2013;111:737–747. Jochman JD, Atkinson DB, Quinonez LG, Brown ML. Twenty years of anesthetic and perioperative management of patients with tetralogy of Fallot with absent pulmonary valve. J Cardiothorac Vasc Anesth . 2017 [pii: S1053-0770(17)300563]. Szwast A, Tian Z, McCann M, et al. Anatomic variability and outcome in prenatally diagnosed absent pulmonary valve syndrome. Ann Thorac Surg . 2014;98(1):152–158.

455.2

Congenital Mitral Insufficiency Daniel Bernstein

Congenital mitral insufficiency is rare as an isolated lesion and is more often associated with other anomalies. It is most frequently encountered in combination with an atrioventricular septal defect , either an ostium primum defect or a complete atrioventricular septal defect (see Chapter 453.5 ). Mitral insufficiency is also seen in patients with dilated cardiomyopathy (see Chapter 466.1 ) as their left ventricular (LV) function deteriorates, secondary to dilation of the valve ring. Mitral insufficiency may also be encountered in conjunction with coarctation of the aorta, VSD, corrected transposition of the great vessels, anomalous origin of the left coronary artery from the pulmonary artery, or Marfan syndrome. In the absence of other congenital heart disease, endocarditis or rheumatic fever should be suspected in a patient with isolated severe mitral insufficiency (Table 455.1 ).

Table 455.1

Causes and Mechanisms of Mitral Regurgitation ORGANIC Type I* Nonischemic Endocarditis (perforation); degenerative (annular calcification); congenital (cleft leaflet) Ischemic —

Type II †

Type IIIa ‡

Degenerative (billowing/flail leaflets); endocarditis (ruptured chordae); traumatic (ruptured chord/PM); rheumatic (acute RF)

Rheumatic (chronic RF); iatrogenic (radiation/drug); inflammatory (lupus/anticardiolipin), eosinophilic (endocardial disease, endomyocardial fibrosis) —

Ruptured PM

FUNCTIONAL Type I* /TYPE IIIb ‡ Cardiomyopathy; myocarditis; leftventricular dysfunction (any cause)

Functional ischemic

* Mechanism involves normal leaflet movement. †

Mechanism involves excessive valve movement.

‡ Restricted valve movement, IIIa in diastole, IIIb in systole.

PM, Papillary muscle; RF, rheumatic fever. Adapted from Sarano ME, Akins CW, Vahanian A: Mitral regurgitation, Lancet 373:1382–1394, 2009, Table 1.

In isolated mitral insufficiency, the mitral valve annulus is usually dilated, the chordae tendineae are short and may insert anomalously, and the valve leaflets are deformed. When mitral insufficiency is severe enough to cause clinical symptoms, the left atrium enlarges as a result of the regurgitant flow, and the left ventricle becomes hypertrophied and dilated. Pulmonary venous pressure is increased, and the increased pressure ultimately results in pulmonary hypertension and RV hypertrophy and dilation. Mild lesions produce no symptoms; the only abnormal sign is the apical holosystolic murmur of mitral regurgitation. Severe regurgitation results in symptoms that can appear at any age, including poor physical development, frequent respiratory infections, fatigue on exertion, and episodes of pulmonary edema or congestive heart failure. Often, a diagnosis of reactive airways disease will have been made because of the similarity in pulmonary symptoms, including wheezing, which may be a dominant finding in infants and young children. The typical murmur of mitral insufficiency is a moderately high-pitched, apical blowing holosystolic murmur. If the insufficiency is moderate to severe, it is usually associated with a low-pitched, apical mid-diastolic rumbling murmur indicative of increased diastolic flow across the mitral valve. The pulmonic

component of the second heart sound will be accentuated in the presence of pulmonary hypertension. The ECG usually shows bifid P waves consistent with left atrial enlargement, signs of LV hypertrophy, and sometimes signs of RV hypertrophy. Radiographic examination shows enlargement of the left atrium, which at times is massive. The left ventricle is prominent, and pulmonary vascularity is normal or prominent. The echocardiogram demonstrates the enlarged left atrium and ventricle. Color Doppler demonstrates the extent of the insufficiency, and pulsed Doppler of the pulmonary veins detects retrograde flow when mitral insufficiency is severe. Cardiac catheterization shows elevated left atrial pressure. Pulmonary artery hypertension of varying severity may be present. Selective left ventriculography reveals the severity of mitral regurgitation. Mitral valvuloplasty can result in striking improvement in symptoms and heart size, but in some patients, installation of a prosthetic mechanical mitral valve may be necessary. Before surgery, associated anomalies must be identified. Clinical studies using stent-valves in the mitral position show early encouraging results in selected patients.

455.3

Mitral Valve Prolapse Daniel Bernstein

Mitral valve prolapse results from an abnormal mitral valve mechanism that causes billowing of 1 or both mitral leaflets, especially the posterior cusp, into the left atrium toward the end of systole. The abnormality is predominantly congenital but may not be recognized until adolescence or adulthood. Mitral valve prolapse is usually sporadic, is more common in girls, and may be inherited as an autosomal dominant trait with variable expression. It is common in patients with Marfan syndrome, straight back syndrome, pectus excavatum, scoliosis, Ehlers-Danlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. The dominant abnormal signs are auscultatory,

although occasional patients may have chest pain or palpitations. The apical murmur is late systolic and may be preceded by a click, but these signs may vary in the same patient, and at times, only the click is audible. In the standing or sitting position the click may occur earlier in systole, and the murmur may be more prominent in late systole. Arrhythmias may occur and are primarily unifocal or multifocal premature ventricular contractions. The ECG is usually normal but may show biphasic T waves, especially in leads II, III, aVF, and V6 ; the T-wave abnormalities may vary at different times in the same patient. The chest radiograph is normal. The echocardiogram shows a characteristic posterior movement of the posterior mitral leaflet during mid- or late systole or demonstrates pansystolic prolapse of both the anterior and posterior mitral leaflets. These echocardiographic findings must be interpreted cautiously because the appearance of minimal mitral prolapse may be a normal variant. Prolapse is more precisely defined by single or bileaflet prolapse of >2 mm beyond the long axis annular plane with or without leaflet thickening. Prolapse with valve thickening >5 mm is “classic”; a lesser degree is “nonclassic.” Two-dimensional real-time echocardiography shows that both the free edge and the body of the mitral leaflets move posteriorly in systole toward the left atrium. Doppler can assess the presence and severity of mitral regurgitation. This lesion is not progressive in childhood, and specific therapy is not indicated. Antibiotic prophylaxis is no longer recommended during surgery and dental procedures (see Chapter 464 ). Adults (men more often than women) with mitral valve prolapse are at increased risk for cardiovascular complications (sudden death, arrhythmia, cerebrovascular accident, progressive valve dilation, heart failure, and endocarditis) in the presence of thickened (>5 mm) and redundant mitral valve leaflets. Risk factors for morbidity also include poor LV function, moderate to severe mitral regurgitation, and left atrial enlargement. Often, confusion exists concerning the diagnosis of mitral valve prolapse. The high frequency of mild prolapse on the echocardiogram in the absence of clinical findings suggests that, in these cases, true mitral valve prolapse syndrome is not present. These patients and their parents should be reassured of this fact, and no special recommendations should be made regarding management or frequent laboratory studies.

Bibliography Bouknight DP, O'Rourke RA. Current management of mitral valve prolapse. Am Fam Physician . 2000;61:3343–3350 [3353–3354]. Briffa N. Surgery for degenerative mitral valve disease. BMJ . 2010;341:c5339. Feldman T, Foster E, Glower DG, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med . 2011;364:1395–1406. Gripari P, Muratori M, Fusini L, et al. Three-dimensional echocardiography: advancements in qualitative and quantitative analyses of mitral valve morphology in mitral valve prolapse. J Cardiovasc Echogr . 2014;24(1):1–9. Guy TS, Hill AC. Mitral valve prolapse. Annu Rev Med . 2012;63:277–292. Hepner ADS, Morrell H, Greaves S, et al. Prevalence of mitral valve prolapse in young athletes. Cardiol Young . 2008;18:402–404. Honda S, Kawasaki T, Shiraishi H, et al. Mitral valve prolapse revisited. Circulation . 2016;133(6):e380–e382. Judge DP, Rouf R, Habashi J, et al. Mitral valve disease in Marfan syndrome and related disorders. J Cardiovasc Transl Res . 2011;4:741–747. Maron BJ, Ackerman MJ, Nishimura RA, et al. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol . 2005;45:1340–1345. Padang R, Bagnall RD, Semsarian C. Genetic basis of familial valvular heart disease. Circ Cardiovasc Genet . 2012;5:569– 580.

455.4

Tricuspid Regurgitation Daniel Bernstein

Isolated tricuspid regurgitation is most often associated with Ebstein anomaly of the tricuspid valve . Ebstein anomaly may occur either without cyanosis or with varying degrees of cyanosis, depending on the severity of the tricuspid regurgitation and the presence of an atrial-level communication (patent foramen ovale or atrial septal defect). Older children tend to have the acyanotic form, whereas if detected in the newborn period, Ebstein anomaly is usually associated with severe cyanosis (see Chapter 457.7 ). Tricuspid regurgitation often accompanies RV dysfunction. When the right ventricle becomes dilated because of volume overload or intrinsic myocardial disease, or both, the tricuspid annulus also enlarges, with resultant valve insufficiency. This form of regurgitation may improve if the cause of the RV dilation is corrected, or it may require surgical plication of the valve annulus. Tricuspid regurgitation is also encountered in newborns with perinatal asphyxia. The cause may be related to an increased susceptibility of the papillary muscles to ischemic damage and subsequent transient papillary muscle dysfunction. Lastly, tricuspid regurgitation is seen in up to 30% of children after heart transplantation, which can be a risk factor for graft dysfunction, but is also seen as a result of valve injury caused by endomyocardial biopsy.

Bibliography Ben Sivarajan V, Chrisant MR, Ittenbach RF, et al. Prevalence and risk factors for tricuspid valve regurgitation after pediatric heart transplantation. J Heart Lung Transplant . 2008;27:494–500. Hetzer R, Javier M, Delmo Walter EM. The double-orifice

valve technique to treat tricuspid valve incompetence. J Heart Valve Dis . 2016;25(1):66–71. Sachdeva R, Fiser RT, Morrow WR, et al. Ruptured tricuspid valve papillary muscle: a treatable cause of neonatal cyanosis. Ann Thorac Surg . 2007;83:680–682.

CHAPTER 456

Cyanotic Congenital Heart Disease Evaluation of the Critically Ill Neonate With Cyanosis and Respiratory Distress Daniel Bernstein

See also Chapter 122 . A severely ill neonate with cardiorespiratory distress and cyanosis is a diagnostic challenge. The clinician must perform a rapid evaluation to determine whether congenital heart disease is a cause so that potentially lifesaving measures can be instituted. The differential diagnosis of neonatal cyanosis is presented in Table 119.2 (Chapter 119 ).

Cardiac Disease Leading to Cyanosis Congenital heart disease (CHD) produces cyanosis when obstruction to right ventricular inflow or outflow causes intracardiac right-to-left shunting or when complex anatomic defects cause an admixture of pulmonary (deoxygenated) and systemic (oxygenated) venous return in the heart. Cyanosis from pulmonary edema may also develop in patients with heart failure caused by left-to-right shunts, although the degree is usually less severe. Cyanosis may be caused by persistence of fetal pathways, such as right-to-left shunting across the foramen ovale and ductus arteriosus in the presence of pulmonary outflow tract obstruction or persistent pulmonary hypertension of the newborn (PPHN) (see Chapter 122.9 ).

Differential Diagnosis The hyperoxia test is one method of distinguishing cyanotic CHD from pulmonary disease. Neonates with cyanotic CHD usually are unable to significantly raise their arterial blood partial pressure of oxygen (PaO 2 ) during administration of 100% oxygen. This test is usually performed using a hood rather than nasal cannula or face mask, to best guarantee delivery of almost 100% oxygen to the patient. False-positive tests can occur if this is not done correctly. If the PaO 2 rises above 150 mm Hg during 100% oxygen administration, an intracardiac right-to-left shunt can usually be excluded. This is not 100% confirmative, however, because some patients with cyanotic CHD may be able to increase their PaO 2 to >150 mm Hg because of favorable intracardiac streaming patterns. In patients with pulmonary disease, PaO 2 generally increases significantly with 100% oxygen as ventilation-perfusion inequalities are overcome. In infants with cyanosis from a central nervous system disorder, the PaO 2 usually normalizes completely during artificial ventilation. Hypoxia in many heart lesions is profound and constant, whereas in respiratory disorders and in PPHN, PaO 2 often varies with time or changes in ventilator management. Hyperventilation may improve the hypoxia in neonates with PPHN and only occasionally in those with cyanotic CHD. Although a significant heart murmur usually suggests a cardiac basis for the cyanosis, several of the more severe cardiac defects (e.g., transposition of the great vessels) may not initially be associated with a murmur. The chest radiograph may be helpful in the differentiation of pulmonary and cardiac disease; in the latter, it indicates whether pulmonary blood flow is increased, normal, or decreased (Fig. 456.1 ).

FIG. 456.1 Physiology of congenital heart disease delineated by chest radiography. A,

Mild cardiomegaly with an upturned cardiac apex, a concave main pulmonary artery segment, and symmetric, severely diminished pulmonary blood flow in a 4 yr old child with tetralogy of Fallot/pulmonary atresia. B, Moderate cardiomegaly and symmetric, increased pulmonary blood flow in a 3 mo old infant with a large atrial septal defect and ventricular septal defect. C, Moderate cardiomegaly with interstitial edema in an 8 day old newborn with critical aortic stenosis. (From Frost JL, Krishnamurthy R, Sena L: Cardiac imaging. In Walters MM, Robertson RL, editors: Pediatric radiology—the requisites, ed 4, Philadelphia, 2017, Elsevier, Fig 3.9, p 68.)

Two-dimensional echocardiography with Doppler is the definitive noninvasive test to determine the presence of CHD. Cardiac catheterization is less often used for diagnostic purposes and is usually performed to examine structures that are sometime less well visualized by echocardiography, such as distal branch pulmonary arteries or aortopulmonary collateral arteries in patients with tetralogy of Fallot with pulmonary atresia (see Chapter 457.2 ), or coronary arteries and right ventricular sinusoids in patients with pulmonary atresia and intact ventricular septum (see Chapter 457.3 ). If echocardiography is not immediately available to confirm a diagnosis of cyanotic CHD, the clinician caring for a newborn with possible cyanotic CHD should not hesitate to start a prostaglandin infusion (for a possible ductal-dependent lesion). Because of the risk of hypoventilation associated with prostaglandins, a practitioner skilled in neonatal endotracheal intubation must be available.

CHAPTER 457

Cyanotic Congenital Heart Disease Lesions Associated With Decreased Pulmonary Blood Flow 457.1

Tetralogy of Fallot Daniel Bernstein

Tetralogy of Fallot is one of the conotruncal family of heart lesions in which the primary defect is an anterior deviation of the infundibular septum (the muscular septum that separates the aortic and pulmonary outflows). The consequences of this deviation are the 4 components: (1) obstruction to right ventricular (RV) outflow (pulmonary stenosis), (2) a malalignment type of ventricular septal defect (VSD), (3) dextroposition of the aorta so that it overrides the ventricular septum, and (4) right ventricular hypertrophy (Fig. 457.1 ). Obstruction to pulmonary artery blood flow is usually at both the right ventricular infundibulum (subpulmonic area) and the pulmonary valve. The main pulmonary artery (MPA) may also be small, and various degrees of branch pulmonary artery stenosis may be present. Complete obstruction of RV outflow (tetralogy with pulmonary atresia) is classified as an extreme form of tetralogy of Fallot (see Chapter 457.2 ). The degree of pulmonary outflow obstruction and whether the ductus arteriosus is open or closed determine the degree of the patient's cyanosis and the age at first presentation.

FIG. 457.1 Physiology of tetralogy of Fallot. Circled numbers represent oxygen saturation values. The numbers next to the arrows represent volumes of blood flow (in L/min/m2 ). Atrial (mixed venous) oxygen saturation is decreased because of the systemic hypoxemia. A volume of 3 L/min/m2 of desaturated blood enters the right atrium and traverses the tricuspid valve. Two liters flows through the right ventricular outflow tract into the lungs, whereas 1 L shunts right to left through the ventricular septal defect (VSD) into the ascending aorta. Thus, pulmonary blood flow is two-thirds normal (Qp:Qs [pulmonary-to-systemic blood flow ratio] of 0.7 : 1). Blood returning to the left atrium is fully saturated. Only 2 L of blood flows across the mitral valve. Oxygen saturation in the left ventricle may be slightly decreased because of right-to-left shunting across the VSD. Two liters of saturated left ventricular blood mixing with 1 L of desaturated right ventricular blood is ejected into the ascending aorta. Aortic saturation is decreased, and cardiac output is normal.

Pathophysiology The pulmonary valve annulus may range from being nearly normal in size to being severely hypoplastic. The valve itself is often bicuspid or unicuspid and, occasionally, is the only site of stenosis. More often, the subpulmonic or infundibular muscle, known as the crista supraventricularis, is hypertrophic, which contributes to the subvalvar stenosis and results in an infundibular chamber of variable size and contour. When the right ventricular outflow tract (RVOT) is completely obstructed (pulmonary atresia ), the anatomy of the branch pulmonary arteries is extremely variable. An MPA segment may be in continuity with right ventricular outflow, separated by a fibrous but imperforate

pulmonary valve; the MPA may be moderately or severely hypoplastic but still supply part or all of the pulmonary bed; or the entire main pulmonary artery segment may be absent. Occasionally, the branch pulmonary arteries may be discontinuous. Pulmonary blood flow may be supplied by a patent ductus arteriosus (PDA) or by multiple major aortopulmonary collateral arteries (MAPCAs) arising from the ascending and/or descending aorta and supplying various lung segments. The VSD is usually nonrestrictive and large, is located just below the aortic valve, and is related to the posterior and right aortic cusps. Rarely, the VSD may be in the inlet portion of the ventricular septum (atrioventricular septal defect). The normal fibrous continuity of the mitral and aortic valves is usually maintained, and if not (because of the presence of a subaortic muscular conus), the classification is usually that of double-outlet right ventricle (DORV) instead of tetralogy of Fallot (see Chapter 457.5 ). The aortic arch is right sided in 20% of cases, and the aortic root is usually large and overrides the VSD to varying degrees. When the aorta overrides the VSD by >50% (in which case they may also be a subaortic conus) this defect may be classified as a form of DORV; however, the circulatory dynamics and the method of repair are the same as for tetralogy of Fallot. Systemic venous return to the right atrium and right ventricle is normal. When the right ventricle contracts in the presence of marked pulmonary stenosis, blood is shunted across the VSD into the aorta. Persistent arterial desaturation and cyanosis result, with the degree of abnormality dependent on the severity of the pulmonary obstruction. Pulmonary blood flow, when severely restricted by the obstruction to RV outflow, may be supplemented by a PDA. Peak systolic and diastolic pressures in each ventricle are similar and at systemic level. A large pressure gradient occurs across the obstructed RVOT, and pulmonary artery pressure is either normal or lower than normal. The degree of RV outflow obstruction determines the timing of the onset of symptoms, the severity of cyanosis, and the degree of right ventricular hypertrophy (RVH). When obstruction to RV outflow is mild to moderate and a balanced shunt is present across the VSD, the patient may not be visibly cyanotic (acyanotic or “pink” tetralogy of Fallot). When obstruction is severe, cyanosis will be present from birth and worsen when the ductus arteriosus begins to close.

Clinical Manifestations

Infants with mild degrees of RV outflow obstruction may initially even have symptoms of heart failure caused by a ventricular-level left-to-right shunt. In these patients, cyanosis is not present at birth; but with increasing hypertrophy of the RV infundibulum as the patient grows, cyanosis occurs later in the 1st few mo of life. In contrast, in infants with severe degrees of RV outflow obstruction, neonatal cyanosis is noted immediately. In these infants, pulmonary blood flow may be partially or almost totally dependent on flow through the ductus arteriosus. When the ductus begins to close in the 1st few hr or days of life, severe cyanosis and circulatory collapse may occur. All degrees of variation exist between these 2 clinical extremes. Older children with long-standing cyanosis who have not undergone surgery may have dusky blue skin, gray sclerae with engorged blood vessels, and marked clubbing of the fingers and toes. Chapter 461 describes the extracardiac manifestations of long-standing cyanotic congenital heart disease. In older children with unrepaired tetralogy, dyspnea occurs on exertion. They may play actively for a short time and then sit or lie down. Older children may be able to walk a block or so before stopping to rest. Characteristically, children assume a squatting position for the relief of dyspnea caused by physical effort; the child is usually able to resume physical activity after a few minutes of squatting. These findings occur most often in patients with significant cyanosis at rest. Paroxysmal hypercyanotic attacks (hypoxic, “blue,” or “tet” spells) are a problem during the 1st year of life. The infant becomes hyperpneic and restless, cyanosis increases, gasping respirations ensue, and syncope may follow. The spells occur most frequently in the morning on initially awakening or after episodes of vigorous crying. Temporary disappearance or a decrease in intensity of the systolic murmur is usual as flow across the RVOT diminishes during the spell. Tet spells may last from a few minutes to a few hours. Short episodes are followed by generalized weakness and sleep. Severe spells may progress to unconsciousness and occasionally to convulsions or hemiparesis. The onset is usually spontaneous and unpredictable. Spells are associated with reduction of an already compromised pulmonary blood flow, which, when prolonged, results in severe systemic hypoxia and metabolic acidosis. Infants who are only mildly cyanotic at rest may be more prone to the development of hypoxic spells because they have not acquired the homeostatic mechanisms to tolerate rapid lowering of arterial oxyhemoglobin saturation (SaO 2 ), such as polycythemia. Depending on the frequency and severity of hypercyanotic attacks, 1 or more

of the following procedures should be instituted in sequence: (1) placement of the infant on the abdomen in the knee-chest position while making certain that the infant's clothing is not constrictive, (2) administration of oxygen (although increasing inspired oxygen will not reverse cyanosis caused by intracardiac shunting), and (3) injection of morphine subcutaneously in a dose not in excess of 0.2 mg/kg. Calming and holding the infant in a knee-chest position may abort progression of an early spell. Premature attempts to obtain blood samples may cause further agitation and may be counterproductive. Because metabolic acidosis develops when arterial oxygen tension (PaO 2 ) is L

ANOMALOUS INNOMINATE Cough Stridor Reflex apnea

AP—normal Normal Lat.—anterior tracheal compression

Pulsatile anterior tracheal compression

ABERRANT RIGHT SUBCLAVIAN Occasional swallowing

Normal

AP— oblique

Usually normal

dysfunction

defect upward to right Lat.— small defect on right posterior wall



PULMONARY SLING Expiratory stridor Respiratory distress

AP—low l. hilum, r. emphysema/atelectasis Lat.—anterior bowing of right bronchus and trachea

±Anterior indentation above carina between esophagus and trachea

Tracheal displacement to left Compression of right main bronchus

AP, Anteroposterior; L and l., left; Lat., lateral; MRI, magnetic resonance imaging; R and r., right. From Kliegman RM, Greenbaum LA, Lye PS: Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, Elsevier, p 88.

FIG. 459.1 Double aortic arch. A, Small anterior segment of the double aortic arch (most common type). B, Operative procedure for release of the vascular ring. L., Left; a. and art., artery; ant., anterior; innom., innominate; duct. arterios., ductus arteriosus; pulm., pulmonary.

Clinical Manifestations

If the vascular ring produces compression of the trachea and esophagus, symptoms are frequently present during infancy. Chronic wheezing is exacerbated by crying, feeding, and flexion of the neck. Extension of the neck tends to relieve the noisy respiration. Vomiting may also be a component. Affected infants may have a brassy cough, pneumonia, or rarely, sudden death from aspiration.

Diagnosis Standard radiographic examination is not usually helpful. In the past, performing a barium esophagogram was the standard method of diagnosis (Fig. 459.2 ), now replaced by echocardiography in combination with either MRI or CT. Cardiac catheterization is reserved for cases with associated anomalies or in rare cases where these other modalities are not diagnostic. Bronchoscopy may be helpful in more severe cases to determine the extent of airway narrowing.

FIG. 459.2 Double aortic arch in an infant age 5 mo. A, Anteroposterior view. The barium-filled esophagus is constricted on both sides. B, Lateral view. The esophagus is displaced forward. The anterior arch was the smaller and was divided at surgery.

Treatment Surgery is advised for symptomatic patients who have evidence of tracheal compression. The anterior vessel is usually divided in patients with a double aortic arch (see Fig. 459.1B ). Compression produced by a right aortic arch and left ligamentum arteriosum is relieved by division of the latter. Anomalous

innominate or carotid arteries cannot be divided; attaching the adventitia of these vessels to the sternum usually relieves the tracheal compression. An anomalous left pulmonary artery is corrected by division at its origin and reanastomosis to the main pulmonary artery after it has been brought in front of the trachea. Severe tracheomalacia, if present, may require reconstruction of the trachea as well.

Bibliography Kellenberger CJ. Aortic arch malformations. Pediatr Radiol . 2010;40:876–884. Kussman BD, Geva T, McGowan FX. Cardiovascular causes of airway compression. Paediatr Anaesth . 2004;14:60–74. Murdison KA, Andrews BA, Chin AJ. Ultrasonographic display of complex vascular rings. J Am Coll Cardiol . 1990;15:1645–1653. Smith BM, Lu JC, Dorfman AL, et al. Rings and slings revisited. Magn Reson Imaging Clin North Am . 2015;23(1):127–135.

459.2

Anomalous Origin of the Coronary Arteries Daniel Bernstein

Table 459.2 provides a classification system for coronary artery anomalies. Although many of these are isolated, congenital anomalies of the coronary arteries may also be seen in patients with congenital heart disease (tetralogy of

Fallot, transposition of the great arteries, congenitally corrected transposition of the great arteries, single ventricle, tricuspid atresia, truncus arteriosus, quadricuspid or bicuspid aortic valves, double-outlet ventricle). In addition, acquired lesions of the coronary arteries caused by existing congenital heart disease may develop as a consequence of hypertension or alterations in blood flow; congenital heart lesions include coarctation of the aorta, supravalvular aortic stenosis, aortic regurgitation, pulmonary atresia with intact ventricular septum, hypoplastic left heart syndrome, and coronary ectasia secondary to cyanotic heart disease.

Table 459.2

Congenital Anomalies of Coronary Arteries Unassociated With Congenital Heart Disease Anomalous Aortic Origin • Eccentric ostium within an aortic sinus • Ectopic ostium above an aortic sinus • Conus artery from the right aortic sinus • Circumflex coronary artery from the right aortic sinus or from the right coronary artery • Origin of left anterior descending and circumflex coronary arteries from separate ostia in the left aortic sinus (absence of left main coronary artery) • Atresia of the left main coronary artery • Origin of the left anterior descending coronary artery from the right aortic sinus or from the right coronary artery • Origin of the right coronary artery from the left aortic sinus, from posterior aortic sinus, or from left coronary artery • Origin of a single coronary artery from the right or left aortic sinus • Anomalous origin from a noncardiac systemic artery

Anomalous Aortic Origin With Anomalous Proximal Course • Acute proximal angulation • Ectopic right coronary artery passing between aorta and pulmonary trunk

• Ectopic left main coronary artery • Between aorta and pulmonary trunk • Anterior to the pulmonary trunk • Posterior to the aorta • Within the ventricular septum (intramyocardial) • Ectopic left anterior descending coronary artery that is anterior, posterior, or between the aorta and pulmonary trunk

Anomalous Origin of a Coronary Artery From the Pulmonary Trunk • Left main coronary artery • Left anterior descending coronary artery • Right coronary artery • Both right and left coronary arteries • Circumflex coronary artery • Accessory coronary artery From Perloff JK, Marelli J: Perloff's clinical recognition of congenital heart disease, ed 6, Philadelphia, 2012, Elsevier Saunders (Table 32-3, p 532).

Anomalous Origin of Left Coronary Artery From Pulmonary Artery In anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA ), the blood supply to the left ventricular (LV) myocardium is severely compromised. Soon after birth, as pulmonary artery pressure falls, perfusion pressure to the left coronary artery (LCA) becomes inadequate; myocardial ischemia, infarction, and fibrosis result. In some cases, interarterial collateral anastomoses develop between the right coronary artery (RCA) and LCA. Blood flow in the LCA is then reversed, and it empties into the pulmonary artery, a condition known as the “myocardial steal” syndrome. The left ventricle becomes dilated, and its performance is decreased. Mitral insufficiency is a frequent complication secondary to a dilated valve ring or infarction of a

papillary muscle. Localized aneurysms may also develop in the LV free wall. Occasional patients have adequate myocardial blood flow during childhood and, later in life, a continuous murmur and a small left-to-right shunt via the dilated coronary system (aorta to RCA to LCA to pulmonary artery).

Clinical Manifestations Evidence of heart failure becomes apparent within the 1st few mo of life and may be exacerbated by respiratory infection. Recurrent attacks of discomfort, restlessness, irritability, sweating, dyspnea, and pallor occur and probably represent an infantile version of angina pectoris . Cardiac enlargement ranges from moderate to massive. A gallop rhythm is common. Murmurs may be of the nonspecific ejection type or may be holosystolic because of mitral insufficiency. Older patients with abundant intercoronary anastomoses may have continuous murmurs and minimal LV dysfunction. During adolescence, they may experience angina during exercise. Rare patients with an anomalous RCA may also have such clinical findings.

Diagnosis Radiographic examination confirms cardiomegaly. The electrocardiogram (ECG) resembles the pattern described in lateral wall myocardial infarction in adults. A QR pattern followed by inverted T waves is seen in leads I and aVL. The LV surface leads (V5 and V6 ) may also show deep Q waves and exhibit elevated ST segments and inverted T waves (Fig. 459.3 ). Two-dimensional (2D) echocardiography with color Doppler usually confirms the diagnosis; however, in rare cases, echocardiography may not be reliable in diagnosing this condition. On 2D imaging alone, the LCA may appear as though it is arising from the aorta. Color Doppler ultrasound has improved the accuracy of diagnosis of this lesion, demonstrating the presence of retrograde flow in the LCA. CT or MRI can confirm the origin of the coronary arteries. Cardiac catheterization is diagnostic; aortography shows immediate opacification of the RCA only. This vessel is large and tortuous. After filling of the intercoronary anastomoses, the LCA is opacified, and contrast can be seen to enter the pulmonary artery. Pulmonary arteriography may also opacify the origin of the anomalous LCA. Selective left ventriculography usually demonstrates a dilated left ventricle that empties poorly and mitral regurgitation.

FIG. 459.3 Electrocardiogram of a 3 mo old child with anomalous origin of the left coronary artery from the pulmonary artery. Lateral myocardial infarction is present as evidenced by abnormally large and wide Q waves in leads I, V5 , and V6 ; an elevated ST segment in V5 and V6 ; and inversion of TV6 .

Treatment and Prognosis Untreated, death often occurs from heart failure within the 1st 6 mo of life. Those who survive generally have abundant intercoronary collateral anastomoses. Medical management includes standard therapy for heart failure (diuretics, angiotensin-converting enzyme inhibitors) and for controlling ischemia (nitrates, β-blocking agents). Surgical treatment consists of detaching the anomalous coronary artery from the pulmonary artery and anastomosing it to the aorta to establish normal myocardial perfusion. In patients who have already sustained a significant myocardial infarction, cardiac transplantation may be the only option (see Chapter 470.1 ).

Anomalous Origin of Right Coronary Artery From Pulmonary Artery Anomalous origin of the RCA from the pulmonary artery is rarely manifested in infancy or early childhood. The LCA is enlarged, whereas the RCA is thin walled and mildly enlarged. In early infancy, perfusion of the RCA is from the pulmonary artery, whereas later, perfusion is from collaterals of the left coronary

vessels. Angina and sudden death can occur in adolescence or adulthood. When recognized, this anomaly should be repaired by reanastomosis of the RCA to the aorta.

Ectopic Origin of a Coronary Artery From the Aorta With Aberrant Proximal Course In ectopic origin of the coronary artery from the aorta with an aberrant proximal course, the aberrant artery may be a left, right, or major branch coronary artery. The site of origin may be the wrong sinus of Valsalva (anomalous origin of a coronary artery from the opposite sinus, ACAOS ) or a proximal coronary artery. The ostium may be hypoplastic, slit-like, or of normal caliber. The aberrant vessel may pass anteriorly, posteriorly, or between the aorta and right ventricular outflow tract (RVOT); it may tunnel in the conal or interventricular septal tissue. Obstruction resulting from hypoplasia of the ostia, tunneling between the aorta and RVOT or interventricular septum, and acute angulation produces myocardial infarction. Unobstructed vessels produce no symptoms (Table 459.3 ). Patients with this rare abnormality are often initially seen with severe myocardial infarction, ventricular arrhythmias, angina pectoris, or syncope; sudden death may occur, especially in young athletes. Table 459.3 Classification of Coronary Anomalies Based on Ischemia ISCHEMIA Absence of ischemia Episodic ischemia Typical ischemia

CLASSIFICATION Most anomalies (split RCA, ectopic RCA from right cusp; ectopic RCA from left cusp) Anomalous origin of a coronary artery from the opposite sinus (ACAOS); coronary artery fistulas; myocardial bridge Anomalous left coronary artery from the pulmonary artery (ALCAPA); coronary ostial atresia or severe stenosis

RCA, Right coronary artery. From Mehran R, Dangas GD: Coronary angiography and intravascular imaging. In Braunwald's heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018, Elsevier (Fig 20.8, p 385).

Diagnostic modalities include ECG, stress testing, 2D echocardiography, CT or MRI, radionuclide perfusion scan, and cardiac catheterization with selective coronary angiography.

Treatment is indicated for obstructed vessels and consists of aortoplasty with reanastomosis of the aberrant vessel or, occasionally, coronary artery bypass grafting. The management of asymptomatic patients with these forms of ectopic coronary origin remains controversial. Previously, the risk of sudden cardiac death attributed to certain coronary anomalies was thought to be quite high, since the risk assessment was based on autopsy series. The risk attributed to certain anomalous coronary arteries is much lower than once believed (Table 459.3 ). The risk appears to be highest with anomalous LCA from the right sinus of Valsalva with interarterial course, notably when the young patient is participating in vigorous physical exertion, such as with competitive sports. A multicenter registry, the Anomalous Aortic Origin of the Coronary Artery (AAOCA) Registry of the Congenital Heart Surgeons Society, is developing data to understand the risk for sudden cardiac death in this population.

Bibliography Brothers JA. Coronary artery anomalies in children: what is the risk? Curr Opin Pediatr . 2016;28(5):590–596. Brothers JA, Frommelt MA, Jaquiss RD, et al. Expert consensus guideline: anomalous aortic origin of a coronary artery. J Thorac Cardiovasc Surg . 2017 [pii: S0022-5223(17)301344]. Frommelt PC, Berger S, Pelech AN, et al. Prospective identification of anomalous origin of left coronary artery from the right sinus of valsalva using transthoracic echocardiography: importance of color doppler flow mapping. Pediatr Cardiol . 2001;22:327–332. Hoffman JI. Electrocardiogram of anomalous left coronary artery from the pulmonary artery in infants. Pediatr Cardiol . 2013;34:489–491. Kayalar N, Burkhart HM, Dearani JA, et al. Congenital coronary anomalies and surgical treatment. Congenit Heart Dis . 2009;4:239–251.

459.3

Pulmonary Arteriovenous Fistula Daniel Bernstein

Fistulous vascular communications in the lungs may be large and localized or multiple, scattered, and small. The most common form of this unusual condition is the Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia type I), which is also associated with angiomas of the nasal and buccal mucous membranes, gastrointestinal (GI) tract, or liver. Mutations in the endoglin gene, a cell surface component of the transforming growth factor (TGF)-β receptor complex, causes this syndrome. The usual communication is between the pulmonary artery and pulmonary vein; direct communication between the pulmonary artery and left atrium is extremely rare. Desaturated blood in the pulmonary artery is shunted through the fistula into the pulmonary vein, thus bypassing the lungs, and then enters the left side of the heart, resulting in systemic arterial desaturation and sometimes clinically detectable cyanosis. The shunt across the fistula is at low pressure and resistance, so pulmonary artery pressure is normal; cardiomegaly and heart failure are not present. The clinical manifestations depend on the magnitude of the shunt. Large fistulas are associated with dyspnea, cyanosis, clubbing, a continuous murmur, and polycythemia. Hemoptysis is rare, but when it occurs, it may be massive. Features of the Osler-Weber-Rendu syndrome are seen in approximately 50% of patients (or other family members) and include recurrent epistaxis and GI tract bleeding. Transitory dizziness, diplopia, aphasia, motor weakness, or convulsions may result from cerebral thrombosis, abscess, or paradoxical emboli. Soft systolic or continuous murmurs may be audible over the site of the fistula. The ECG is normal. Chest radiographs may show opacities produced by large fistulas; multiple small fistulas may be visualized by fluoroscopy (as abnormal pulsations), MRI, or CT. Selective pulmonary arteriography demonstrates the site, extent, and distribution of the fistulas. Treatment consisting of excision of solitary or localized lesions by lobectomy or wedge resection results in complete disappearance of symptoms. In most

patients, fistulas are so widespread that surgery is not possible. Any direct communication between the pulmonary artery and the left atrium can be obliterated. Patients who have undergone a Glenn cavopulmonary anastomosis for cyanotic congenital heart disease (see Chapter 457.4 ) are also at risk for the development of pulmonary arteriovenous malformations (AVMs). In these patients the AVMs are usually multiple, and the risk increases over time after the Glenn procedure. Pulmonary AVMs rarely occur after the heart disease is fully palliated by completion of the Fontan operation . This finding suggests that the pulmonary circulation requires an as yet undetermined hepatic factor to suppress the development of AVMs. The hallmark of the development of pulmonary AVMs is a decrease in the patient's oxygen saturation. The diagnosis can often be made with contrast echocardiography; cardiac catheterization is the definitive test. Completion of the Fontan circuit, so that inferior vena cava blood flow (containing hepatic venous drainage) is routed through the lungs, usually results in improvement or resolution of the malformations.

Bibliography Feinstein JA, Moore P, Rosenthal DN, et al. Comparison of contrast echocardiography versus cardiac catheterization for detection of pulmonary arteriovenous malformations. Am J Cardiol . 2002;89:281–285. Freedom RM, Yoo SJ, Perrin D. The biological “scrabble” of pulmonary arteriovenous malformations: considerations in the setting of cavopulmonary surgery. Cardiol Young . 2004;14:417–437. Paterson A. Imaging evaluation of congenital lung abnormalities in infants and children. Radiol Clin North Am . 2005;43:303–323. Srivastava D, Preminger T, Lock JE, et al. Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation . 1995;92:1217–1222.

459.4

Ectopia Cordis Daniel Bernstein

In the most common thoracic form of ectopia cordis, the sternum is split and the heart protrudes outside the chest. In other forms, the heart protrudes through the diaphragm into the abdominal cavity or may be situated in the neck. Associated intracardiac anomalies are common. Pentalogy of Cantrell consists of ectopia cordis, midline supraumbilical abdominal defect, deficiency of the anterior diaphragm, defect of the lower sternum, and an intracardiac defect (ventricular septal defect, tetralogy of Fallot, or diverticulum of left ventricle). Death may occur early in life, usually from infection, cardiac failure, or hypoxemia. Surgical therapy for neonates without overwhelmingly severe cardiac anomalies consists of covering the heart with skin without compromising venous return or ventricular ejection. Repair or palliation of associated defects is also necessary.

459.5

Diverticulum of the Left Ventricle Daniel Bernstein

Left ventricular diverticulum is a rare anomaly in which the diverticulum protrudes into the epigastrium. The lesion may be isolated or associated with complex cardiovascular anomalies. A pulsating mass is usually visible and palpable in the epigastrium. Systolic or systolic-diastolic murmurs produced by blood flow into and out of the diverticulum may be audible over the lower part

of the sternum and the mass. The ECG shows a pattern of complete or incomplete left bundle branch block. The chest radiograph may or may not show the mass. Associated abnormalities include defects of the sternum, abdominal wall, diaphragm, and pericardium (see earlier). Surgical treatment of the diverticulum and associated cardiac defects can be performed in selected cases. Occasionally, a diverticulum may be small and not associated with clinical signs or symptoms. These small diverticula are diagnosed at echocardiographic examination for other indications.

CHAPTER 460

Pulmonary Hypertension 460.1

Primary Pulmonary Hypertension Daniel Bernstein, Jeffrey A. Feinstein

Pathophysiology Pulmonary hypertension (PH , elevated pressure in the pulmonary arteries) is characterized by pulmonary vascular obstructive disease and right-sided heart failure. The etiologies are varied, but all lead to similar symptoms (Tables 460.1 and 460.2 ). PH occurs at any age, although in pediatric patients the mean age at diagnosis is 7-10 yr. In patients with idiopathic or familial disease, females outnumber males 1.7 : 1; in other patients, both genders are represented equally. Mutations in the gene for bone morphogenetic protein receptor-2 (BMPR2 , a member of the transforming growth factor [TGF]-β receptor family) on chromosome 2q33 have been identified in 70% of patients with familial primary pulmonary hypertension (known as PPH1 ) and in 10–20% with idiopathic sporadic PH. Other potential disease causing genes include PPH2 , ALK1, ENG, SMAD9, CAV1, and KCNK3 , which cause a channelopathy in familial and sporadic cases of primary PH. Viral infection, such as with the vasculotropic human herpesvirus 8, has been suggested as a trigger factor in some patients.

Table 460.1

Updated Classification of Pulmonary Hypertension (PH)* 1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK1, ENG, SMAD9 , CAV1 , KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1′. Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis 1″. Persistent pulmonary hypertension of the newborn (PPHN) 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematologic disorders: chronic hemolytic anemia , myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH BMPR2, Bone morphogenetic protein receptor type II; CAV1, caveolin 1; ENG, endoglin; KCNK3, potassium channel K3.

* Modified as compared with the Dana Point classification.

From Simonneau G, Gatzoulis MA, Adatia I: Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 62:D34–D41, 2013.

Table 460.2

Developmental Lung Diseases Associated With Pulmonary Hypertension Congenital diaphragmatic hernia Bronchopulmonary dysplasia Alveolar capillary dysplasia (ACD) ACD with misalignment of veins Lung hypoplasia (“primary” or “secondary”) Surfactant protein abnormalities Surfactant protein B (SPB) deficiency SPC deficiency ATP-binding cassette A3 mutation Thyroid transcription factor 1/Nkx2.1 homeobox mutation Pulmonary interstitial glycogenosis Pulmonary alveolar proteinosis Pulmonary lymphangiectasia

From Ivy DD, Abman SH, Barst RJ, et al: Pediatric pulmonary hypertension, J Am Coll Cardiol 62(25): D118–D126, 2013 (Table 2, p D119). PH is associated with precapillary obstruction of the pulmonary vascular bed as a result of hyperplasia of the muscular and elastic tissues and a thickened intima of the small pulmonary arteries and arterioles (Fig. 460.1 ). Secondary atherosclerotic changes may be found in the larger pulmonary arteries as well. In children, pulmonary venoocclusive disease may account for some cases of primary PH. Before a diagnosis of primary PH can be made, other causes of elevated pulmonary artery pressure must be eliminated; these include chronic pulmonary parenchymal disease, persistent obstruction of the upper airway, congenital cardiac malformations, recurrent pulmonary emboli, alveolar capillary dysplasia, liver disease, autoimmune disease, and moyamoya disease (Table 460.2 ). PH associated with congenital heart disease is currently the most common in pediatric patients (40–55%), followed by chronic respiratory disorders (20–35%) and idiopathic or familial disease (10–15%). PH associated with chronic lung disease (bronchopulmonary dysplasia) in premature infants is growing to encompass a larger portion of new cases.

FIG. 460.1 Vascular abnormalities associated with pulmonary arterial hypertension: abnormal muscularization of distal and medial precapillary arteries, loss of precapillary arteries, thickening of large pulmonary arterioles, and new vascular intimal formation that is occlusive in vessels 65%). Table 461.1

Extracardiac Complications of Cyanotic Congenital Heart Disease and Eisenmenger Physiology PROBLEM Polycythemia Relative anemia CNS abscess CNS thromboembolic stroke Low-grade DIC, thrombocytopenia Hemoptysis

Plastic bronchitis Gum disease Gout Arthritis, clubbing Pregnancy complications: miscarriage, fetal growth retardation, prematurity increase, maternal illness Infections

Failure to thrive

Protein-losing enteropathy Chylothorax

Neurodevelopmental disabilities Psychosocial adjustment

ETIOLOGY Persistent hypoxia Nutritional deficiency Right-to-left shunting Right-to-left shunting or polycythemia Polycythemia Pulmonary infarct, thrombosis, or rupture of pulmonary artery plexiform lesion Fontan procedure Polycythemia, gingivitis, bleeding Polycythemia, diuretic agent Hypoxic osteoarthropathy Poor placental perfusion, poor ability to increase cardiac output Associated asplenia, DiGeorge syndrome, endocarditis Fatal RSV pneumonia with pulmonary hypertension Increased oxygen consumption, decreased nutrient intake s/p Fontan; high right-sided pressures Injury to thoracic duct

Chronic hypoxia, cardiac surgery, genetic Limited activity, cyanotic appearance, chronic disease, multiple hospitalizations

THERAPY Phlebotomy if symptomatic Iron replacement Antibiotics, drainage Anticoagulation, phlebotomy None for DIC unless bleeding, then phlebotomy Embolization

Bronchoscopy, vascular coiling, lymphatic ablation Dental hygiene Allopurinol None Pregnancy prevention counseling, high-risk obstetric management Antibiotics Ribavirin; RSV immunoglobulin (prevention) Treat heart failure; correct defect early; increase caloric intake Oral budesonide or sildenafil Medium-chain triglyceride diet Octreotide Surgical ligation of thoracic duct Early school-based evaluation and intervention Counseling

CNS, Central nervous system; DIC, disseminated intravascular coagulation; RSV, respiratory syncytial virus; s/p, status post (after).

Patients with moderate to severe forms of CHD or a history of rhythm disturbance should be carefully monitored during anesthesia for even routine surgical or dental procedures. Consultation with an anesthesiologist experienced in the care of children with CHD is recommended even if the surgical procedure is not cardiac related.

Women with unrepaired severe CHD should be counseled on the risks associated with childbearing and on the use of contraceptives and other methods to prevent pregnancy, such as tubal ligation. Women with mild to moderate CHD and many who have had corrective surgery can have normal pregnancies, although those with residual hemodynamic derangements or with systemic right ventricles should be followed by a high-risk perinatologist and a cardiologist with expertise in caring for adults with CHD. Pregnancy may be highly dangerous to both mother and fetus for patients with palliated complex CHD, chronic cyanosis, or pulmonary arterial hypertension; for patients with a Fontan circulation, the miscarriage rate has been reported as ranging from 27–50%, and the rate of prematurity at 69%. Risks to the mother include heart failure, thromboembolism, and arrhythmia. Several risk stratification schemes have been developed for pregnant women with CHD, including the Cardiac Disease in Pregnancy (CARPREG ) score, the ZAHARA (Zwangerschap bij Aangeboren HARtAfwijkingen) score, and the World Health Organization (WHO) classification. Based on the WHO system, patients for whom pregnancy is associated with a significantly increased risk of mortality of morbidity include those with a systemic right ventricle (e.g., corrected transposition), Fontan circulation, bicuspid aortic valve with enlarged aortic root of 45-50 mm, Marfan syndrome with enlarged aortic root of 40-45 mm, and those with a mechanical valve replacement. Patients for whom pregnancy is considered contraindicated include those with pulmonary arterial hypertension, severe aortic or mitral stenosis or unrepaired coarctation of the aorta, bicuspid aortic valve with aortic root >50 mm, Marfan syndrome with dilated aortic root >45 mm, and patients with systemic ventricular dysfunction with ejection fraction 7 days, polymerase chain reaction on blood or valve for 16SrRNA (bacteria) or 18SrRNA (fungi), or serologic tests. † The HACEK group includes Haemophilus spp. (H. paraphrophilus, H.

parainfluenzae, H. aphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella spp. ‡ Candida spp., Aspergillus spp., Pseudallescheria boydii, Histoplasma

capsulatum. Pseudomonas aeruginosa or Serratia marcescens is seen more frequently in intravenous drug users; and fungal organisms are encountered after open heart surgery. Coagulase-negative staphylococci are common in the presence of an indwelling central venous catheter.

Epidemiology Infective endocarditis is often a complication of congenital or rheumatic heart disease but can also occur in children without any abnormal valves or cardiac malformations. In developed countries, congenital heart disease (CHD) is the overwhelming predisposing factor. Endocarditis is rare in infancy; in this age-

group it usually follows open heart surgery or is associated with a central venous line. Patients with congenital heart lesions where there is turbulent blood flow because of a hole or stenotic orifice, especially if there is a high-pressure gradient across the defect, are most susceptible to endocarditis. This turbulent flow traumatizes the vascular endothelium, creating a substrate for deposition of fibrin and platelets, leading to the formation of a nonbacterial thrombotic embolus (NBTE) that is thought to be the initiating lesion for infective endocarditis. Biofilm forms on the surface of implanted mechanical devices such as valves, catheters, or pacemaker wires, which also serve as the adhesive substrate for infection. The development of transient bacteremia then colonizes this NBTE or biofilm, leading to proliferation of bacteria within the lesion. Bacterial surface proteins, such as the FimA antigen in viridans streptococci, act as adhesion factors to the NBTE or biofilm, after which bacteria can rapidly proliferate within the vegetation. Given the heavy colonization of mucosal surfaces (the oropharynx, or gastrointestinal, vaginal, or urinary tracts) by potentially pathogenic bacteria, these surfaces are thought to be the origin of this transient bacteremia. There is controversy over the extent to which daily activities (e.g., brushing or flossing the teeth) vs invasive procedures (e.g., dental cleaning or surgery) contribute to this bacteremia. Transient bacteremia is reported to occur in 20–68% of patients after tooth brushing and flossing, and even in 7–51% of patients after chewing food. The magnitude of this bacteremia is also similar to that resulting from dental procedures. Maintenance of good oral hygiene may be a more important factor in decreasing the frequency and magnitude of bacteremia. Children at highest risk of adverse outcome after infective endocarditis include those with prosthetic cardiac valves or other prosthetic material used for cardiac valve repair, unrepaired cyanotic CHD (including those palliated with shunts and conduits), completely repaired defects with prosthetic material or device during the 1st 6 mo after repair, repaired CHD with residual defects at or adjacent to the site of a prosthetic patch or device, valve stenosis or insufficiency occurring after heart transplantation, permanent valve disease from rheumatic fever (mitral stenosis, aortic regurgitation), and previous infective endocarditis. Patients with high-velocity blood flow lesions such as ventricular septal defects and aortic stenosis are also at high risk. In older patients, congenital bicuspid aortic valves and mitral valve prolapse with regurgitation pose additional risks for endocarditis. Surgical correction of CHD may reduce but does not eliminate

the risk of endocarditis, except for the repair of a simple atrial septal defect or patent ductus arteriosus without prosthetic material. In approximately 30% of patients with infective endocarditis, a predisposing factor is presumably recognized. Although a preceding dental procedure may be identified in 10–20% of patients, the time of the procedure may range from 1-6 mo before the onset of symptoms; thus the continued controversy over the absolute risk of infective endocarditis after dental procedures. Primary bacteremia with S. aureus is thought to be another risk for endocarditis. The occurrence of endocarditis directly after most routine heart surgery is relatively low, but it can be an antecedent event, especially if prosthetic material is used. In the small group of patients with culture-negative endocarditis, epidemiologic or exposure factors may contribute to the diagnosis (Table 464.2 ). Table 464.2 Epidemiologic Clues in Etiologic Diagnosis of Culture-Negative Endocarditis EPIDEMIOLOGIC FEATURE Injection drug use (IDU)

Indwelling cardiovascular medical devices

Genitourinary disorders, infection, and manipulation, including pregnancy, delivery, and abortion

Chronic skin disorders, including recurrent infections

Poor dental health, dental procedures

Alcoholism, cirrhosis

COMMON MICROORGANISM Staphylococcus aureus , including communityacquired oxacillin-resistant strains Coagulase-negative staphylococci β-Hemolytic streptococci Fungi Aerobic gram-negative bacilli, including Pseudomonas aeruginosa Polymicrobial S. aureus Coagulase-negative staphylococci Fungi Aerobic gram-negative bacilli Corynebacterium spp. Enterococcus spp. Group B streptococci (S. agalactiae ) Listeria monocytogenes Aerobic gram-negative bacilli Neisseria gonorrhoeae S. aureus β-Hemolytic streptococci S. aureus β-Hemolytic streptococci Viridans group streptococci Nutritionally variant streptococci Abiotrophia defectiva Granulicatella spp. Gemella spp. HACEK organisms Bartonella spp. Aeromonas spp. Listeria spp.

Burns

Diabetes mellitus

Early (≤1 yr) prosthetic valve placement

Late (>1 yr) prosthetic valve placement

Dog or cat exposure

Contact with contaminated milk or infected farm animals

Homeless, body lice HIV/AIDS

Pneumonia, meningitis Solid-organ transplantation

Gastrointestinal lesions

Streptococcus pneumoniae β-Hemolytic streptococci S. aureus Aerobic gram-negative bacilli, including P. aeruginosa Fungi S. aureus β-Hemolytic streptococci S. pneumoniae Coagulase-negative staphylococci S. aureus Aerobic gram-negative bacilli Fungi Corynebacterium spp. Legionella spp. Coagulase-negative staphylococci S. aureus Viridans group streptococci Enterococcus spp. Fungi Corynebacterium spp. Bartonella spp. Pasteurella spp. Capnocytophaga spp. Brucella spp. Coxiella burnetii Erysipelothrix spp. Bartonella spp. Salmonella spp. S. pneumoniae S. aureus S. pneumoniae S. aureus Aspergillus fumigatus Enterococcus spp. Candida spp. Streptococcus gallolyticus (bovis ) Enterococcus spp. Clostridium septicum

HACEK, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp; HIV/AIDS, human immunodeficiency virus infection and acquired immunodeficiency syndrome. From Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications. A scientific statement for healthcare professionals from the American Heart Association. Circulation 132:1435-1486, 2015.

Clinical Manifestations Table 464.3 outlines the manifestations of infective endocarditis. Early manifestations are usually mild, especially when viridans group streptococci are

the infecting organisms. Prolonged fever without other manifestations (except occasionally weight loss) that persists for as long as several months may be the only symptom. Alternatively, with pathogenic organisms such as S. aureus , the onset may be acute and severe, with high intermittent fever and prostration. Usually the onset and course vary between these 2 extremes. The symptoms are often nonspecific and consist of low-grade fever with afternoon elevations, fatigue, myalgia, arthralgia, headache, and at times chills, nausea, and vomiting. New or changing heart murmurs are common, particularly with associated heart failure. Splenomegaly and petechiae are seen in 36.3 kg, 20-30 mL for both. Three to 5 separate blood collections should be obtained after careful preparation of the phlebotomy site. Contamination presents a special problem because bacteria

found on the skin may cause infective endocarditis. The timing of collections is not important because bacteremia can be expected to be relatively constant. In 90% of cases of endocarditis, the causative agent is recovered from the 1st 2 blood cultures. Bacteremia is low grade in 80% (5 days) to detect nutritionally deficient and fastidious bacteria or fungi. Although bacteremia may occur in the absence of endocarditis, bacteremia secondary to Streptococcus mutans , S. bovis I , S. mitis , S. sanguinis, and Staphylococcus aureus (in the absence of focal musculoskeletal infection) is highly concerning for endocarditis. Antimicrobial pretreatment of the patient reduces the yield of blood cultures by 50–60%. Other specimens that may be cultured include scrapings from cutaneous lesions, urine, synovial fluid, abscesses, and in the presence of manifestations of meningitis, cerebrospinal fluid. Serologic diagnosis or polymerase chain reaction of resected valve tissues is necessary in patients with unusual or fastidious microorganisms, when there is suspicion of culture-negative endocarditis or if the patient has received prior antibiotics (Table 464.4 and Fig. 464.1 ). Suspicion should be high when evaluating infection in a child with an underlying contributing factor. The combination of transthoracic and transesophageal echocardiography enhances the ability to diagnose endocarditis. Two-dimensional echocardiography can identify the size, shape, location, and mobility of the lesion; when combined with Doppler studies, the presence of valve dysfunction (regurgitation, obstruction) can be determined and its effect on left ventricular performance quantified (Fig. 464.2 ). Echocardiography may also be helpful in predicting embolic complications, given that lesions >1 cm and fungating masses are at greatest risk for embolization. The absence of vegetations does not exclude endocarditis, and vegetations are often not visualized in the early phases of the disease or in patients with complex congenital heart lesions. Electrocardiography should be part of the evaluation and can demonstrate new rhythm disorders such as ventricular ectopy and conduction disorders such as complete heart block . The presence of either of these findings, particularly heart block, may signal a serious or even life-threatening complication of endocarditis. Table 464.4 Diagnostic Approach to Uncommon Pathogens Causing Endocarditis

PATHOGEN Brucella spp. Coxiella burnetii Bartonella spp. Chlamydia spp. Mycoplasma spp. Legionella spp. Tropheryma whipplei

DIAGNOSTIC PROCEDURE Blood cultures; serology; culture, immunohistology, and PCR of surgical material Serology (IgG phase I >1 in 800); tissue culture, immunohistology, and PCR of surgical material Blood cultures; serology; culture, immunohistology, and PCR of surgical material Serology; culture, immunohistology, and PCR of surgical material Serology; culture, immunohistology, and PCR of surgical material Blood cultures; serology; culture, immunohistology, and PCR of surgical material Histology and PCR of surgical material

IgG, Immunoglobulin G; PCR, polymerase chain reaction. From Moreillon P, Que YA: Infective endocarditis, Lancet 363:139–148, 2004.

FIG. 464.1 Diagnostic tests applied to clinical specimens for the identification of the causative agents of blood culture–negative endocarditis. Septifast, LightCycler SeptiFast (Roche). Serum should be considered a priority specimen, with Q fever and Bartonella serologic analysis routinely done. We also suggest that detection of antinuclear antibodies and rheumatoid factor should be routinely done for diagnosis of noninfective endocarditis. (From Thuny F, Grisoli D, Collart F, et al. Management of infective endocarditis: challenges and perspectives, Lancet 379:965–975, 2012, Fig 2, p 969.)

FIG. 464.2 Infective endocarditis of the native aortic valve. A, Transthoracic echocardiography shows vegetations (small arrows) attached to the left ventricular aspects of the valve cusps and prolapsing into the left ventricular outflow tract (large arrow) during diastole. B, Severe aortic regurgitation (arrow) is shown by color Doppler. Ao, Ascending aorta; LA, left atrium; LV, left ventricle. (From Baddour LM, Freeman WK, Suri RM, Wilson WR: Cardiovascular infections. In Braunwald's heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018, Elsevier, Fig 73-1, p 1490.)

The Duke criteria help in the diagnosis of endocarditis (Table 464.5 ). Two major criteria, 1 major and 3 minor, or 5 minor criteria suggest definite endocarditis. Additional minor criteria to those listed include newly diagnosed clubbing, splenomegaly, splinter hemorrhages, or petechiae; high erythrocyte sedimentation rate or C-reactive protein level; presence of central nonfeeding or peripheral lines; and microscopic hematuria.

Table 464.5

Definition of Infective Endocarditis (IE): Modified Duke Criteria Definite Infective Endocarditis Pathologic Criteria • Microorganisms demonstrated by results of cultures or histologic examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or • Pathologic lesions; vegetation, or intracardiac abscess confirmed by results of histologic examination showing active endocarditis Clinical Criteria

• 2 major criteria, or • 1 major criterion and 3 minor criteria, or • 5 minor criteria

Possible Infective Endocarditis • 1 major criterion and 1 minor criterion, or • 3 minor criteria

Rejected Diagnosis of Infective Endocarditis • Firm alternate diagnosis explaining evidence of suspected IE, or • Resolution of IE syndrome with antibiotic therapy for ≤4 days, or • No evidence of IE at surgery or autopsy, on antibiotic therapy for ≤4 days, or • Does not meet criteria for possible IE

Definition of Terms Used in Modified Duke Criteria Major Criteria • Blood culture findings positive for IE Typical microorganisms consistent with IE from 2 separate blood cultures: • Viridans streptococci, Streptococcus gallolyticus (formerly known as S. bovis ), Staphylococcus aureus, HACEK group, or • Community-acquired enterococci, in the absence of a primary focus, or Microorganisms consistent with IE from persistently positive blood culture findings, defined as: • ≥2 positive culture findings of blood samples drawn >12 hr apart, or • 3 or most of ≥4 separate culture findings of blood (with first and last sample drawn ≥1 hr apart)

• Single positive blood culture for Coxiella burnetii or anti– phase I lgG titer ≥1 : 800 • Evidence of endocardial involvement Echocardiographic findings positive for IE (TEE recommended in patients with prosthetic valves, rated at least possible IE by clinical criteria or complicated IE [paravalvular abscess]; TTE as 1st test in other patients), defined as follows: • Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or • Abscess, or • New partial dehiscence of prosthetic valve New valvular regurgitation; worsening or changing of preexisting murmur not sufficient Minor Criteria • Predisposition, predisposing heart condition, or intravenous drug use • Fever—temperature >38°C • Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions • Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor • Microbiologic evidence: positive blood culture finding but does not meet a major criterion as noted above (excludes single positive culture findings for coagulase-negative staphylococci and organisms that do not cause endocarditis) or serologic evidence of active infection with organism consistent with IE TEE, Transesophageal echocardiography; TTE, transthoracic echocardiography. Modified from Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis, Clin Infect Dis 30:633,

2000.

Prognosis and Complications Despite the use of antibiotic agents, mortality remains high, in the range of 20– 25%. Serious morbidity occurs in 50–60% of children with documented infective endocarditis; the most common is heart failure caused by vegetations involving the aortic or mitral valve. Myocardial abscesses and toxic myocarditis may also lead to heart failure without characteristic changes in auscultatory findings and, occasionally, to life-threatening arrhythmias. Systemic emboli, often with central nervous system manifestations, are a major threat. Pulmonary emboli may occur in children with ventricular septal defect (VSD) or tetralogy of Fallot, although massive life-threatening pulmonary embolization is rare. Other complications include mycotic aneurysms, rupture of a sinus of Valsalva, obstruction of a valve secondary to large vegetations, acquired VSD, and heart block as a result of involvement (abscess) of the conduction system. Additional complications include meningitis, osteomyelitis, arthritis, renal abscess, purulent pericarditis, and immune complex–mediated glomerulonephritis.

Treatment Antibiotic therapy should be instituted immediately once a definitive diagnosis of infectious endocarditis is made. When virulent organisms are responsible, small delays may result in progressive endocardial damage and are associated with a greater likelihood of severe complications. The choice of antibiotics, method of administration, and length of treatment should be coordinated with consultants from both cardiology and infectious diseases (Tables 464.6 and 464.7 ). Empirical therapy after appropriate blood cultures are drawn but before the identifiable agent is recovered may be initiated with vancomycin plus gentamicin in patients without a prosthetic valve and when there is a high risk of S. aureus, enterococcus, or viridans streptococci (the 3 most common organisms). High serum bactericidal levels must be maintained long enough to eradicate organisms that are growing in relatively inaccessible avascular vegetations. Between 5 and 20 times the minimal in vitro inhibiting concentration must be produced at the site of infection to destroy bacteria growing at the core of these lesions. Several weeks are required for a vegetation

to organize completely; therapy must be continued through this period so that recrudescence can be avoided. A total of 4-6 wk of treatment is usually recommended. Depending on the clinical and laboratory responses, antibiotic therapy may require modification, and some patients require more prolonged treatment. With highly sensitive viridans group streptococcal infections, shortened regimens that include oral penicillin for some portion have been recommended for certain adults, but effectiveness studies in children are lacking. In nonstaphylococcal disease, bacteremia usually resolves in 24-48 hr, whereas fever resolves in 5-6 days with appropriate antibiotic therapy. Resolution with staphylococcal disease takes longer. Table 464.6

Therapy of Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus bovis REGIMEN Aqueous crystalline penicillin G sodium Or Ceftriaxone sodium

DOSAGE* AND ROUTE DURATION COMMENTS 12-18 million U/24 hr IV 4 wk Preferred in patients with impairment of 8th cranial either continuously or in 4 or nerve function or renal function 6 equally divided doses

Aqueous crystalline penicillin G sodium

2 wk regimen not intended for patients with known cardiac or extracardiac abscess or for those with creatinine clearance of 10 mm* One or more embolic events during the 1st 2 wk of antimicrobial therapy* Increase in vegetation size despite appropriate antimicrobial therapy* †

Valvular Dysfunction Acute aortic or mitral insufficiency with signs of ventricular failure † Heart failure unresponsive to medical therapy † Valve perforation or rupture †

Perivalvular Extension Valvular dehiscence, rupture, or fistula †

New heart block † ‡ Large abscess or extension of abscess despite appropriate antimicrobial therapy †

* Surgery may be required because of risk of embolization. † Surgery may be required because of heart failure or failure of medical therapy. ‡ Echocardiography should not be the primary modality used to detect or

monitor heart block. From Baddour LM, Freeman WK, Suri RM, Wilson WR: Cardiovascular infections. In Braunwald's heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2018, Elsevier (Table 73-5, p 1492). Fungal endocarditis is difficult to manage and has a poorer prognosis. It has been encountered after cardiac surgery, in severely debilitated or immunosuppressed patients, and in patients on a prolonged course of antibiotics. The drugs of choice are amphotericin B (liposomal or standard preparation) and 5-fluorocytosine. Surgery to excise infected tissue is occasionally attempted, but often with limited success. Recombinant tissue plasminogen activation may help lyse intracardiac vegetations and avoid surgery in some high-risk patients.

Prevention The American Heart Association (AHA) recommendations for antimicrobial prophylaxis before dental and other surgical procedures underwent a major revision in 2007. A substantial reduction in the number of patients who require prophylactic treatment and the procedures requiring coverage was recommended. The primary reasons for these revised recommendations were that (1) infective endocarditis is much more likely to result from exposure to the more frequent random bacteremias associated with daily activities than from a dental or surgical procedure; (2) routine prophylaxis may prevent “an exceedingly small” number of cases; and (3) the risk of antibiotic- related adverse events exceeds the benefits of prophylactic therapy. Improving general dental hygiene was thought to be a more important factor in reducing the risk of

infective endocarditis resulting from routine daily bacteremias. The current recommendations limit the use of prophylaxis to those patients with cardiac conditions associated with the greatest risk of an adverse outcome from infective endocarditis (Table 464.9 ). Patients with permanently damaged valves from rheumatic heart disease should also be considered for prophylaxis. Prophylaxis for these patients is recommended for “all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa.” Furthermore, “placement of removable prosthodontic or endodontic appliances, adjustment of orthodontic appliances, placement of orthodontic brackets, shedding of deciduous teeth and bleeding from trauma to the lips or oral mucosa” are not indications for prophylaxis. Given that many invasive respiratory tract procedures do cause bacteremia, prophylaxis for many of these procedures is considered reasonable. In contrast to prior recommendations, prophylaxis for gastrointestinal or genitourinary procedures is no longer recommended in the majority of cases. Prophylaxis for patients undergoing cardiac surgery with placement of prosthetic material is still recommended. Given the highly individual nature of these recommendations and the continued concern among some cardiologists over their adoption, direct consultation with the child's cardiologist is still the best method for determining a specific patient's ongoing need for prophylaxis (Table 464.10 ).

Table 464.9

Cardiac Conditions Associated with Highest Risk of Adverse Outcome from Infective Endocarditis for Which Prophylaxis with Dental Procedures Is Reasonable (2007 AHA Statement) Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous infective endocarditis

Congenital Heart Disease (CHD)* Unrepaired cyanotic CHD, including palliative shunts and conduits Completely repaired CHD with prosthetic material or device, whether

placed by surgery or catheter intervention, during the 1st 6 mo after the procedure † Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch, or prosthetic device (which inhibit endothelialization) Cardiac transplantation recipients who develop cardiac valvulopathy

* Except for the conditions listed here, antibiotic prophylaxis is no longer

recommended by the AHA for any other form of CHD. † Prophylaxis is reasonable because endothelialization of prosthetic material

occurs within 6 mo after the procedure. From Wilson W, Taubert KA, Gewitz M, et al: Prevention of infective endocarditis: guidelines from the American Heart Association, Circulation 116:1736–1754, 2007. Table 464.10

Prophylactic Antibiotic Regimens for a Dental Procedure (2007 AHA Statement) SITUATION Oral Unable to take oral medication

Allergic to penicillins or ampicillin—oral

Allergic to penicillins or ampicillin and unable to take oral medication

AGENT Amoxicillin Ampicillin or Cefazolin or ceftriaxone Cephalexin* † or Clindamycin or Azithromycin or clarithromycin Cefazolin or ceftriaxone † or Clindamycin

ADULTS 2 g 2 g IM or IV 1 g IM or IV 2 g 600 mg 500 mg

CHILDREN 50 mg/kg 50 mg/kg IM or IV 50 mg/kg IM or IV 50 mg/kg 20 mg/kg 15 mg/kg

1 g IM or IV 600 mg IM or IV

50 mg/kg IM or IV 20 mg/kg IM or IV

* Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage. † Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema,

or urticaria with penicillins or ampicillin.

IM, Intramuscularly; IV, intravenously. From Wilson W, Taubert KA, Gewitz M, et al: Prevention of infective endocarditis: guidelines from the American Heart Association, Circulation 116:1736–1754, 2007.

Continuing education regarding both oral hygiene and in appropriate cases the need for prophylaxis is important, especially in teenagers and young adults. Vigorous treatment of sepsis and local infections and careful asepsis during heart surgery and catheterization reduce the incidence of infective endocarditis.

Bibliography Abdelhady W, Bayer AS, Gonzales R, et al. Telavancin is active against experimental aortic valve endocarditis caused by daptomycin- and methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother . 2017;61(2):e1877– e1916. Baddour LM, Wilson WR, Bayer AS, et al. Diagnosis, antimicrobial therapy, and management of complications. A scientific statement for healthcare professionals from the American heart association. Circulation . 2015;132(15):1435–1486. Baltimore RS, Gewitz M, Baddour LM, et al. Infective endocarditis in childhood: 2015 update. A scientific statement from the American heart association. Circulation . 2015;132:1487–1515. Britt NS, Potter EM, Patel N, Steed ME. Comparative effectiveness and safety of standard-, medium-, and high-dose daptomycin strategies for the treatment of vancomycinresistant enterococcal bacteremia among veterans affairs patients. Clin Infect Dis . 2017;64:605–613. Elder RW, Baltimore RS. The changing epidemiology of pediatric endocarditis. Infect Dis Clin North Am . 2015;29:513–524. Fleischauer AT, Ruhl L, Rhea S, Barnes E. Hospitalizations for endocarditis and associated health care costs among persons

with diagnosed drug dependence, North carolina, 2010–2015. MMWR Morb Mortal Wkly Rep . 2017;66(22):569–572. Tissieres P, Gervaix A, Beghetti M, et al. Value and limitations of the von reyn, Duke, and modified duke criteria for the diagnosis of infective endocarditis in children. Pediatrics . 2003;112:e467. Toyoda N, Chikwe J, Itaaki S, et al. Trends in infective endocarditis in California and New York, 1998–2013. JAMA . 2017;317(16):1652–1660. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis. guidelines from the American heart association. Circulation . 2007;116:1736–1754.

CHAPTER 465

Rheumatic Heart Disease Michael R. Carr, Stanford T. Shulman

Rheumatic involvement of the cardiac valves is the most important sequela of acute rheumatic fever (ARF) and also the 2nd most common major manifestation after arthritis (see Chapter 210.1 ). The valvular lesions begin as small verrucae composed of fibrin and blood cells along the borders of 1 or more of the heart valves. The mitral valve is affected most often, followed in frequency by the aortic valve. Isolated aortic valve disease is rare and generally seen with concomitant mitral valve involvement. Right-sided heart manifestations are quite rare and are virtually only associated with left-sided valve disease. As the inflammation subsides, the verrucae tend to disappear and leave scar tissue. With repeated attacks of rheumatic fever, new verrucae form near the previous ones, and the mural endocardium and chordae tendineae become involved. A single episode of acute rheumatic carditis often results in complete healing of the valvular lesions, while repeated episodes, especially involving previously affected valves, result in chronic rheumatic heart disease (RHD ), which is the rationale for secondary prophylaxis. The diagnosis of ARF requires the fulfillment of the Jones criteria (see Chapter 210.1 ), with carditis being a major criterion. Previously, the diagnosis of RHD was based on cardiac auscultatory findings of mitral or aortic valve involvement, which was insensitive for early valve injury. This was based on endocarditis or valvulitis being seen more frequently in ARF compared with pericarditis or myocarditis, both of which lack more readily apparent physical examination findings. Screening large, high-risk populations with echocardiography demonstrated a substantially greater number of patients with RHD than those detected by auscultation alone. Because access to echocardiography is often available, the current version of the Jones Criteria focused on the concept of subclinical carditis (SCC) detected by

echocardiography. SCC is defined as echocardiographic evidence of mitral or aortic valvulitis in the absence of auscultatory findings and not consistent with physiologic mitral or aortic insufficiency (Table 465.1 ). Echocardiography with Doppler should be performed for all cases of confirmed or suspected ARF. Additional recommendations are that echocardiography should be performed in moderate- to high-risk patient populations if ARF is considered likely, and that echocardiography can be used to exclude cardiac findings consistent with ARF in patients with cardiac murmurs thought to be suggestive of rheumatic carditis. Additionally, serial echocardiography should be considered in patients with diagnosed or suspected ARF even if there is no evidence of valvulitis by echocardiography at diagnosis. The echocardiographic finding of SCC now fulfills the major criterion for carditis. Table 465.1

Echocardiographic Findings in Rheumatic Valvulitis PATHOLOGIC MITRAL REGURGITATION* 1. Seen in at least 2 views 2. Jet length ≥2 cm in at least 1 view 3. Peak velocity >3 meters/sec 4. Pan-systolic jet in at least 1 envelope

PATHOLOGIC AORTIC REGURGITATION* 1. Seen in at least 2 views 2. Jet length ≥1 cm in at least 1 view 3. Peak velocity >3 meters/sec 4. Pan-diastolic jet in at least 1 envelope

* All 4 criteria need to be met.

Adapted from Gewitz MH, Baltimore RS, Tani LY, etal: On behalf of the American Heart Association Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease of the Council on Cardiovascular Disease in the Young. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association, Circulation 131:1806–1818, 2015.

Patterns of Valvular Disease Mitral Insufficiency Pathophysiology Mitral insufficiency is the result of structural changes that may include some loss of valvular substance and/or changes to the subvalvular apparatus, including elongation of the chordae, both of which can lead to valve dysfunction. During ARF with severe cardiac involvement, heart failure is caused by a combination of mitral insufficiency coupled with a pancarditis , involving the pericardium

and myocardium in addition to the endocardium/valve. Because of the increased volume load from the mitral insufficiency and the inflammatory process, the left ventricle dilates. The left atrium also enlarges to accommodate the regurgitant volume. Increased left atrial pressure results in pulmonary congestion and symptoms of left-sided heart failure. Spontaneous improvement often occurs with time, even in patients in whom mitral insufficiency is severe at the onset. The resultant chronic lesion is most often mild or moderate in severity, and the patient is often asymptomatic. More than half of patients with acute mitral insufficiency no longer have an audible mitral insufficiency murmur 1 yr later, although they still may demonstrate insufficiency on echocardiography. In patients with severe chronic mitral insufficiency, pulmonary artery pressure (PAP) becomes elevated, the right ventricle and atrium become enlarged, and right-sided heart failure subsequently develops.

Clinical Manifestations The physical signs of mitral insufficiency depend on its severity. With mild disease, signs of heart failure are not present, the precordium is quiet, and auscultation reveals a high-pitched holosystolic murmur at the apex that radiates to the axilla. With severe mitral insufficiency, signs of acute or chronic heart failure may be noted. The heart is enlarged, with a heaving apical left ventricular (LV) impulse and often an apical systolic thrill . The second heart sound (S2 ) may be accentuated if pulmonary hypertension is present. A third heart sound or gallop is generally prominent. A holosystolic murmur is heard at the apex with radiation to the axilla. A short mid-diastolic rumbling murmur is caused by increased blood flow across the mitral valve as a result of the significant insufficiency. Therefore, auscultation of a diastolic murmur, often referred to as relative mitral stenosis (Carey-Coombs murmur ), does not necessarily mean that true mitral stenosis is present. The latter lesion takes many years to develop and is characterized by a diastolic murmur of greater length, usually with presystolic accentuation. The electrocardiogram and chest radiographs are normal if the mitral insufficiency is mild. With more severe insufficiency, the ECG shows prominent, longer duration and often bifid P waves, signs of LV hypertrophy, and associated right ventricular (RV) hypertrophy if pulmonary hypertension is present. On chest radiograph, prominence of the left atrium and ventricle can be seen, the former of which is better seen on lateral projections. Congestion of the perihilar vessels, a sign of pulmonary venous hypertension, may also be evident.

Calcification of the mitral valve is rare in children. Echocardiography in the acute phase may demonstrate enlargement of the left atrium and ventricle. LV systolic function can be impaired if there is also a component of myocardial inflammation. Mitral annular dilation, chordal elongation, and at times, evidence of chordal rupture resulting in a flail leaflet may be noted. The leaflet tips demonstrate a nodular appearance and prolapse of the anterior mitral valve leaflet tip (much more often than the posterior leaflet) is seen. Doppler evaluation demonstrates the severity of the mitral regurgitation. Chronic mitral insufficiency from RHD is characterized on echocardiography by leaflet and chordal thickening, chordal fusion, and restricted leaflet motion. These changes often lead to stenosis, but poor coaptation of the abnormal leaflets can also lead to variable degrees of regurgitation. Cardiac catheterization and left ventriculography are considered only if diagnostic questions are not completely resolved by noninvasive assessment, or in rare cases with a concern for significantly elevated PAP.

Complications Severe mitral insufficiency may result in cardiac failure that may be precipitated by progression of the rheumatic process, recurrent episodes of ARF, the onset of atrial fibrillation (AF) or other arrhythmias, or infective endocarditis. The effects of chronic mitral insufficiency may become manifest after many years and include LV and RV failure and atrial and ventricular arrhythmias.

Treatment In patients with mild mitral insufficiency, prophylaxis against recurrences of rheumatic fever is all that is required, in addition to the typical treatment for ARF (see Chapter 210.1 ). For more significant insufficiency, corticosteroids are added in the acute phase. Treatment of complicating heart failure (see Chapter 469 ), arrhythmias (Chapter 462 ), and infective endocarditis (Chapter 464 ) is described elsewhere. Afterload-reducing agents—angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may reduce the regurgitant volume, attenuate pathologic compensatory mechanisms, and preserve left ventricular function, but these have not been proven to alter the natural history of the disease process. Diuretics may also provide some symptomatic and clinical benefit in select cases. In rare cases, phosphodiesterase inhibitors such as milrinone may be used in the acute stage, because of their

inotropic, lusitropic, and systemic vascular dilating effects. Surgical treatment is indicated for patients who, despite adequate medical therapy, have persistent heart failure, dyspnea with moderate activity, and progressive cardiomegaly, often with pulmonary hypertension. Although annuloplasty provides good results in some children and adolescents, valve replacement may be required, which can be more complicated in younger children. In patients with a prosthetic mitral valve replacement, prophylaxis against bacterial endocarditis is warranted for dental procedures, as the routine antibiotics taken by these patients for rheumatic fever prophylaxis are insufficient to prevent endocarditis. Additionally, current recommendations suggest selecting a different class of antibiotic for such procedures, rather than increasing the dose of the antibiotic taken for rheumatic fever prophylaxis. Lastly, it is important to remember that all attempts should be made at maximizing medical management of severe mitral insufficiency during the acute phase of the disease process, before considering surgical intervention, since surgery carries a poorer prognosis and an increased risk for reoperation when performed during the acute phase.

Mitral Stenosis Pathophysiology Mitral stenosis of rheumatic origin results from fibrosis of the mitral ring, commissural adhesions, and contracture of the valve leaflets, chordae, and papillary muscles over time. This is a chronic process and often takes ≥10 yr for the lesion to become fully established, although the process may occasionally be accelerated. In the developed world, rheumatic mitral stenosis is seldom encountered before adolescence and is not usually recognized until adult life. Significant mitral stenosis results in increased left atrial pressure and subsequent enlargement and hypertrophy of the left atrium, pulmonary venous hypertension, increased pulmonary vascular resistance, and eventually overt pulmonary hypertension (see Chapter 460 ). RV hypertrophy and right atrial dilation ensue and are followed by RV dilation, tricuspid regurgitation, and clinical signs of right-sided heart failure.

Clinical Manifestations Generally, the correlation between symptoms and the severity of obstruction is good. Patients with mild stenosis are asymptomatic. More severe degrees of

obstruction are associated with exercise intolerance and dyspnea. Critical lesions can result in orthopnea, paroxysmal nocturnal dyspnea, and overt pulmonary edema, as well as atrial arrhythmias. When pulmonary hypertension has developed, RV dilation may result in functional tricuspid insufficiency, hepatomegaly, ascites, and edema. Hemoptysis caused by rupture of bronchial or pleurohilar veins and, occasionally, pulmonary infarction may occur. Jugular venous pressure is increased in severe disease with heart failure, tricuspid valve disease/regurgitation, or severe pulmonary hypertension. In mild disease, heart size is normal; however, moderate cardiomegaly is typical with severe mitral stenosis. Cardiac enlargement can be massive when AF and heart failure supervene. A parasternal RV lift is palpable when PAP is high. The principal auscultatory findings are a loud first heart sound, an opening snap of the mitral valve, and a long, low-pitched, rumbling mitral diastolic murmur with presystolic accentuation at the apex. The mitral diastolic murmur may be virtually absent in patients who are in significant heart failure from the elevated LV filling pressures. A holosystolic murmur secondary to tricuspid insufficiency may be audible at the left lower sternal border. In the presence of pulmonary hypertension, the pulmonic component of S2 is accentuated. An early diastolic murmur may be caused by associated rheumatic aortic insufficiency or pulmonary valvular insufficiency secondary to pulmonary hypertension. ECGs and chest radiographs are normal if the stenosis is mild; as the severity increases, prominent and notched P waves and varying degrees of RV hypertrophy become evident. AF or other atrial arrhythmias are common late manifestations. Moderate to severe lesions are associated with radiographic signs of left atrial enlargement and prominence of the pulmonary artery and rightsided heart chambers; calcifications may be noted in the region of the mitral valve. Severe stenosis is associated with a redistribution of pulmonary blood flow so that the apices of the lung have greater perfusion (the reverse of normal). Lastly, horizontal lines in the lower lung periphery, called Kerley B lines , may be evident. Echocardiography demonstrates thickening of the mitral valve and chordal apparatus, as well as restricted motion of the valve. The typical “elbow” or “dog leg” appearance of the anterior leaflet of the mitral valve can aid in the distinction of a rheumatic valve from the various forms of congenital mitral stenosis. Left atrial dilation is common; color Doppler flow across the mitral valve shows a narrow jet with flow acceleration, and variable degrees of tricuspid insufficiency can be seen from left atrial hypertension. Doppler can estimate the transmitral pressure gradient but can underestimate the gradient

if there is LV dysfunction. Cardiac catheterization quantitates the diastolic gradient across the mitral valve well, allows for the calculation of cross-sectional valve area in older children, and assesses the degree of PAP elevation.

Treatment Intervention is indicated in patients with clinical signs and hemodynamic evidence of severe obstruction, but before the onset of severe manifestations. Pharmacologic therapy (diuretics and β-blockers) can be considered but is generally used only for symptom control and much less often in children. Surgical valvotomy or balloon catheter mitral valvuloplasty generally yields good results; valve replacement is avoided unless absolutely necessary. Balloon valvuloplasty is indicated for symptomatic, stenotic, pliable, noncalcified valves of patients without significant atrial arrhythmias or thrombi.

Aortic Insufficiency In acute rheumatic aortic insufficiency, poor coaptation of the leaflets or leaflet prolapse is seen. Chronic rheumatic aortic insufficiency leads to sclerosis of the valve and results in distortion and retraction of the cusps. In both settings, regurgitation of blood leads to LV volume overload with dilation and hypertrophy of the left ventricle, as it attempts to compensate for the excessive volume load. Combined mitral and aortic insufficiency in the acute phase of ARF is much more common than aortic involvement alone.

Clinical Manifestations Symptoms are unusual except in severe aortic insufficiency, or in the presence of significant concomitant mitral valve involvement or myocardial dysfunction. The large stroke volume and forceful LV contractions may result in palpitations. Sweating and heat intolerance are related to excessive vasodilation. Dyspnea on exertion can progress to orthopnea and pulmonary edema; angina may be precipitated by heavy exercise. Nocturnal attacks with sweating, tachycardia, chest pain, and hypertension may occur. The pulse pressure is wide with bounding peripheral pulses (water-hammer or Corrigan pulse ). Systolic blood pressure is elevated, and diastolic pressure is lowered. In severe aortic insufficiency, the heart is enlarged, with an LV apical heave. A diastolic thrill may be present. The typical murmur begins immediately

with S2 and continues until late in diastole. The murmur is heard over the upper left and mid-left sternal border with radiation to the apex and upper right sternal border. Characteristically, it has a high-pitched blowing quality and is easily audible in full expiration with the diaphragm of the stethoscope placed firmly on the chest and the patient leaning forward. An aortic systolic ejection murmur is frequently heard because of the increased stroke volume. An apical presystolic murmur (Austin Flint murmur ) resembling that of mitral stenosis is sometimes heard and is caused by the large regurgitant aortic flow in diastole preventing the mitral valve from opening fully. Chest radiographs demonstrate enlargement of the left ventricle and aorta. The ECG may be normal, but in advanced cases it reveals signs of LV hypertrophy with a strain pattern and prominent P waves. Echocardiography shows a dilated left ventricle and diastolic mitral valve flutter or oscillations caused by aortic regurgitant flow hitting the valve leaflets. The aortic valve may demonstrate irregular or focal thickening, decreased systolic excursion, a coaptation defect, and leaflet prolapse. Doppler evaluation demonstrates the degree of aortic insufficiency. Magnetic resonance angiography (MRA) can be useful in quantitating regurgitant volume, as well as assessing LV size and systolic function. Cardiac catheterization is generally only necessary when echocardiographic or axial imaging data are equivocal.

Prognosis and Treatment Mild and moderate degrees of aortic insufficiency are well tolerated. Unlike mitral insufficiency, aortic insufficiency does not generally regress. Patients with combined lesions during the episode of ARF may have only aortic involvement 1-2 yr later. Treatment consists of ACE inhibitors or ARBs and prophylaxis against ARF recurrence. Surgical intervention, which is typically aortic valve replacement, but occasionally can involve aortic valve repair, should be done well in advance of the onset of heart failure, pulmonary edema, and angina or when signs of decreasing myocardial performance become evident, as manifested by increasing LV dimensions and decreasing systolic function on echocardiography. Surgery is considered when early symptoms are present, ST-T wave changes are seen on the ECG, or evidence of decreasing LV ejection fraction is noted.

Tricuspid Valve Disease

Primary tricuspid valve involvement is rare during both the acute and chronic stages of rheumatic fever. Tricuspid insufficiency is more common secondary to RV dilation, resulting from significant left-sided cardiac lesions. The clinical signs of tricuspid insufficiency include prominent pulsations of the jugular veins, systolic pulsations of the liver, and a blowing holosystolic murmur at the lower left sternal border that increases in intensity during inspiration. Concomitant signs of mitral or aortic valve disease, with or without AF, are common. In these cases, signs of tricuspid insufficiency often decrease or even disappear when heart failure produced by the left-sided valvular lesions is successfully treated. Tricuspid valvuloplasty may be required in very rare cases.

Pulmonary Valve Disease Pulmonary insufficiency secondary to ARF is rare and usually occurs on a functional basis secondary to pulmonary hypertension and is a late finding with severe mitral stenosis. The murmur (Graham Steell murmur ) is similar to that of aortic insufficiency, but peripheral arterial signs (bounding pulses) are absent. The correct diagnosis is confirmed by two-dimensional echocardiography and Doppler studies.

Bibliography Camara EJ, Neubauer C, Camara GF, et al. Mechanisms of mitral valvar insufficiency in children and adolescents with severe rheumatic heart disease: an echocardiographic study with clinical and epidemiological correlations. Cardiol Young . 2004;14:527–532. Chang C. Cutting edge issues in rheumatic fever. Clin Rev Allergy Immunol . 2012;42:213–237. Gewitz MH, Baltimore RS, Tani LY, et al. On behalf of the American Heart Association Committee on Rheumatic Fever, Endocarditis and Kawasaki disease of the council on cardiovascular disease in the young. Revision of the jones criteria for the diagnosis of acute rheumatic fever in the era of doppler echocardiography: a scientific statement from the

American Heart Association. Circulation . 2015;131:1806– 1818. Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheumatic heart disease: genetics and pathogenesis. Scand J Immunol . 2007;66:199–207. Kerdemelidis M, Lennon DR, Arroll B, et al. The primary prevention of rheumatic fever. J Paediatr Child Health . 2010;46:534–548. Lawrence JG, Carapetis JR, Griffiths K, et al. Acute rheumatic fever and rheumatic heart disease. Incidence and progression in the northern territory of Australia, 1997–2010. Circulation . 2013;128:492–501. Marijon E, Mirabel M, Celermajer DS, et al. Rheumatic heart disease. Lancet . 2012;379:953–962. Narula J, Chandrasekhar Y, Rahimtoola S. Diagnosis of active rheumatic carditis. Circulation . 1999;100:1576–1581. Reményi B, Wilson N, Steer A, et al. World heart federation criteria for echocardiographic diagnosis of rheumatic heart disease—an evidence-based guideline. Nat Rev Cardiol . 2012;9:297–309. Reményi B, ElGuindy A, Smith SC, et al. Valvular aspects of rheumatic heart disease. Lancet . 2016;387:1335–1346. Watkins DA, Johnson CO, Colquhoan SM, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med . 2017;377(8):713–722. Yacoub M, Mayosi B, ElGuindy A, et al. Eliminating acute rheumatic fever and rheumatic heart disease. Lancet . 2017;390:212–213. Zuhlke LJ, Beaton A, Engel ME, et al. Group a Streptococcus, acute rheumatic fever and rheumatic heart disease: epidemiology and clinical considerations. Curr Treat Options Cardio Med . 2017;19:15.

SECTION 6

Diseases of the Myocardium and Pericardium OUTLINE Chapter 466 Diseases of the Myocardium Chapter 467 Diseases of the Pericardium Chapter 468 Tumors of the Heart

CHAPTER 466

Diseases of the Myocardium John J. Parent, Stephanie M. Ware

The extremely heterogeneous heart muscle diseases associated with structural remodeling and abnormalities of cardiac function (cardiomyopathy ) are important causes of morbidity and mortality in the pediatric population. Several classification schemes have been formulated in an effort to provide logical, useful, and scientifically based etiologies for the cardiomyopathies. Insight into the molecular genetic basis of cardiomyopathies has increased exponentially, and etiologic classification schemes continue to evolve (Table 466.1 ). Table 466.1

Classification of the Cardiomyopathies by Phenome and Genome PHENOTYPE TYPE Dilated (DCM)

Restrictive (RCM)

GENOME

Systemic Conditions, Clinical Features, Risk Factors Dilation of LV Reduced Myocyte Hypertension, and RV with contractility hypertrophy; alcohol, minimal or no is the scattered fibrosis thyrotoxicosis, wall primary myxedema, persistent thickening defect; tachycardia, toxins variable (e.g., chemotherapy, degree of especially diastolic anthracyclines), dysfunction radiation

Morphology

Usually normal chamber sizes; minimal wall thickening

Physiology

Contractility normal or near-normal with a marked increase in

Pathology

Specific to type, diagnosis: amyloid, iron, glycogen storage disease, others

Endomyocardial fibrosis, amyloid, sarcoid, scleroderma, Churg-Strauss syndrome, cystinosis, lymphoma,

Nonsyndromic, Usually Single Gene Diverse gene ontology with >30 genes implicated

If not associated with systemic genetic disease, genetic cause usually from sarcomeric gene mutations

Hypertrophic (HCM)

Usually normal or reduced internal chamber dimension; wall thickening pronounced, especially septal hypertrophy Arrhythmogenic Scattered right ventricular fibrofatty cardiomyopathy infiltration, (ARVC) classically of RV but also of LV; dilation of RV or LV, or both, is common but not universal

enddiastolic filling pressure Systolic function increased or normal

Myocyte hypertrophy, classically with disarray

pseudoxanthoma elasticum, hypereosinophilic syndrome, carcinoid Severe hypertension Mutations of genes can confound clinical, encoding sarcomeric morphologic proteins diagnosis

Ventricular arrhythmias (VT, VF) early or late, reduced contractility with progressive disease; can mimic DCM Left ventricular Ratio of Normal to noncompaction noncompacted reduced (LVNC) to compacted systolic myocardium function increased with normal LV or RV or any other phenotype Infiltrative Usually Restrictive thickened physiology; walls; systolic occasional function dilation usually mildly reduced Inflammatory Normal or Reduced dilated systolic without function hypertrophy Ischemic Normal or Reduced dilated systolic without function hypertrophy

Islands of fatty replacement; fibrosis

Palmoplantar keratoderma, wooly hair in Naxos syndrome

Mutations of genes encoding proteins of desmosome

Myocardium normal and ranging to findings consistent with other coexisting cardiomyopathies

Phenotype observed in setting of other types of cardiomyopathy

Various cardiomyopathy genes associated, but uncertain whether genetic cause or developmental defect during organogenesis

Infectious

Specific to infection

Normal or dilated without

Reduced systolic function

Specific to type, diagnosis: amyloid, iron, glycogen storage disease, others

See RCM, above

Inflammatory infiltrates

Hypereosinophilic syndrome, acute myocarditis

Areas of infarcted myocardium

Hypercholesterolemia, hypertension, diabetes, cigarette smoking, family history Viral (especially acute myocarditis); protozoal (e.g.,

Familial hypercholesterolemia; other heritable lipid disorders Genetic predisposition to infection and/or

hypertrophy

Chagas disease); variable response to infective agent bacterial, direct infection (e.g., Lyme disease) or from acute cellular toxicity as result of systemic toxins (e.g., Streptococcus , gramnegative, others)

LV, Left ventricle; MELAS, mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms; MERRF, myoclonic epilepsy associated with ragged-red fibers; RV, right ventricle; VF, ventricular fibrillation; VT, ventricular tachycardia. From Falk RH, Hershberger RE: The dilated, restrictive, and infiltrative cardiomyopathies. In Zipes DP, Libby P, Bonow RO, editors: Braunwald's heart disease, ed 11, Philadelphia, 2019, Saunders (Table 77.1 ).

Table 466.2 classifies the cardiomyopathies based on their anatomic (ventricular morphology) and functional pathophysiology. Dilated cardiomyopathy , the most common form of cardiomyopathy, is characterized predominantly by left ventricular (LV) dilation and decreased LV systolic function (Fig. 466.1 ). Hypertrophic cardiomyopathy demonstrates increased ventricular myocardial wall thickness, normal or increased systolic function, and often, diastolic (relaxation) abnormalities (Table 466.3 and Figs. 466.2 and 466.3 ). Restrictive cardiomyopathy is characterized by near-normal ventricular chamber size and wall thickness with preserved systolic function, but dramatically impaired diastolic function leading to elevated filling pressures and atrial enlargement (Fig. 466.4 ). Arrhythmogenic right ventricular cardiomyopathy is characterized by fibrofatty infiltration and replacement of the normal right ventricular (RV) myocardium and occasionally the left ventricle, leading to RV (and LV) systolic and diastolic dysfunction and arrhythmias. Left ventricular noncompaction is characterized by a trabeculated LV apex and lateral wall, with a heterogeneous group of associated phenotypes (most often a dilated phenotype with LV dilation and dysfunction). Cardiomyopathies may be primary or associated with other organ involvement (Tables 466.4 to 466.6 ). Table 466.2

Etiology of Pediatric Myocardial Disease CARDIOMYOPATHY Dilated Cardiomyopathy (DCM) Neuromuscular Muscular dystrophies (e.g., Duchenne, Becker, limb-girdle, Emery-Dreifuss, congenital

diseases Inborn errors of metabolism

Genetic mutations in cardiomyocyte structural apparatus Genetic syndromes Ischemic Chronic tachyarrhythmias

muscular dystrophy), myotonic dystrophy, myofibrillar myopathy Fatty acid oxidation disorders (trifunctional protein, VLCAD), carnitine abnormalities (carnitine transport, CPTI, CPTII), mitochondrial disorders (including Kearns-Sayre syndrome), organic acidemias (propionic acidemia), Danon disease (DCM more common in females). Familial or sporadic DCM

Alström syndrome, Barth syndrome (phospholipid disorders)

Most common in adults Atrial tachycardias (intractable reentrant supraventricular tachycardia [AVRT, AVNRT], multifocal atrial tachycardia, permanent junctional reciprocating tachycardia), ventricular tachycardia Hypertrophic Cardiomyopathy (HCM) Inborn errors of Mitochondrial disorders (including Friedreich ataxia, mutations in nuclear or mitochondrial metabolism genome), storage disorders (glycogen storage disorders, especially Pompe; mucopolysaccharidoses; Fabry disease; sphingolipidoses; hemochromatosis; Danon disease) Genetic Familial or sporadic HCM mutations in cardiomyocyte structural apparatus Genetic Noonan, Costello, cardiofaciocutaneous, and Beckwith-Wiedemann syndromes syndromes Infant of a Transient hypertrophy diabetic mother Restrictive Cardiomyopathy (RCM) Neuromuscular Myofibrillar myopathies disease Metabolic Storage disorders Genetic Familial or sporadic RCM mutations in cardiomyocyte structural apparatus Secondary Rare in children; radiation therapy of thorax, amyloidosis, sarcoidosis, hemochromatosis, βthalassemia Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Genetic Familial or sporadic ARVC mutations in cardiomyocyte structural apparatus Left Ventricular Noncompaction Genetic LVNC phenotype associated with HCM or DCM mutations in cardiomyocyte structural apparatus Other X-linked (Barth syndrome), autosomal recessive, mitochondrial inheritance, 1p36 deletion syndrome, and other chromosome abnormalities or genomic disorders; associated with congenital heart defects

SECONDARY OR ACQUIRED MYOCARDIAL DISEASE Myocarditis (see also Table 466.8 )

Systemic inflammatory disease Nutritional deficiency Drugs, toxins

Coronary artery disease Hematologyoncology Endocrineneuroendocrine Stress (takotsubo) cardiomyopathy

Viral: parvovirus B19, adenovirus, coxsackievirus A and B, echovirus, rubella, varicella, influenza, mumps, Epstein-Barr virus, cytomegalovirus, measles, poliomyelitis, smallpox vaccine, hepatitis C virus, human herpesvirus 6, HIV, opportunistic infections Rickettsial: psittacosis, Coxiella , Rocky Mountain spotted fever, typhus Bacterial: diphtheria, mycoplasma, meningococcus, leptospirosis, Lyme disease, typhoid fever, tuberculosis, streptococcus, listeriosis Parasitic: Chagas disease, toxoplasmosis, Loa loa, Toxocara canis, schistosomiasis, cysticercosis, echinococcus, trichinosis Fungal: histoplasmosis, coccidioidomycosis, actinomycosis SLE, infant of mother with SLE, scleroderma, Churg-Strauss vasculitis, rheumatoid arthritis, rheumatic fever, sarcoidosis, dermatomyositis, periarteritis nodosa, hypereosinophilic syndrome (Löffler syndrome), acute eosinophilic necrotizing myocarditis, giant cell myocarditis, Kawasaki disease Beriberi (thiamine deficiency), kwashiorkor, Keshan disease (selenium deficiency) Doxorubicin (Adriamycin), cyclophosphamide, chloroquine, ipecac (emetine), sulfonamides, mesalazine, chloramphenicol, alcohol, hypersensitivity reaction, envenomations, irradiation, herbal remedy (blue cohosh) Kawasaki disease, medial necrosis, anomalous left coronary artery from pulmonary artery, other congenital coronary anomalies (anomalous right coronary artery, coronary ostial stenosis), familial hypercholesterolemia Anemia, sickle cell disease, leukemia Hyperthyroidism, carcinoid tumor, pheochromocytoma, adrenal crisis Endocrine (see above) Neurologic (stroke, bleed) Induction of anesthesia Fright Medications/drugs (sympathomimetic agents, venlafaxine)

CPTI/CPTII, Carnitine palmitoyltransferase 1/2; LVNC, left ventricular noncompaction; SLE, systemic lupus erythematosus; VLCAD, very-long-chain acyl-coenzyme A dehydrogenase.

FIG. 466.1 Echocardiogram of a patient with dilated cardiomyopathy. A, Parasternal long axis view showing the enlarged left ventricle. B, Apical 4-chamber view showing the large left ventricle compressing the right ventricle. Ao, Ascending aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.

Table 466.3

Cardiomyopathies Prevalence Causes

DCM 50/100,000 Sarcomeric/cytoskeletal/desmosomal gene mutation, neuromuscular disease, inborn error of metabolism, mitochondrial disease, genetic syndrome, infection

HCM 1/500 Sarcomeric/cytoskeletal/desmosomal gene mutation, genetic syndrome, inborn error of metabolism/mitochondrial disease

RCM Unknown Sarcomeric gene mutation, neuromuscular disease, genetic syndrome

LVNC Unknown Sarcomericcytoskeletaldesmosomal gene mutation, neuromuscular disease, inborn error of metabolism, mitochondrial disease, genetic

Inheritance

30–50% AD, AR, X-L, Mt

Sudden Yes death Arrhythmias Atrial, ventricular, and conduction disturbances

Ventricular function

Systolic and diastolic dysfunction

50% AD, Mt

AD, % unknown

syndrome AD, X-L, Mt, % unknown

Yes

Yes

Yes

Atrial and ventricular

Atrial fibrillation

Diastolic dysfunction Dynamic systolic outflow obstruction

Atrial, ventricular, and conduction disturbances Diastolic Systolic or dysfunction diastolic Normal dysfunction systolic function

ACE, Angiotensin-converting enzyme; AD, autosomal dominant inheritance; AR, autosomal recessive inheritance; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; LVNC, left ventricular noncompaction; Mt, mitochondrial inheritance; RCM, restrictive cardiomyopathy; X-L, X-linked inheritance.

FIG. 466.2 Locations of genes within the cardiac sarcomere known to cause hypertrophic cardiomyopathy. Prevalence of every gene (derived from data of unrelated hypertrophic cardiomyopathy probands with positive genotyping) is shown in parentheses. (From Maron BJ, Maron MS: Hypertrophic cardiomyopathy, Lancet

381:242–252, 2013, Fig 1, p 243.)

FIG. 466.3 Echocardiograms demonstrating hypertrophic cardiomyopathy. A, Parasternal long axis view of a patient with severe concentric left ventricular hypertrophy. B, Four-chamber view of a patient with asymmetric septal hypertrophy. LV, Left ventricle; LVPW, left ventricular posterior wall; RV, right ventricle; SEPT, septum.

FIG. 466.4 Echocardiogram of a patient with restrictive cardiomyopathy. Apical 4chamber view shows the greatly enlarged right and left atria, compared to the normalsize left and right ventricular chambers. LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Table 466.4

Nuclear DNA Abnormalities Associated With Cardiomyopathy and Arrhythmias or Conduction Defects* GENETIC HEART DEFECT FINDINGS ISOLATED COMPLEX DEFICIENCIES Complex I Multiple complex I HCM, DCM, deficiency subunit genes, LVNC, WPW ACAD9, FOXRED 1 Complex II SDHA, SDHD HCM, DCM, deficiency LVNC, AF, heart block Complex III BCS1L HCM deficiency Complex IV SCO2, SURF1, HCM, DCM deficiency C2orf64, Cl2orf62, COX6B1 MITOCHONDRIAL TRANSLATION DEFECTS GTP-binding GTPBP3 HCM, DCM, protein-3 deficiency heart block, WPW Mitochondrial MTOI HCM, heart translational block activator protein deficiency Alanyl-tRNA AARS2 HCM synthetase deficiency CONDITION

OTHER CLINICAL FEATURES Leigh syndrome, FILA. MELAS, leukoencephalopathy, seizures, hypotonia, pigmentary retinopathy, optic atrophy, hearing loss, liver dysfunction Leukoencephalopathy, cerebellar atrophy, seizures, spasticity, myopathy, liver dysfunction, kidney dysfunction Developmental delay, psychosis, hearing loss Leigh syndrome, encephalopathy, ataxia, liver dysfunction, kidney dysfunction

Leigh syndrome, encephalopathy

Encephalopathy, hypotonia

Leukoencephalopathy, myopathy

Tyrosyl-tRNA YARS2 synthetase deficiency tRNA TRMTS methyltransferase-5 deficiency RNA processing ELAC2 defect Mitochondrial MRPS22, MRPl3, ribosomal subunit MRPL44 deficiencies mtDNA DEPLETION SYNDROMES MNGIE TYMP

F-box protein FBXL4 deficiency Coenzyme Q10 COQ2, COQ4, biosynthesis defects COQ9

HCM

MLASA syndrome

HCM

Developmental delay, hypotonia, peripheral neuropathy, renal tubulopathy

HCM, PSVE

Microcephaly, growth deficiency, hearing loss

HCM, WPW

Leukoencephalopathy, seizures, liver dysfunction, renal tubulopathy

Mild or asymptomatic HCM Cardiomyopathy, unspecified HCM

Leukoencephalopathy, severe gastrointestinal dysmotility, ophthalmoplegia, hearing loss, peripheral neuropathy Encephalopathy, brain atrophy

3-METHYLGLUTACONIC ACIDURIAS Barth syndrome TAZ HCM, DCM, LVNC, EFE, VT, LQTS Dilated DNAJC19 DCM, LVNC cardiomyopathy and ataxia syndrome Complex V TMEM70 HCM deficiency Sengers syndrome AGK HCM

Leigh syndrome, encephalomyopathy, retinitis pigmentosa, hearing loss, liver dysfunction, renal tubulopathy Myopathy, short stature, neutropenia

Ataxia, optic ataxia, short stature, testicular abnormalities, liver disease

Cataracts, leukodystrophy, ataxia, myopathy, short stature Cataracts, myopathy, exercise intolerance, short stature

* Examples of conditions that are associated with heart disease and feature abnormal nDNA are

shown, along with the causative molecular defects and clinical findings. The genetic defects noted above are provided as major contributors to the various mitochondrial conditions but are not a comprehensive compilation. AF, Atrial fibrillation; DCM, dilated cardiomyopathy; EFE, endocardial fibroelastosis; FILA, fatal infantile lactic acidosis; GTP, guanosine triphosphate; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MLASA, myopathy, lactic acidosis, sideroblastic anemia; MNGIE, mitochondrial neurogastrointestinal encephalopathy; PSVE, paroxysmal supraventricular extrasystoles; LVNC, left ventricular noncompaction; VT, ventricular tachycardia; WPW, Wolff-Parkinson-White syndrome. From Enns GM: Pediatric mitochondrial diseases and the heart, Curr Opin Pediatr 29:541–551, 2017 (Table 2, p 543).

Table 466.5

Mitochondrial DNA Abnormalities Associated With

Cardiomyopathy and Arrhythmias or Conduction Defects* CONDITION Kearns-Sayre syndrome MELAS

MERRF

Complex I deficiency

Complex III deficiency Complex IV deficiency Complex V deficiency

GENETIC DEFECT mtDNA deletion tRNALou point mutation tRNALys point mutation Multiple complex I subunit genes MTCYB MT-CO1, MT-CO2, MT-CO3 MT-ATP6, MT-ATP8

HEART FINDINGS HCM, DCM, heart block, PMVT HCM, DCM, LVNC, RCM, heart block, WPW HCM, DCM, HiCM, WPW

OTHER CLINICAL FEATURES Progressive external ophthalmoplegia, pigmentary retinopathy, cerebellar ataxia, hearing loss, increased CSF protein, diabetes mellitus, renal tubulopathy Encephalopathy, seizures, stroke-like episodes, headaches, hearing loss, myopathy Myoclonus, seizures, ataxia, optic atrophy, hearing loss, short stature

HCM, DCM

Leigh syndrome, leukoencephalopathy, seizures, optic atrophy

HCM, DCM, HiCM HCM, DCM, HiCM

Exercise intolerance, myopathy, seizures, optic atrophy, short stature Encephalopathy, seizures, pigmentary retinopathy, hearing loss, myopathy, liver dysfunction

HCM

Ataxia, peripheral neuropathy

* Relatively common conditions that are associated with heart disease and feature abnormal

mtDNA are shown, along with the most common molecular defects and clinical findings. Although the most common molecular defects are indicated in the table, in most cases multiple genetic abnormalities can cause similar clinical presentations. CSF, Cerebrospinal fluid; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HiCM, histiocytoid cardiomyopathy; LVNC, left ventricular noncompaction; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; PMVT, polymorphic ventricular tachycardia; RCM, restrictive cardiomyopathy; WPW, Wolff-Parkinson-White syndrome. From Enns GM: Pediatric mitochondrial diseases and the heart, Curr Opin Pediatr 29:541–551, 2017 (Table 3, p 546).

Table 466.6

Gene Mutations and Cardiac Manifestations of Neuromuscular Disorders DISORDER Duchenne muscular dystrophy (DMD)

GENE CARDIOMYOPATHY ECG MUTATION Dystrophin Dilated Short PR interval, prolonged QT interval, increased QT:PT ratio, right ventricular

ARRHYTHMIA Increased baseline HR, decreased rate variability, premature

DMD—female carrier Becker muscular dystrophy Emery-Dreifuss autosomal dominant or proximal dominant limbgirdle muscular dystrophy IB Limb-girdle muscular dystrophy

Dystrophin Dystrophin

Dilated Dilated

Lamin A/C

Dilated

Congenital muscular dystrophy Limb-girdle muscular dystrophy 21

Laminin α2

Dilated

Fukutin

Dilated

α, β, γ, δ Dilated sarcoglycans

Emery-Dreifuss X-linked Emerin

Friedreich ataxia

Rare

Frataxin gene Hypertrophic

Myotonic dystrophy type Myotonic 1, infantile dystrophy protein kinase gene Myotonic dystrophy type Myotonic 1 dystrophy protein kinase gene

Hypertrophic

LVNC

hypertrophy, deep Q waves II, III, aVF, V5 , V6 None Conduction system disease Conduction abnormalities: prolonged PR interval, sinus bradycardia Incomplete right bundle branch block, tall R waves in VI and V2, left anterior hemiblock None AV node and bundle branch block; age at onset: late teens and early 20s Conduction abnormalities: prolonged PR interval, sinus bradycardia T-wave inversion, left axis deviation, repolarization abnormalities Conduction disease, prolonged PR interval, widening of QRS complex Conduction disease, prolonged PR interval, widening of QRS complex

ventricular beats (58% of patients by 24 yr of age) Uncommon Similar to DMD Atrial fibrillation or flutter and atrial standstill; ventricular dysrhythmias Uncommon

None Atrial arrhythmias and/or ventricular arrhythmias Atrial fibrillation or flutter and atrial standstill Ventricular arrhythmias

Atrial fibrillation and flutter, complete heart block Atrial fibrillation and flutter, complete heart block

AV, Atrioventricular; HR, heart rate; LVNC, left ventricular noncompaction. From Hsu DT: Cardiac manifestations of neuromuscular disorders in children, Pediatr Respir Rev 11:35–38, 2010 (Table 1, p 37).

466.1

Dilated Cardiomyopathy

John J. Parent, Stephanie M. Ware

Keywords cardiac transplantation heart failure systolic dysfunction inotrope pacemaker

Etiology and Epidemiology Dilated cardiomyopathy (DCM ), the most common form of cardiomyopathy in children, is the cause of significant morbidity and mortality as well as a common indication for cardiac transplantation. The etiologies are diverse. Unlike adult patients with DCM, ischemic etiologies are rare in children, although these include anomalous origin of the left coronary artery from the pulmonary artery, premature coronary atherosclerosis (homozygous familial hypercholesterolemia, rare genetic syndromic disease such as progeria), and coronary inflammatory diseases, such as Kawasaki disease. It is estimated that up to 50% of cases are genetic (usually autosomal dominant; some are autosomal recessive or Xlinked), including some with metabolic causes (see Tables 466.1 and 466.2 ). Although the most common etiology of DCM remains idiopathic , it is likely that undiagnosed familial/genetic conditions and myocarditis predominate. The annual incidence of DCM in children younger than 18 yr is 0.57 cases per 100,000 per year. Incidence is higher in males, blacks, and infants 10 mm Hg) with inspiration. This pulsus paradoxus can be assessed by careful auscultatory blood pressure determination (automated blood pressure cuffs are inadequate), arterial pressure line waveform, or pulse oximeter tracing inspection. Conditions other than cardiac tamponade that may result in pulsus paradoxus include severe dyspnea, obesity, and positive pressure ventilator support.

Diagnosis

The electrocardiogram is often abnormal in acute pericarditis, although the findings are nonspecific. Low-voltage QRS amplitude may be seen as a result of pericardial fluid accumulation. Tachycardia and abnormalities of the ST segments (diffuse ST segment elevation), PR segments, and T waves (inversion or flattening) may be present as well. Although the chest x-ray findings in a patient with pericarditis without effusion are usually normal in the presence of a significant effusion, cardiac enlargement will be seen and cardiac contour may be unusual (Erlenmeyer flask or water bottle appearance) (Fig. 467.1 ). Echocardiography is the most sensitive technique for identifying the size and location of a pericardial effusion. Compression and collapse of the right atrium and/or right ventricle are present with cardiac tamponade (Fig. 467.2 ). Abnormal diastolic filling parameters have also been described in cases of tamponade.

FIG. 467.1 “Water bottle” silhouette. This chest radiograph shows marked cardiomegaly, also known as a water bottle silhouette, which is seen in the presence of large pericardial effusions. Also note the associated pulmonary edema from associated high left atrial and left ventricular filling pressures. (Courtesy of Dr. Steven M. Selbst, Wilmington, DE; from Durani Y, Giordani K, Goudie BW: Myocarditis and pericarditis in children, Pediatr Clin North Am 57:1281–1303, 2010, Fig 7.)

FIG. 467.2 Echocardiographic images of large pericardial effusion with features of tamponade. A, Apical 4-chamber view of LV, LA, and RV that shows large PE with diastolic right atrial collapse (arrow). B, M-mode image with cursor placed through RV, IVS, and LV in parasternal long axis. The view shows circumferential PE with diastolic collapse of RV free wall (arrow) during expiration. C, M-mode image from subcostal window in same patient that shows IVC plethora without inspiratory collapse. IVC, Inferior vena cava; IVS, interventricular septum; LA, left atrium; LV, left ventricle; PE, pericardial effusion; RV, right ventricle. (From Troughton RW, Asher CR, Klein AL: Pericarditis, Lancet 363:717–727, 2004.)

Differential Diagnosis Chest pain similar to that present in pericarditis can occur with lung diseases, especially pleuritis, and with gastroesophageal reflux or costochondritis, with the latter being reproducible on palpation. Pain related to myocardial ischemia is usually more severe and prolonged and occurs with exercise, allowing distinction from pericarditis-induced pain. The presence of a pericardial effusion by echocardiography is virtually diagnostic of pericarditis.

Infectious Pericarditis A number of viral agents are known to cause pericarditis, and the clinical course of the majority of these infections is mild and spontaneously resolving. The term acute benign pericarditis is synonymous for viral pericarditis. Agents identified as causing pericarditis include the enteroviruses, influenza, adenovirus, respiratory syncytial virus, and parvovirus. Because the course of this illness is usually benign, symptomatic treatment with nonsteroidal antiinflammatory drugs

(NSAIDs) is often sufficient. Persistent or early recurrence episodes may need courses of corticosteroids. Patients with large effusions and tamponade may require pericardiocentesis . Presumed viral but often idiopathic pericarditis may have an autoimmune component. Up to 30% of patients may have recurrences of pericarditis. Treatment and prevention of recurrences with colchicine improve symptoms and avoid recurrences in most of these patients. Patients with idiopathic recurrent pericarditis may also respond to treatment with anakinra . If the condition becomes chronic or relapsing, surgical pericardiectomy or creation of a pericardial window may be necessary. Echocardiography is useful in differentiating pericarditis from myocarditis, which will show evidence of diminished myocardial contractility or valvular dysfunction (see Chapter 466.5 ). Pericarditis and myocarditis may occur together in some cases of viral infection. Purulent pericarditis , often caused by bacterial infections, has become much less common with the advent of new immunizations for Haemophilus influenzae and pneumococcal disease. Historically, purulent pericarditis was seen in association with severe pneumonias, epiglottitis, meningitis, or osteomyelitis. Patients with purulent pericarditis are acutely ill. Unless the infection is recognized and treated expeditiously, the course can be fulminant, leading to tamponade and death. Tuberculous pericarditis is rare in developed countries but can be a relatively common complication of HIV infection in regions where tuberculosis is endemic and access to antiretroviral therapy is limited. Immune complex–mediated pericarditis is a rare complication that may result in a nonpurulent (sterile) effusion following systemic bacterial infections such as meningococcus or Haemophilus.

Noninfectious Pericarditis Systemic inflammatory diseases such as autoimmune, rheumatologic, and connective tissue disorders may involve the pericardium and result in serous pericardial effusions. Pericardial inflammation may be a component of the type II hypersensitivity reaction seen in patients with acute rheumatic fever. It is often associated with rheumatic valvulitis and responds quickly to antiinflammatory agents, including corticosteroids. Tamponade is very uncommon (see Chapters 210.1 and 465 ). Juvenile idiopathic arthritis, usually systemic-onset disease, can manifest with pericarditis. Differentiating rheumatoid pericardial inflammation from that seen

with systemic lupus erythematosus is difficult and requires careful rheumatologic evaluation. Aspirin and corticosteroids can result in rapid resolution of a pericardial effusion but may be needed on a chronic basis to prevent relapse. Many of the autoinflammatory recurrent fever syndromes present with pericarditis, usually with other manifestations of those disorders (see Chapter 188 ). Patients with chronic renal failure or hypothyroidism may have pericardial effusions. Clinical suspicion warrants careful screening with physical examination and, if indicated, imaging studies during the course of their illness. Especially common in referral centers with hematology/oncology units is the presence of pericardial effusion related to neoplastic disease. Conditions resulting in effusion include Hodgkin disease, lymphomas, and leukemia. Radiation therapy directed to the mediastinum of patients with malignancy can result in pericarditis and later constrictive pericardial disease. The postpericardiotomy syndrome occurs in patients having undergone cardiac surgery and is characterized by fever, lethargy, anorexia, irritability, and chest/abdominal discomfort beginning 1-4 wk postoperatively. There can be associated pleural effusions and serologic evidence of elevated antiheart antibodies. Postpericardiotomy syndrome is effectively treated with aspirin, NSAIDs, and in severe cases, corticosteroids. Pericardial drainage is necessary in those patients with cardiac tamponade. In many patients the etiology of pericarditis is not known. Approximately 30% of these patients have multiple occurrences and are treated with colchicine to reduce the risk of recurrent pericarditis. Other treatments have included NSAIDs and corticosteroids. Refractory idiopathic recurrent pericarditis may require pericardiectomy; anakinra has demonstrated promise to treat steroiddependent patients.

467.2

Constrictive Pericarditis John J. Parent, Stephanie M. Ware

Keywords fibrosis pericardial calcification malignancy Rarely, chronic pericardial inflammation can result in fibrosis, calcification, and thickening of the pericardium. Pericardial scarring may lead to impaired cardiac distensibility and filling and is termed constrictive pericarditis. Constrictive pericarditis can result from recurrent or chronic pericarditis, cardiac surgery, or radiation to the mediastinum as a treatment for malignancies, most often Hodgkin disease or lymphoma. Clinical manifestations of systemic venous hypertension predominate in cases of restrictive pericarditis. Jugular venous distention, peripheral edema, hepatomegaly, and ascites may precede signs of more significant cardiac compromise, such as tachycardia, hypotension, and pulsus paradoxus. A pericardial knock, rub, and distant heart sounds might be present on auscultation. Abnormalities of liver function tests, hypoalbuminemia, hypoproteinemia, and lymphopenia may be present. On occasion, chest radiographs demonstrate calcifications of the pericardium. Constrictive pericarditis may be difficult to distinguish clinically from restrictive cardiomyopathy because both conditions result in impaired myocardial filling (see Chapter 466.3 ). Echocardiography may be helpful in distinguishing constrictive pericardial disease from restrictive cardiomyopathy, but MRI and CT are more sensitive in detecting abnormalities of the pericardium. In rare cases, exploratory thoracotomy with direct examination of the pericardium may be required to confirm the diagnosis. Although acute pericardial constriction is reported to respond to antiinflammatory agents, the more typical chronic constrictive pericarditis will respond only to pericardiectomy with extensive resection of the pericardium.

Bibliography Bergmann KR, Kharbanda A, Haveman L. Myocarditis and pericarditis in the pediatric patient: validated management

strategies. Pediatr Emerg Med Pract . 2015;12:1–22 [quiz 23]. Brucato A, Imazio M, Gattorno M, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA . 2016;316(18):1906–1911. Del Fresno MR, Peralta JE, Granados MA, et al. Intravenous immunoglobulin therapy for refractory recurrent pericarditis. Pediatrics . 2014;134:e1441–e1446. Finetti M, Insalaco A, Cantarini L, et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroiddependent and colchicine-resistant recurrent pericarditis. J Pediatr . 2014;164:1425–1431. Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med . 2013;369:1522–1528. LeWinter MM. Acute pericarditis. N Engl J Med . 2014;371:2410–2416. Shakti D, Hehn R, Gauvreau K, et al. Idiopathic pericarditis and pericardial effusion in children: contemporary epidemiology and management. J Am Heart Assoc . 2014;3:e001483. Vistarini N, Chen C, Mazine A, et al. Pericardiectomy for constrictive pericarditis: 20 years of experience at the Montreal Heart Institute. Ann Thorac Surg . 2015;100:107– 113.

CHAPTER 468

Tumors of the Heart John J. Parent, Stephanie M. Ware

Although cardiac tumors occur rarely in pediatric patients, they may result in serious hemodynamic or electrophysiologic abnormalities depending on tumor type and location. The vast majority of tumors originating from the heart are benign. Rhabdomyomas are the most common pediatric cardiac tumors and are associated with tuberous sclerosis in 70–95% of cases (see Chapter 614.2 ). Rhabdomyomas may occur at any age, from fetal life through late adolescence. They are often multiple, can occur in any cardiac chamber, and originate within the myocardium, often extending into the atrial or ventricular cavities (Fig. 468.1 ). Depending on their location and size, rhabdomyomas can result in inflow or outflow obstruction, leading to cyanosis or cardiac failure; many are asymptomatic. Atrial and ventricular arrhythmias have been reported with rhabdomyomas, and on occasion, ventricular preexcitation (Wolff-ParkinsonWhite syndrome) is present on electrocardiogram (ECG).

FIG. 468.1 Echocardiograms demonstrating rhabdomyomas. A, Apical 4-chamber view showing multiple rhabdomyomas (arrows) within the septum and left ventricular myocardium. B, Short axis view showing a large rhabdomyoma (arrow) extending into the right ventricular outflow tract. Ao, Ascending aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle.

Fibromas are the 2nd most common pediatric cardiac tumor and, in contrast to rhabdomyomas, are usually solitary and intramyocardial. The size and location of fibromas can lead to heart failure, cyanosis, or rhythm disturbances. Loss of the tumor suppressor PTCH1 is associated with the development of cardiac fibromas in sporadic cases. There is an increased incidence in patients with Gorlin syndrome (3%). Myxomas , the most common cardiac tumor seen in adults, occur infrequently in the pediatric population. Myxomas are predominantly intraatrial, appear pedunculated, and are rather mobile. They may cause obstruction to inflow or outflow and may present with a murmur, heart failure, or syncope. On occasion,

atrial myxomas are associated with systemic symptoms of fever, malaise, and arthralgia. Carney complex is a familial autosomal dominant multiple neoplasia (often endocrine: pituitary adenoma, thyroid, testis, ovarian) and lentiginosis syndrome in which cardiac myxomas can occur at a young age in any or all cardiac chambers. Pathogenic variants in the PRKAR1A gene are causative in some families. Other benign tumors include hemangiomas, Purkinje cell tumors, papillomas, lipomas, and mesotheliomas. Depending on their location, these benign tumors can result in valvular function abnormalities, myocardial dysfunction, or heart block and other arrhythmias. Malignant pediatric cardiac tumors are much less common than benign tumors (75% vs 25%), and the vast majority of such malignancies are sarcomas, including angiosarcomas, rhabdosarcomas, or fibrosarcomas. Lymphomas and pheochromocytomas are reported but rare. Tumors originating from noncardiac sources that invade, extend, or metastasize to the heart are more frequently seen than primary malignant cardiac tumors. In pediatric patients, Wilms tumor and lymphoma/leukemia are the most common causes of such secondary tumors. Although the manifestations of cardiac tumors in pediatric patients are protean, when a tumor is suspected, noninvasive imaging with echocardiography and/or MRI may be diagnostic and can determine tumor type, location, extent, and hemodynamic impact. ECG and Holter studies are valuable adjuncts when rhythm abnormalities are suspected. Cardiac catheterization is rarely indicated but may be used to confirm tumor location, assess intracardiac hemodynamics, and perform biopsy for histologic assessment. Such risks as blood loss, perforation, arrhythmia, and vessel injury should be considered when discussing catheterization and biopsy. Because the natural history of rhabdomyomas is one of spontaneous diminution or complete resolution, treatment of the majority of cardiac tumors in pediatric patients is usually unnecessary. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), may enhance resolution in symptomatic patients with cardiac rhabdomyomas. Careful clinical follow-up and imaging are important. Antiarrhythmic medications may be prescribed to control rhythm disorders. Surgical removal of a cardiac tumor may be indicated to relieve obstruction, improve myocardial or valve function, or control arrhythmias. Heart transplantation has been performed in cases of unresectable tumors with significant hemodynamic compromise. Wilms tumors extending from the inferior vena cava into the atrium may require cardiopulmonary bypass

support during the course of primary resection of the renal tumor. Radiation or chemotherapy can improve cardiac function in rare cases of lymphoma or leukemia compressing the heart with hemodynamic compromise.

Bibliography Goyer I, Dahdah N, Major P. Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. Pediatr Neurol . 2015;52(4):450–453. Kwiatkowska J, Wałdoch A, Meyer-Szary J, et al. Cardiac tumors in children: a 20-year review of clinical presentation, diagnostics and treatment. Adv Clin Exp Med . 2017;26(2):319–326. Shen Q, Shen J, Qiao Z, et al. Cardiac rhabdomyomas associated with tuberous sclerosis complex in children: from presentation to outcome. Herz . 2015;40(4):675–678. Shenoy S, Shetty S, Lankala S, et al. Cardiovascular oncologic emergencies. Cardiology . 2017;138(3):147–158. Shi L, Wu L, Fang H, et al. Identification and clinical course of 166 pediatric cardiac tumors. Eur J Pediatr . 2017;176(2):253–260.

SECTION 7

Cardiac Therapeutics OUTLINE Chapter 469 Heart Failure Chapter 470 Pediatric Heart and Heart-Lung Transplantation

CHAPTER 469

Heart Failure Joseph W. Rossano

The International Society for Heart and Lung Transplantation (ISHLT) defines heart failure as follows: A clinical and pathological syndrome that results from ventricular dysfunction, volume, or pressure overload, alone or in combination. It leads to characteristic signs and symptoms, such as poor growth, feeding difficulties, respiratory distress, exercise intolerance, and fatigue, and is associated with circulatory, neurohormonal, and molecular abnormalities. Heart failure has numerous etiologies that are a consequence of cardiac and noncardiac disorders, either congenital or acquired.

Pathophysiology The heart can be viewed as a pump with an output proportional to its filling volume and inversely proportional to the resistance against which it pumps. As ventricular end-diastolic volume increases, a healthy heart increases cardiac output until a maximum is reached and cardiac output can no longer be augmented (the Frank-Starling principle ; Fig. 469.1 ). The increased stroke volume obtained in this manner is a result of stretching of myocardial fibers, but it also results in increased wall tension, which elevates myocardial oxygen consumption. Hearts working under various types of stress function along different Frank-Starling curves. Cardiac muscle with compromised intrinsic contractility requires a greater degree of dilation to produce increased stroke volume and does not achieve the same maximal cardiac output as normal myocardium does. If a cardiac chamber is already dilated because of a lesion

causing increased preload (e.g., a left-to-right shunt or valvular insufficiency), there is little room for further dilation as a means of augmenting cardiac output. The presence of lesions that result in increased afterload to the ventricle (e.g., aortic or pulmonic stenosis, coarctation of the aorta) decreases cardiac performance, thereby resulting in a depressed Frank-Starling relationship.

FIG. 469.1 The Frank-Starling relationship. As left ventricular end-diastolic (LVED) pressure increases, the cardiac index increases, even in the presence of congestive heart failure, until a critical level of LVED pressure is reached. Adding an inotropic agent (digoxin) shifts the curve from I to II. (From Gersony WM, Steep CN. In Dickerman JD, Lucey JF, editors: Smith's The critically ill child: diagnosis and medical management, ed 3, Philadelphia, 1984, Saunders.)

Systemic oxygen transport is calculated as the product of cardiac output and systemic oxygen content. Cardiac output can be calculated as the product of heart rate and stroke volume. The primary determinants of stroke volume are the afterload (pressure work), preload (volume work), and contractility (intrinsic myocardial function). Abnormalities in heart rate can also compromise cardiac output; for example, tachyarrhythmias shorten the diastolic time interval for ventricular filling. Alterations in the oxygen-carrying capacity of blood (e.g., anemia or hypoxemia) also lead to a decrease in systemic oxygen transport and, if compensatory mechanisms are inadequate, can result in decreased delivery of substrate to tissues. In some cases of heart failure, cardiac output is normal or increased, yet because of decreased systemic oxygen content (e.g., secondary to anemia) or increased oxygen demands (e.g., secondary to hyperventilation,

hyperthyroidism, or hypermetabolism), an inadequate amount of oxygen is delivered to meet the body's needs. This condition, high-output failure , results in the development of signs and symptoms of heart failure when there is no basic abnormality in myocardial function and cardiac output is greater than normal. It is also seen with large systemic arteriovenous fistulas (e.g., vein of Galen malformation). These conditions reduce peripheral vascular resistance and cardiac afterload and increase myocardial contractility. Heart failure results when the demand for cardiac output exceeds the ability of the heart to respond. Chronic severe high-output failure may eventually result in a decrease in myocardial performance as the metabolic requirements of the myocardium are not met. There are multiple systemic compensatory mechanisms used by the body to adapt to chronic heart failure. Some are mediated at the molecular/cellular level, such as upregulation or downregulation of various metabolic pathway components leading to changes in efficiency of oxygen and other substrate utilizations. Others are mediated by neurohormones such as the reninangiotensin system and the sympathoadrenal axis. One of the principal mechanisms for increasing cardiac output is an increase in sympathetic tone secondary to increased secretion of circulating epinephrine by the adrenals and increased release of norepinephrine at the neuromuscular junction. The initial beneficial effects of sympathetic stimulation include an increase in heart rate and myocardial contractility, mediated by these hormones’ action on cardiac βadrenergic receptors, increasing cardiac output. These hormones also cause vasoconstriction, mediated by their action on peripheral arterial α-adrenergic receptors. Some vascular beds may constrict more readily than others, so that blood flow is redistributed from the cutaneous, visceral, and renal beds to the heart and brain. Whereas these acute effects are beneficial, chronically increased sympathetic stimulation can have deleterious effects, including hypermetabolism, increased afterload, arrhythmogenesis, and increased myocardial oxygen requirements. Peripheral vasoconstriction can result in decreased renal, hepatic, and gastrointestinal tract function. Chronic exposure to circulating catecholamines leads to a decrease in the number of cardiac βadrenergic receptors (downregulation) and also causes direct myocardial cell damage. Therapeutic agents for heart failure are directed at restoring balance to these neuroendocrine systems.

Clinical Manifestations The clinical manifestations of heart failure depend in part on the degree of the child's cardiac reserve. A critically ill infant or child who has exhausted the compensatory mechanisms to the point that cardiac output is no longer sufficient to meet the basal metabolic needs of the body may present in cardiogenic shock . Other patients may be comfortable when quiet but are incapable of increasing cardiac output in response to even mild activity without experiencing significant symptoms. Conversely, it may take rather vigorous exercise to compromise cardiac function in children who have less severe heart disease. A thorough history is extremely important in making the diagnosis of heart failure and in evaluating the possible causes. Parents who observe their child on a daily basis may not recognize subtle changes that have occurred over the course of days or weeks. Gradually worsening perfusion or increasing respiratory effort may not be recognized as an abnormal finding. Edema, which is general absent in infants and young children, may be passed off as normal weight gain, and exercise intolerance as lack of interest in an activity. The history of a young infant should also focus on feeding . An infant with heart failure often takes less volume per feeding, becomes dyspneic while sucking, and may perspire profusely. Eliciting a history of fatigue in an older child requires detailed questions about activity level and its course over several months. In children, the signs and symptoms of heart failure may be similar to those in adults and include fatigue, effort intolerance, anorexia, dyspnea, edema, and cough. Many children, however, may have primarily abdominal symptoms (abdominal pain, nausea, anorexia) and a surprising lack of respiratory complaints. Attention to the cardiovascular system may come only after an abdominal radiograph unexpectedly catches the lower end of an enlarged heart. The elevation in systemic venous pressure may be gauged by clinical assessment of jugular venous pressure and liver enlargement. Orthopnea and basilar rales are variably present; edema is usually discernible in dependent portions of the body, or anasarca may be present. Cardiomegaly is invariably noted. A gallop rhythm is common; when ventricular dilation is advanced, the holosystolic murmur of mitral or tricuspid valve regurgitation may be heard. In infants, heart failure may be difficult to distinguish from other causes of respiratory distress. Prominent manifestations of heart failure include tachypnea, feeding difficulties, poor weight gain, excessive perspiration, irritability, weak

cry, and noisy, labored respirations with intercostal and subcostal retractions, as well as flaring of the alae nasi. The signs of cardiac-induced pulmonary congestion may be indistinguishable from those of bronchiolitis; wheezing is often a more prominent finding in young infants with heart failure than rales. Pneumonitis with or without atelectasis is common as result of bronchial compression by the enlarged heart. Hepatomegaly usually occurs, and cardiomegaly is invariably present. Despite pronounced tachycardia, a gallop rhythm can frequently be recognized. The other auscultatory signs are those produced by the underlying cardiac lesion. Clinical assessment of jugular venous pressure in infants may be difficult because of the shortness of the neck and the difficulty of observing a relaxed state; palpation of an enlarged liver is a more reliable sign. The etiologies of heart failure are age dependent (Table 469.1 ).

Table 469.1

Etiology of Heart Failure Fetal Severe anemia (hemolysis, fetal-maternal transfusion, parvovirus B19– induced anemia, hypoplastic anemia) Supraventricular tachycardia Ventricular tachycardia Complete heart block Severe Ebstein anomaly or other severe right-sided lesions Myocarditis

Premature Neonate Fluid overload Patent ductus arteriosus Ventricular septal defect Cor pulmonale (bronchopulmonary dysplasia) Hypertension Myocarditis Genetic/metabolic cardiomyopathy

Full-Term Neonate

Asphyxial cardiomyopathy Arteriovenous malformation (vein of Galen, hepatic) Left-sided obstructive lesions (coarctation of aorta, hypoplastic left heart syndrome) Large mixing cardiac defects (single ventricle, truncus arteriosus) Myocarditis Genetic/metabolic cardiomyopathy

Infant-Toddler Left-to-right cardiac shunts (ventricular septal defect) Hemangioma (arteriovenous malformation) Anomalous left coronary artery Genetic/metabolic cardiomyopathy Acute hypertension (hemolytic-uremic syndrome) Supraventricular tachycardia Kawasaki disease Myocarditis

Child-Adolescent Congenital heart disease (various forms including single-ventricle heart disease) Rheumatic fever Acute hypertension (glomerulonephritis) Myocarditis Thyrotoxicosis Hemochromatosis-hemosiderosis Cancer therapy (radiation, doxorubicin) Sickle cell anemia Endocarditis Cor pulmonale (cystic fibrosis) Genetic/metabolic cardiomyopathy (hypertrophic, dilated)

Diagnosis

X-ray films of the chest show cardiac enlargement. Pulmonary vascularity is variable and depends on the cause of the heart failure. Infants and children with large left-to-right shunts have exaggeration of the pulmonary arterial vessels to the periphery of the lung fields, whereas patients with cardiomyopathy may have a relatively normal pulmonary vascular bed early in the course of disease. Fluffy perihilar pulmonary markings suggestive of venous congestion and acute pulmonary edema are seen only with more severe degrees of heart failure. Cardiac enlargement is often noted as an unexpected finding on a chest radiography performed to evaluate for a possible pulmonary infection, bronchiolitis, or asthma. Chamber hypertrophy noted by electrocardiography may be helpful in assessing the cause of heart failure but does not establish the diagnosis. In cardiomyopathies, left or right ventricular ischemic changes may correlate with other noninvasive parameters of ventricular function. Low-voltage QRS morphologic characteristics with ST-T–wave abnormalities may also suggest myocardial inflammatory disease but can be seen with pericarditis as well. The electrocardiogram (ECG) is the best tool for evaluating rhythm disorders as a potential cause of heart failure, especially tachyarrhythmias. Echocardiography is the standard technique for assessing ventricular function. Ventricular function as be quantitated simply and reliably with commonly used parameters such as fractional shortening (a single-dimensional variable) and an ejection fraction. The fractional shortening is determined as the difference between end-systolic and end-diastolic diameter divided by enddiastolic diameter. Normal fractional shortening is between approximately 28% and 42%. The ejection fraction uses 2-dimensional data to calculate a 3dimensional volume; the normal range is 55–65%. In children with right ventricular enlargement or other cardiac pathology resulting in flattening of the interventricular septum, ejection fraction is used because fractional shortening measured in the standard echocardiographic short axis view will not be accurate. Doppler studies can also be used to estimate cardiac output. Doppler assessment of transmitral flow can also be used as a noninvasive assessment of diastolic function. Magnetic resonance angiography (MRA) is also very useful in quantifying left and right ventricular function, volume, and mass as well as coronary artery anatomy. If valvular regurgitation is present, MRA can quantify the regurgitant fraction. Arterial oxygen levels may be decreased when ventilation-perfusion inequalities occur secondary to pulmonary edema. When heart failure is severe,

respiratory acidosis or metabolic acidosis, or both, may be present. Infants with heart failure often display hyponatremia as a result of renal water retention. Chronic diuretic treatment can decrease serum sodium levels further. Serum Btype (brain) natriuretic peptide (BNP) (or N-terminal pro-BNP), a cardiac neurohormone released in response to increased ventricular wall tension, is elevated in patients with heart failure. In children, BNP may be elevated in patients with heart failure as a result of systolic dysfunction (e.g., cardiomyopathy), as well as in children with volume overload (e.g., left-to-right shunts such as ventricular septal defect). Table 469.2 lists other causes of an elevated BNP.

Table 469.2

Caused of Elevated Concentrations of Natriuretic Peptides Cardiac Heart failure (HFpEF, HFrEF) Acute coronary symptoms Pulmonary embolism Myocarditis Left ventricular hypertrophy Hypertrophic or restrictive cardiomyopathy Valvular heart disease Congenital heart disease Atrial and ventricular tachyarrhythmias Heart contusion Cardioversion ICD shock Surgical procedures involving the heart Pulmonary hypertension

Noncardiac Ischemic stroke Subarachnoid hemorrhage Renal dysfunction

Liver dysfunction (mainly liver cirrhosis with ascites) Paraneoplastic syndrome Chronic obstructive pulmonary disease Severe infections (including pneumonia and sepsis) Severe burns Anemia Severe metabolic and hormone abnormalities (e.g., thyrotoxicosis, diabetic ketosis) HFpEF, Heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator. Adapted from Ponikowski P, Voors AA, Anker SD, et al: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure, Eur Heart J 37(27):2129–2200, 2016 (Table 12-3, p 2175).

Treatment The underlying cause of cardiac failure must be removed or alleviated if possible. If the cause is a congenital cardiac anomaly amenable to surgery, medical treatment of the heart failure is indicated to prepare the patient for surgery. With the current excellent outcomes of primary surgical repair of congenital heart defects, even in the neonatal period, few children require aggressive heart failure management to grow big enough for surgery. In contrast, if the cause of heart failure is cardiomyopathy, medical management provides temporary relief from symptoms and may allow the patient to recover if the insult is reversible (e.g., myocarditis). If the lesion is not reversible, heart failure management usually allows the child to return to normal activities for some period and to delay, sometimes for months or years, the need for heart transplantation.

General Measures Strict bed rest is rarely necessary except in extreme cases, but it is important that the child be allowed to rest during the day as needed and sleep adequately at night. Some older patients feel better sleeping in a semi-upright position, using several pillows (orthopnea ). As patients respond to treatment, restrictions on

activities can often be modified within the context of the specific diagnosis and the patient's ability. Formal cardiopulmonary exercise testing can be used to assess the patient's ability to perform exercise in a controlled environment and is useful for recommending rational exercise restrictions. For patients with pulmonary edema, positive pressure ventilation (PPV) may be required along with other drug therapies. For those in low-output heart failure, PPV can significantly reduce total body oxygen consumption by eliminating the work of breathing and help to reverse metabolic acidosis. β-Adrenergic agonists such as dopamine, dobutamine, and epinephrine may be needed in combination with phosphodiesterase inhibitors such as milrinone for patients with markedly advanced heart failure and cardiogenic shock. If the blood pressure will permit, afterload-reducing agents such as nitroprusside, angiotensin-converting enzyme inhibitors (ACEIs ), or angiotensin receptor blockers (ARBs ) may be beneficial. These agents are initiated in an intensive care setting with proper invasive monitoring of central venous and arterial blood pressure.

Diet Infants with heart failure usually fail to thrive because of a combination of increased metabolic demands and decreased caloric intake. Increasing daily calories is an important aspect of their management. Increasing the number of calories per ounce of infant formula (or supplementing breastfeeding) may be beneficial. Many infants do not tolerate an increase beyond 24 calories/oz because of diarrhea or because these formulas provide too large a solute load for compromised kidneys. Severely ill infants and children may lack sufficient strength for effective sucking because of extreme fatigue, rapid respirations, and generalized weakness. In these circumstances, nasogastric feedings may be helpful. In many patients with cardiac enlargement, gastroesophageal reflux is a major problem. The use of continuous drip nasogastric feedings at night, administered by pump, may improve caloric intake while decreasing problems with reflux. Occasionally, especially in infants with heart failure caused by complex congenital heart disease, medical or surgical intervention to correct reflux is necessary (Nissen fundoplication). Continued malnutrition may be an important factor in the decision to undertake earlier surgical intervention in patients who have an operable congenital heart lesion or to proceed with mechanical circulatory support and/or listing for transplantation in patients with cardiomyopathy.

The use of low-sodium formulas in the routine management of infants with heart failure is not recommended because these preparations are often poorly tolerated and may exacerbate diuretic-induced hyponatremia. Human breast milk is the ideal low-sodium nutritional source. The use of more potent diuretic agents allows more palatable standard formulas to be used for nutrition while controlling salt and water balance by chronic diuretic administration. Most older children can be managed with “no added salt” diets and abstinence from foods containing large amounts of sodium. A strict, extremely-low-sodium diet is rarely required or followed.

Diuretics Diuretics interfere with reabsorption of water and sodium by the kidneys, which results in a reduction in circulating blood volume and thereby reduces pulmonary fluid overload and ventricular filling pressure. Diuretics are usually the first mode of therapy initiated in patients with congestive heart failure. Furosemide is the most commonly used diuretic in pediatric patients with heart failure. It inhibits the reabsorption of sodium and chloride in the distal tubules and the loop of Henle. Patients requiring acute diuresis should be given intravenous (IV) or intramuscular (IM) furosemide at an initial dose of 1-2 mg/kg, which usually results in rapid diuresis and prompt improvement in clinical status, particularly if symptoms of pulmonary congestion are present. Chronic furosemide therapy is then prescribed at a dose of 1-4 mg/kg/24 hr given between 1 and 4 times a day. Careful monitoring of electrolytes is necessary with long-term furosemide therapy because of the potential for significant loss of potassium. Potassium chloride supplementation is usually required unless the potassium-sparing diuretics are given concomitantly. Chronic administration of furosemide may cause contraction of the extracellular fluid compartment and result in “contraction alkalosis” (see Chapter 68.7 ). Diureticinduced hyponatremia may become difficult to manage in patients with severe heart failure. Spironolactone is an inhibitor of aldosterone and enhances potassium retention, often eliminating the need for oral potassium supplementation, which is frequently poorly tolerated. This drug is usually given orally in 2 divided doses of 2 mg/kg/24 hr. Combinations of spironolactone and chlorothiazide are sometimes used for convenience. Adults with heart failure have improved survival when an aldosterone inhibitor is included in the diuretic regimen, likely

through multiple effects, including a favorable effect on cardiac fibrosis. Eplerenone is an alternative to spironolactone and does not have the side effect of gynecomastia. Chlorothiazide is also used for diuresis in children with heart failure. It is less immediate in action and less potent than furosemide, and it affects the reabsorption of electrolytes in the renal tubules only. The usual dose is 10-40 mg/kg/24 hr in 2 divided doses. Potassium supplementation is often required if chlorothiazide is used alone.

Afterload Reducers, Including AngiotensinConverting Enzyme Inhibitors and Angiotensin II Receptor Blockers The ACEIs and ARBs reduce ventricular afterload by decreasing peripheral vascular resistance and thereby improving myocardial performance. Some of these agents also decrease systemic venous tone, which significantly reduces preload. Afterload reducers may be useful in children with heart failure secondary to cardiomyopathy and in patients with severe mitral or aortic insufficiency. They may also be effective in patients with heart failure caused by left-to-right shunts. ACEIs and ARBs may have additional beneficial effects on cardiac remodeling independent of their influence on afterload by directly influencing cardiac intracellular signaling pathways. In adult patients with dilated cardiomyopathy, the addition of an ACEI to standard medical therapy reduces both morbidity and mortality. Afterload-reducing agents are most often used in conjunction with other anticongestive drugs such as diuretics and, in some patients, digoxin. Intravenously administered agents such as nitroprusside should be administered only in an intensive care setting and for as short a time as possible. Nitroprusside's short IV half-life makes it ideal for titrating the dose in critically ill patients. Peripheral arterial vasodilation and afterload reduction are the major effects, but venodilation causing a decrease in venous return to the heart may also be beneficial. Blood pressure must be continuously monitored because sudden hypotension can occur. Consequently, nitroprusside is contraindicated in patients with preexisting hypotension. Because the drug is metabolized, small amounts of circulating cyanide are produced and detoxified in the liver to thiocyanate, which is excreted in urine. When high doses of nitroprusside are

administered for several days, toxic symptoms related to thiocyanate poisoning may occur (fatigue, nausea, disorientation, acidosis, and muscular spasm). If nitroprusside use is prolonged, blood thiocyanate levels should be monitored. Phosphodiesterase inhibitors (see later) are also excellent, although somewhat less potent afterload reducers but without the toxicity of nitroprusside. The orally active ACEIs captopril and enalapril produce arterial dilation by blocking the production of angiotensin II, thereby resulting in significant afterload reduction. Venodilation and consequent preload reduction also have been reported. In addition, these agents interfere with aldosterone production and therefore also help control salt and water retention. ACEIs have additional beneficial effects on cardiac structure and function that may be independent of their effect on afterload. Adverse reactions to ACEIs include hypotension and its sequelae (weakness, dizziness, syncope) and hyperkalemia. A maculopapular pruritic rash is encountered in a small number of patients, but the drug may be continued because the rash often disappears spontaneously with time. Neutropenia, renal toxicity, and chronic cough also occur. While ACEIs/ARBs along with β-adrenergic blocking agents have been shown in multiple prospective, randomized, controlled trials in adults to improve symptoms and mortality in adult heart failure patients, it is unclear if these medications improve the natural history of heart failure in children. Nonetheless, these medications are commonly used for the treatment of heart failure and are recommended by consensus guidelines from the ISHLT and Canadian Cardiovascular Society.

Digitalis Glycosides Digoxin, once the mainstay of heart failure management in both children and adults, is currently used less frequently, as a result of the introduction of other therapies and the recognition of its potential toxicities. Some cardiologists will use digitalis as an adjunct to ACEIs and diuretics in patients with symptomatic heart failure, whereas others have stopped using it altogether. Despite multiple clinical studies, predominantly in adults, the controversy over digitalis remains. Some data suggest a beneficial effect of digoxin on reducing death among infants with single-ventricle heart disease. Digoxin is the digitalis glycoside used most often in pediatric patients. It has a half-life of 36 hr and it is absorbed well by the gastrointestinal tract (60–85%), even in infants. An initial effect is seen as early as 30 min after administration,

and the peak effect for oral digoxin occurs at 2-6 hr. When the drug is administered intravenously, the initial effect is seen in 15-30 min, and the peak effect occurs at 1-4 hr. The kidney eliminates digoxin, so dosing must be adjusted according to the patient's renal function. The half-life of digoxin may be up to 6 days in patients with anuria because slower hepatic excretion pathways are used in these patients. Rapid digitalization of infants and children may be carried out intravenously. This should be done with caution in patients with severe heart failure. The dose depends on the patient's age (Table 469.3 ). The recommended digitalization schedule is to give half the total digitalizing dose immediately and the succeeding 2 one-quarter doses at 12-hr intervals later. The ECG must be closely monitored, and rhythm strips obtained before each of the 3 digitalizing doses. Digoxin should be discontinued if a new rhythm disturbance is noted. Prolongation of the P-R interval is not necessarily an indication to withhold digitalis, but a delay in administering the next dose or a reduction in the dosage should be considered, depending on the patient's clinical status. Minor ST segment or T-wave changes are frequently noted with digitalis administration and should not affect the digitalization regimen. Baseline serum electrolyte levels should be measured before and after digitalization. Hypokalemia and hypercalcemia exacerbate digitalis toxicity. Because hypokalemia is relatively common in patients receiving diuretics, potassium levels should be monitored closely in those receiving a potassium-wasting diuretic in combination with digitalis. In patients with active myocarditis, some cardiologists recommend avoiding digitalis altogether and if used, maintenance digitalis should be started at half the normal dose without digitalization because of the increased risk of arrhythmia in these patients. Table 469.3

Dosage of Drugs Commonly Used for the Treatment of Congestive Heart Failure DRUG DIGOXIN Digitalization ( initially, followed by q12h × 2) Maintenance

DOSAGE* Premature: 20 µg/kg Full-term neonate (up to 1 mo): 20-30 µg/kg Infant or child: 25-40 µg/kg Adolescent or adult: 0.5-1 mg in divided doses Note: These doses are PO; IV dose is 75% of PO dose 5-10 µg/kg/day, divided q12h

digoxin † DIURETICS Furosemide (Lasix)

Note: These doses are PO; IV dose is 75% of PO dose IV: 0.5-2 mg/kg/dose PO: 1-4 mg/kg/day, divided qd-qid IV: 0.01-0.1 mg/kg/dose PO: 0.01-0.1 mg/kg/day q24-48h PO: 20-40 mg/kg/day, divided bid or tid

Bumetanide (Bumex) Chlorothiazide (Diuril) Spironolactone PO: 1-3 mg/kg/day, divided bid or tid (Aldactone) ADRENERGIC AGONISTS (ALL IV) Dobutamine 2-20 µg/kg/min Dopamine 2-20 µg/kg/min Epinephrine 0.01-1.0 µg/kg/min PHOSPHODIESTERASE INHIBITORS (ALL IV) Milrinone 0.25-1.0 µg/kg/min AFTERLOAD-REDUCING AGENTS Captopril (Capoten), Prematures: start at 0.01 mg/kg/dose; 0.1-0.4 mg/kg/day, divided q6-24h all PO Infants: start at 0.15-0.3 mg/kg/dose; 1.5-6 mg/kg/day, divided q6-12h Children: start at 0.3-0.5 mg/kg/dose; 2.5-6 mg/kg/day, divided q6-12h Enalapril (Vasotec), 0.08-0.5 mg/kg/day, divided q12-24h all PO Hydralazine IV: 0.1-0.5 mg/kg/dose (maximum: 20 mg) (Apresoline) PO: 0.75-5 mg/kg/day, divided q6-12h Nitroglycerin IV: 0.25-0.5 µg/kg/min start; increase to 20 µg/kg/min maximum Nitroprusside IV: 0.5-8 µg/kg/min (Nipride) β-ADRENERGIC BLOCKERS Carvedilol (Coreg) PO: initial dose: 0.1 mg/kg/day (maximum: 6.25 mg) divided bid (may use tid in infants), increase gradually (usually 2 wk intervals) to maximum of 0.5-1 mg/kg/day over 8-12 wk as tolerated; adult maximum dose: 50-100 mg/day Metoprolol PO, non–extended-release form: 0.2 mg/kg/day divided bid, increase gradually (usually 2 (Lopressor, Toprol- wk intervals) to maximum dose of 1-2 mg/kg/day XL) PO, extended-release form (Toprol-XL): given once daily; adult initial dose: 25 mg/day, maximum: 200 mg/day * Pediatric doses based on weight should not exceed adult doses. Because recommendations

may change, these doses should always be double-checked. Doses may also need to be modified in any patient with renal or hepatic dysfunction. † Maintenance digitalis therapy is started approximately 12 hr after full digitalization. The daily

dosage, one quarter of the total digitalizing dose, is divided in 2 and given at 12 hr intervals. The oral maintenance dose is usually 20–25% higher than when digoxin is used parenterally. The normal daily dose of digoxin for older children (>5 yr of age) calculated by body weight should not exceed the usual adult dose of 0.125-0.5 mg/24 hr. IV, Intravenous; PO, oral; bid, twice daily, tid, 3 times daily; qid, 4 times daily; qd, every day.

Patients who are not critically ill may be given digitalis initially by the oral route, and in most instances, digitalization is completed within 24 hr. When slow digitalization is desirable, for example, in the immediate postoperative period, initiation of a maintenance digoxin schedule without a previous loading dose

achieves full digitalization in 7-10 days. Measurement of serum digoxin levels is useful (1) when an unknown amount of digoxin has been administered or ingested accidentally, (2) when renal function is impaired or if drug interactions are possible, (3) when questions regarding compliance are raised, and (4) when a toxic response is suspected. In suspected toxicity, elevated serum digoxin levels are not in themselves diagnostic of toxicity but must be interpreted as an adjunct to other clinical and electrocardiographic findings (rhythm and conduction disturbances). Hypokalemia, hypomagnesemia, hypercalcemia, cardiac inflammation secondary to myocarditis, and prematurity may all potentiate digitalis toxicity. A cardiac arrhythmia that develops in a child who is taking digitalis may also be related to the primary cardiac disease rather than the drug, however, any arrhythmia occurring after the institution of digitalis therapy must be considered to be drug related until proven otherwise. Many drugs interact with digoxin and may increase levels or risk of toxicity, so care should be taken when a patient receiving digoxin is being considered for any additional pharmacologic therapy.

Alpha- and β-Adrenergic Agonists The α- and β-adrenergic receptor agonists are usually administered in an intensive care setting, where the dose can be carefully titrated to hemodynamic response. Continuous determinations of arterial blood pressure and heart rate are performed; measuring serial mixed venous oxygen saturations or cardiac output directly with a pulmonary thermodilution (Swan-Ganz) catheter may be helpful in assessing drug efficacy, although this technique is used much less in children than adults. Although extremely efficacious in the acute intensive care setting, long-term administration of adrenergic agonists has been shown to increase morbidity and mortality in adults with heart failure and is usually avoided unless the patient is totally dependent on these agents. Dopamine is a predominantly β-adrenergic receptor agonist, but it has αadrenergic effects at higher doses. Dopamine has less chronotropic and arrhythmogenic effect than the pure β-agonist isoproterenol. At a dose of 2-10 µg/kg/min, dopamine results in increased contractility with little peripheral vasoconstrictive effect. If the dose is increased beyond 15 µg/kg/min, however, its peripheral α-adrenergic effects may result in vasoconstriction. Fenoldopam is a dopamine DA1 receptor agonist and is used at a low dose (0.03 µg/kg/min) to increase renal blood flow and urine output. It can cause

hypotension, so blood pressure should be carefully monitored. Dobutamine , a derivative of dopamine, is also useful in treating low cardiac output. It has direct inotropic effects and causes a moderate reduction in peripheral vascular resistance. Dobutamine can be used alone or as an adjunct to dopamine therapy to avoid the vasoconstrictive effects of higher-dose dopamine. Dobutamine is also less likely to cause cardiac rhythm disturbances than isoproterenol. Isoproterenol is a pure β-adrenergic agonist that has a marked chronotropic effect; it is most effective in patients with slow heart rate. It is often used in the immediate post–heart transplant period. Epinephrine is a mixed α- and β-adrenergic receptor agonist that is usually reserved for patients with cardiogenic shock and low arterial blood pressure. Although epinephrine can raise blood pressure effectively, it also increases systemic vascular resistance, and therefore increases the afterload against which the heart has to work and is associated with an increased risk of arrhythmia. Additionally, epinephrine is proarrhythmic and can result in direct cardiac toxicity, including myocardial necrosis and apoptosis.

Phosphodiesterase Inhibitors Milrinone is useful in treating patients with low cardiac output who are refractory to standard therapy. It has been shown to be highly effective in managing the low-output state present in children after open heart surgery. It works by inhibition of phosphodiesterase, which prevents the degradation of intracellular cyclic adenosine monophosphate. Milrinone has both positive inotropic effects on the heart and peripheral vasodilatory effects and has generally been used as an adjunct to dopamine or dobutamine therapy in the intensive care unit. It is given by IV infusion at 0.25-1 µg/kg/min, sometimes with an initial loading dose of 50 µg/kg. A major side effect is hypotension secondary to peripheral vasodilation, especially when a loading dose is used. The hypotension can generally be managed by the administration of IV fluids to restore adequate intravascular volume. Long-term milrinone is often used to support patients while listed for heart transplantation, and in select patients can be used in the outpatient setting.

Chronic Treatment With β-Blockers

Studies in adults with dilated cardiomyopathy show that β-adrenergic blocking agents, introduced gradually as part of a comprehensive heart failure treatment program, improve exercise tolerance, decrease hospitalizations, and reduce overall mortality. The agents most often used are carvedilol , with both α- and βadrenergic receptor–blocking as well as free radical–scavenging effects, and metoprolol , a β1 -adrenergic receptor selective antagonist. β-Blockers are used for the chronic treatment of patients with heart failure and should not be administered when patients are still in the acute phase of heart failure (i.e., receiving IV adrenergic agonist infusions). Although very efficacious in adults, clinical studies in children have shown mixed results, potentially from the significant heterogeneity of the populations being studied and differences in the types of β-blocking agents.

New Therapies Several newer medications have shown promise in the treatment of adult heart failure patients are now also being studied in pediatric patients. Serelaxin , recombinant human relaxin-2, resulted in fewer deaths when used for the treatment of acute heart failure in hospitalized patients. For chronic heart failure, ivabradine has been studied in patients with elevated heart rates. Ivabradine is a selective inhibitor of the If current in the sinus node and lowers heart rates without decreasing myocardial contractility. The use of ivabradine was associated with improved outcomes in heart failure patients, including decreased hospital admissions and cardiovascular death. A large, prospective randomized trial showed that the combination of an ARB and a neprilysin inhibitor can lead to several beneficial effects, including vasodilation, decreased aldosterone levels, and improved natriuresis, and patients randomized to the medication had a lower risk of death and hospitalization. Further studies are needed to determine what role, if any, these medications will have in the treatment of pediatric heart failure.

Electrophysiologic Approaches to Heart Failure Management Significant improvements in symptomatology and functional capacity have been achieved in select adult patients with cardiomyopathy using biventricular

resynchronization pacing . This technique improves cardiac output by restoring normal synchrony between right and left ventricular contraction, which is often lost in patients with dilated cardiomyopathy (these patients usually manifest a left bundle branch block on ECG). There is growing experience with resynchronization pacing in children, but it remains uncertain which population of patients with heart failure benefit from this therapy. Arrhythmias are a leading cause of sudden death in patients with severe cardiomyopathy (both dilated and hypertrophic). Although antiarrhythmic medications can sometimes reduce this risk, for patients at particularly high risk (e.g., those with a condition known to be associated with a high risk of ventricular arrhythmia or those who have already experienced a “missed sudden death” episode), use of an implantable cardioverter-defibrillator can be lifesaving (see Chapter 463 ).

469.1

Cardiogenic Shock Joseph W. Rossano

Cardiogenic shock may be caused by (1) severe cardiac dysfunction before or after cardiac surgery, (2) septicemia, (3) severe burns, (4) anaphylaxis, (5) cardiomyopathy, (6) myocarditis, (7) myocardial infarction or stunning, and (8) acute central nervous system (CNS) disorders. It is characterized by low cardiac output and results in inadequate tissue perfusion (see Chapter 88 ). Treatment is aimed at reinstitution of adequate cardiac output to prevent the untoward effects of prolonged ischemia on vital organs, as well as management of the underlying cause. Under normal physiologic conditions, cardiac output is increased as a result of sympathetic stimulation, which increases both contractility and heart rate. If contractility is depressed, cardiac output may be improved by increasing heart rate, increasing ventricular filling pressure (preload) through the Frank-Starling mechanism, or by decreasing systemic vascular resistance (afterload). Optimal filling pressure is variable and depends

on a number of extracardiac factors, including ventilatory support and intraabdominal pressure. The increased pressure necessary to fill a relatively noncompliant ventricle should also be considered, particularly after open heart surgery, or in patients with restrictive or hypertrophic cardiomyopathies. If carefully administered incremental fluid does not result in improved cardiac output, abnormal myocardial contractility or an abnormally high afterload, or both, must be implicated as the cause of the low cardiac output. Although an increase in heart rate may improve cardiac output, an excessive increase in heart rate may reduce cardiac output because of decreased time for diastolic filling. Additionally, high heart rates will increase myocardial oxygen demand, which may be counterproductive in a state of limited tissue oxygen supply. Myocardial contractility usually improves when treatment of the basic cause of shock is instituted, hypoxia is eliminated, and acidosis is corrected. βAdrenergic agonists such as dopamine, epinephrine, and dobutamine improve cardiac contractility, increase heart rate, and ultimately increase cardiac output. However, some of these agents also have α-adrenergic effects, which cause peripheral vasoconstriction and increase afterload, so careful consideration of the balance of these effects in an individual patient is important. The use of cardiac glycosides to treat acute low cardiac output states should be avoided. Patients in cardiogenic shock may have a marked increase in systemic vascular resistance (SVR) resulting in high afterload and poor peripheral perfusion. If the increased SVR is persistent and the administration of positive inotropic agents alone does not improve tissue perfusion, the use of afterloadreducing agents may be appropriate, such as nitroprusside or milrinone in combination with a β-adrenergic agonist. Milrinone, a phosphodiesterase inhibitor (see earlier), is also a positive inotropic agent, and combined with a βadrenergic agonist, it works synergistically to increase levels of myocardial cyclic adenosine monophosphate. Sequential evaluation and management of cardiovascular shock are mandatory (see Chapter 88 ). Table 469.4 outlines the general treatment principles for acute cardiac circulatory failure under most circumstances. In addition to cardiacspecific medications, other treatments aimed at improving oxygen capacity (e.g., blood transfusion for patients with anemia) and decreasing oxygen demand (e.g., intubation, mechanical ventilation, sedation) can be beneficial. Treatment of infants and children with low cardiac output after cardiac surgery also depends on the nature of the operative procedure, any intraoperative complications, and the physiology of the circulation after repair or palliation (see Chapter 461 ). If

cardiogenic shock does not respond rapidly to medical therapy, consideration of mechanical support is warranted. Table 469.4

Treatment of Cardiogenic Shock*

Parameters measured Treatment to improve cardiac output

DETERMINANTS OF STROKE VOLUME Preload Contractility CVP, PCWP, LAP, cardiac CO, BP, fractional shortening or chamber size on ejection fraction on echocardiography, echocardiography MV O2 saturation Volume expansion β-Adrenergic agonists, (crystalloid, colloid, blood) phosphodiesterase inhibitors

Afterload BP, peripheral perfusion, SVR Afterload-reducing agents: milrinone, nitroprusside, ACEIs

* The goal is to improve peripheral perfusion by increasing cardiac output, where: cardiac output =

heart rate × stroke volume. ACEIs, Angiotensin-converting enzyme inhibitors; BP, blood pressure; CO, cardiac output (measured with a thermodilation catheter); CVP, central venous pressure; LAP, left atrial pressure (measured with an indwelling LA line); MV O2 saturation, mixed venous oxygen saturation (measured with a central venous catheter); PCWP, pulmonary capillary wedge pressure (measured with a thermodilation catheter); SVR, systemic vascular resistance (calculated from CO and mean BP).

Mechanical Circulatory Support Extracorporeal membrane oxygenation (ECMO) , which can provide total cardiopulmonary support, is the most common short-term modality to support circulatory failure in children. In experienced centers, children can be placed on ECMO rapidly, and therefore the modality can be used in multiple settings, including low cardiac output syndrome (low-output heart failure) after cardiac surgery, rapidly deteriorating hemodynamics in several scenarios (e.g., myocarditis), and as resuscitation from refractory cardiac arrest. The modality is ideal for short-term support when the underlying disease requiring EMCO is expected to resolve within days to weeks. For multiple reasons, including the relatively high complication rate and decreased mobility of many patients on ECMO, it is not an ideal support modality for long-term myocardial support. Given of limitations of ECMO, there is a need to develop long-term support options for children with refractory heart failure. With advancements in the current era, almost 50% of children with dilated cardiomyopathy will be

supported on a ventricular assist device (VAD) prior to heart transplantation. For infants and small children, the most commonly used VAD is the Berlin Heart EXCOR. This device can be used for left, right, or biventricular support. It is classified as a paracorporeal pneumatic pulsatile device, and the pump sits outside the body. Among adults, these older types of devices have been replaced by newer-generation devices classified as intracorporeal continuous flow devices. These are completely internalized except for a drive line that connects to the power source (Fig. 469.2 ). These VADs have fewer complications and can provide long-term durable support outside the hospital. These devices are often used in older children and adolescents, with many of these patients discharged home on VAD support.

FIG. 469.2 Commonly used ventricular assist devices in children. A, Paracorporeal pneumatic pulsatile Berlin Heart EXCOR. B and C, Continuous flow devices: B, axial flow HeartMate II; C, centrifugal flow HeartWare HVAD. (A, Courtesy Berlin Heart, LLC; B, reproduced with permission of St. Jude Medical, ©2017 [All rights reserved. HeartMate II and St. Jude Medical are trademarks of St. Jude Medical, LLC or its related companies]; C, courtesy Medtronic, Inc.)

Other types of devices, including temporary VAD for short-term support and the total artificial heart for long-term support, have also been used in children, but less frequently. In children, most of these devices are used with the intention of subsequently performing a heart transplantation, although the devices can be removed if myocardial function recovers. This is in contrast to adult patients, many of whom are placed on these devices with no plan for heart transplantation, the so-called destination therapy. Successfully managing patients

on VAD support requires a dedicated multidisciplinary team.

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CHAPTER 470

Pediatric Heart and Heart-Lung Transplantation 470.1

Pediatric Heart Transplantation Joseph W. Rossano

Pediatric heart transplantation is considered the standard therapy that offers long-term survival for end-stage heart disease in children. In adults, ventricular assist devices (VADs) are usually employed as a long-term therapy for patients not eligible for heart transplantation, but in children the vast majority of VADs are used as a bridge to transplantation as opposed to an alternative to transplantation. As of January 2017, almost 9000 heart transplants had been performed on children in the United States since 1988, with about 400 transplants annually; a quarter of these in children 50% of heart transplants in pediatric patients older than 1 yr, with the percentage of patients with previously repaired complex CHD at approximately 30%. In infants younger than 1 yr, CHD previously represented >80% of transplants; this has decreased to 60% as standard surgical results for complex CHD (e.g., HLHS) have improved.

Recipient and Donor Selection Potential heart transplant recipients must be free of serious noncardiac medical problems such as neurologic disease, active systemic infection, severe hepatic or renal disease, and severe malnutrition. Many children with ventricular dysfunction are at risk for the development of pulmonary vascular disease , which if severe enough would also preclude heart transplantation. Therefore, pulmonary vascular resistance (PVR) is measured at cardiac catheterization in heart transplant candidates, both at rest and, if elevated, in response to vasodilators. Patients with fixed elevated PVR are at higher risk for heart transplantation and may be considered candidates for heart-lung transplantation (see Chapter 470.2 ). However, with advances in postoperative management of pulmonary hypertension (e.g., inhaled nitric oxide), many patients with moderate elevation in PVR can undergo heart transplant alone. A comprehensive social services evaluation is an important component of the recipient evaluation. Because of the complex posttransplantation medical regimen, the family must have a history of compliance. Detailed informed consent must be obtained, indicating that the family (and if old enough, the patient) understand the lifelong commitment to immunosuppressive medication and careful monitoring. Donor shortage is a serious problem for both adults and children. At the national registry of transplant recipients in the United States, the United Network for Organ Sharing (UNOS) , allografts are matched by ABO blood group and body weight. ABO matching may not be required for young infants; the exact age under which ABO tolerance develops has not yet been determined. Patients, especially with a history of CHD, who have undergone prior operations may have antibodies against human leukocyte antigens (HLAs). Patients with elevated anti-HLA antibodies are at risk for a positive crossmatch and early graft dysfunction. These antibodies can also contribute to late graft dysfunction through antibody-mediated rejection and development of cardiac allograft

vasculopathy. For patients with these elevated antibodies, there are strategies to avoid a positive crossmatch through a prospective crossmatch or a virtual crossmatch, although this may prolong the waiting list time. Contraindications to organ donation include prolonged cardiac arrest with persistent moderate to severe cardiac dysfunction, ongoing systemic illness or infection, and preexisting severe cardiac disease. Physicians caring for a patient who may be a potential donor should always contact the organ donor coordinator at their institution, who can best judge the appropriateness of organ donation and has experience in interacting with potential donor families. A history of resuscitation alone or reparable CHD is not an automatic exclusion for donation. The decision of when to place a patient on the transplant waiting list is based on many factors, including poor ventricular function, markedly decreased exercise tolerance as determined by cardiopulmonary exercise testing (see Chapter 450.5 ), poor response to medical heart failure therapy, multiple hospitalizations for heart failure, arrhythmia, progressive deterioration in renal or hepatic function, early stages of pulmonary vascular disease, and poor nutritional status. In patients awaiting transplantation, those with poor left ventricular function are often started on a regimen of anticoagulation to reduce the risk of mural thrombosis and thromboembolism. Patients with progressive heart failure resulting in decreases in end-organ (renal or hepatic) function unresponsive to standard pharmacologic treatment may be candidates for a VAD. The use of these devices has increased dramatically over the last decade, and currently almost half of patients with dilated cardiomyopathy are on VAD support before transplant. VADs can improve hemodynamics and end-organ function, and some patients can even be discharged home on VAD support (see Chapter 469 ).

Perioperative Management In the classic operation , both donor and recipient hearts were excised so that the posterior portions of the atria containing the venae cavae and pulmonary veins are left intact. The aorta and pulmonary artery are divided above the level of the semilunar valves. The anterior portion of the donor's atria was then connected to the remaining posterior portion of the recipient's atria, thereby avoiding the need for delicate suturing of the venae cavae or pulmonary veins. The donor and recipient great vessels were connected via end-to-end anastomoses. This has been supplanted in many centers by the bicaval

anastomosis, with the donor right atrium (and sinus node) left intact and the suture lines at the superior and inferior vena cavae; the left atrial connection is still performed as in the classic procedure. Heterotopic heart transplantation has been used occasionally for patients with left ventricular cardiomyopathy and elevated PVR. In this operation the donor and recipient hearts are connected in parallel so that the recipient right ventricle (which has hypertrophied over time because of elevated pulmonary pressures) pumps mostly to the lungs, and the donor left ventricle pumps mostly to the body. This operation may be preferable to heart-lung transplant for appropriate candidates (patients with pulmonary hypertension but without parenchymal lung disease, without evidence of right ventricular failure, and without serious CHD). However, this procedure is very uncommon in the current era. In the immediate postoperative period, immunosuppression is achieved with either a triple-drug or a double-drug regimen, with more centers adopting a minimal corticosteroid or steroid-free regimen. The most common combinations are a calcineurin inhibitor (cyclosporine or tacrolimus) plus an antiproliferative agent (mycophenolate mofetil or azathioprine), plus or minus prednisone . In many centers, induction therapy (usually an antilymphocyte preparation) is added in the 1st week; common agents include antithymocyte globulin (ATG) and the humanized anti–interleukin-2 receptor antibodies (basiliximab). In children who do not experience significant graft rejection, corticosteroids can be gradually eliminated in the early transplant period. Some centers do not use steroids as part of maintenance immunosuppression, but do use them as bolus treatment for acute rejection episodes. Many pediatric heart transplant recipients can be extubated from endotracheal intubation and mechanical ventilation support within the 1st 48 hr after transplantation and are out of bed in several days. In patients with preexisting high-risk factors, postoperative recovery may be considerably prolonged. For those with preoperative pulmonary hypertension, the use of nitric oxide in the postoperative period can allow the donor right ventricle to hypertrophy in response to elevated pulmonary artery pressures. Occasionally, these patients will require right ventricular assist device support or extracorporeal membrane oxygenation (ECMO).

Diagnosis and Management of Acute

Graft Rejection Posttransplantation management consists of adjusting medications to maintain a balance between the risk of rejection and the side effects of overimmunosuppression. Acute graft rejection is a leading cause of death in pediatric heart transplant recipients. The incidence of acute rejection is greatest in the 1st 3 mo after transplantation and decreases considerably thereafter. Many pediatric patients experience at least 1 episode of acute rejection in the 1st 2 yr after transplantation, although modern immunosuppressive regimens have decreased the frequency of serious rejection episodes. Because the symptoms of rejection can mimic many routine pediatric illnesses (e.g., pneumonia, gastroenteritis), the transplant center should be notified whenever a heart transplant recipient is seen in the pediatrician's office or emergency department for acute illnesses. Clinical manifestations of acute rejection may include fatigue, fluid retention, fever, diaphoresis, abdominal symptoms, and a gallop rhythm. The electrocardiogram (ECG) may show reduced voltage, atrial or ventricular arrhythmias, or heart block but is usually nondiagnostic. X-ray examination may show an enlarged heart, effusions, or pulmonary edema but typically only in the more advanced stages of rejection. Natriuretic peptide levels are usually increased during episodes of acute rejection. Most rejection episodes occur without any detectable clinical symptoms. On echocardiography, indices of systolic left ventricular function may be decreased; however, these usually do not deteriorate until rejection is at least moderately severe. Techniques to evaluate wall thickening and left ventricular diastolic function have not fulfilled their promise as predictors of early rejection. Most transplant centers do not rely on echocardiography alone for rejection surveillance. Myocardial biopsy is the most reliable method of monitoring patients for rejection. Biopsy specimens are taken from the right ventricular side of the interventricular septum and can be harvested relatively safely, even in small infants. In infants, surveillance biopsies are usually performed less often and may be as infrequent as once or twice per year. Children may have clinically unsuspected rejection episodes even 5-10 yr after transplantation; most pediatric transplant centers continue routine surveillance biopsies, although at less frequent intervals. Criteria for grading cardiac rejection are based on a system developed by the International Society for Heart and Lung Transplantation (ISHLT) that

takes into account the degree of cellular infiltration and whether myocyte necrosis is present. ISHLT rejection grade 1R is usually mild enough that it is often not treated with bolus steroids, and many of these episodes resolve spontaneously. For patients with ISHLT grade 2R rejection, treatment is instituted with either intravenous (IV) methylprednisolone or a “bump and taper” of oral prednisone. Asymptomatic patients further out from transplant with normal echocardiograms are may treated as outpatients. Patients with grade 3R, or anyone with hemodynamic instability, are admitted to the hospital for IV corticosteroid and potentially more aggressive antirejection therapy. For rejection episodes resistant to steroid therapy, additional therapeutic regimens include antilymphocyte preparation (antithymocyte globulin), methotrexate, or total lymphoid irradiation. Patients with repeated episodes of rejection may also benefit from the switch from cyclosporine to tacrolimus (or vice versa) or the addition of a proliferation single inhibitor (e.g., sirolimus). Refractory rejection is not considered a good indication for retransplantation because of the relatively poor outcomes compared with other indications for retransplantation. Gene expression profiling of peripheral blood mononuclear cells has been validated in adults as a highly sensitive, moderately selective method of rejection surveillance. These results have not been confirmed in children. Other promising current techniques include the profiling of donor cell–free DNA released in the serum of patients during episodes of graft injury. Progress has also been made in genetic profiling as a means to determine which patients are most at risk for rejection. Children who have single nucleotide polymorphisms (SNPs) leading to greater activity of inflammatory cytokines or decreased activity of regulatory cytokines are at increased risk of rejection. Some rejection episodes are not associated with a cellular infiltrate on biopsy. These cases of antibody-mediated rejection are mediated by circulating donorspecific antibodies (DSAs) and can be detected by immunostaining of the biopsy specimen for the complement component C4d, for macrophages expressing CD68, and for evidence of histologic damage. Antibody-mediated rejection is less responsive to standard therapies for acute cellular rejection (e.g., bolus corticosteroids) and has been treated with plasmapheresis, intravenous immune globulin (IVIG), the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor bortezomib, all with mixed results. The long-term outcome of patients with persistent DSAs is poor, with many having early graft failure.

Complications of Immunosuppression Infection Infection is also a leading cause of death in pediatric transplant patients (Fig. 470.2 ). The incidence of infection is greatest in the 1st 3 mo after transplantation, when immunosuppressive doses are highest. Viral infections are most common and account for as many as 25% of infectious episodes. Cytomegalovirus (CMV) infection was once a leading cause of morbidity and mortality and may occur as a primary infection in patients without previous exposure to the virus or as a reactivation. Severe CMV infection can be disseminated or associated with pneumonitis or gastroenteritis and may provoke an episode of acute graft rejection or graft coronary disease. Most centers use IV ganciclovir or CMV immune globulin (CytoGam), or both, as prophylaxis in any patient receiving a heart from a donor who is positive for CMV or in any recipient who has serologic evidence of previous CMV disease. Oral preparations of ganciclovir with improved absorption profiles are available for chronic therapy and have largely replaced IV preparations for prophylaxis. These regimens have significantly reduced the burden of CMV disease in heart transplant patients. Polymerase chain reaction (PCR) enhances the ability to diagnose CMV infection and monitor the efficacy of therapy serially.

FIG. 470.2 Major causes of death after pediatric heart transplantation by

time since transplant. CAV, Cardiac allograft vasculopathy; CMV, cytomegalovirus. (From Rossano JW, Dipchand AI, Edwards LB, et al: The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report—2016. Focus theme: primary diagnostic indications for transplant, J Heart Lung Transplant 35(10):1185–1195, 2016, Fig 10.)

Most normal childhood viral illnesses are well tolerated and do not usually require special treatment. Otitis media and routine upper respiratory tract infections can be treated in the outpatient setting, although fever or symptoms that last beyond the usual course require further investigation. Gastroenteritis , especially with vomiting, can result in greatly reduced absorption of immunosuppressive medications and provoke a rejection episode. In this setting, drug levels should be closely monitored and use of IV medications considered. Gastroenteritis can also be a sign of rejection, so a high index of suspicion must always be maintained. Varicella is another childhood illness of concern for immunosuppressed patients. If a heart transplant recipient acquires clinical varicella infection, treatment with IV acyclovir usually attenuates the illness. Bacterial infections occur next in frequency after viral, with the lung the most common site of infection, followed by blood, urinary tract, and less often the sternotomy site. Other sources of posttransplantation infection include fungi and protozoa. Many centers use nystatin mouthwash to decrease fungal colonization and trimethoprim-sulfamethoxazole during a patient's corticosteroid prophylaxis to prevent Pneumocystis jiroveci infection.

Growth Retardation Patients requiring chronic corticosteroid therapy usually have decreased linear growth. Thus, many pediatric transplant programs aim for steroid-free immunosuppression within the 1st yr after transplant. In patients who experience rejection when steroids are withdrawn, alternate-day corticosteroid regimens may result in improved linear growth. Total lymphoid irradiation has also shown promise as a steroid-sparing protocol. Despite these concerns, the majority of long-term survivors of pediatric heart transplantation have normal growth.

Hypertension Hypertension is common in patients treated with calcineurin inhibitors, caused

by a combination of plasma volume expansion and defective renal sodium excretion. Corticosteroids usually potentiate calcineurin-induced hypertension.

Renal Function Chronic administration of cyclosporine or tacrolimus can lead to a tubulointerstitial nephropathy in adults, but severe renal dysfunction is less common in children. Most pediatric patients gradually have an increase in serum creatinine in the 1st yr after transplantation; if renal dysfunction occurs, it usually responds to a decrease in calcineurin inhibitor (CNI) dosage. The addition of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, instead of mycophenolate mofetil (MMF) allows a reduction in CNI dose in patients with renal dysfunction, although it is unclear whether this strategy leads to long-term improved renal function. Infection with BK virus, a growing problem in renal transplant patients, has been described as a source of renal dysfunction in heart transplant patients. Fortunately, pediatric heart transplant patients infrequently require renal transplantation.

Neurologic Complications Neurologic side effects of cyclosporine and tacrolimus include tremor, myalgias, paresthesias, and rarely, seizures. These complications can be treated with reduced doses of medication and occasionally with oral magnesium supplementation. Intracranial infections pose a significant risk, especially because some of the more frequent signs (nuchal rigidity) may be absent in immunosuppressed patients. Potential organisms include Aspergillus, Cryptococcus neoformans, and Listeria monocytogenes. A rare form of encephalopathy known as posterior reversible encephalopathy syndrome (PRES) can occur in patients taking CNIs (cyclosporine or tacrolimus). PRES presents with hypertension, headaches and seizures, requires MRI for diagnosis, and is usually managed by changing CNI or in rare cases eliminating CNIs totally in favor of other immunosuppressive agents (e.g., sirolimus, MMF).

Tumors One of the serious complications limiting long-term survival in pediatric heart transplant patients is the risk of neoplastic disease. The most common is

posttransplant lymphoproliferative disease (PTLD), a condition associated with Epstein-Barr virus (EBV) infection. Patients who are EBV seronegative at transplant (usually infants and young children) are at increased risk of developing PTLD if they subsequently seroconvert, acquiring the virus either from the donor organ or from primary infection. Unlike true cancer, many cases of PTLD respond to a reduction in immunosuppression. A monoclonal antibody directed against the CD20 antigen on activated lymphocytes (rituximab) has been effective against some forms of PTLD. However, PTLD can behave more aggressively, and many patients eventually require chemotherapy. An increased risk of skin cancer requires that children use appropriate precautions when exposed to sunlight.

Cardiac Allograft Vasculopathy Cardiac allograft vasculopathy (CAV) is a disease of the coronary arteries that occurs in approximately 20% of children 5 yr after transplant. The cause is still unclear, although it is thought to be a form of immunologically mediated vessel injury. Multiple factors, including rejection episodes, infections, hypercholesterolemia, and hyperglycemia, are thought to increase the risk of CAV. Unlike native coronary atherosclerosis, CAV is a diffuse process with a high degree of distal vessel involvement. Because the transplanted heart has been denervated, patients may not experience symptoms such as angina pectoris during ischemic episodes, and the initial manifestation may be cardiovascular collapse or sudden death. Most centers perform coronary angiography annually to screen for coronary abnormalities; some also perform coronary intravascular ultrasound in larger children and adolescents. Standard coronary artery bypass procedures are usually not helpful because of the diffuse nature of the process, although transcatheter stenting can sometimes be effective for isolated lesions. For patients with severe CAV, repeat heart transplantation has been the only effective treatment. Thus, prevention has been the focus of most current research. The cell-cycle inhibitors sirolimus and everolimus have been shown to decrease coronary arterial intimal thickening in adult transplant patients. Other drugs that have been associated with a lower the risk of CAV include the calcium channel blockers (e.g., diltiazem) and the cholesterol-lowering HMG-CoA (3hydroxy-3-methyl-coenzyme A) reductase inhibitors (e.g., pravastatin, atorvastatin).

Other Complications Corticosteroids usually result in cushingoid facies, steroid acne, and striae. Cyclosporine can cause a subtle change in facial features, such as hypertrichosis and gingival hyperplasia. These cosmetic features can be particularly disturbing to adolescents and may be the motivation for noncompliance, one of the leading risks for late morbidity and mortality. Most of these cosmetic complications are dose related and improve as immunosuppressive medications are weaned. Tacrolimus does not have the cosmetic side effects of cyclosporine. Osteoporosis and aseptic necrosis are additional reasons for reducing the steroid dosage as soon as possible. Diabetes and pancreatitis are rare but serious complications.

Rehabilitation Despite the potential risks of immunosuppression, the prospect for rehabilitation in pediatric heart transplant recipients is excellent; most have no functional limitations in their daily lives. They can attend daycare or school and participate in competitive sports and other age-appropriate activities. Standardized measurements of ventricular function are close to normal. Because the transplanted heart is denervated, the increase in heart rate and cardiac output during exercise is slower in transplant recipients, and maximal heart rate and cardiac output responses are mildly attenuated. These subtle abnormalities are rarely noticeable by the patient. Growth of the transplanted heart is excellent, although a mild degree of ventricular hypertrophy is usually seen, even years after transplantation. The sites of atrial and great vessel anastomoses usually grow without the development of obstruction. In neonates who undergo transplantation for HLHS, however, juxtaductal aortic coarctation may recur. A serious problem with noncompliance may occur once patients reach adolescence, and life-threatening rejection may result. Early intervention by social workers, counselors, and psychologists may be able to reduce this risk.

Bibliography Castleberry C, Ryan TD, Chin C. Transplantation in the highly sensitized pediatric patient. Circulation . 2014;129(22):2313– 2319.

Colvin MM, Cook JL, Chang P, et al. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation . 2015;131(18):1608–1639. Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al. Berlin heart study: prospective trial of a pediatric ventricular assist device. N Engl J Med . 2012;367(6):532–541. Hammond ME, Revelo MP, Miller DV, et al. ISHLT pathology antibody mediated rejection score correlates with increased risk of cardiovascular mortality: a retrospective validation analysis. J Heart Lung Transplant . 2016;35(3):320–325. Mehra MR, Canter CE, Hannan MM, et al. The 2016 international society for heart lung transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant . 2016;35(1):1–23. Rossano JW, Dipchand AI, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: nineteenth pediatric heart transplantation report—2016. Focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant . 2016;35(10):1185–1195. Rossano JW, Jefferies JL, Pahl E, et al. Use of sirolimus in pediatric heart transplant patients: a multi-institutional study from the Pediatric Heart Transplant Study Group. J Heart Lung Transplant . 2017;36(4):429–433. Stein ML, Bruno JL, Konopacki KL, et al. Cognitive outcomes in pediatric heart transplant recipients bridged to transplantation with ventricular assist devices. J Heart Lung Transplant . 2013;32(2):212–220. Tran A, Fixler D, Huang R, et al. Donor-specific HLA alloantibodies: impact on cardiac allograft vasculopathy, rejection, and survival after pediatric heart transplantation. J Heart Lung Transplant . 2016;35(1):87–91.

Urschel S, Larsen IM, Kirk R, et al. ABO-incompatible heart transplantation in early childhood: an international multicenter study of clinical experiences and limits. J Heart Lung Transplant . 2013;32(3):285–292.

470.2

Heart-Lung and Lung Transplantation Joseph W. Rossano, Samuel B. Goldfarb

More than 700 heart-lung and 2,200 lung (single or double) pediatric transplants have been performed and reported to ISHLT, with >100 procedures performed annually. The majority of these are lung transplantation, with only 11 heart-lung transplants reported in 2014. Primary indications for lung transplantation include cystic fibrosis, pulmonary hypertension, interstitial lung disease, surfactant deficiencies, and retransplant. Indications for heart-lung transplant include complex CHD along with either pulmonary parenchymal or vascular disease. Patients with normal hearts are candidates for lung transplantation even in the setting of right ventricular dysfunction. This had led to the marked decline in heart-lung transplant procedures in the current era. In some patients with CHD, double-lung transplantation can be performed in combination with repair of intracardiac defects. Patients with cystic fibrosis are not candidates for singlelung grafts because of the risk of infection from the diseased contralateral lung. Patients are selected according to many of the same criteria as for heart transplant recipients (see Chapter 470.1 ). Posttransplant immunosuppression is usually achieved with a triple-drug regimen, combining a CNI (cyclosporine or tacrolimus) with an antiproliferative agent (MMF or azathioprine) and prednisone. Most patients receive induction therapy with an antithymocyte or anti–T-cell preparation. Unlike patients with

isolated heart transplants, patients with lung or heart-lung transplants cannot be weaned totally off steroids. Prophylaxis against P. jiroveci infection is achieved with trimethoprim-sulfamethoxazole or aerosolized pentamidine. Ganciclovir and CMV immune globulin prophylaxis are used as in heart transplant recipients (see Chapter 470.1 ). Antifungal medications are used in the perioperative and posttransplant periods in patients who have pretransplant colonization. Pulmonary rejection is common in lung or heart-lung transplant recipients, whereas heart rejection is encountered much less often than in patients with isolated heart transplants. Acute rejection occurs in approximately 25% of patients in the 1st yr after transplant. Symptoms of lung rejection may include fever and fatigue, although many episodes are minimally symptomatic. Signs of rejection could include changes in lung function testing and radiographic findings. Surveillance for rejection is performed by monitoring pulmonary function (forced vital capacity; forced expiratory volume in 1 sec [FEV1 ]; forced expiratory flow, midexpiratory phase [FEF25-75% ]), systemic arterial oxygen tension, chest radiographs, chest CT, transbronchial biopsy, and open lung biopsy. In heart-lung transplant recipients, hearts are assessed for rejection similar to the approach described in Chapter 470.1 . Actuarial survival rates after lung or heart-lung transplantation in children are currently 75–80% at 1 yr and 50% at 5 yr after transplant; improved patient selection and postoperative management are continually improving these survival statistics from prior eras. Some groups, such as patients with CHD in the absence of Eisenmenger syndrome, have particular poor outcomes with transplant. Graft failure and infection are the leading cause of early death, whereas a form of chronic rejection known as bronchiolitis obliterans accounts for almost 50% of late mortality. Other causes of early morbidity and mortality include technical complications, multiorgan failure, primary graft dysfunction, and cardiovascular causes. Additional late complications include the development of late graft failure, malignancies, infection, and other side effects of chronic immunosuppression. Postoperative indices of cardiopulmonary function and exercise capacity show significant improvement. Problems of donor availability are even more severe with lung transplantation than with isolated heart transplantation. However, significant advances in ex vivo lung perfusion has great potential to expand the number of organs available for transplantation.

Bibliography Goldfarb SB, Levvey BJ, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: nineteenth pediatric lung and heart-lung transplantation report —2016. Focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant . 2016;35(10):1196– 1205. Hayes D Jr, Sweet SC, Benden C, et al. Transplant center volume and outcomes in lung transplantation for cystic fibrosis. Transpl Int . 2016; 10.1111/tri.12911 . Keeshan BC, Goldfarb SB, Lin KY, et al. Impact of congenital heart disease on outcomes of pediatric heart-lung transplantation. Pediatr Transplant . 2014;18(2):204–210. Snell GI, Paraskeva M, Westall GP. Managing bronchiolitis obliterans syndrome (BOS) and chronic lung allograft dysfunction (CLAD) in children: what does the future hold? Paediatr Drugs . 2013;15(4):281–289. Yeung JC, Krueger T, Yasufuku K, et al. Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study. Lancet Respir Med . 2017;5(2):119–124.

SECTION 8

Diseases of the Peripheral Vascular System OUTLINE Chapter 471 Diseases of the Blood Vessels (Aneurysms and Fistulas) Chapter 472 Systemic Hypertension

CHAPTER 471

Diseases of the Blood Vessels (Aneurysms and Fistulas) 471.1

Kawasaki Disease Daniel Bernstein

Keywords aneurysm arteriovenous fistula hemangioma vein of Galen malformation embolization generalized arterial calcification of infancy pseudoxanthoma elasticum arterial calcification of CD73 deficiency arterial tortuosity syndrome See also Chapter 191 . Aneurysms of the coronary and occasionally the systemic arteries may complicate Kawasaki disease and are the leading cause of morbidity in this disease (Figs. 471.1 and 471.2 ). Other than in Kawasaki disease, aneurysms are not common in children and occur most frequently in the aorta in association

with coarctation of the aorta, patent ductus arteriosus, Ehlers-Danlos syndrome type IV (arterial ecchymotic form), hyper-IgE syndrome, Marfan syndrome, and the 4 forms of Loeys-Dietz syndrome in intracranial vessels (see Chapter 619 ). Aneurysms may also occur secondary to an infected embolus; infection contiguous to a blood vessel; trauma; congenital abnormalities of vessel structure, especially the medial wall; and arteritis, including polyarteritis nodosa, Behçet syndrome, and Takayasu arteritis (see Chapter 192.2 ).

FIG. 471.1 Two-dimensional echocardiograms comparing a normal left main coronary artery (arrow in A ) with a giant coronary artery aneurysm (outlined by cross marks in B ) in a patient with Kawasaki disease. Ao, Aorta.

FIG. 471.2 Pathologic specimen showing giant aneurysm of left main coronary artery (arrow). Ao, Ascending aorta.

471.2

Arteriovenous Fistulas Daniel Bernstein

Arteriovenous fistulas may be limited and small or may be extensive, producing systemic complications (see Chapters 532 and 669 ). The most common sites in infants and children are within the cranium, in the liver, in the lung, in the extremities, and in vessels in or near the thoracic wall. These fistulas, although usually congenital , may follow trauma or may be a manifestation of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). Femoral arteriovenous fistulas are a rare complication of percutaneous femoral catheterization.

Clinical Manifestations Clinical symptoms occur only in association with large arteriovenous communications when arterial blood flows into a low-pressure venous system without the resistance of the capillary bed; local venous pressure is increased, and arterial flow distal to the fistula is decreased. Systemic arterial resistance falls because of the runoff of blood through the fistula. Compensatory mechanisms include tachycardia and increased stroke volume so that cardiac output rises. Total blood volume is also increased. In large fistulas, left ventricular dilation, a widened pulse pressure, and high-output heart failure occur. CT, MRI, or injection of contrast material into an artery proximal to the fistula confirms the diagnosis. Large intracranial arteriovenous fistulas most often occur in newborn infants in association with a vein of Galen malformation . The large intracranial leftto-right shunt results in heart failure secondary to the demand for high cardiac output. Patients with smaller communications may not have cardiovascular manifestations but may later be disposed to hydrocephalus (see Chapter 609.11 ) or seizure disorders. The diagnosis can often be made by auscultation of a continuous murmur over the cranium. Older children with more diffuse intracranial arteriovenous malformations may be recognized on the basis of intracranial calcification and high cardiac output without cardiac failure. Hepatic arteriovenous fistulas may be generalized or localized in the liver and may be hemangioendotheliomas or cavernous hemangiomas. The fistula may be located between the hepatic artery and the ductus venosus or portal vein. Congenital hemorrhagic telangiectasia may also be present. Large arteriovenous fistulas are associated with increased cardiac output and heart failure. Hepatomegaly is usual, and systolic or continuous murmurs may be audible over the liver. Peripheral arteriovenous fistulas generally involve the extremities and are associated with disfigurement, swelling of the extremity, and visible hemangiomas. Some are located in areas that result in upper airway obstruction. Because only a small minority results in large arterial runoff, cardiac failure is uncommon.

Treatment Medical management of heart failure is initially helpful in neonates with these

conditions; with time, the size of the shunt may diminish and symptoms spontaneously regress. Hemangiomas of the liver often eventually disappear completely. Large liver hemangiomas have been treated with corticosteroids, βblockers, ε-aminocaproic acid, interferon, local compression, embolization, or local irradiation; the beneficial effects of these management options are not firmly established because individual patients display marked variation in clinical course without treatment. Catheter embolization is becoming the treatment of choice for many patients with a symptomatic arteriovenous fistula. Embolic agents that have been used include detachable balloons, steel (Gianturco) coils, and liquid tissue adhesives (cyanoacrylate). Often, multiple procedures are necessary before flow is significantly reduced. Gamma knife radiosurgery has been used successfully in patients with cerebral arteriovenous malformations. Surgical removal of a large fistula may be attempted in patients with severe cardiac failure and lack of improvement with medical treatment. Surgical treatment may be contraindicated or unsuccessful when the lesion is extensive and diffuse or is located in a position where adjoining tissue may be injured during the surgery or related procedures. β-Adrenergic blockers such as propranolol have dramatically changed the treatment for cutaneous hemangiomas, with excellent results.

471.3

Generalized Arterial Calcification of Infancy/Idiopathic Infantile Arterial Calcification Robert M. Kliegman

Generalized arterial calcification of infancy (GACI) is a rare and often lethal autosomal recessive disorder characterized by calcification of muscular arteries with fibrotic myointimal proliferation and subsequent vascular stenosis leading

to tissue ischemia, poor function, or infarction. Diffuse arterial calcification may begin in utero, leading to hydrops fetalis; in the neonate, diffuse arterial calcification leads to respiratory distress and heart failure or myocardial infarction (coronary, pulmonary arteries), hypertension (renal arteries), and poor femoral pulses (aorta, femoral arteries). Mutations in the ectonucleotide pyrophosphatase 1 gene (ENPP1 ) are noted in 75% of patients. Serum calcium, phosphate, and alkaline phosphatase levels are normal; the vascular calcification may be seen on plain x-ray films (Fig. 471.3 ), ultrasonography (Fig. 471.4 ), or CT scans (Fig. 471.5 ), which may reveal calcifications not visible on plain films.

FIG. 471.3 Lateral radiograph of the neonate showing calcification of descending aorta and its bifurcation (arrows) . (From Karthikeyan G: Generalized arterial calcification of infancy, J Pediatr 162:1074, 2013, Fig 3.)

FIG. 471.4 Ultrasonography of abdominal aorta showing calcification of descending aorta and its branches (arrows). (From Karthikeyan G: Generalized arterial calcification of infancy, J Pediatr 162:1074, 2013, Fig. 1, p. 1074.)

FIG. 471.5 Coronal maximum intensity projection (MIP) CT scans demonstrate an endotracheal tube (ETT) and extensive vascular

calcifications. PA, Pulmonary artery; SA, splenic artery; RA, renal artery; CIA, common iliac artery; BA, brachial artery; CA, celiac axis; SMA, superior mesenteric artery; SCA, subclavian artery. (From Bolster F, Ali Z, Southall P, Fowler D: Generalized arterial calcification of infancy—findings at post-mortem computed tomography and autopsy, Forensic Sci Int 254:e7–e12, 2015, Fig 3.)

A subset of patients with GACI have monoallelic or biallelic mutations in the adenosine triphosphate–binding cassette subfamily C number 6 gene (ABCC6 ), which is the gene responsible for pseudoxanthoma elasticum (PXE). PXE, an autosomal recessive disorder, is classically associated with a later onset of ectopic mineralization of elastic fibers in the skin, eyes, joints, and arteries. In addition, some surviving infants with ENPP1 mutation develop PXE symptoms involving skin and retina (angioid streaking). Infants with GACI have been treated with bisphosphonates with variable success. In addition, some survivors with the ENPP1 mutation have developed hypophosphatemic-hyperphosphaturic rickets. In the absence of stroke or encephalomalacia, most survivors are developmentally normal. In some survivors the vascular calcification resolves and is replaced by fibrosis. The differential diagnosis includes Singleton-Merten syndrome (aortic calcification, dental anomalies, osteopenia), hypervitaminosis D, hyperparathyroidism, congenital syphilis (aortitis), twin-twin transfusion syndrome (recipient), and idiopathic iliac artery calcification of infancy.

Arterial Calcifications Caused by Deficiency of CD73 This rare autosomal recessive disorder, caused by mutations in the 5exonucleotidase CD73 (NT5E ), results in joint and arterial (lower-extremity) calcification in adults. Patients present with intermittent claudication and joint pain. Onset is probably before adulthood, since patients may be undiagnosed with nonspecific findings during adolescence.

471.4

Arterial Tortuosity

Robert M. Kliegman

Arterial tortuosity may be seen in many different diseases and genes (Table 471.1 ). These disorders are usually recognized by their phenotype, and all may present during childhood. Tortuosity is best defined by magnetic resonance angiography (Fig. 471.6 ). When present, it often increases the risk for early cardiovascular morbidity for patients with Marfan or Loeys-Dietz syndromes. Table 471.1 Genetic Disorders Associated With Aortic Disease and Arterial Tortuosity GENE TGFBR1 TGFBR2

DISORDER Loeys-Dietz syndrome, FTAAD Loeys-Dietz syndrome, FTAAD

FBN1 SMAD3 SLC2A10 TGFB2 PRKG1 FBLN4 /EFEMP2 ATP7A Monosomy X/mosaic monosomy X FTAAD

Marfan syndrome Osteoarthritis-aneurysm syndrome, FTAAD Arterial tortuosity syndrome FTAAD FTAAD Cutis laxa Occipital horn syndrome, Menkes syndrome Turner syndrome Familial aortic aneurysm and dissection

FTAAD, Familial thoracic aortic aneurysm and dissection. Adapted from Morris SA: Arterial tortuosity in genetic arteriopathies, Curr Opin Cardiol 30:587– 593, 2015 (Table 1, p 590).

FIG. 471.6 Examples of vertebral artery tortuosity in A, Marfan syndrome with FBN1 mutation, and B, Loeys-Dietz syndrome with a TGFBR2 mutation. (From Morris SA: Arterial tortuosity in genetic arteriopathies, Curr Opin Cardiol 30:587–593, 2015, Fig 1.)

Arterial tortuosity syndrome is another genetic arteriopathy, caused by mutations in the SCL2A10 gene. It has many features of other connective tissue diseases, including hyperextensible and soft velvety skin, high-arched palate, micrognathia, abdominal hernias, and joint hypermobility. The prognosis for patients with the arterial tortuosity syndrome is quite variable, but the presence of vascular stenosis is associated with a poorer prognosis.

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infancy: genotypic overlap with pseudoxanthoma elasticum. J Invest Dermatol . 2014;34(3):658–665. Lunsford LD, Niranjan A, Kano H, et al. The technical evolution of gamma knife radiosurgery for arteriovenous malformations. Prog Neurol Surg . 2013;27:22–34. MacCarrick G, Black JH III, Bowdin S, et al. Loey-dietz syndrome: a premier for diagnosis and management. Genet Med . 2014;16(8):576–587. Markello TC, Pak LK, St. Hilaire C, et al. Vascular pathology of medical arterial calcifications in NT5E deficiency: implications for the role of adenosine in pseudoxanthoma elasticum. Mol Genet Metab . 2011;103:44–50. Moran JJ. Idiopathic arterial calcification of infancy: a clinicopathologic study. Pathol Annu . 1975;10:393–417. Morris SA. Arterial tortuosity in genetic arteriopathies. Curr Opin Cardiol . 2015;30:587–593. Nitschke Y, Baujat G, Botschen U, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6 . Am J Hum Genet . 2012;90:25–39. Ramjam KA, Roscioli T, Rutsch F, et al. Generalized arterial calcifications of infancy: treatment with bisphosphonates. Nat Clin Pract Endocrinol Metab . 2009;5:167–172. Ritelli M, Chiarelli N, Dordoni C, et al. Arterial tortuosity syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review. BMC Med Genet . 2014;15:122. Ryerson LM, Chiletti R, Zacharin M, et al. Two cases of idiopathic infantile arterial calcification. J Paediatr Child Health . 2010;46:777–779. Saigal G, Azouz EM. The spectrum of radiologic findings in idiopathic arterial calcification of infancy: pictorial essay.

Pediatr Radiol . 2004;55:102–107. Singh S, Nautital A. Aortic dissection and aortic aneurysms associated with fluoroquinolones: a systematic review and meta-analysis. Am J Med . 2017;130(12):1449–1457.e9. St Hilaire C, Ziegler SG, Markello TC, et al. NT5E mutations and arterial calcifications. N Engl J Med . 2011;364:432–442.

CHAPTER 472

Systemic Hypertension Ian R. Macumber, Joseph T. Flynn

Primary (essential) hypertension occurs frequently in adults and, if untreated, is a major risk factor for myocardial infarction, cerebrovascular accident (stroke), and renal failure. In adults with hypertension, a 5 mm Hg increase in diastolic blood pressure (BP) increases the risk of coronary artery disease by 20% and the risk of stroke by 35%. Furthermore, along with diabetes, hypertension is 1 of the 2 leading causes of end-stage renal disease in adults. The prevalence of adult hypertension increases with age, ranging from 15% in young adults to 60% in individuals older than 65 yr. Hypertensive children, although frequently asymptomatic, already may manifest evidence of target organ damage. Up to 40% of hypertensive children have left ventricular hypertrophy, and hypertensive children have increased carotid intima-to-media thickness, a marker of early atherosclerosis. Primary hypertension occurring during childhood often continues into adulthood. Children with BP >90th percentile exhibit a 2.4-fold greater risk of having hypertension as adults. Similarly, almost half of hypertensive adults had a BP >90th percentile as children. Adolescent hypertension is also an independent predictor of both end-stage renal disease and left ventricular dysfunction in middle-aged men.

Prevalence of Hypertension in Children In infants and young children, systemic hypertension is uncommon, with a prevalence of 95 g/BSA for girls. According to the 2017 AAP guideline, echocardiography should be obtained when treatment with antihypertensive medications is being considered.

Prevention Prevention of high BP may be viewed as part of the prevention of cardiovascular disease and stroke, the leading cause of death in adults in the United States. Other risk factors for cardiovascular disease include obesity, elevated serum cholesterol levels, high dietary sodium intake, and a sedentary lifestyle, as well as alcohol and tobacco use. The increase in arterial wall rigidity and blood viscosity that is associated with exposure to the components of tobacco may exacerbate hypertension. Public health, population-based approaches to prevention of primary hypertension in both adults and children include a reduction in obesity, reduced sodium intake, avoidance of tobacco intake, and an increase in physical activity through school- and community-based programs. The DASH (Dietary Approaches to Stop Hypertension) diet has been suggested as a nutritional approach to prevent or even treat hypertension (www.dashdiet.org ). The diet focuses on lowering sodium intake and increasing potassium-, calcium-, and magnesium-containing foods, such as 6-8 servings of whole grains, 4-5 servings of fruits, and 4-5 servings of vegetables per day and low-fat dairy foods. For adults, the standard DASH diet contains 2300 mg of sodium (also recommended by the American Heart Association) and the lowsodium DASH diet recommends up to 1500 mg of sodium per day.

Treatment The mainstay of therapy for children with asymptomatic mild hypertension without evidence of target-organ damage is therapeutic lifestyle modification with dietary changes and regular exercise. Weight loss is the primary therapy in obesity-related hypertension. It is recommended that all hypertensive children have a diet increased in fresh fruits, fresh vegetables, fiber, and nonfat dairy and reduced in sodium. The DASH diet is beneficial in lowering BP in adolescents as

well as in adults. In addition, regular aerobic physical activity for at least 30-60 min on most days along with a reduction of sedentary activities to 72 hr) nitroprusside vasodilator infusion use or in renal failure; or co-administer with sodium thiosulfate. USEFUL FOR SEVERELY HYPERTENSIVE PATIENTS WITH LESS SIGNIFICANT SYMPTOMS Clonidine Central α- 0.05-0.1 mg/dose, may PO Side effects include dry mouth and drowsiness. agonist be repeated up to 0.8 mg total dose Fenoldopam Dopamine 0.2-0.8 µg/kg/min IV Produced modest reductions in blood pressure in receptor infusion a pediatric clinical trial in patients up to age 12 agonist yr Hydralazine Direct 0.25 mg/kg/dose, up to PO Extemporaneous suspension stable for only 1 wk vasodilator 25 mg/dose Isradipine Calcium 0.05-0.15 mg/kg/dose, PO Stable suspension can be compounded. channel up to 5 mg/dose blocker

Minoxidil

Direct 0.1-0.2 mg/kg/dose, up vasodilator to 10 mg/dose

PO

Most potent oral vasodilator; long acting

ACE, Angiotensin-converting enzyme; IM, intramuscular; IV, intravenous; PO, oral. Adapted from Flynn JT, Tullus K: Correction to severe hypertension in children and adolescents: pathophysiology and treatment, Pediatr Nephrol 27(3):503–504, 2012.

Treatment of secondary hypertension must also focus on the underlying disease, such as chronic renal disease, hyperthyroidism, pheochromocytoma, coarctation of the aorta, or renovascular hypertension. The treatment of renovascular stenosis includes antihypertensive medications, angioplasty, or surgery (Fig. 472.5 ). If bilateral renovascular hypertension or renovascular disease in a solitary kidney is suspected, drugs acting on the RAAS are usually contraindicated because they may reduce glomerular filtration rate and lead to acute kidney injury.

FIG. 472.5 Diagnostic pathway for renovascular hypertension. (From Tullus K, Brennan E, Hamilton G, et al: Renovascular hypertension in children, Lancet 371:1453–1463, 2008, Fig 6, p 1458.)

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hypertension in children. Lancet . 2008;371:1453–1463. Wühl E, Witte K, Soergel M, German Working Group on Pediatric Hypertension, et al. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimension. J Hypertens . 2003;20:1995–2007. Wright JT Jr, Williamson JD, Whelton PK, SPRINT Research Group, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015;373:2103–2116. Wühl E, Trivelli A, Picca S, ESCAPE Trial Group, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med . 2009;361:1639–1650. Yamaguchi I, Flynn JT. Pathophysiology of hypertension. Avner ED, Harmon WE, Niaudet P, et al. Pediatric nephrology . ed 7. Springer: New York; 2016:1951–1996. * http://pediatrics.aappublications.org/content/early/2017/08/21/peds.2017-1904

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PA R T X X

Diseases of the Blood OUTLINE Section 1 The Hematopoietic System Section 2 Anemias of Inadequate Production Section 3 Hemolytic Anemias Section 4 Polycythemia (Erythrocytosis) Section 5 The Pancytopenias Section 6 Blood Component Transfusions Section 7 Hemorrhagic and Thrombotic Diseases Section 8 The Spleen Section 9 The Lymphatic System

SECTION 1

The Hematopoietic System OUTLINE Chapter 473 Development of the Hematopoietic System Chapter 474 The Anemias

CHAPTER 473

Development of the Hematopoietic System Stella T. Chou

Hematopoiesis in the Human Embryo and Fetus Hematopoiesis is the process by which the cellular elements of blood are formed. In the developing human embryo and fetus, hematopoiesis has 3 developmental waves and is conceptually divided into 3 anatomic stages: mesoblastic, hepatic, and myeloid. Mesoblastic hematopoiesis occurs in extraembryonic structures, principally in the yolk sac, and begins between the 10th and 14th days of gestation. By 6-8 wk of gestation, the liver replaces the yolk sac as the primary site of blood cell production, and during this time the placenta also contributes as a hematopoietic site. By 10-12 wk, extraembryonic hematopoiesis has ceased. Hepatic hematopoiesis occurs through the remainder of gestation and then diminishes during the second trimester while bone marrow (myeloid ) hematopoiesis increases. The liver is the predominant erythropoietic organ through 20-24 wk of gestation. Each hematopoietic organ houses distinct populations of cells. The yolk sac predominantly produces erythrocytes, megakaryocytes, and macrophages. The fetal liver is primarily an erythropoietic organ, while the bone marrow produces erythrocytes, megakaryocytes, and leukocytes. The types of leukocytes present in the fetal liver and marrow differ with gestation. Macrophages precede neutrophils in the marrow, and the ratio of macrophages to neutrophils decreases as gestation progresses. Regardless of gestational age or anatomic location, production of all hematopoietic tissues begins with multipotent cells capable of both self-renewal and clonal maturation into all blood cell lineages. Progenitor

cells differentiate under the influence of transcription factors and hematopoietic growth factors (Table 473.1 ). Table 473.1

Characteristics of Hematopoietic Growth Factors MOLECULAR MASS (kDa) ERYTHROPOIETIN 30-39 GROWTH FACTOR

CHROMOSOMAL PRINCIPAL TARGET CELL LOCATION 7q11-12 CFU-E, fetal BFU-E, endothelial cells, neurons, astrocytes, oligodendrocytes

COLONY-STIMULATING FACTORS G-CSF 18-22 GM-CSF 18-30

17q11.2-21 5q23-31

M-CSF

45-70 (Dimer of 2 subunits) 36 25 Homodimeric protein 192 Amino acid protein

5q33.1

CFU-G, CFU-MIX, mature neutrophils CFU-MIX, CFU-GM, BFU-E, monocytes, mature neutrophils CFU-M, macrophages

12q21.32 19q13.2

CFU-MIX, BFU-E, CFU-GM, mast cells BL-CFC

1p13.3

Monocytes, macrophages, dendritic cells, Langerhans cells

INTERLEUKINS IL-1

17

Hepatocytes, macrophages, lymphocytes

IL-2 IL-3

15-20 14-30

Alpha 2q13 Beta 2q13-21 4q26-27 5q23-31

IL-4 IL-5

16-20 46 (Dimer of 2 subunits) 19-26

5q23-31 5q23-31

35 8-10 16 18.7 23 70-75 (Dimer of 2 subunits) 9 53 14-15 12-14 20-30 24

8q12-13 4q13.3 5q31-32 1q32.1 19q13 p35/p40

SCF TGF-β CSF-1

IL-6 IL-7 IL-8 IL-9 IL-10 IL-11 IL-12 IL-13 IL-14 IL-15 IL-16 IL-17 IL-18 IL-21 IL-23 IL-25 IL-31

Dimer of subunits 4-Helix bundle

7p21-24

T cells, cytotoxic lymphocytes CFU-MIX, CFU-Meg, CFU-GM, BFU-E, macrophage T cells, B cells, dendritic cells CFU-Eo, B cells

5q23-31 5q31 4q25-35 15q23-26 2q31 9p13 4q26-q27 p19/IL-12p40

CFU-MIX, CFU-GM, BFU-E, monocytes, B cells, T cells, cytotoxic lymphocytes B cells Neutrophils, endothelial cells, T cells BFU-E, CFU-MIX Macrophages, lymphocytes CFU-Meg, B cells, keratinocytes 3 (p35) and 11 (p40) T cells, NK cells, macrophages Pre-B lymphocytes, macrophages B cells B cells, T cells T cells Marrow stromal cells CD4+ T cells, NK cells T cells CD4+ T cells

14q11.2 12q24.31

T cells, monocytes, marrow stromal cells T cells, hematopoietic progenitors

IL-34

222 Amino acid protein THROMBOPOIETIN 35-38

16q22.1

Monocytes, macrophages

3q27–28

Megakaryocyte progenitors, megakaryocytes

BFU-E, Burst-forming units–erythroid; BL-CFU, blast colony-forming cell; CFU-E, colony-forming units–erythroid; CFU-Eo, colony-forming units–eosinophil; CFU-G, colony-forming units– granulocyte; CFU-GM, colony-forming units–granulocyte-macrophage; CFU-M, colony-forming units–macrophage; CFU-Meg, colony-forming units–megakaryocyte; CFU-MIX, colony-forming units–mixed; CSF-1, colony-stimulating factor-1; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; M-CSF, macrophage colony-stimulating factor; NK, natural killer; SCF, stem cell factor; TGF-β, transforming growth factor-beta.

The classical model of hematopoietic differentiation involves differentiation into increasingly lineage-specific progenitors, although there may also be alternate pathways that are used separately or in combination with classical pathways (Fig. 473.1 ). In the classical pathway, long-term repopulating hematopoietic stem cells (LTR-HSCs) are characterized by their ability to selfrenew and differentiate into cells that are multipotent. Multipotent progenitors (MPPs) have reduced self-renewal capacity and differentiate into common lymphoid progenitors (CLPs) or common myeloid progenitors (CMPs). The CMP differentiates into all the blood lineages except for lymphoid. The commitment of hematopoietic cells to increasingly lineage-restricted cells requires cytokine stimulation and regulation by transcription factors.

FIG. 473.1 Major cytokine sources and actions to promote hematopoiesis. Cells of the bone marrow microenvironment, such as macrophages, endothelial cells, and reticular fibroblasts, produce macrophage colony-stimulating factor (M-CSF), granulocytemacrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) after stimulation. These cytokines and others listed in the text have overlapping interactions during hematopoietic differentiation, as indicated; for all lineages, optimal development requires a combination of early- and late-acting factors. BFU, Burst-forming unit; CFU, colony-forming unit; Epo, erythropoietin; MSC, myeloid stem cells; PSC, pluripotent stem cells; SCF, stem cell factor; TNF, tumor necrosis factor; Tpo, thrombopoietin. (From Sieff CA, Daley GO, Zon LI: The anatomy and physiology of hematopoiesis. In Orkin SH, Nathan DG, Ginsburg D, et al, editors: Nathan and Oski's hematology of infancy and childhood , ed 8, Philadelphia, 2015, Elsevier.)

Erythrocytes in the fetus are larger than in adults, and at 22-23 wk gestation the mean corpuscular volume can be as high as 135 femtoliters (fL) (Fig. 473.2 , upper panel ). Similarly, the mean corpuscular hemoglobin is very high at 22-23

wk and falls relatively linearly with advancing gestation (Fig. 473.2 , lower panel ). In contrast, the mean corpuscular hemoglobin concentration is constant throughout gestation at 34 ±1 g/dL. While the size and quantity of hemoglobin in erythrocytes diminish during gestation, the hematocrit and blood hemoglobin concentration gradually increase (Fig. 473.3 , upper and lower panels , respectively).

FIG. 473.2 Erythrocyte mean corpuscular volume (MCV, top ) and mean corpuscular hemoglobin (MCH, bottom ) from 22 wk gestation through term. The lines represent the 5th percentile, the mean, and the 95th percentile reference range. (From Christensen RD, Jopling J, Henry E, et al: The erythrocyte indices of neonates, defined using data from over 12,000 patients in a multihospital healthcare system, J Perinatol 28:24–28, 2008.)

FIG. 473.3 Reference ranges of fetal hematocrit (A) and fetal red blood cell count (B) by cordocentesis throughout gestations.

Concentrations of platelets in the blood increase gradually between 22 and 40 wk gestation (Fig. 473.4 ), but the platelet size, assessed by mean platelet volume, remains constant at 8 ±1 fL. No differences are observed between males and females in fetal and neonatal reference ranges for erythrocyte indices, hematocrit, hemoglobin, platelet counts, or mean platelet volume measurements.

FIG. 473.4 Platelet count from 22 wk gestation through term. The lines represent the 5th percentile, the mean, and the 95th percentile reference range. (From Wiedmeier SE, Henry E, Sola-Visner MC, et al: Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system, J Perinatol 29:130– 136, 2009.)

Fetal Granulocytopoiesis Neutrophils are first observed in the human fetus about 5 wk after conception as small clusters of cells around the aorta. The fetal bone marrow space begins to develop around the 8th wk, and from 8-10 wk the marrow space enlarges, but no neutrophils appear there until 10.5 wk. From 14 wk through term, the most common granulocytic cell type in the fetal bone marrow space is the neutrophil. Neutrophils and macrophages originate from a common progenitor cell, but macrophages appear before neutrophils in the fetus, first in the yolk sac, liver, lung, and brain, all before the bone marrow cavity is formed. Granulocyte colony-stimulating factor (G-CSF) and macrophage colonystimulating factor (M-CSF) are expressed in developing fetal bone as early as 6 wk after conception, and both are expressed in the fetal liver as early as 8 wk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) also are distributed widely in human fetal tissues. However, no changes in expression of any of these factors, or of their specific receptors, appear to be the signal for fetal production of neutrophils or macrophages,

because those signals have not yet been identified. Fetal blood contains few neutrophils until the third trimester. At 20 wk gestation the blood neutrophil count is 0-500/mm3 . Although mature neutrophils are scarce, progenitor cells with the capacity to generate neutrophil clones are abundant in fetal blood. When cultured in vitro in the presence of recombinant G-CSF, they mature into large colonies of neutrophils. The physiologic role of G-CSF includes upregulating neutrophil production, and this appears to be the case for the fetus and neonate as well as for adults. Thus the low number of circulating neutrophils in the mid-trimester human fetus may be caused in part by low production of G-CSF. Monocytes isolated from the blood of adults produce G-CSF when stimulated with a variety of inflammatory mediators, such as bacterial lipopolysaccharide (LPS) or interleukin (IL)-1. In contrast, monocytes isolated from the blood or organs of fetuses up to 24 wk gestation generate only small quantities of G-CSF protein and messenger RNA (mRNA) after LPS or IL-1 stimulation. Despite this, G-CSF receptors on the surface of neutrophils of newborn infants are equal in number and affinity to those on adult neutrophils. In the fetus, actions of the granulocytopoietic factors (G-CSF, M-CSF, GMCSF, and SCF) are not limited to hematopoiesis. Receptors for each of these are located in areas of the fetal central nervous system and gastrointestinal tract, where their patterns of expression change with development.

Fetal Thrombopoiesis Several biologic differences exist between fetal/neonatal and adult megakaryopoiesis and thrombopoiesis. There is a developmentally unique pattern of fetal/neonatal megakaryopoiesis characterized by rapid proliferation, followed by full cytoplasmic maturation without polyploidization. Fetal and neonatal megakaryocytes are significantly smaller, exhibit lower ploidy, and produce fewer platelets. However, fetal and neonatal megakaryocytes have a higher proliferative potential than adult progenitors. These differences allow fetuses and neonates to populate their rapidly expanding bone marrow space and blood volume while maintaining normal platelet counts. Megakaryocyte progenitors are categorized as burst-forming unit– megakaryocytes (BFU-MK), which are primitive megakaryocyte progenitors, and colony-forming unit–megakaryocytes (CFU-MK), which are more differentiated. BFU-MK produce large multifocal colonies containing ≥50

megakaryocytes, whereas CFU-MK generate smaller (3-50 cells/colony) unifocal colonies. Megakaryocytes are identified by their morphologic characteristics as they undergo endoreduplication, which results in large cells with polyploid nuclei. Megakaryocytes, unlike megakaryocyte progenitors, do not have the capacity to generate colonies. Rather, they undergo maturation, progressing from small mononuclear cells to large polyploid cells. The modal megakaryocyte ploidy (the number of sets of complete chromosomes) in normal adult marrow is 16N. In the fetus and neonate, ploidy is lower, primarily 2N and 4N, and megakaryocyte size is smaller. Large megakaryocytes generate more platelets than do small megakaryocytes; it is assumed that megakaryocytes of neonates produce fewer platelets than do their adult counterparts. The exact mechanisms by which megakaryocytes release platelets into the circulation remain incompletely understood. In situ examination of this process suggests that mature megakaryocytes migrate to a perivascular site and extend a process through the endothelium, giving rise to proplatelets, which then release platelets. An alternate mechanism is that platelets are released from megakaryocytes in the lungs as a result of shear forces. Thrombopoietin (TPO) is the dominant regulator of megakaryocyte development and platelet production (see Table 473.1 ). TPO is predominantly produced in the liver from early fetal to adult life but is also expressed by cells in the kidney, and to a lesser extent, by smooth muscle and marrow cells. TPO concentrations are higher in healthy neonates of any gestational age than in healthy adults. TPO is a primary stimulator of megakaryocyte and platelet production, but SCF, IL-3, IL-11, IL-6, and erythropoietin also stimulate megakaryopoiesis and thrombopoiesis in vitro and in vivo. Importantly, TPO also promotes expansion of hematopoietic stem cells (HSCs) and progenitor cells, and the TPO receptor is expressed on HSCs and erythroid progenitors in addition to megakaryocyte progenitors, megakaryocytes, and mature platelets.

Fetal Erythropoiesis Similar to hematopoietic production of other cell lineages, fetal erythropoiesis is regulated by growth factors produced by the fetus, not by the mother. Erythropoietin (EPO) does not cross the human placenta. Stimulating maternal EPO production does not enhance fetal erythropoiesis, and suppressing maternal erythropoiesis by hypertransfusion does not suppress fetal erythropoiesis. EPO plays a central regulatory role on the proliferation and maturation of

erythroid progenitors. Erythroid-committed progenitors consist of burst-forming unit–erythroid (BFU-E) and colony-forming unit–erythroid (CFU-E) cells. In colony-forming assays, human BFU-E are more proliferative, forming colonies of multiple clusters of erythroblasts, vs CFU-E, which form 1 or 2 clusters with each containing 8-100 hemoglobinized erythroblasts. EPO is essential for erythrocyte production from CFU-E cells by inducing survival and proliferation of erythroblasts. EPO binds to specific receptors on the surface of committed erythroid precursors, and its expression is regulated by an oxygen-sensing mechanism through the hypoxia-inducible factor (HIF) family of proteins. HIF1α and HIF-2α are regulated by oxygen tension, whereas HIF-1β is constitutively expressed. Together, HIF proteins maintain oxygen homeostasis and regulate erythropoiesis by inducing EPO under hypoxic conditions. EPO is produced by monocytes and macrophages in the fetal liver during the first and second trimesters. After birth, the anatomic site of EPO production shifts to the kidney. The specific stimulus for this shift is unknown but may involve the increase in arterial oxygen tension that occurs at birth. Epigenetic modification of gene expression may also play a role, since it appears that renal and hepatic EPO genes are methylated to different degrees. Although EPO mRNA and protein can be found in the human fetal kidney, it is not known whether this production is biologically relevant. It appears that renal production of EPO is not essential for normal fetal erythropoiesis, as evidenced by the normal serum EPO concentration and normal hematocrit of anephric fetuses.

Hemoglobins in the Fetus and Neonate Hemoglobin is a tetramer of 4 globin chains with an iron-containing porphyrin ring called heme bound to each chain. A dynamic interaction between heme and globin gives hemoglobin its unique properties in the reversible transport of oxygen. The hemoglobin molecule consists of 2 alpha (α)-like and 2 beta (β)-like polypeptide chains, with each chain having a heme group attached. The α-globin and β-globin gene clusters are located on chromosome 16 and 11, respectively (Fig. 473.5 ). There are 2 β-globin genes and 4 α-globin genes. Within erythrocytes of an early embryo, fetus, child, and adult, 6 different hemoglobins may normally be detected (Fig. 473.6 ): the embryonic hemoglobins (Gower-1, Gower-2, and Portland), fetal hemoglobin (HbF), and the adult hemoglobins (HbA and HbA2 ). The electrophoretic mobilities of hemoglobins vary with their chemical structures.

FIG. 473.5 Organization of the globin genes. The bottom line reflects the scale in kilobases. The upper segment represents the β-like globin genes on chromosome 11, and the lower segment the α-like genes on chromosome 16. Regions of the gene that code for primary globin proteins are shown as blue segments , and regions that code for pseudogenes (“ψ,” nonexpressed remnants) are shown as pink segments . The composition of embryonic, fetal, and adult hemoglobins is listed. α, Alpha; β, beta; γ, gamma; δ, delta; ε, epsilon; ζ, zeta.

FIG. 473.6 Changes in hemoglobin tetramers (A ) and in globin subunits (B ) during human development from embryo to early infancy. (From Polin RA, Fox WW: Fetal and neonatal physiology , ed 2, Philadelphia, 1998, Saunders, p 1769.)

Expression and quantitative relationships among the hemoglobins are determined by complex developmental processes. Globin chain expression is developmental stage specific and occurs through 2 hemoglobin switches, mediated primarily through changes of the β-globin genes expressed. There are 5 functional β-like globin chain genes: embryonic (HBE1 ), 2 fetal (HBG1, HBG2 ), and 2 adult (HBD, HBB ); and 3 α-like globin chain genes: embryonic (HBZ ) and 2 adult (HBA1, HBA2 ). Primitive erythroid cells primarily express embryonic globins. The 1st β-globin switch occurs at approximately 6 wk gestation to fetal globin (HBG ), which coincides with the onset of definitive hematopoiesis. The major hemoglobin in the fetus (HbF) consists of 2 α and 2 gamma (γ) globin chains (α2 γ2 ). The 2nd globin switch is responsible for the expression of the major hemoglobin of a normal adult (HbA), consisting of 2 α and 2 β polypeptide chains (α2 β2 ) and is first expressed at mid-gestation. A key regulator of the fetal-to-adult hemoglobin switch is the transcription factor BCL11A , which binds to the β-globin gene and acts to silence γ-globin

expression and thus HbF.

Embryonic Hemoglobins The blood of early human embryos contains 2 slowly migrating hemoglobins, Gower-1 and Gower-2, and Hb Portland, which has HbF-like mobility. The zeta (ζ) chains of Hb Portland and Gower-1 are structurally quite similar to α chains. Both Gower hemoglobins contain the epsilon (ε) β-like globin polypeptide chain. Hb Gower-1 has the structure ζ2 ε2 , whereas Gower-2 has α2 ε2 . Hb Portland has the structure ζ2 γ2 . In embryos up to 6 wk gestation, the Gower hemoglobins predominate but are no longer detectable by 3 mo of gestation.

Fetal Hemoglobin By 6-8 wk gestation, HbF (α2 γ2 ) is the predominant hemoglobin; at 24 wk gestation it constitutes 90% of the total hemoglobin. HbF declines modestly in the third trimester, such that the HbF comprises 70–80% of the total hemoglobin. HbF production decreases rapidly postnatally (Fig. 473.7 ), and by 6-12 mo of age reaches adult levels of 3.4% are found in most persons with the β-thalassemia trait and in those with megaloblastic anemias secondary to vitamin B12 and folic acid deficiency. Decreased HbA2 levels are found in those with iron-deficiency anemia (see Chapter 482 ) and α-thalassemia (see Chapter 489.10 ).

Red Cell Life Span in the Fetus and Neonate In general, the highest hematocrit during a person's lifetime occurs at birth, and the lowest hematocrit occurs at the physiologic nadir that occurs 8-10 wk postnatally. A shortened life span of fetal and neonatal red blood cells (RBCs) has been suggested as an important component. The average erythrocyte life span in normal adults is approximately 120 days. The life span of fetal/neonatal erythrocytes was once estimated to be considerably less, with an average of 6090 days suggested by chromium (51 Cr)-labeled erythrocyte studies. However, newer studies indicate that the life span of fetal/neonatal RBCs is similar to that of adults. Neocytolysis is the active removal of young erythrocytes that were generated in relatively hypoxic conditions, following normoxic or hyperoxic conditions. This process has also been suggested as an explanation for the physiologic nadir of neonates.

Bibliography Christensen RD, Jopling J, Henry E, et al. The erythrocyte indices of neonates, defined using data from over 12,000 patients in a multihospital healthcare system. J Perinatol . 2008;28:24–28. Deutsch VR, Toner A. Megakaryocyte development and platelet production. Br J Haematol . 2006;134:453–466. Jopling J, Henry E, Wiedmeier SE, et al. Reference ranges for hematocrit and blood hemoglobin concentration during the neonatal period: data from a multihospital healthcare system. Pediatrics . 2009;123:e333–e337. Julien E, Omar RE, Tavian M. Origin of the hematopoietic system in the human embryo. FEBS Lett . 2016;590:3987– 4001. Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med . 2006;354:2034–2045. Liang R, Ghaffari S. Advances in understanding the

mechanisms of erythropoiesis in homeostasis and disease. Br J Haematol . 2016;174:661–673. Liu A, Sola-Visner M. Neonatal and adult megakaryopoiesis. Curr Opin Hematol . 2011;18(5):330–337. Nandakumar SK, Ulrisch JC, Sankaran VG. Advances in understanding erythropoiesis: evolving perspectives. Br J Haematol . 2016;173:206–218. Sola-Visner MC, Christensen RD, Hutson AD, et al. Megakaryocyte size and concentration in the bone marrow of thrombocytopenic and nonthrombocytopenic neonates. Pediatr Res . 2007;61:479–484. Spangrude GJ, Perry SS, Slayton WB. Early stages of hematopoietic differentiation. Ann NY Acad Sci . 2003;996:186–194. Vats A, Bielby RC, Tolley NS, et al. Stem cells. Lancet . 2005;366:592–602. Wang Y, Hayes V, Jarocha D, et al. Comparative analysis of human ex vivo–generated platelets vs megakaryocytegenerated platelets in mice: a cautionary tale. Blood . 2015;125(23):3627–3636. Wiedmeier SE, Henry E, Sola-Visner MC, et al. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol . 2009;29:130–136. Yoshimoto M, Yoder MC. Developmental biology: birth of the blood cell. Nature . 2009;457:801–813.

CHAPTER 474

The Anemias Courtney D. Thornburg

Anemia is defined as a reduction of the hemoglobin concentration or red blood cell (RBC) volume below the range of values occurring in healthy persons. “Normal” hemoglobin and hematocrit (packed red cell volume) vary substantially with age and sex (Table 474.1 ). There are also racial differences, with significantly lower hemoglobin levels in African American children than in white non-Hispanic children of comparable age (Table 474.2 ). Anemia is a significant global health problem affecting children and reproductive-age women (Figs. 474.1 and 474.2 ). Table 474.1

Normal Mean and Lower Limits of Normal for Hemoglobin, Hematocrit, and Mean Corpuscular Volume HEMOGLOBIN (g/dL) Mean Lower Limit 0.5-1.9 12.5 11.0 2-4 12.5 11.0 5-7 13.0 11.5 8-11 13.5 12.0 12-14 female 13.5 12.0 12-14 male 14.0 12.5 15-17 female 14.0 12.0 15-17 male 15.0 13.0 18-49 female 14.0 12.0 18-49 male 16.0 14.0 AGE (yr)

HEMATOCRIT (%) Mean Lower Limit 37 33 38 34 39 35 40 36 41 36 43 37 41 36 46 38 42 37 47 40

MEAN CORPUSCULAR VOLUME (µM3 ) Mean Lower Limit 77 70 79 73 81 75 83 76 85 78 84 77 87 79 86 78 90 80 90 80

From Brugnara C, Oski FJ, Nathan DG: Nathan and Oski's hematology of infancy and childhood , ed 7, Philadelphia, 2009, Saunders, p 456.

Table 474.2

NHANES-III Hemoglobin Values for Non-Hispanic Whites and African Americans Ages 2-18 Yr* AGE (yr) 2-5 6-10 11-15 male 11-15 female 16-18 male 16-18 female

WHITE NON-HISPANIC Mean −2 SD 12.21 10.8 12.87 11.31 13.76 11.76 13.32 11.5 15.00 13.24 13.39 11.61

AFRICAN AMERICAN Mean −2 SD 11.95 10.37 12.40 10.74 13.06 10.88 12.61 10.85 14.18 12.42 12.37 10.37

* Sample size is 5,142 (white, 2,264; African-American, 2,878).

NHANES-III, Third National Health and Nutrition Examination Survey; SD, standard deviation. Adapted from Robbins EB, Blum S: Hematologic reference values for African American children and adolescents, Am J Hematol 82:611–614, 2007.

FIG. 474.1 Global prevalence of anemia in children of preschool age (0-5 yr). (Adapted from Worldwide prevalence of anaemia 1993–2005. In WHO global database on anaemia, Geneva, 2008, World Health Organization.)

FIG. 474.2 Causes of anemia in countries with low- or middle-income populations. (From Balarajan Y, Ramakrishnan U, Özaltin E, et al: Anaemia in low-income and middle-income countries, Lancet 378:2123–2134, 2011, Fig 3.)

Physiologic adjustments to anemia include increased cardiac output, augmented oxygen extraction (increased arteriovenous oxygen difference), and a shunting of blood flow toward vital organs and tissues. In addition, the concentration of 2,3-diphosphoglycerate increases within the RBC. The resultant “shift to the right” of the oxygen dissociation curve reduces the affinity of hemoglobin for oxygen and results in more complete transfer of oxygen to the tissues. The same shift in the oxygen dissociation curve can also occur at high altitude. Higher levels of erythropoietin (EPO) and consequent increased RBC production by the bone marrow further assist the body to adapt.

History and Physical Examination As with any medical condition, a detailed history and thorough physical exam are essential when evaluating an anemic child. Important historical facts should include age, sex, race and ethnicity, diet, medications, chronic diseases, infections, travel, and exposures. A family history of anemia and associated difficulties (e.g., splenomegaly, jaundice, early-age onset of gallstones) is also important. Often, few physical symptoms or signs result solely from a low

hemoglobin, particularly when the anemia develops slowly. Clinical findings generally do not become apparent until the hemoglobin level falls to 12 mo at onset. Only 10% of affected patients are >3 yr of age. The annual incidence is estimated to be 4.3 cases per 100,000 children, although it is likely higher, because many cases may go undiagnosed and because TEC usually resolves spontaneously. The suppression of erythropoiesis has been linked to IgG, IgM, and cell-mediated mechanisms. Familial cases have been reported, suggesting a hereditary component. TEC often follows a viral illness, although no specific virus has been consistently implicated. The temporary suppression of erythropoiesis results in reticulocytopenia and moderate to severe normocytic anemia. Some degree of neutropenia occurs in up to 20% of cases. Platelet numbers are normal or elevated. Similar to the situation observed in iron-deficiency anemia and other red blood cell (RBC) hypoplasias, thrombocytosis is presumably caused by increased erythropoietin (EPO), which has some homology with thrombopoietin (TPO). Mean corpuscular volume (MCV) is characteristically normal for age, and fetal hemoglobin (HbF) levels are normal before the recovery phase. RBC adenosine deaminase levels are normal in TEC, thus contrasting with the elevation noted in most cases of

congenital hypoplastic anemia (Table 477.1 ). Differentiation from DBA is sometimes difficult, but differences in age at onset and in age-related MCV, HbF, and adenosine deaminase are usually helpful. The peak occurrence of TEC coincides with that of iron-deficiency anemia in infants receiving milk as their main caloric source; differences in MCV should help to distinguish between TEC and DBA. Table 477.1

Comparison of Diamond-Blackfan Anemia and Transient Erythroblastopenia of Childhood FEATURE Male : female AGE AT DIAGNOSIS, MALE (mo) Mean Median Range AGE AT DIAGNOSIS, FEMALE (mo) Mean Median Range Boys >1 yr Girls >1 yr Etiology Antecedent history Physical examination abnormal (congenital anomalies present) LABORATORY Hemoglobin (g/dL) WBCs 400,000/µL Adenosine deaminase MCV increased at diagnosis MCV increased during recovery MCV increased in remission HbF increased at diagnosis HbF increased during recovery HbF increased in remission i Antigen increased i Antigen increased during recovery i Antigen increased in remission

DBA 1 : 1

TEC 1 : 3

10 2 0-408

26 23 1-120

14 3 0-768 9% 12% Genetic None 25%

26 23 1-192 82% 80% Acquired, possibly familial Viral illness 0%

1.2-14.8 15% 20% Increased 80% 100% 100% 100% 100% 85% 100% 100% 90%

2.2-12.5 20% 45% Normal 5% 90% 0% 20% 100% 0% 20% 60% 0%

DBA, Diamond-Blackfan anemia; HbF, fetal hemoglobin; MCV, mean cell volume; TEC, transient erythroblastopenia of childhood; WBC, white blood cell. From Nathan DG, Orkin SH, Ginsburg D, et al, editors: Nathan and Oski's hematology of infancy and childhood , ed 6, vol 1, Philadelphia, 2003, Saunders, p. 329. Adapted from Alter BP: The bone marrow failure syndromes. In Nathan DG, Oski FA, editors: Hematology of infancy and childhood , ed 3, Philadelphia, 1987, Saunders, p 159; and Link MP, Alter BP: Fetal erythropoiesis

during recovery from transient erythroblastopenia of childhood (TEC), Pediatr Res 15:1036–1039, 1981.

Virtually all children recover within 1-2 mo. RBC transfusions may be necessary for severe anemia in the absence of signs of early recovery. The anemia develops slowly, and significant symptoms usually develop only with severe anemia. Corticosteroid therapy is of no value in this disorder. Any child with presumed TEC who requires >1 transfusion should be reevaluated for another possible diagnosis. In rare instances, a prolonged case of apparent TEC may be caused by parvovirus-induced RBC aplasia, occurring in children with hemolytic anemia or congenital or acquired immunodeficiencies .

Red Cell Aplasia Associated With Parvovirus B19 Infection Parvovirus B19 is a common infectious agent that causes erythema infectiosum (fifth disease) (see Chapter 278 ). It is also the best-documented viral cause of RBC aplasia in patients with chronic hemolysis , patients who are immunocompromised, and fetuses in utero. This small, nonenveloped singlestranded virus is particularly infective and cytotoxic to marrow erythroid progenitor cells, interacting specifically by binding to the red cell P antigen. In addition to decreased or absent erythroid precursors, characteristic nuclear inclusions in erythroblasts and giant pronormoblasts may be seen under light microscopy in bone marrow specimens. The virus does not cause significant anemia in immunocompetent individuals with normal RBC life span. Because parvovirus infection is usually transient, with recovery occurring in 1 child affected with a hemolytic disorder, parents should be warned that a similar aplastic episode can occur in the other children if they have not been previously infected. During the episode of aplastic crisis, the child is potentially contagious and should be isolated from at-risk patients. Persistent parvovirus infection may occur in children with congenital immunodeficiency diseases, lymphoproliferative disorders, those being treated with immunosuppressive agents, and those with HIV/AIDS, because these children may be unable to mount an adequate antibody response. The resultant pure RBC aplasia may be severe, and affected children may be thought to have TEC. This type of RBC aplasia differs from TEC in that there is no spontaneous recovery, and >1 transfusion is often needed. The diagnosis of parvovirus infection is made by PCR of peripheral blood or bone marrow DNA because the usual serologic responses, reflected by parvovirus serum IgM or IgG titers, are impaired in immunodeficient children. In chronically infected patients the disease may be treated with high doses of intravenous immune globulin, which contains neutralizing antibody to parvovirus and is effective in the short term. Parvovirus infection and destruction of erythroid precursors can also occur in utero. Such events are associated with increased fetal wastage in the first and second trimesters. Infants may be born with hydrops fetalis and anemia (see Chapter 124 ). The presence of persistent congenital parvovirus infection is detected by PCR of peripheral blood and/or bone marrow DNA, because immunologic tolerance to the virus can prevent the usual development of specific antibodies.

Other Red Cell Aplasias in Children Acquired red cell aplasia in adults is usually mediated by a chronic antibody and often associated with disorders such as chronic lymphocytic leukemia, lymphoma, thymoma, lymphoproliferative disorders, and systemic lupus erythematosus. This chronic antibody-mediated type of RBC aplasia, often responsive to immunosuppressive therapy, is quite rare in childhood. Cases of acquired pure RBC aplasia attributable to T-cell suppression have also been described. Infections other than parvovirus, such as cytomegalovirus and Epstein-Barr virus, may cause pure RBC aplasia. Certain drugs, such as chloramphenicol, also

can inhibit erythropoiesis in a dose-dependent manner. Reticulocytopenia, erythroid hypoplasia, and vacuolated pronormoblasts in the bone marrow are reversible effects of this drug. These effects are distinct from the idiosyncratic and rare development of severe aplastic anemia in chloramphenicol recipients. Acquired antibody-mediated pure RBC aplasia has also been found to be a rare complication in chronic kidney disease patients treated with erythropoiesisstimulating agents. In addition to discontinuing erythropoiesis-stimulating agents therapy and addressing anemia with red cell transfusions, further treatment may include immunosuppression and renal transplantation.

Bibliography Aoki K, Ono Y, Tabata S, et al. Successful treatment of antierythropoietin antibody–mediated pure red cell aplasia with low-dose prednisolone. Int J Hematol . 2013;97:272–274. Crabol Y, Terrier B, Rozenberg F, Groupe d'experts de l'Assistance Publique-Hopitaux, et al. Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus B19 infection: a retrospective study of 10 patients and review of the literature. Clin Infect Dis . 2013;56:968–977. Karabulut A, Gok S, Kocyigit A. Non–immune hydrops fetalis without anemia due to parvovirus B19. Int J Gynaecol Obstet . 2014;124:82. MacDougall IC, Casadevall N, Locatelli F, et al. Incidence of erythropoietin antibody–mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS). Nephrol Dial Transplant . 2015;30:451–460. Makhlouf MM, Elwakil SG, Ibrahim NS. Molecular and serological assessment of parvovirus B-19 infection in Egyptian children with sickle cell disease. J Microbiol Immunol Infect . 2015 [Dec 1. pii: S1684-1182(15), 00914-7]. Ruiz Gutierrez L, Albarran F, Moruno H, Cuende E. Parvovirus B19 chronic monoarthritis in a patient with common variable

immunodeficiency. Reumatol Clin . 2015;11:58–59. Van den Akker M, Dror Y, Odame I. Transient erythroblastopenia of childhood is an underdiagnosed and self-limiting disease. Acta Paediatr . 2014;103:e288–e294. Welcker S, Heckmann M. Non-immune hydrops fetalis due to parvovirus B19 infection in 2 extremely preterm infants: perinatal management and long-term neurodevelopmental outcome. Z Geburtshilfe Neonatol . 2015;219:144–147. Xu LH, Fang JP, Weng WJ, et al. Pure red cell aplasia associated with cytomegalovirus and Epstein-barr virus infection in seven cases of Chinese children. Hematology . 2013;18:56–59.

CHAPTER 478

Anemia of Chronic Disease and Renal Disease 478.1

Anemia of Chronic Disease Courtney D. Thornburg

The anemia of chronic disease (ACD ), also referred to as anemia of inflammation , is found in conditions where there is ongoing immune activation. It occurs in a wide a range of disorders, including infections, malignancies, chronic renal disease, autoimmunity, and graft-versus-host disease. A similar anemia is associated with chronic kidney disease. ACD is typically a mild to moderate normocytic, normochromic, hypoproliferative anemia associated with a decreased serum iron and low transferrin saturation.

Etiology Decreased red cell life span, impaired erythropoiesis, and an increased uptake of iron in the reticuloendothelial system are important mechanisms contributing to the anemia. The modest reduction in erythrocyte longevity is perhaps the least understood part of the pathophysiology of ACD. Elevated levels of cytokines such as interleukin-1 may increase the macrophage's ability to ingest and destroy erythrocytes. Defective erythropoiesis, both proliferation and differentiation of precursors, has been attributed to immune cell/cytokine–driven inhibition of

erythropoietin production and suppression of the bone marrow. ACD-associated alterations in iron recycling are characterized by an accumulation of iron in reticuloendothelial macrophages despite low levels of serum iron. The diversion of iron from the circulation into the reticuloendothelial system results in functional iron deficiency, which results in the impaired heme synthesis and iron-restricted erythropoiesis that contribute to anemia. These alterations in iron metabolism have been attributed to inflammation-associated excess synthesis of hepcidin , a key regulatory protein that controls intestinal iron absorption and tissue distribution. Hepcidin, although mainly synthesized by hepatocytes, is also expressed in other cells, including monocytes and macrophages. It functions by binding to and initiating the degradation of the iron exporter, ferroportin (Fig. 478.1 ).

FIG. 478.1 Central role of hepcidin in iron metabolism. Hepcidin, produced by hepatocytes, downregulates iron export to circulating transferrin from iron “donor” cells (hepatocytes, macrophages, and duodenal enterocytes) by promoting the internalization and lysosomal degradation of ferroportin. Hepatocytes take up iron in a number of forms, whereas enterocytes obtain their iron predominantly from the gut lumen, and macrophages are specialized to deal with the high throughput of iron from senescent red cells. (From Pippard M: Iron deficiency anemia, anemia of chronic disorders and iron overload. In Porwit A, McCullough J, Erber WN, editors: Blood and bone marrow pathology, ed 2, London, 2011, Elsevier, Fig 11-5.)

Clinical Manifestations Although the important symptoms and signs associated with ACD are those of the underlying disease, the mild to moderate anemia can affect the patient's quality of life.

Laboratory Findings Hemoglobin concentrations are generally 6-9 g/dL. The anemia is usually normochromic and normocytic, although some patients have modest hypochromia and microcytosis, particularly if there is concomitant iron deficiency. Absolute reticulocyte counts are normal or low, and leukocytosis is common. The serum iron level is low, without the increase in serum transferrin (the iron transport protein) that occurs in iron deficiency. This pattern of low serum iron and low-to-normal serum transferrin is a regular but valuable diagnostic feature. The serum ferritin level may be elevated secondary to inflammation . Soluble transferring receptor (sTfR) is a diagnostic test used to distinguish ACD from iron-deficiency anemia (IDA); sTfR levels are high in IDA and normal in ACD. The bone marrow has normal cellularity; the red blood cell precursors are decreased or adequate, marrow hemosiderin may be increased, and granulocytic hyperplasia may be present.

Treatment The best approach to ACD is the treatment, when possible, of the underlying disorder. If the associated systemic disease can be controlled, the anemia will improve or resolve. Transfusions raise the hemoglobin concentration temporarily but are rarely indicated. Erythropoietic stimulating agents (ESAs), such as recombinant human erythropoietin (EPO) or related extended–half-life formulations, increase the hemoglobin level and improve activity and the sense of well-being. When using ESAs, treatment with iron is usually necessary to produce optimal effect. Response to these agents is highly variable, and poorly responsive patients may require high doses to reach target hemoglobin levels. In adults, such high doses are associated with a higher incidence of adverse events, such as stroke, cardiovascular events, cancer progression, and death, leading the U.S. Food and Drug Administration (FDA) to require a “black box” warning on labels. ACD does not respond to iron alone unless there is concomitant deficiency. Unfortunately, it is a common clinical challenge to identify iron deficiency in patients with an inflammatory disease (see Chapters 474 and 482 ). In this circumstance, a trial of iron therapy might be helpful, although there may be no response because persistent inflammation impairs iron absorption and utilization; intravenous iron may further increase hepcidin production. Therapeutic agents

that target the hepcidin-ferroportin axis are under investigation.

Bibliography Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematology . 2013;2013:1–8. Fraenkel PG. Understanding anemia of chronic disease. Hematology . 2015;2015:14–18. Gangat N, Wolanskyj AP. Anemia of chronic disease. Semin Hematol . 2013;50(3):232–238. Poggiali E, Migone De Amicis M, Motta I. Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Intern Med . 2014;25:12–17. Turgeon O'Brien H, Blanchet R, Gagné D, et al. Using soluble transferrin receptor and taking inflammation into account when defining serum ferritin cutoffs improved the diagnosis of iron deficiency in a group of Canadian preschool inuit children from Nunavik. Anemia . 2016;2016:6430214.

478.2

Anemia of Renal Disease Courtney D. Thornburg

Anemia is common in children with chronic kidney disease (CKD). The anemia is usually normocytic, and the absolute reticulocyte count is normal or low. Although most patients with end-stage renal disease (ESRD) are anemic, earlier stages of CKD are associated with a lower prevalence. In adults, lower glomerular filtration rate (GFR) has been correlated with lower hemoglobin concentration, and hemoglobin has been reported to decline below a GFR

threshold of 40-60 mL/min/1.73 m2 . In children with CKD, hemoglobin levels decline as the GFR decreases below 43 mL/min/1.73 m2 . Decreased hemoglobin values are linked to increased incidence of left ventricular hypertrophy, impaired physical activity, and a reduced quality of life in pediatric patients with CKD. In those with ESRD who are on dialysis, anemia is also associated with increased risk of hospitalization and mortality.

Etiology Although the anemia of CKD shares many features with anemia of chronic disease, its predominant cause is decreased erythropoietin (EPO) production by diseased kidneys. Other important causes include absolute and/or functional iron deficiency as a result of chronic blood loss (from blood sampling, surgeries, and dialysis) and disturbances in the iron metabolic pathway. Higher hepcidin levels have also been implicated in the anemia of CKD. Hepcidin is filtered by the glomerulus and excreted by the kidney; serum concentrations are increased in patients with decreased GFR. Inflammation may also be a contributing factor in pediatric dialysis patients who have elevated levels of proinflammatory cytokines. Hyperparathyroidism and deficiencies of vitamin B12 , folate, and carnitine may also have a role in anemia of CKD.

Laboratory Findings Anemia in children with CKD is defined by age: hemoglobin 10% have abdominal pain, and >5% have thrombosis. The mortality in PNH is related primarily to the development of aplastic anemia or thrombotic complications. The predicted survival rate for children before the development of eculizumab was 80% at 5 yr, 60% at 10 yr, and 28% at 20 yr. Table 488.2

Classification of Paroxysmal Nocturnal Hemoglobinuria

Classic clinical PNH

RATE OF INTRAVASCULAR HEMOLYSIS* Florid (markedly abnormal LDH, often with episodic macroscopic hemoglobinuria)

Clinical PNH in the setting of another bone marrow failure syndrome ‡

Mild (often with minimal abnormalities of biochemical markers of hemolysis)

CATEGORY

BONE MARROW

FLOW CYTOMETRY

Cellular marrow Large population caused by erythroid (>50%) of GPIhyperplasia and AP– PMNs § normal or nearnormal morphology

BENEFIT FROM ECULIZUMAB Yes

†

Evidence of a concomitant bone marrow failure syndrome ‡

Although variable, the percentage of GPl-AP– PMNs is usually relatively small (3.5%), although HbA2 is not elevated in the newborn period. In newborns with a hemoglobin analysis of HbFSC , the pattern supports a diagnosis of HbSC. In newborns with a hemoglobin analysis of HbFAS , the pattern supports a diagnosis of HbAS (sickle cell trait); however, in this circumstance, care must be taken to confirm that the newborn has not received a red cell transfusion before testing. A newborn with a hemoglobin analysis of AFS either has been transfused with RBCs before collection of the newborn screen to account for the greater amount

of HbA than HbF, or there has been an error. The patient may have either sickle cell disease or sickle cell trait and should be started on penicillin prophylaxis until the final diagnosis can be determined. Given the implications of a diagnosis of sickle cell disease vs sickle cell trait in a newborn, the importance of repeating the Hb identification analysis in the patient and obtaining a Hb identification analysis and CBC to evaluate the peripheral blood smear and RBC parameters in the parents for genetic counseling cannot be overemphasized. Unintended mistakes do occur in state newborn screening programs. Newborns who have the initial phenotype of HbFS but whose final true phenotype is HbSβ+ -thalassemia have been described as one of the more common errors identified in newborn screening hemoglobinopathy programs. Determining an accurate phenotype is important for appropriate genetic counseling for the parents. In addition, distinguishing HbSS from HbSHPFH in the newborn period usually requires parental or genetic testing. In infants who maintain HbF percentages above 25% after 12 mo of age without evidence of hemolysis should have testing for β-globin gene deletions consistent with HPFH. These children have a much milder clinical course and do not require penicillin prophylaxis or hydroxyurea therapy. If the parents are tested for sickle cell trait or hemoglobinopathy trait full disclosure to the parents must be provided, and in some circumstances the issue of paternity may be disclosed. For this reason and because of healthcare privacy, common practice is to always seek permission for the genetic testing and to report the hemoglobinopathy trait results back to each parent separately. In the United States, sickle cell disease is the most common genetic disorder identified through the state-mandated newborn screening program, occurring in 1 : 2,647. In regard to race in the United States, sickle cell disease occurs in African Americans at a rate of 1 : 396 births and in Hispanics at a rate of 1 : 36,000 births. In the United States, an estimated 100,000 people are affected by sickle cell disease, with an ethnic distribution of 90% African American and 10% Hispanic. The U.S. sickle cell disease population represents a fraction of the worldwide burden of the disease, with global estimates of 312,000 neonates born annually with HbSS disease.

Clinical Manifestations and Treatment of Sickle Cell Anemia (HbSS)

For a comprehensive discussion of the clinical management of children and adolescents with sickle cell disease, refer to National Heart, Lung and Blood Institute (NHLBI) 2014 Expert Panel Report on the Evidence-based Management of Sickle Cell Disease (https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-diseasereport.pdf ).

Fever and Bacteremia Fever in a child with sickle cell anemia is a medical emergency, requiring prompt medical evaluation and delivery of antibiotics because of the increased risk of bacterial infection and subsequent high mortality rate. As early as 6 mo of age, infants with sickle cell anemia develop abnormal immune function because of splenic dysfunction. By 5 yr of age, most children with sickle cell anemia have complete functional asplenia. Regardless of age, all patients with sickle cell anemia are at increased risk of infection and death from bacterial infection, particularly encapsulated organisms such as Streptococcus pneumoniae , Haemophilus influenzae type b, and Neisseria meningitidis . The rate of bacteremia in children with sickle cell disease presenting with fever is 4 hr should be treated by aspiration of blood from the corpora cavernosa, followed by irrigation with dilute epinephrine to produce immediate and sustained detumescence. Urology consultation is required to initiate this procedure, with appropriate input from a hematologist. Simple blood transfusion with exchange transfusion has been proposed for the acute treatment of priapism, but limited evidence supports this strategy as the initial management. If no benefit is obtained from surgical management, transfusion therapy should be considered. However, detumescence may not occur for up to 24 hr (much longer than with urologic aspiration) after transfusion, and transfusion for priapism has been associated with acute neurologic events. Consultation with a hematologist and urologist will help identify therapies to prevent recurrences.

Neurologic Complications Neurologic complications associated with sickle cell disease are varied and complex, ranging from acute ischemic stroke with focal neurologic deficit to clinically silent abnormalities found on radiologic imaging. Before the development of transcranial Doppler ultrasonography to screen for stroke risk among children with sickle cell anemia, approximately 11% experienced an overt stroke and 20% a silent stroke before age 18 yr. A functional definition of overt stroke is the presence of a focal neurologic deficit lasting for >24 hr and/or abnormal neuroimaging of the brain indicating a cerebral infarct on T2-weighted MRI corresponding to the focal neurologic deficit (Figs. 489.2 and 489.3 ). A silent cerebral infarct lacks focal neurologic findings lasting >24 hr and is diagnosed by abnormal imaging on T2-weighted MRI. Children with other types of sickle cell disease, such as HbSC or HbSβ+ -thalassemia, develop overt or

silent cerebral infarcts as well, but at a lower frequency than children with HbSS and HbSβ0 -thalassemia. Other neurologic complications include transient ischemic attacks, headaches that may or may not correlate to degree of anemia, seizures, cerebral venous thrombosis, and posterior reversible encephalopathy syndrome (PRES) . Chiari I malformations can occur in older children with sickle cell disease. Fat embolism syndrome is a rapidly progressive, potentially fatal complication involving pain, respiratory distress, changes in mental status, and multiorgan system failure. When this syndrome is identified early, exchange transfusion therapy has improved patient survival in small case series.

FIG. 489.2 MRI and magnetic resonance angiography of the brain. A, T2-weighted MRI shows remote infarction of the territories of the left anterior cerebral artery and middle cerebral artery. B, MRA shows occlusion of the left internal carotid artery siphon distal to the takeoff of the ophthalmic artery.

FIG. 489.3 Fast fluid-attenuated inversion recovery sequence MRI of the brain showing a right hemisphere border-zone cerebral infarction in a child with sickle cell anemia. (From Switzer JA, Hess DC, Nichols F, et al: Pathophysiology and treatment of stroke in sickle-cell disease: present and future, Lancet Neurol 5:501–512, 2006.)

For patients presenting with acute focal neurologic deficit, a prompt pediatric neurologic evaluation and consultation with a pediatric hematologist is recommended. In addition, oxygen administration to keep oxygen saturation (SO 2 ) >96% and simple blood transfusion within 1 hr of presentation, with a goal of increasing Hb to a maximum of 10 g/dL, is warranted. A timely simple blood transfusion is important because this is the most efficient strategy to dramatically increase oxygen content of the blood, if SO 2 is >96%. However, greatly exceeding this posttransfusion Hb limits oxygen delivery to the brain as a result of hyperviscosity by increasing the Hb significantly over the patient's baseline values. Subsequently, prompt treatment with an exchange transfusion should be considered, either manually or with automated erythrocytapheresis, to reduce the HbS percentage to at least 200 different mutations resulting in absent or decreased globin production. Although most are rare, the 20 most common abnormal alleles constitute 80% of the known thalassemias worldwide; 3% of the world's population carries alleles for β-thalassemia, and in Southeast Asia 5–10% of the population carry alleles for α-thalassemia. In a particular region, there are fewer common alleles. In the United States, an estimated 2,000 persons have βthalassemia major.

Pathophysiology Two related features contribute to the sequelae of β-thalassemia syndromes : inadequate β-globin gene production leading to decreased levels of normal hemoglobin (HbA) and unbalanced α- and β-globin chain production leading to ineffective erythropoiesis. In β-thalassemia α-globin chains are in excess to non– α-globin chains, and α-globin tetramers (α4 ) are formed and appear as RBC inclusions. The free α-globin chains and inclusions are very unstable, precipitate in RBC precursors, damage the RBC membrane, and shorten RBC survival, leading to anemia and increased erythroid production (Table 489.7 ). This results in a marked increase in erythropoiesis, with early erythroid precursor death in the bone marrow. Clinically, this is characterized by a lack of maturation of erythrocytes and an inappropriately low reticulocyte count. This ineffective erythropoiesis and the compensatory massive marrow expansion with erythroid hyperactivity characterize β-thalassemia. Due to the low or absent production of β-globin, the α-chains combine with γ-chains, resulting in HbF (α2 γ2 ) being the dominant hemoglobin. In addition to the natural survival effect, the γ-globin chains may be produced in increased amounts, regulated by genetic polymorphisms. The δ-chain synthesis is not usually affected in β-thalassemia or β-thalassemia trait, and therefore patients have a relative or absolute increase in HbA2 production (α2 δ2 ).

Table 489.7

The Thalassemias THALASSEMIA α-Thalassemia 1 Gene deletion 2 Gene deletion (α-thalassemia trait) 3 Gene deletion hemoglobin H 2 Gene deletion + Constant Spring

RED BLOOD GLOBIN CELL GENOTYPE FEATURES −,α/α,α −,α/−,α −, −/ α,α −,−/−,α −,−/ α,αConstant

CLINICAL FEATURES

HEMOGLOBIN ANALYSIS

Normal Microcytosis, mild hypochromasia Microcytosis, hypochromic Microcytosis, hypochromic

Normal Normal, mild anemia

Newborn: Bart: 1–2% Newborn: Bart: 5–10%

Mild anemia, transfusions not Newborn: Bart: 20–30% required Moderate to severe anemia, 2–3% Constant Spring, 10– transfusion, splenectomy. 15% HbH

Spring

4 Gene deletion

−,−/−,−

Anisocytosis, poikilocytosis

Hydrops fetalis

Nondeletional

α,α/α,αvariant

Microcytosis, mild anemia

Normal

Variable microcytosis, mild anemia Microcytosis, nucleated RBC

Normal

Elevated A2 , variable elevation of F

Transfusion dependent

Hyopchromic, microcytosis

Mild to moderate anemia, intermittent transfusions

F 98% and A2 2%, E 30– 40% (E/β0 ); variably low Hb A with β+ A2 2–5%, F 10–30%, Hb A variably low levels

Moderately severe anemia, splenomegaly Normal Mild anemia

Elevated F and A2

β-Thalassemia β0 or β+ β0 /A,β+ /A heterozygote: trait β0 or β+ Thalassemia severe β0 or β+ thalassemia intermedia Dominant (rare)

β0 /β0 , β+ /β0 , β+ β+ E/β0

B0 /A

Newborn: 89–90% Bart with Gower-1, Gower-2, and Portland 1–2% variant hemoglobin

δ-Thalassemia (δβ)0 Thalassemia (δβ)+ Thalassemia Lepore Homozygous Hb Lepore

A/A (δβ)0 /A

Microcytosis, abnormal RBCs Normal Hypochromic

βLepore /A

Microcytosis

Mild anemia

Lepore 8–20%

βLepore / βLepore

Microcytic, hypochromic

Thalassemia intermedia

F 80%, Lepore 20%

γδβ-Thalassemia

(γA δβ)0/ A

γ-Thalassemia

(γA γG )0 /A

Microcytosis, microcytic, hypochromic Microcytosis

Moderate anemia, splenomegaly, homozygote: thalassemia intermedia Insignificant unless homozygote

Decreased F and A2 compared with δβthalassemia Decreased F

A2 absent F 5–20%

In the α-thalassemia syndromes , there is a reduction in α-globin production. Normally, there are 4 α-globin genes (2 from each parent) that control α-globin

production. α-thalassemia syndromes vary from complete absence (hydrops fetalis) to only slightly reduced (α-thalassemia silent carrier) α-globin production. In the α-thalassemia syndromes, an excess of β- and γ-globin chains are produced. These excess chains form Bart hemoglobin (γ4 ) in fetal life and HbH (β4 ) after birth. These abnormal tetramers are nonfunctional hemoglobins with very high oxygen affinity. They do not transport oxygen and result in extravascular hemolysis. A fetus with the most severe form of α-thalassemia (hydrops fetalis ) develops in utero anemia and the pregnancy usually results in fetal loss because HbF production requires sufficient amounts of α-globin. In contrast, infants with β-thalassemia major become symptomatic only after birth when HbA predominates and insufficient β-globin production manifests in clinical symptoms.

Homozygous β-Thalassemia (Thalassemia Major, Cooley Anemia) Clinical Manifestations If not treated, children with homozygous β0 -thalassemia usually become symptomatic from progressive anemia, with profound weakness and cardiac decompensation during the 2nd 6 mo of life. Depending on the mutation and degree of HbF production, regular transfusions are necessary beginning in the 2nd mo to 2nd yr of life, but rarely later. The decision to transfuse is multifactorial but is not determined solely by the degree of anemia. The presence of signs of ineffective erythropoiesis, such as growth failure, bone deformities secondary to marrow expansion, and hepatosplenomegaly, are important variables in determining transfusion initiation. The classic presentation of children with severe disease includes thalassemic facies (maxilla hyperplasia, flat nasal bridge, frontal bossing), pathologic bone fractures, marked hepatosplenomegaly, and cachexia and is primarily seen in countries without access to chronic transfusion therapy. Occasionally, patients with moderate anemia develop these features because of severe compensatory, ineffective erythropoiesis. In nontransfused patients with severe ineffective erythropoiesis, marked splenomegaly can develop with hypersplenism and abdominal symptoms. The features of ineffective erythropoiesis include expanded medullary spaces (with

massive expansion of the marrow of the face and skull), extramedullary hematopoiesis, and higher metabolic needs (Fig. 489.7 ). The chronic anemia and increased erythroid drive produce an increase in iron absorption from the gastrointestinal tract and secondary hemosiderosis-induced organ injury.

FIG. 489.7 Ineffective erythropoiesis in 3 yr old patient who has β-thalassemia major and has not received a transfusion. A, Massive widening of the diploic spaces of the skull as seen on MRI. B, Radiographic appearance of the trabeculae as seen on plain radiograph. C, Obliteration of the maxillary sinuses with hematopoietic tissue as seen on CT scan.

Chronic transfusion therapy dramatically improves the quality of life and reduces the complications of severe thalassemia. Transfusion-induced hemosiderosis becomes the major clinical complication of transfusion-

dependent thalassemia. Each mL of packed red cells contains approximately 1 mg of iron. Physiologically, there is no mechanism to eliminate excess body iron. Iron is initially deposited in the liver and is followed by deposition in the endocrine organs and the heart. This leads to a high rate of hypothyroidism, hypogonadotrophic gonadism, growth hormone deficiency, hypoparathyroidism, and diabetes mellitus. Iron deposition in the heart causes heart failure and arrhythmias, and heart disease is the leading cause of death in inadequately chelated patients. Eventually, most patients not receiving adequate iron chelation therapy die from cardiac failure or cardiac arrhythmias secondary to hemosiderosis. Hemosiderosis-induced morbidity can be prevented by adequate iron chelation therapy.

Laboratory Findings In the United States, some children with β-thalassemia major will be identified on newborn screening as a result of the detection of only HbF on hemoglobin electrophoresis. However, infants with β+ mutations might be missed on newborn screen if small amounts of hemoglobin A are present. A hemoglobin FE pattern can be consistent with hemoglobin E β0 -thalassemia, or the more benign hemoglobin EE disease, and needs to be followed up. The lack of standardized neonatal diagnosis of thalassemia disorders requires close follow-up of newborns with unclear thalassemia mutations and babies from high-risk ethnic groups. Infants with serious β-thalassemia disorders have a progressive anemia after the newborn period. Microcytosis, hypochromia, and targeting characterize the RBCs. Nucleated RBCs, marked anisopoikilocytosis, and a relative reticulocytopenia are typically seen (see Fig. 489.5E ). The Hb level falls progressively often to 25%. Obtaining supporting evidence from the parents is helpful. Later in childhood, there is an excess of βglobin chain tetramers that results in HbH. A definitive diagnosis of HbH disease requires DNA analysis. Brilliant cresyl blue can stain HbH, but it is rarely used for diagnosis. Patients with HbH disease have a marked microcytosis, anemia, mild splenomegaly, and, occasionally, scleral icterus or cholelithiasis. Chronic transfusion is not usually required for therapy because the Hb range is 7-11 g/dL, with MCV 51-73 fL, but intermittent transfusions for worsening anemia may be needed. Individuals with non-deletional Hb H disease are more likely to require transfusions than individuals with deletional Hb H disease. The deletion of all 4 α-globin gene alleles causes profound anemia during fetal life, resulting in hydrops fetalis ; the ζ-globin gene must be present for fetal survival. There are no normal hemoglobins present at birth (primarily Hb Bart, with Hb Gower-1, Gower-2, and Portland). Intrauterine transfusions may rescue the fetus, but congenital abnormalities and neurodevelopmental delay often result. Infants with severe α-thalassemia will have lifelong transfusion dependence, and hematopoietic stem cell transplantation is the only cure. Treatment of HbH disease requires ongoing monitoring of growth and organ dysfunction. Dietary supplement with folate and multivitamins without iron is indicated. Older patients may develop decreased bone density with calcium and vitamin D deficiency. Vitamin D supplementation is indicated if the level is low, and adequate dietary calcium intake should be encouraged to promote bone health. Iron supplementation should be avoided as patients are at risk of developing iron overload. Intermittent transfusion requirements during intercurrent infection may occur, particularly in nondeletional HbH. Splenectomy is occasionally indicated, and because of the high risk of

postsplenectomy thrombosis, aspirin or other anticoagulant therapy following splenectomy should be considered. Hemosiderosis, secondary to GI iron absorption or transfusion exposure, may develop in older patients and require chelation therapy. Because HbH is an unstable hemoglobin sensitive to oxidative injury, oxidative medications should be avoided. At-risk couples for hydrops fetalis should be identified and offered molecular diagnosis on fetal tissue obtained early in pregnancy. Later in pregnancy, intrauterine transfusion can improve fetal survival, but chronic transfusion therapy or bone marrow transplantation for survivors will be required.

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methemoglobinemia in a toddler secondary to topical dapsone exposure. Pediatrics . 2016;138(2):e1–e2. Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassemia. Lancet . 2012;379:373–382. Hussein AA, Al-Zaben A, Ghatasheh L, et al. Risk adopted allogeneic hematopoietic stem cell transplantation using a reduced intensity regimen for children with thalassemia major. Pediatr Blood Cancer . 2013;60:1345–1349. Key NS, Derebail VK. Sickle-cell trait: novel clinical significance. Hematology Am Soc Hematol Educ Program . 2010;2010:418–422. Kwiatkowski JL. Current recommendations for chelation for transfusion-dependent thalassemia. Ann N Y Acad Sci . 2016;1368:107–114. Lal A, Goldrich ML, Haines DA, et al. Heterogeneity of hemoglobin H disease in childhood. N Engl J Med . 2011;364:710–718. Martin A, Thompson AA. Thalassemias. Pediatr Clin North Am . 2013;60:1383–1391. Musallam KM, Taher AT, Cappellini MD, et al. Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood . 2013;121:2199–2212 [quiz 372]. Patel K, Livni N, Macdonald D. Renal medullary carcinoma, a rare cause of haematuria in sickle cell trait. Br J Haematol . 2006;132:1. Percy MJ, Lappin TR. Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency. Br J Haematol . 2008;141:298–308. Peters M, Heijboer H, Smiers F, et al. Diagnosis and management of thalassaemia. BMJ . 2012;344:40–44. Songdej D, Babbs C, Higgs DR. BHFS international consortium: an international registry of survivors with hb

Bart's hydrops fetalis syndrome. Blood . 2017;9:1251–1259. Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood . 2010;115(10):1886– 1892. Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood . 2010;115:1886–1892. Taher AT, Vichinsky E, Musallam KM, et al. Guidelines for the management of non transfusion dependent thalassaemia (NTDT) . Thalassaemia Internation Federation: Nicosia, Cyprus; 2013. Tsaras G, Owusu-Ansah A, Boateng FO, et al. Complications associated with sickle cell trait: a brief narrative review. Am J Med . 2009;122:507–512. Vichinsky EP. Clinical manifestations of alpha-thalassemia. Cold Spring Harb Perspect Med . 2013;3:a011742. Vichinsky E, Levine L. Standard of care guidelines for thalassemia . Children's Hospital: Oakland, CA; 2012. Vichinsky EP, MacKlin EA, Waye JS, et al. Changes in the epidemiology of thalassemia in north America: a new minority disease. Pediatrics . 2005;116:e818–e825. Vichinsky E, Cohen A, Thompson AA, et al. Epidemiologic and clinical characteristics of nontransfusion-dependent thalassemia in the United States. Pediatr Blood Cancer . 2018;65(7):e27067. Wood JC. Impact of iron assessment by MRI. Hematology Am Soc Hematol Educ Program . 2011;2011:443–450.

CHAPTER 490

Enzymatic Defects 490.1

Pyruvate Kinase Deficiency Amanda M. Brandow

Keywords adenosine triphosphate ATP congenital hemolytic anemia hemolysis polychromatophilia PK deficiency pyruvate kinase reticulocytosis Congenital hemolytic anemia occurs in persons homozygous or compound heterozygous for autosomal recessive genes that cause either a marked reduction in red blood cell (RBC) pyruvate kinase (PK) or production of an abnormal enzyme with decreased activity resulting in impaired conversion of phosphoenolpyruvate to pyruvate. Generation of adenosine triphosphate (ATP) within RBCs at this step is impaired, and low levels of ATP, pyruvate, and the oxidized form of nicotinamide adenine dinucleotide (NAD+ ) are found (Fig.

490.1 ). The concentration of 2,3-diphosphoglycerate is increased; this isomer is beneficial in facilitating oxygen release from hemoglobin but detrimental in inhibiting hexokinase and enzymes of the hexose monophosphate shunt. In addition, an unexplained decrease occurs in the sum of the adenine (ATP, adenosine diphosphate, and adenosine monophosphate) and pyridine (NAD+ and reduced form of NAD) nucleotides, further impairing glycolysis. As a consequence of decreased ATP, RBCs cannot maintain their potassium and water content; the cells become rigid, and their life span is considerably reduced.

FIG. 490.1 Red blood cell metabolism: glycolysis and hexose monophosphate pathway. The enzyme deficiencies clearly associated with hemolysis are shown in bold . ATP, Adenosine triphosphate; ADP, adenosine diphosphate; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of NADP.

Etiology There are 2 mammalian PK genes, but only the PKLR gene is expressed in RBCs. The human PKLR gene is located on chromosome 1q21. More than 180 mutations are reported in this structural gene, which codes for a 574–amino acid

protein that forms a functional tetramer. These mutations include missense, splice site, and insertion-deletion alterations, and there is some correlation of the type, location, and amino acid substitution with disease severity. Most affected patients are compound heterozygotes for 2 different PK gene defects. The many possible combinations likely account for the variability in clinical severity. The mutations 1456 C to T and 1529 G to A are the most common mutations in the white population.

Clinical Manifestations and Laboratory Findings The clinical manifestations of PK deficiency vary from severe neonatal hemolytic anemia to mild, well-compensated hemolysis first noted in adulthood (Table 490.1 ). Severe jaundice and anemia may occur in the neonatal period, and kernicterus has been reported. The hemolysis in older children and adults varies in severity, with hemoglobin (Hb) values ranging from 8-12 g/dL associated with some pallor, jaundice, and splenomegaly. Reticulocyte counts are often extremely elevated, reflecting the severe ongoing hemolysis. Patients with these findings usually do not require transfusion. A severe form of the disease has a relatively high incidence among the Amish of the Midwestern United States. PK deficiency may possibly provide protection against falciparum malaria. Table 490.1

Hexokinase Variants Associated With Hemolytic Anemia CLINICAL FEATURES Inheritance Anemia Other — Recessive Recessive Recessive

+ ++ ++ +++

Recessive Recessive

+ ++

Recessive Recessive Dominant

++ + +

Congenital malformations

Hydrops fetalis

Low platelet and fibroblast HK activity Low platelet HK activity Spherocytes, ovalocytes

PROPERTIES OF RBC HEXOKINASE Kinetic Activity Stability Mobility Abnormalities 13-24* 0 — — 15-20* + Normal Abnormal 16* 0 — Abnormal 17 20* 20*

0 0

Normal Low

Normal Normal

25* 25* 30*

+ 0 0

Normal Low Low

Abnormal Normal Normal

Recessive

+

Recessive — Recessive —

+ + + +

Dominant Dominant Recessive

+ ++ ±

Developmental and cognitive delays Congenital malformations

WBC HK activity low

45 †

+

Normal

Normal

50* 33* 40-53* 50* 53 45-91 † 75* 77 †

0 + + +

Normal — Low —

Normal — Normal —

+ +

Normal Normal

Abnormal Abnormal

* Maximal enzyme activity (V max ) compared with reticulocytosis controls. † Maximal enzyme activity (V max ) compared with normal red cells.

HK, Hexokinase; RBC, red blood cell; WBC, white blood cell. From Nathan and Oski's hematology and oncology of infancy and childhood, ed 8, vol 1, Philadelphia, 2015, Elsevier (Table 17-2, p 583).

Polychromatophilia and mild macrocytosis reflect the elevated reticulocyte count. Spherocytes are uncommon, but a few spiculated pyknocytes may be found. Diagnosis relies on demonstration of a marked reduction of RBC PK activity or an increase in the Michaelis-Menten dissociation constant (K m ) for its substrate, phosphoenolpyruvate (high K m variant). Other RBC enzyme activity is normal or elevated, reflecting the reticulocytosis. No abnormalities of hemoglobin are noted. The white blood cells (WBCs) have normal PK activity and must be rigorously excluded from the RBC hemolysates used to measure PK activity. Heterozygous carriers usually have moderately reduced levels of PK activity.

Treatment Phototherapy and exchange transfusions may be indicated for hyperbilirubinemia in newborns. Transfusions of packed RBCs are necessary for severe anemia or for aplastic crises. If the anemia is consistently severe and frequent transfusions are required, iron chelation may be necessary. Splenectomy should be considered after the child is 5-6 yr of age to decrease the need for transfusions and minimize iron overload. Although not curative, splenectomy may be followed by higher Hb levels and by strikingly high (30–60%) reticulocyte counts. Death resulting from overwhelming pneumococcal sepsis has followed splenectomy; thus immunization with vaccines for encapsulated organisms should be given before splenectomy and prophylactic penicillin

administered after the procedure. Splenectomy has also been associated with thrombosis and pulmonary hypertension. Gallstones should be considered in any patient with congenital hemolytic anemia and recurrent abdominal pain. There is currently no curative therapy; a pharmacologic PK activator is being studied in early-phase clinical trials. The natural history of the disease is limited and is currently being studied through an international registry.

490.2

Other Glycolytic Enzyme Deficiencies Amanda M. Brandow

Keywords aldolase glucose phosphate isomerase glycogen storage disease Heinz bodies hexokinase phosphofructokinase deficiency phosphoglycerate kinase triose phosphate isomerase deficiency Chronic nonspherocytic hemolytic anemias of varying severity have been associated with deficiencies of other enzymes in the glycolytic pathway, including hexokinase, glucose phosphate isomerase, and aldolase, which are inherited as autosomal recessive disorders. Phosphofructokinase deficiency, which occurs primarily in Ashkenazi Jews in the United States, results in hemolysis associated with a myopathy classified as glycogen storage disease type VII (see Chapter 105.1 ). Clinically, hemolytic anemia is complicated by muscle weakness, exercise intolerance, cramps, and possibly myoglobinuria.

Enzyme assays for phosphofructokinase yield low values for RBCs and muscle. Triose phosphate isomerase deficiency is an autosomal recessive disorder affecting many systems. Affected patients have hemolytic anemia, cardiac abnormalities, and lower motor neuron and pyramidal tract impairment, with or without evidence of cerebral impairment. They usually die in early childhood. The gene for triose phosphate isomerase has been cloned and sequenced and is located on chromosome 12. Phosphoglycerate kinase (PGK) is the first ATP-generating step in glycolysis. At least 23 kindreds with PGK deficiency have been described. PGK is the only glycolytic enzyme inherited on the X chromosome. Affected males may have progressive extrapyramidal disease, myopathy, seizures, and variable mental retardation in conjunction with hemolytic anemia. Nine Japanese patients had neural or myopathic symptoms with hemolysis; 6 had hemolysis alone; 7 had neural or myopathic symptoms alone; and 1 had no symptoms. The gene for PGK is particularly large, spanning 23 kb, and various genetic abnormalities, including nucleotide substitutions, gene deletions, missense, and splicing mutations, result in PGK deficiency.

Deficiencies of Enzymes of Hexose Monophosphate Pathway The most important function of the hexose monophosphate pathway is to maintain glutathione in its reduced state (GSH) as protection against the oxidation of RBCs (see Fig. 490.1 ). Approximately 10% of the glucose taken up by RBCs passes through this pathway to provide the reduced form of NAD phosphate (NADPH) necessary for the conversion of oxidized glutathione to GSH. Maintenance of GSH is essential for the physiologic inactivation of oxidant compounds, such as hydrogen peroxide, that are generated within RBCs. If glutathione, or any compound or enzyme necessary for maintaining it in the reduced state, is decreased, the SH groups of the RBC membrane are oxidized, and the hemoglobin becomes denatured and may precipitate into RBC inclusions called Heinz bodies . Once Heinz bodies have formed, an acute hemolytic process results from damage to the RBC membrane by the precipitated hemoglobin, the oxidant agent, and the action of the spleen. The damaged RBCs then are rapidly removed from the circulation.

490.3

Glucose-6-Phosphate Dehydrogenase Deficiency and Related Deficiencies Amanda M. Brandow

Keywords anisopoikilocytosis bite cells favism G6PD deficiency nonspherocytic hemolytic anemia oxidant threats polychromasia X-linked deficiency Glucose-6-phosphate dehydrogenase (G6PD ) deficiency, the most frequent disease involving enzymes of the hexose monophosphate pathway, is responsible for 2 clinical syndromes, episodic acute hemolytic anemia and chronic nonspherocytic hemolytic anemia. The most common manifestations are neonatal jaundice and episodic acute hemolytic anemia, which is induced by infections, certain drugs, and rarely, fava beans. This X-linked deficiency affects >400 million people worldwide, representing an overall 4.9% global prevalence. The global distribution of this disorder parallels that of malaria, representing an example of “balanced polymorphism,” in which there is an evolutionary advantage of resistance to falciparum malaria in heterozygous females that outweighs the small negative effect of affected hemizygous males. The deficiency is caused by inheritance of any of a large number of abnormal alleles of the gene responsible for the synthesis of the G6PD protein. About 140 mutations have been described in the gene responsible for the synthesis of the

G6PD protein. Many of these mutations are single-base changes leading to amino acid substitutions and destabilization of the G6PD enzyme. A webaccessible database catalogs G6PD mutations (http://www.bioinf.org.uk/g6pd ). Fig. 490.2 shows some of the mutations that cause episodic vs chronic hemolysis. Milder disease is associated with mutations near the amino terminus of the G6PD molecule, and chronic nonspherocytic hemolytic anemia is associated with mutations clustered near the carboxyl terminus. The normal enzyme found in most populations is designated G6PD B+. A normal variant, designated G6PD A+, is common in Americans of African descent.

FIG. 490.2 Most common mutations along coding sequence of G6PD gene. Exons are shown as open numbered boxes . Open circles are mutations causing classes II and III variants. Filled circles represent sporadic mutations giving rise to severe variants (class I). Open ellipses are mutations causing class IV variants. X is a nonsense mutation; f, a splice site mutation; filled squares, small deletions. 202A and 968C are the 2 sites of base substitution in G6PD-A. (From Cappellini MD, Fiorelli G: Glucose-6phosphate dehydrogenase deficiency, Lancet 371:64–74, 2008.)

Episodic or Induced Acute Hemolytic Anemia Etiology G6PD catalyzes the conversion of glucose 6-phosphate to 6-phosphogluconic acid. This reaction produces NADPH, which maintains GSH (glutathione in its reduced, functional state; see Fig. 490.1 ). GSH provides protection against oxidant threats from certain drugs and infections that would otherwise cause precipitation of hemoglobin (Heinz bodies) or damage the RBC membrane. Synthesis of RBC G6PD is determined by a gene on the X chromosome.

Thus, heterozygous females have intermediate enzymatic activity and have 2 populations of RBCs: one is normal, and the other is deficient in G6PD activity. Because they have fewer susceptible cells, most heterozygous females do not have clinically evident hemolysis after exposure to oxidant drugs. Rarely, the majority of RBCs is G6PD deficient in heterozygous females because the inactivation of the normal X chromosome is random and sometimes exaggerated (Lyon-Beutler hypothesis). Disease involving this enzyme therefore occurs more frequently in males than in females. Approximately 13% of male Americans of African descent have a mutant enzyme (G6PD A−) that results in a deficiency of RBC G6PD activity (5–15% of normal). Italians, Greeks, and other Mediterranean, Middle Eastern, African, and Asian ethnic groups also have a high incidence, ranging from 5– 40%, of a variant designated G6PD B− (G6PD Mediterranean ). In these variants, the G6PD activity of homozygous females or hemizygous males is 12 yr old. Hemolysis may continue for many months or years. Abnormalities involving other blood elements are common, and the response to glucocorticoids is variable and inconsistent.

Laboratory Findings In many cases, anemia is profound with hemoglobin levels 10% platelet, and kidney damage Exposure of Tantigen on RBC and kidney Disseminated Sepsis, shock, endotoxin Decreased fibrinogen, increased intravascular fibrin split products, decreased coagulation clotting factors and platelets

MANAGEMENT Acquired: Plasmapheresis with plasma Congenital: Scheduled plasma infusions

Supportive ? Value of plasmapheresis Eculizumab (Ab to C5) Plasmapheresis not indicated Plasmapheresis with albumin for neuraminidase and endogenous T Ab removal Avoid plasma infusions, which will exacerbate RBC hemolysis Treat underlying condition; replace factors and platelets if bleeding

(DIC) * All show fragmentation hemolytic anemia, thrombocytopenia, and potential renal and other organ

damage. An elevated lactate dehydrogenase and reduced haptoglobin usually are present secondary to hemolysis. † May be related to inherited defect in factor H or I.

Ab, Antibody; RBC, red blood cell.

Thermal Injury Extensive burns may directly damage the RBCs and cause hemolysis that results in the formation of spherocytes. Blood loss and marrow suppression may contribute to anemia and require blood transfusion. Erythropoietin (EPO ) has been used as treatment for diminished RBC production.

Renal Disease The anemia of uremia is multifactorial in origin. Erythropoietin production may be decreased, and the marrow suppressed by toxic metabolites. Furthermore, the RBC life span often is shortened because of retention of metabolites and organic acidemia. The use of EPO in chronic renal disease can decrease the need for blood transfusion.

Liver Disease A change in the ratio of cholesterol to phospholipids in the plasma may result in changes in the composition of the RBC membrane and shortening of the RBC life span. Some patients with liver disease have many target RBCs on the blood film, whereas others have a preponderance of spiculated cells. These morphologic changes reflect the alterations in the plasma lipid composition.

Toxins and Venoms Bacterial sepsis caused by Haemophilus influenzae, staphylococci, or streptococci may be complicated by accompanying hemolysis. Particularly severe hemolytic anemia has been observed in clostridial infections and results

from a hemolytic clostridial toxin. Large numbers of spherocytes may be seen on the blood film. Spherocytic hemolysis also may be noted after bites by various snakes, including cobras, vipers, and rattlesnakes, which have phospholipases in their venom. Large numbers of bites by insects, such as bees, wasps, and yellow jackets, also may cause spherocytic hemolysis by a similar mechanism (see Chapter 746 ).

Wilson Disease See Chapter 384.2 . An acute and self-limited episode of hemolytic anemia may precede by years the onset of hepatic or neurologic symptoms in Wilson disease. This event appears to result from the toxic effects of free copper on the RBC membrane. The blood film often (but not always) shows large numbers of spherocytes, and the Coombs test result is negative. Because early diagnosis of Wilson disease permits prophylactic treatment with penicillamine and prevention of hepatic and neurologic disease, correct assessment of this rare type of hemolysis is important.

Bibliography Bose S, Sonny A, Rahman N. A teenager presents with fulminant hepatic failure and acute hemolytic anemia. Chest . 2015;147:e100–e104. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet . 2017;390(10095):681–696. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med . 2014;371:654–666. Hedera P. Update on the clinical management of Wilson's disease. Appl Clin Genet . 2017;10:9–19. Riedl M, Fakhouri F, Le Quintrec M, et al. Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches. Semin Thromb Hemost . 2014;40:444–464. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on

Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr . 2013;25:203–208. Trachtman H. HUS and TTP in children. Pediatr Clin North Am . 2013;60:1513–1526. Ye XN, Mao LP, Lou YJ, Tong HY. Hemolytic anemia as first presentation of Wilson's disease with uncommon ATP7B mutation. Int J Clin Exp Med . 2015;8:4708–4711.

SECTION 4

Polycythemia (Erythrocytosis) OUTLINE Chapter 493 Polycythemia Chapter 494 Nonclonal Polycythemia

CHAPTER 493

Polycythemia Amanda M. Brandow, Bruce M. Camitta

Polycythemia exists when the red blood cell (RBC) count, hemoglobin level, and total RBC volume all exceed the upper limits of normal. In postpubertal individuals, an RBC mass >25% above the mean normal value (based on body surface area) or a hemoglobin level >18.5 g/dL (in males) or >16.5 g/dL (in females) indicate absolute erythrocytosis . A decrease in plasma volume, such as occurs in acute dehydration and burns, may result in a high hemoglobin value. These situations are more accurately designated as hemoconcentration or relative polycythemia because the RBC mass is not increased and normalization of the plasma volume restores hemoglobin to normal levels. Once the diagnosis of true polycythemia is made, sequential studies should be done to determine the underlying etiology (Fig. 493.1 ).

FIG. 493.1 Sequential studies to evaluate polycythemia. CBC, Complete blood count; CNS, central nervous system; COHgb, carboxyhemoglobin; 2,3-DPG, 2,3diphosphoglycerate.

Clonal (Primary) Polycythemia (Polycythemia Vera) Pathogenesis Polycythemia vera is an acquired clonal myeloproliferative disorder. Although primarily manifesting as erythrocytosis, thrombocytosis and leukocytosis can also be seen. When isolated severe thrombocytosis exists in the absence of erythrocytosis, the myeloproliferative disorder is called essential thrombocythemia . Polycythemia vera is rare in children. A gain-of-function mutation of JAK2, a cytoplasmic tyrosine kinase, is found in >90% of adult patients with polycythemia vera, but in 18.5 g/dL (men) or Hb >16.5 g/dL (women) or Hb or Hct >99th percentile of reference range for age, sex, or altitude of residence or Hb >17 g/dL (men) or Hb >15 g/dL (women) if associated with a sustained increase of ≥2 g/dL from baseline that cannot be attributed to correction of iron deficiency or Elevated red cell mass >25% above mean normal predicted value 2. Presence of JAK2 or similar mutation Minor Criteria 1. Bone marrow trilineage myeloproliferation 2. Subnormal serum erythropoietin level 3. Endogenous erythroid colony growth Diagnosis Both major criteria and 1 minor criterion or First major criteria and 2 minor criteria

Hb, Hemoglobin; Hct, hematocrit. From Tefferi A, Vardiman JW: Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms, Leukemia 22:14– 22, 2008.

Treatment Phlebotomy is the initial treatment of choice to alleviate symptoms of hyperviscosity and decrease the risk of thrombosis. Iron supplementation should be given to prevent viscosity problems from iron-deficient microcytosis or

thrombocytosis. In patients with marked thrombocytosis, antiplatelet agents (e.g., aspirin) may reduce the risks of thrombosis and bleeding. If these treatments are unsuccessful or the patient has progressive hepatosplenomegaly, antiproliferative treatments (hydroxyurea, anagrelide, interferon-α) may be helpful. The use of JAK2 inhibitors is an active area of investigation in the treatment of pediatric polycythemia vera. Transformation of the disease into myelofibrosis or acute leukemia is rare in children. Prolonged survival is not unusual.

Bibliography Barbui T. How to manage children and young adults with myeloproliferative neoplasms. Leukemia . 2012;26(7):1452– 1457. Cario H, McMullin MF, Bento C, et al. Erythrocytosis in children and adolescents: classification, characterization, and consensus recommendations for the diagnostic approach. Pediatr Blood Cancer . 2013;60:1734–1738. Cario H, McMullin MF, Pahl HL. Clinical and hematological presentation of children and adolescents with polycythemia vera. Ann Hematol . 2009;88(8):713–719. Cario H, Schwarz K, Herter JM, et al. Clinical and molecular characterization of a prospectively collected cohort of children and adolescents with polycythemia vera. Br J Haematol . 2008;142:622–626. Cazzola M. Introduction to a review series on myeloproliferative neoplasms. Blood . 2017;129:667–703. Geyer H, Scherber R, Kosiorek H, et al. Symptomatic profiles of patients with polycythemia vera: implications of inadequately controlled disease. J Clin Oncol . 2016;34(2):151–159. Hofmann I. Myeloproliferative neoplasms in children. J Hematop . 2015;8(3):143–157. Karow A, Nienhold R, Lundberg P, et al. Mutational profile of

childhood myeloproliferative neoplasms. Leukemia . 2015;29:2407–2409. Patnaik MM, Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired. Leukemia . 2009;23:834–844. Pemmaraju N, Mesa R. Evidence for janus kinase (JAK) inhibitors for the prevention of major morbid events in patients with myeloproliferative neoplasms (MPNs). Hematology Am Soc Hematol Educ Program . 2015;649– 651:2015. Radia D, Geyer HL. Management of symptoms in polycythemia vera and essential thrombocythemia patients. Hematology Am Soc Hematol Educ Program . 2015;2015:340–348. Spivak JL, Silver RT. The revised world health organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood . 2008;112(2):231–239. Tefferi A. Myeloproliferative neoplasms: a decade of discoveries and treatment advances. Am J Hematol . 2016;91(1):50–58. Teofili L, Foa R, Giona F, et al. Childhood polycythemia vera and essential thrombocytopenia: does their pathogenesis overlap with that of adult patients? Haematologica . 2008;93:169–172. Teofili L, Giona F, Martini M, et al. Markers of myeloproliferative diseases in childhood polycythemia vera and essential thrombocythemia. J Clin Oncol . 2007;25:1048–1053.

CHAPTER 494

Nonclonal Polycythemia Amanda M. Brandow, Bruce M. Camitta

Pathogenesis Nonclonal polycythemia is diagnosed when polycythemia is caused by a physiologic process that is not derived from a single cell (Table 494.1 ). Nonclonal polycythemia can be congenital or acquired (secondary). Table 494.1

Differential Diagnosis of Polycythemia CLONAL (PRIMARY) Polycythemia vera NONCLONAL Congenital High–oxygen affinity hemoglobinopathy (e.g., hemoglobin Chesapeake, Malmo, San Diego) Erythropoietin receptor mutations (primary familial and congenital polycythemia [PFCP]) Methemoglobin reductase deficiency Hemoglobin M disease 2,3-Diphosphoglycerate deficiency Acquired Hormonal Adrenal disease: virilizing hyperplasia, Cushing syndrome Anabolic steroid therapy Malignant tumors: adrenal, cerebellar, hepatic, other Renal disease: cysts, hydronephrosis, renal artery stenosis Hypoxia Altitude Cardiac disease Lung disease Central hypoventilation Chronic carbon monoxide exposure Neonatal: delayed cord clamping (placental-fetal transfusion) Normal intrauterine environment Placental insufficiency (preeclampsia, maternal chronic hypertension, placental abruption) Twin-twin or maternal-fetal hemorrhage

Perinatal asphyxia Infants of diabetic mothers Intrauterine growth restriction Trisomy 13, 18, or 21 Adrenal hyperplasia Maternal-congenital hyperthyroidism Spurious Plasma volume decrease

Congenital Polycythemia Lifelong or familial polycythemia should trigger a search for a congenital problem. These inherited conditions may be transmitted as dominant or recessive disorders. Autosomal dominant causes include hemoglobins that have increased oxygen affinity (P50 [partial pressure of oxygen in the blood at which the hemoglobin is 50% saturated] 65%, clinical manifestations of

hyperviscosity , such as headache and hypertension, may require phlebotomy. Living at high altitudes also causes hypoxic polycythemia; the hemoglobin level increases approximately 4% for each rise of 1,000 m (~3,300 ft) in altitude. Partial obstruction of a renal artery rarely results in polycythemia. Polycythemia has also been associated with benign and malignant tumors that secrete erythropoietin. Exogenous or endogenous excess of anabolic steroids also may cause polycythemia. A common spurious cause is a decrease in plasma volume, as occurs in moderate to severe dehydration.

Diagnosis See Chapter 493 ; Fig. 493.1 outlines sequential studies to evaluate polycythemia.

Treatment For mild disease, observation is sufficient. When the hematocrit is >65–70% (hemoglobin >23 g/dL), blood viscosity greatly increases. Periodic phlebotomy may prevent or decrease symptoms such as headache, dizziness, or exertional dyspnea. Apheresed blood should be replaced with plasma or saline to prevent hypovolemia in patients accustomed to a chronically elevated total blood volume. Increased demand for red blood cell production may cause iron deficiency. Iron-deficient microcytic red cells are more rigid, further increasing the risk of intracranial and other thromboses in patients with polycythemia. Periodic assessment of iron status should be performed, and iron deficiency should be treated.

Bibliography Alsafadi TR, Hashmi SM, Youssef HA, et al. Polycythemia in neonatal intensive care unit: risk factors, symptoms, pattern, and management controversy. J Clin Neonatol . 2014;3(2):93–98. Cario H, McMullin MF, Bento C, et al. Erythrocytosis in children and adolescents: classification, characterization, and

consensus recommendations for the diagnostic approach. Pediatr Blood Cancer . 2013;60(11):1734–1738. Chauveau A, Luque Paz D, Lecucq L, et al. A new point mutation in EPOR inducing a short deletion in congenital erythrocytosis. Br J Haematol . 2016;172(3):475–477. Giona F, Teofili L, Moleti ML, et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and long-term outcome. Blood . 2012;119(10):2219–2227. Huang LJ, Shen YM, Bulut GB. Advances in understanding the pathogenesis of primary familial and congenital polycythaemia. Br J Haematol . 2010;148(6):844–852. Pagon RA, Adam MP, Ardinger HH, et al: Primary familial and congenital polycythemia. In GeneReviews [Internet], Seattle, 1993–2017, University of Washington. Remon JI, Raghavan A, Maheshwari A. Polycythemia in the newborn. Neoreviews . 2011;12:e20. Sergueeva AI, Miasnikova GY, Polyakova LA, et al. Complications in children and adolescents with chuvash polycythemia. Blood . 2015;125(2):414–415. Sidhu A, Bhambhani K, Callaghan MU. Novel mutations in the von Hippel–lindau gene associated with congenital polycythemia. Pediatr Blood Cancer . 2015;62(6):1113– 1114. Siehr SL, Shi S, Hao S, et al. Exploring the role of polycythemia in patients with cyanosis after palliative congenital heart surgery. Pediatr Crit Care Med . 2016;17(3):216–222. Watchko JF. Common hematologic problems in the newborn nursery. Pediatr Clin North Am . 2015;62(2):509–524.

SECTION 5

The Pancytopenias OUTLINE Chapter 495 Inherited Bone Marrow Failure Syndromes With Pancytopenia Chapter 496 The Acquired Pancytopenias

CHAPTER 495

Inherited Bone Marrow Failure Syndromes With Pancytopenia Yigal Dror, Michaela Cada

Pancytopenia refers to a reduction below normal values of all 3 peripheral blood lineages: leukocytes, platelets, and erythrocytes. Identifying the etiology of pancytopenia usually requires microscopic examination of the peripheral blood smear, as well as bone marrow biopsy and aspirate specimens to assess overall cellularity and morphology. The 3 general categories of pancytopenia are related to bone marrow pathologies and can frequently be differentiated based on bone marrow findings. Pancytopenia with hypocellular bone marrow on biopsy is seen with inherited bone marrow failure syndromes (IBMFSs) with pancytopenia, acquired aplastic anemia of varied etiologies, and the hypoplastic variant of myelodysplastic syndrome (MDS). Pancytopenia with cellular bone marrow is seen with primary bone marrow disease (e.g., acute leukemia, myelodysplasia) and secondary to autoimmune disorders (e.g., autoimmune lymphoproliferative syndrome, systemic lupus erythematosus), vitamin B12 or folate deficiency, storage diseases (e.g., Gaucher, Niemann-Pick), overwhelming infection, sarcoidosis, and hypersplenism. Pancytopenia with bone marrow infiltration can be seen in metastatic solid tumors, myelofibrosis, hemophagocytic lymphohistiocytosis, and osteopetrosis. It is important to note that exceptions exist with regard to this classification. For example, IBMFSs can manifest as normocellular or hypercellular bone marrow at early stages of presentation or in cases where MDS develops. Inherited pancytopenias with hypocellular bone marrow are IBMFSs that feature decreased bone marrow production of the 3 major hematopoietic lineages occurring on an inherited basis and resulting in anemia, neutropenia, and

thrombocytopenia. It is noteworthy that patients may have single-lineage or bilineage cytopenia at presentation and gradually develop pancytopenia over time. All disorders for which a genetic basis has been deciphered have thus far been shown to be monogenic. Transmission of mutant genes is mendelian and in an autosomal dominant, autosomal recessive, or X-linked manner (Table 495.1 ). Modifying genes and acquired factors may also be operative. Inherited pancytopenias account for approximately 30% of cases of pediatric bone marrow failure. Fanconi anemia is considered the most common of the inherited pancytopenias. Table 495.1

Inherited Bone Marrow Failure Syndromes SYNDROME Fanconi anemia (FA, MIM # 227650)

Dyskeratosis congenita (DC)

PERIPHERAL ASSOCIATED INHERITANCE BLOOD MALIGNANT PATTERN MANIFESTATIONS DISEASES AR Pancytopenia MDS/AML SCC XLR Other tumors AR AR AR AML Wilms tumor Medulloblastoma AR MDS/AML SCC AR Other tumors AR AR AR AR AR AR Wilms tumor Medulloblastoma AR ? AR ? XLR (MIM # Pancytopenia MDS/AML 305000) SCC Other tumors AD (MIM # 127550) AD (MIM # 613989) AD (MIM # 613990) AR (MIM # 224230)

GENE

CHROMOSOMA LOCATION

FANCA FANCB FANCC FANCD1/BRCA2 FANCD2

16q24.3 Xp22.31 9q22.3 13q12-13 3p25.3

FANCE FANCF FANCG/XRCC FANCI FANCJ/BACH1/BRIP1 FANCL FANCM FANCN/PALB2

6p21.3 11p15 9p13 15q26.1 17q22-q24 2p16.1 14q21.3 16p12.2

FANCO/RAD51C FANCP/ SLX4 DKC1

17q22 16p13.3 Xq28

TERC

3q26.2

TERT

5p15.33

Unknown

TINF2

14q11.2

Unknown

NOP10/NOLA3

15q14-q15

AR (MIM # 613987)

Unknown

NHP2/NOLA2

AR (MIM # 613988) AR (MIM # 612199) AR (MIM # 615190)

Unknown

WDR79/TCAB1/WRAP53 17p13.1

Unknown

CTC1

17p13.1

Unknown

RTEL1

20q13.3

MDS/AML

SBDS

7q11.21

RMRP

9p13.3

ShwachmanAR Diamond syndrome (SDS, MIM # 260400) Cartilage-hair AR hypoplasia (CHH, MIM # 250250)

Neutropenia with progression to pancytopenia

Pearson marrowpancreas syndrome (PS, MIM # 557000) DiamondBlackfan anemia (DBA, MIM # 105650)

Mitochondrial

Neutropenia with progression to pancytopenia

AR

Anemia with rare progression to pancytopenia

XLR

Anemia and neutropenia Neutropenia Pancytopenia

Hyper-IgM XLR immunodeficiency syndrome (XHIM, MIM # 308230) Congenital AR amegakaryocytic thrombocytopenia (CAMT, MIM #60448) Amegakaryocytic AD thrombocytopenia with radioulnar

Neutropenia Lymphopenia Anemia

Lymphoma Basal cell carcinoma

None

5q35.5

mtDNA deletion

RPS19 RPS24 RPS17 RPS10 RPS26 RPS7 RPS29 RPL35a RPL5 PRL11 RPL26 RPL15 GATA1

19q13.2 10q22-23 15q25.2 6p21.31 12q13.2 2p25.3 14q21.3 3q29-qter 1p22.1 1p36.1-35 17p13.1 3p24.2 Xp11.23

None reported

CD40LG (HIGM1)

Xq26.3

Thrombocytopenia with progression to pancytopenia

AML

c-MPL

1q35

Thrombocytopenia with progression to pancytopenia

AML

HOXA11

7p15-p14.2

MDS/AML* Osteosarcoma

synostosis (ARTUS, MIM # 605432) RARE FORMS OF INHERITED BONE MARROW FAILURE SYNDROMES Nijmegen AR Pancytopenia AML breakage Lymphoma syndrome (NBS, MIM # 251260) DNA ligase IV AR Pancytopenia Leukemia syndrome (LIG4, MIM # 606593) Seckel syndrome AR Pancytopenia (not Leukemia (SCKL1, MIM # genetically subtyped) Lymphoma 210600) Oropharyngeal cancer (not genetically subtyped) AR

8q21

LIG4

13q22-q34

ATR SKC1 PCNT SCKL4

3q22-q24

CENPJ SCKL4

13q12.12

AR

CEP152 SCKL5

15q21.1

AR

CtIP/RBBP8 SCKL2

18q11.2

AR

Schimke AR syndrome (SIOD, MIM # 242900) Duncan/Purtilo XLR syndrome (XPL, MIM # 308240)

21q22.3

ATRIP

3p21.31

Unknown

Unknown

Pancytopenia

Leukemia Lymphoma Neuroblastoma Cancer Lymphoma

SMARCAL1

2q34-q36

Pancytopenia

EBV lymphoma

SH2D1A/SAP

Xq25

AR

Dubowitz syndrome (MIM %223370)

NSB1

Pancytopenia

* No specific ribosomal gene mutation has been associated with AML/MDS.

AML , Acute myeloid leukemia; AR, autosomal recessive; AD, autosomal dominant; ATR, ataxiatelangiectasia and Rad3 related; EBV, Epstein-Barr virus; GCSF, granulocyte colony-stimulating factor; MDS, myelodysplastic syndrome, myelodysplasia; MIM #, Mendelian Inheritance in Man with responsible gene identified; MIM %, Mendelian Inheritance in Man with responsible gene not identified; SCC, squamous cell carcinoma; XLR, X-linked recessive. Adapted from Nathan and Oski's hematology and oncology of infancy and childhood, ed 8, vol 1, Philadelphia, 2015, Elsevier (Table 7.1, p 183).

Fanconi Anemia

Etiology and Epidemiology Fanconi anemia (FA) is a rare multisystem hereditary disorder resulting in the development of bone marrow failure in those affected and a predisposition to malignancy, including myelodysplasia (MDS), acute myeloid leukemia (AML), and epithelial cancers. Individuals with FA often have congenital malformations and high sensitivity to alkylating agents and radiation. The estimated frequency of FA is 1 in 200,000 in most populations but is higher in Ashkenazi Jews (1 : 30,000) and Afrikaners (1 : 22,000). Carrier frequency is approximately 1 : 200300 in most populations. Currently, mutations in 21 genes, designated FANC genes, have been reported to cause FA or FA-like disease. All these mutations except for one are inherited in an autosomal recessive manner. One uncommon form is X-linked recessive. FA occurs in all racial and ethnic groups. At presentation, patients may have typical physical anomalies and abnormal hematologic findings (majority of patients), normal physical features but abnormal hematologic findings (about one third of patients), or physical anomalies and normal hematologic findings (unknown percentage of patients). There can be sibling discordance in clinical and hematologic manifestations, even in affected monozygotic twins.

Pathology All FA genes code for proteins that play roles in various cellular pathways and most prominently in DNA cross linking and repair. Patients with FA have faulty DNA repair and increased chromosomal fragility caused by DNA interstrand cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC). Cell fusion of FA cells with normal cells or with cells from some unrelated patients with FA produces a corrective effect on chromosomal fragility, a process called complementation. This process was often used in the past to screen for a patient's mutated gene, before next-generation gene panels that include the known FA genes became widely available. The classic FA phenotype that clearly defined the FA-associated genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BACH1/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCP/SLX4, FANCQ/ERCC4, UBE2T, REV7 ) includes the triad of bone marrow failure , congenital anomalies , and elevated chromosome fragility . These genes can be mutated in patients who have one or all of the components of the triad. Genes that were found to be

associated with 1 or 2 but not all 3 of the components are FA-like genes (FANCO/RAD51C, RAD51, FANCS/BRCA1, FANCR/EXCC2 ). FANCA accounts for approximately 64% of FA cases, FANCC for 14%, and FANG for 9%. FANCB , FANCD1 /BRCA2 , FANCD2 , FANCE, and FANCF are collectively mutated in almost 13% of FA patients. The remaining genes are mutated in rare cases. The proteins encoded by wild-type FANC genes are involved in the DNA damage recognition and repair biochemical pathway. Therefore, mutant proteins lead to genomic instability and chromosome fragility. FANC proteins are involved in other cellular activities, such as reactive oxygen species detoxification, energetic metabolism, and cytokine signaling. Thus, FANC mutations likely affect several cellular and biochemical roles of the respective proteins, which eventually leads to the FA phenotype. The observed disease complexity and heterogeneity is likely caused by the involvement of multiple cellular and biochemical pathways both in unrelated individuals and in family members with the same genetic mutation.

Clinical Manifestations The most common congenital anomalies in FA are skeletal and include absence of radii and/or thumbs that are hypoplastic, supernumerary, bifid, or absent. Anomalies of the feet, congenital hip dislocation, and leg abnormalities can also be seen (Fig. 495.1 and Table 495.2 ). Skin hyperpigmentation of the trunk, neck, and intertriginous areas, café-au-lait spots, and vitiligo, alone or in combination, occur with similar frequency. Short stature is common and in some patients is aggravated by subnormal growth hormone (GH) secretion or hypothyroidism. Male patients with FA may have an underdeveloped penis, undescended, atrophic, or absent testes, and hypospadias or phimosis, and all are infertile. Females can have malformations of the vagina, uterus, and ovary, and all have reduced fertility. Many patients have characteristic facial dysmorphisms, including microcephaly, small eyes, epicanthal folds, and abnormal shape, size, or positioning of the ears (Fig. 495.1B ). Kidneys may be ectopic, pelvic, horseshoe shaped, hypoplastic, dysplastic, or absent. Cardiovascular and gastrointestinal (GI) malformations also occur. Approximately 10% of patients with FA are cognitively delayed. Neonates with FA usually have intrauterine growth restriction and low birthweight and may show malformations consistent with VACTERL/VACTERL-H association (vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula with esophageal atresia, renal

and limb structural abnormalities with hydrocephalus).

FIG. 495.1 A 3 yr old boy with Fanconi anemia who exhibits several classic phenotypic features. A, Front view. B, Face. C, Hands. D, Back right shoulder. The features to be noted include short stature, dislocated hips, microcephaly, a broad nasal base, epicanthal folds, micrognathia, thumbs attached by a thread, and café-au-lait spots with hypopigmented areas beneath. (From Nathan DC, Orkin SH, Ginsburg D,