Principles and Practice of Transplant Infectious Diseases [1st ed.] 978-1-4939-9032-0;978-1-4939-9034-4

Table of contents :
Front Matter ....Pages i-xx
Front Matter ....Pages 1-1
Infections in Transplantation: Introduction and Overview (Amar Safdar)....Pages 3-19
Infections in Heart, Lung, and Heart-Lung Transplantation (Andrés F. Henao-Martínez, José G. Montoya)....Pages 21-39
Infections in Liver Transplantation (B. Sharmila Mohanraj, Amol S. Rangnekar, Joseph G. Timpone Jr.)....Pages 41-72
Infections in Kidney and Pancreas Transplantation (Megan K. Morales, Matthew Cooper, Peter Abrams, Joseph G. Timpone Jr.)....Pages 73-109
Infections in Intestinal and Multivisceral Transplantation (Raffaele Girlanda, Joseph G. Timpone Jr, Kevin M. Soriano, Thomas M. Fishbein)....Pages 111-139
Infections in Limbs, Integuments, and Face Transplantation (Justin M. Broyles, Chad R. Gordon)....Pages 141-151
Principles of Hematopoietic Stem Cell Transplantation (Michelle Limei Poon, Richard E. Champlin, Partow Kebriaei)....Pages 153-163
Infections in Pediatric Transplant Recipients (Aspasia Katragkou, Lucy O’Connor, Emmanuel Roilides, Thomas J. Walsh)....Pages 165-182
Front Matter ....Pages 183-183
Febrile Neutropenia in Transplant Recipients (Lior Nesher, Kenneth V. I. Rolston)....Pages 185-198
Cytopenias in Transplant Patients (Maura Barry, Sunandana Chandra, Kenneth B. Hymes)....Pages 199-207
Infections in Allogeneic Stem Cell Transplantation (Marcus R. Pereira, Stephanie M. Pouch, Brian Scully)....Pages 209-226
Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation (Jasmine Zain, Merav Bar, Amar Safdar)....Pages 227-247
Intravascular Catheter and Implantable Device Infections in Transplant Patients (Nasia Safdar, Cybele Lara R. Abad, Dennis G. Maki)....Pages 249-263
Surgical Site Infections: Wound and Stump Infections (Nasia Safdar, Sara A. M. Zerbel, Elizabeth Ann Misch)....Pages 265-272
Endovascular Infections and Endocarditis (Walter Zingg, Didier Pittet)....Pages 273-290
Gastrointestinal Infections and Clostridium difficile Infection (Stephen Harold, Herbert L. DuPont)....Pages 291-301
Hepatobiliary Tract Infections (Jonathan Merola, Robert M. Mocharla, Alexander Z. Jow, Samuel H. Sigal, Amar Safdar)....Pages 303-318
Ocular Infections in Transplant Patients (Ann-Marie Lobo, Lucia Sobrin, Marlene L. Durand)....Pages 319-330
Intracranial, Spinal, and Paraspinal Infections in the Transplant Recipient (Matthew W. McCarthy, Axel Rosengart, Thomas J. Walsh)....Pages 331-338
Respiratory Tract Infections: Sinusitis, Bronchitis, and Pneumonia (Benjamin A. Miko, Marcus R. Pereira, Amar Safdar)....Pages 339-349
Respiratory Tract Diseases That May Be Mistaken for Infection (Robert M. Kotloff, Burton F. Dickey, Nicholas Vander Els)....Pages 351-364
Skin and Soft Tissue Infection in Transplant Recipients (Robert G. Micheletti, Carrie L. Kovarik)....Pages 365-395
Cutaneous Lesions that Mimic Infection in Transplant Patients (Ana Ciurea, Sharon Hymes)....Pages 397-416
Front Matter ....Pages 417-417
Staphylococcus, Streptococcus, and Enterococcus (Amar Safdar, Donald Armstrong)....Pages 419-445
Enterobacteriaceae in Transplantation (Kathryn Whitaker, Valerie Cluzet, Emily A. Blumberg)....Pages 447-460
Pseudomonas, Stenotrophomonas, Acinetobacter, and Other Nonfermentative Gram-Negative Bacteria and Medically Important Anaerobic Bacteria in Transplant Recipients (Kenneth V. I. Rolston, Amar Safdar)....Pages 461-472
Nocardiosis and Actinomycosis (Heather E. Clauss, Bennett Lorber)....Pages 473-480
Listeriosis (Heather E. Clauss, Bennett Lorber)....Pages 481-489
Tuberculosis (Cynthia Portal-Celhay, Jennifer A. Philips)....Pages 491-502
Nontuberculous Mycobacterial Disease in Transplant Recipients (Julie V. Philley, Amar Safdar, Charles L. Daley)....Pages 503-517
Invasive Fungal Disease in the Transplant Population: An Overview (Jennifer L. Saullo, John R. Perfect, Barbara D. Alexander)....Pages 519-541
Candida Infections in Hematopoietic and Solid Organ Transplant Recipients (Alison G. Freifeld, Carol A. Kauffman)....Pages 543-557
Aspergillosis (Michael J. Satlin, Samantha E. Jacobs, Thomas J. Walsh)....Pages 559-576
Mucormycosis (Brad Spellberg, Johan Maertens)....Pages 577-589
Cryptococcus Infections in Transplant Recipients (Raymund R. Razonable, Pearlie P. Chong)....Pages 591-598
Histoplasmosis, Coccidioidomycosis, and Diseases Due to Other Endemic Fungi in Transplant Recipients (Pascalis Vergidis, Chadi A. Hage, L. Joseph Wheat)....Pages 599-609
Cytomegalovirus (Amar Safdar, Donald Armstrong)....Pages 611-642
Epstein-Barr Virus Infection and Posttransplant Lymphoproliferative Disease (Benjamin E. Gewurz, Elizabeth Moulton, Amy Bessnow, David M. Weinstock, Sheila Bond)....Pages 643-666
Herpes Simplex Viruses 1 and 2, Varicella Zoster Virus, and Human Herpes Viruses 6, 7, and 8 in Transplant Recipients (Raymund R. Razonable)....Pages 667-677
Respiratory Viral Infections in Transplant Recipients (Catherine Liu, Dora Y. Ho, Michael Boeckh)....Pages 679-695
Hepatitis A, B, and C (Jonathan Merola, Alexander Z. Jow, Samuel H. Sigal)....Pages 697-710
Enterovirus Infection in Immunocompromised Hosts (Joanna M. D. Schaenman, Dora Y. Ho, Lindsey R. Baden, Amar Safdar)....Pages 711-723
Parvovirus B19 (Morgan Hakki, Lynne Strasfeld)....Pages 725-733
West Nile Virus in Immunocompromised Hosts (Dora Y. Ho, Joanna M. D. Schaenman, Lindsey R. Baden)....Pages 735-752
Rare and Emerging Viral Infections in the Transplant Population (Susanna K. Tan, Jesse J. Waggoner, Stan Deresinski)....Pages 753-773
Parasitic Infections in Transplant Recipients: Toxoplasmosis, Strongyloidiasis, and Other Parasites (Brian G. Blackburn, José G. Montoya)....Pages 775-792
Front Matter ....Pages 793-793
Impacts and Challenges of Advanced Diagnostic Assays for Transplant Infectious Diseases (N. Esther Babady, Yeon Joo Lee, Genovefa Papanicolaou, Yi-Wei Tang)....Pages 795-818
Diagnosis of Systemic Fungal Diseases (Simon Frédéric Dufresne, Kieren A. Marr, Shmuel Shoham)....Pages 819-840
Viral Diagnostics (Robin K. Avery, Belinda Yen-Lieberman)....Pages 841-851
Front Matter ....Pages 853-853
Antibiotic Consideration in Transplant Recipients (Jerry Altshuler, Samuel L. Aitken, Melanie Maslow, John Papadopoulos, Amar Safdar)....Pages 855-901
Pharmacokinetics and Pharmacodynamics of Antibiotics in Transplant Patients (Kelly E. Schoeppler, Scott W. Mueller, Gerard R. Barber)....Pages 903-925
Antifungal Consideration for Transplant Recipients (Yanina Dubrovskaya, Man Yee Merl, David S. Perlin, Amar Safdar)....Pages 927-940
Immunomodulatory Properties of Antifungal Agents on Immune Functions of the Host (Maria Simitsopoulou, Emmanuel Roilides)....Pages 941-951
Antiviral Consideration for Transplantation Including Drug Resistance (Sunwen Chou, Nell S. Lurain)....Pages 953-975
Pharmacokinetics and Pharmacodynamics of Antiviral Drugs in Special Population (Marco R. Scipione, John Papadopoulos)....Pages 977-1001
Antimycobacterial Consideration in Transplantation Including Drug Non-susceptibility and Resistance: Tuberculosis and Nontuberculous Mycobacterial Disease (Julie V. Philley, David E. Griffith)....Pages 1003-1017
Adaptive Immunotherapy for Opportunistic Infections (Aspasia Katragkou, Thomas J. Walsh, Emmanuel Roilides)....Pages 1019-1030
Immunotherapy for Invasive Mold Disease in Transplant Patients: Dendritic Cell Immunotherapy, Interferon Gamma, Recombinant Myeloid Growth Factors, and Healthy Donor Granulocyte Transfusions (William K. Decker, Matthew M. Halpert, Vanaja Konduri, Dan Liang, Christopher N. Hampton, Amar Safdar)....Pages 1031-1040
Antimicrobial Stewardship: Considerations for a Transplant Center (Susan K. Seo, Graeme N. Forrest)....Pages 1041-1051
The Use of Palliative Care in Organ Transplant Patients and End-of-Life Issues (Jenny S. Ayala, Joseph Lowy)....Pages 1053-1066
Front Matter ....Pages 1067-1067
Infection Control Strategies in Transplant Populations (S. Cutro, M. Phillips, H. W. Horowitz)....Pages 1069-1080
Travel and Transplantation (Camille Nelson Kotton, José G. Montoya)....Pages 1081-1094
Vaccination in Organ Transplant Patients (Lara Danziger-Isakov, Camille Nelson Kotton)....Pages 1095-1109
Prevention of Fungal Disease (Shirish Huprikar, John R. Wingard)....Pages 1111-1121
Antimicrobial Drug Prophylaxis: Challenges and Controversies (Gaurav Trikha, Marcio Nucci, John R. Wingard, Amar Safdar)....Pages 1123-1135
Back Matter ....Pages 1137-1173

Citation preview

Amar Safdar  Editor

Principles and Practice of Transplant Infectious Diseases

123

Principles and Practice of Transplant Infectious Diseases

Amar Safdar Editor

Principles and Practice of Transplant Infectious Diseases

Editor Amar Safdar Clinical Associate Professor of Medicine Texas Tech University Health Sciences Center El Paso Paul L. Foster School of Medicine El Paso, TX USA

ISBN 978-1-4939-9032-0    ISBN 978-1-4939-9034-4 (eBook) https://doi.org/10.1007/978-1-4939-9034-4 © Springer Science+Business Media, LLC, part of Springer Nature 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Science+Business Media, LLC part of Springer Nature. The registered company address is: 233 Spring Street, New York, NY 10013, U.S.A.

This book is dedicated to my parents, Taj & Safdar, for enduring inspiration and tenacity of purpose.

Preface

In pursuit of recognizing the risk of infection in patients undergoing transplantation, prescient cognizance requires sagacious understanding of hosts’ home and healthcare environment, factors pertaining to the level of immune suppression that may have accumulated overtime, and, importantly, recent alterations in immune function resulting from additional immunosuppressive treatments such as donor lymphocyte transfusion, antineoplastic therapy, and immune modulatory biologic drugs and medical disorders like graft-versus-host disease, donor allograft rejection, posttransplant opportunistic malignancies, recrudescent or newly acquired cytomegalovirus infection, and relapsed hematologic neoplasms. It is prudent to establish a targeted approach toward diagnosis, an approach which portends recognition of the true etiology with the help of assiduous investigation based on patient-­ specific vulnerability for infection. Special consideration needs to be placed upon the possibility of noninfectious processes that clinically are often difficult to distinguish from infection or sepsis-like syndrome. Toxicity due to commonly used drugs in the posttransplant period, thromboembolic events, acute engraftment syndrome, postsurgical deep tissue and body cavity hematoma, tissue ischemia and necrosis, opportunistic malignancies, and the potential for less common paraneoplastic disorders including tumor fever may initially present as a nonspecific acute febrile illness, with or without features suggestive of systemic inflammatory response syndrome. Similarly, a host of noninfectious maladies involving the skin and skin structures, brain, orointestinal tract, liver, kidneys, and lungs may clinically resemble infection. It is important to take into account that such processes may occur concurrently or sequentially in patients with a known infection diagnosis. Furthermore, in immunosuppressed patients after hematopoietic or solid organ allograft transplantation, plurality of simultaneously occurring infections makes selection of targeted, pathogen-specific empiric therapy a daunting task. Individuals’ genetic haecceity and its influence on susceptibility or inherent resistance to certain infections is evolving. Once validated and available for clinical use, this has the potential to reliably identify select subgroups of transplant recipients that are additionally vulnerable to specific infection(s). Infection prevention and empiric or preemptive treatment strategies in such patients may advance from the putative and arbitrary risk profiles presently in use. This volume aims to provide a comprehensive and in-depth review of the issues pertaining to infectious diseases in patients undergoing transplantation. El Paso, TX, USA

Amar Safdar, MD

vii

Contents

Part I Principles of Transplantation and Overview of Infectious Diseases 1 Infections in Transplantation: Introduction and Overview ���������������������������������    3 Amar Safdar 2 Infections in Heart, Lung, and Heart-­Lung Transplantation �����������������������������   21 Andrés F. Henao-Martínez and José G. Montoya 3 Infections in Liver Transplantation�������������������������������������������������������������������������   41 B. Sharmila Mohanraj, Amol S. Rangnekar, and Joseph G. Timpone Jr. 4 Infections in Kidney and Pancreas Transplantation���������������������������������������������   73 Megan K. Morales, Matthew Cooper, Peter Abrams, and Joseph G. Timpone Jr. 5 Infections in Intestinal and Multivisceral Transplantation�����������������������������������  111 Raffaele Girlanda, Joseph G. Timpone Jr, Kevin M. Soriano, and Thomas M. Fishbein 6 Infections in Limbs, Integuments, and Face Transplantation �����������������������������  141 Justin M. Broyles and Chad R. Gordon 7 Principles of Hematopoietic Stem Cell Transplantation���������������������������������������  153 Michelle Limei Poon, Richard E. Champlin, and Partow Kebriaei 8 Infections in Pediatric Transplant Recipients �������������������������������������������������������  165 Aspasia Katragkou, Lucy O’Connor, Emmanuel Roilides, and Thomas J. Walsh Part II Clinical Disorders in Transplant Recipients 9 Febrile Neutropenia in Transplant Recipients�������������������������������������������������������  185 Lior Nesher and Kenneth V. I. Rolston 10 Cytopenias in Transplant Patients���������������������������������������������������������������������������  199 Maura Barry, Sunandana Chandra, and Kenneth B. Hymes 11 Infections in Allogeneic Stem Cell Transplantation�����������������������������������������������  209 Marcus R. Pereira, Stephanie M. Pouch, and Brian Scully 12 Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation���������������������������������������������������������������������������������  227 Jasmine Zain, Merav Bar, and Amar Safdar 13 Intravascular Catheter and Implantable Device Infections in Transplant Patients���������������������������������������������������������������������������������������������������  249 Nasia Safdar, Cybele Lara R. Abad, and Dennis G. Maki 14 Surgical Site Infections: Wound and Stump Infections�����������������������������������������  265 Nasia Safdar, Sara A. M. Zerbel, and Elizabeth Ann Misch ix

x

15 Endovascular Infections and Endocarditis�������������������������������������������������������������  273 Walter Zingg and Didier Pittet 16 Gastrointestinal Infections and Clostridium difficile Infection�����������������������������  291 Stephen Harold and Herbert L. DuPont 17 Hepatobiliary Tract Infections���������������������������������������������������������������������������������  303 Jonathan Merola, Robert M. Mocharla, Alexander Z. Jow, Samuel H. Sigal, and Amar Safdar 18 Ocular Infections in Transplant Patients���������������������������������������������������������������  319 Ann-Marie Lobo, Lucia Sobrin, and Marlene L. Durand 19 Intracranial, Spinal, and Paraspinal Infections in the Transplant Recipient�����  331 Matthew W. McCarthy, Axel Rosengart, and Thomas J. Walsh 20 Respiratory Tract Infections: Sinusitis, Bronchitis, and Pneumonia�������������������  339 Benjamin A. Miko, Marcus R. Pereira, and Amar Safdar 21 Respiratory Tract Diseases That May Be Mistaken for Infection �����������������������  351 Robert M. Kotloff, Burton F. Dickey, and Nicholas Vander Els 22 Skin and Soft Tissue Infection in Transplant Recipients���������������������������������������  365 Robert G. Micheletti and Carrie L. Kovarik 23 Cutaneous Lesions that Mimic Infection in Transplant Patients�������������������������  397 Ana Ciurea and Sharon Hymes Part III Etiologic Agents in Infectious Diseases 24 Staphylococcus, Streptococcus, and Enterococcus �������������������������������������������������  419 Amar Safdar and Donald Armstrong 25 Enterobacteriaceae in Transplantation�������������������������������������������������������������������  447 Kathryn Whitaker, Valerie Cluzet, and Emily A. Blumberg 26 Pseudomonas, Stenotrophomonas, Acinetobacter, and Other Nonfermentative Gram-Negative Bacteria and Medically Important Anaerobic Bacteria in Transplant Recipients�����������������������������������������������������������������������������������������������  461 Kenneth V. I. Rolston and Amar Safdar 27 Nocardiosis and Actinomycosis�������������������������������������������������������������������������������  473 Heather E. Clauss and Bennett Lorber 28 Listeriosis�������������������������������������������������������������������������������������������������������������������  481 Heather E. Clauss and Bennett Lorber 29 Tuberculosis���������������������������������������������������������������������������������������������������������������  491 Cynthia Portal-Celhay and Jennifer A. Philips 30 Nontuberculous Mycobacterial Disease in Transplant Recipients�����������������������  503 Julie V. Philley, Amar Safdar, and Charles L. Daley 31 Invasive Fungal Disease in the Transplant Population: An Overview�����������������  519 Jennifer L. Saullo, John R. Perfect, and Barbara D. Alexander 32 Candida Infections in Hematopoietic and Solid Organ Transplant Recipients�����������������������������������������������������������������������������������������������  543 Alison G. Freifeld and Carol A. Kauffman 33 Aspergillosis���������������������������������������������������������������������������������������������������������������  559 Michael J. Satlin, Samantha E. Jacobs, and Thomas J. Walsh

Contents

Contents

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34 Mucormycosis�����������������������������������������������������������������������������������������������������������  577 Brad Spellberg and Johan Maertens 35 Cryptococcus Infections in Transplant Recipients�������������������������������������������������  591 Raymund R. Razonable and Pearlie P. Chong 36 Histoplasmosis, Coccidioidomycosis, and Diseases Due to Other Endemic Fungi in Transplant Recipients�������������������������������������������������������������������������������  599 Pascalis Vergidis, Chadi A. Hage, and L. Joseph Wheat 37 Cytomegalovirus�������������������������������������������������������������������������������������������������������  611 Amar Safdar and Donald Armstrong 38 Epstein-Barr Virus Infection and Posttransplant Lymphoproliferative Disease�����������������������������������������������������������������������������������  643 Benjamin E. Gewurz, Elizabeth Moulton, Amy Bessnow, David M. Weinstock, and Sheila Bond 39 Herpes Simplex Viruses 1 and 2, Varicella Zoster Virus, and Human Herpes Viruses 6, 7, and 8 in Transplant Recipients�������������������������������  667 Raymund R. Razonable 40 Respiratory Viral Infections in Transplant Recipients�����������������������������������������  679 Catherine Liu, Dora Y. Ho, and Michael Boeckh 41 Hepatitis A, B, and C �����������������������������������������������������������������������������������������������  697 Jonathan Merola, Alexander Z. Jow, and Samuel H. Sigal 42 Enterovirus Infection in Immunocompromised Hosts �����������������������������������������  711 Joanna M. D. Schaenman, Dora Y. Ho, Lindsey R. Baden, and Amar Safdar 43 Parvovirus B19 ���������������������������������������������������������������������������������������������������������   725 Morgan Hakki and Lynne Strasfeld 44 West Nile Virus in Immunocompromised Hosts ���������������������������������������������������  735 Dora Y. Ho, Joanna M. D. Schaenman, and Lindsey R. Baden 45 Rare and Emerging Viral Infections in the Transplant Population���������������������  753 Susanna K. Tan, Jesse J. Waggoner, and Stan Deresinski 46 Parasitic Infections in Transplant Recipients: Toxoplasmosis, Strongyloidiasis, and Other Parasites���������������������������������������������������������������������  775 Brian G. Blackburn and José G. Montoya Part IV Diagnosis of Infectious Diseases in Special Host 47 Impacts and Challenges of Advanced Diagnostic Assays for Transplant Infectious Diseases���������������������������������������������������������������������������������  795 N. Esther Babady, Yeon Joo Lee, Genovefa Papanicolaou, and Yi-Wei Tang 48 Diagnosis of Systemic Fungal Diseases�������������������������������������������������������������������  819 Simon Frédéric Dufresne, Kieren A. Marr, and Shmuel Shoham 49 Viral Diagnostics�������������������������������������������������������������������������������������������������������  841 Robin K. Avery and Belinda Yen-Lieberman Part V Therapeutics and Management of Patients Undergoing Transplantation 50 Antibiotic Consideration in Transplant Recipients�����������������������������������������������  855 Jerry Altshuler, Samuel L. Aitken, Melanie Maslow, John Papadopoulos, and Amar Safdar

xii

51 Pharmacokinetics and Pharmacodynamics of Antibiotics in Transplant Patients�����������������������������������������������������������������������������������������������  903 Kelly E. Schoeppler, Scott W. Mueller, and Gerard R. Barber 52 Antifungal Consideration for Transplant Recipients �������������������������������������������  927 Yanina Dubrovskaya, Man Yee Merl, David S. Perlin, and Amar Safdar 53 Immunomodulatory Properties of Antifungal Agents on Immune Functions of the Host �����������������������������������������������������������������������������������������������  941 Maria Simitsopoulou and Emmanuel Roilides 54 Antiviral Consideration for Transplantation Including Drug Resistance�����������  953 Sunwen Chou and Nell S. Lurain 55 Pharmacokinetics and Pharmacodynamics of Antiviral Drugs in Special Population �����������������������������������������������������������������������������������������������������������������  977 Marco R. Scipione and John Papadopoulos 56 Antimycobacterial Consideration in Transplantation Including Drug Non-susceptibility and Resistance: Tuberculosis and Nontuberculous Mycobacterial Disease ��������������������������������������������������������������������������������������������� 1003 Julie V. Philley and David E. Griffith 57 Adaptive Immunotherapy for Opportunistic Infections��������������������������������������� 1019 Aspasia Katragkou, Thomas J. Walsh, and Emmanuel Roilides 58 Immunotherapy for Invasive Mold Disease in Transplant Patients: Dendritic Cell Immunotherapy, Interferon Gamma, Recombinant Myeloid Growth Factors, and Healthy Donor Granulocyte Transfusions����������� 1031 William K. Decker, Matthew M. Halpert, Vanaja Konduri, Dan Liang, Christopher N. Hampton, and Amar Safdar 59 Antimicrobial Stewardship: Considerations for a Transplant Center����������������� 1041 Susan K. Seo and Graeme N. Forrest 60 The Use of Palliative Care in Organ Transplant Patients and End-of-Life Issues����������������������������������������������������������������������������������������������������� 1053 Jenny S. Ayala and Joseph Lowy Part VI Infection Prevention 61 Infection Control Strategies in Transplant Populations��������������������������������������� 1069 S. Cutro, M. Phillips, and H. W. Horowitz 62 Travel and Transplantation������������������������������������������������������������������������������������� 1081 Camille Nelson Kotton and José G. Montoya 63 Vaccination in Organ Transplant Patients������������������������������������������������������������� 1095 Lara Danziger-Isakov and Camille Nelson Kotton 64 Prevention of Fungal Disease����������������������������������������������������������������������������������� 1111 Shirish Huprikar and John R. Wingard 65 Antimicrobial Drug Prophylaxis: Challenges and Controversies ����������������������� 1123 Gaurav Trikha, Marcio Nucci, John R. Wingard, and Amar Safdar Index���������������������������������������������������������������������������������������������������������������������������������  1137

Contents

Contributors

Cybele Lara R. Abad  Section of Infectious Diseases, Department of Medicine, University of the Philippines, Philippine General Hospital, Manila, Philippines Peter  Abrams  MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC, USA Samuel L. Aitken  Infectious Diseases, The University of Texas MD Anderson Cancer Center, Division of Pharmacy, Houston, TX, USA Barbara  D.  Alexander Duke University Medical Center, Departments of Medicine and Pathology, Division of Infectious Diseases and International Health, Durham, NC, USA Jerry Altshuler  The Mount Sinai Hospital, Department of Pharmacy, New York, NY, USA Donald  Armstrong  Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Cornell University Medical College (ret), New York, NY, USA Infectious Disease Society of America, Albuquerque, NM, USA Robin K. Avery  Division of Infectious Disease, Johns Hopkins, Baltimore, MD, USA Jenny S. Ayala  Hospice and Palliative Medicine, Hospital Medicine, White Plains Hospital, White Plains, NY, USA N.  Esther  Babady Department of Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Lindsey R. Baden  Division of Infectious Diseases, Brigham and Women’s Hospital, Dana-­ Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Merav  Bar  Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA Gerard  R.  Barber Department of Pharmacy Services, University of Colorado Hospital, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA Maura Barry  University of Vermont College of Medicine, University of Vermont Medical Center, Division of Hematology & Oncology, Burlington, VT, USA Brian G. Blackburn  Stanford University Medical Center, Palo Alto, CA, USA Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA Emily  A.  Blumberg  Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Philadelphia, PA, USA xiii

xiv

Michael  Boeckh Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Washington, DC, USA Justin  M.  Broyles  Department of Plastic and Reconstructive Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA Richard E. Champlin  MD Anderson Cancer Center, Department of Stem Cell Transplantation and Cellular Therapy, Houston, TX, USA Sunandana  Chandra  Northwestern University Feinberg School of Medicine, Division of Hematology & Oncology, Chicago, IL, USA Pearlie P. Chong  Division of Infectious Diseases, Department of Medicine, and the William J. von Liebig Transplant Center, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA University of North Carolina at Chapel Hill, Division of Infectious Diseases, Chapel Hill, NC, USA Sunwen  Chou Oregon Health and Science University, Division of Infectious Diseases, Portland, OR, USA Ana  Ciurea  Department of Dermatology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA Heather  E.  Clauss Section of Infectious Diseases, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA Temple University, Philadelphia, PA, USA Temple University Hospital, Department of Infectious Diseases, Philadelphia, PA, USA Valerie Cluzet  Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Health Quest Medical Practice, Department of Infectious Diseases, Poughkeepsie, NY, USA Matthew Cooper  MedStar Georgetown Transplant Institute, Washington, DC, USA Scott Cutro  Department of Infectious Disease, The Southeast Permanente Medical Group, Kaiser Permanente, Atlanta, GA, USA Charles  L.  Daley Division of Mycobacterial and Respiratory Infections, National Jewish Health and University of Colorado, Denver, CO, USA Lara Danziger-Isakov  Pediatric Infectious Diseases, Immunocompromised Host Infectious Disease, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA William K. Decker  Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA Stan Deresinski  Stanford University School of Medicine, Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford, CA, USA Burton F. Dickey  Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA Yanina Dubrovskaya  NYU Langone Medical Center, NYU Langone Health, Department of Pharmacy, New York, NY, USA Simon  Frédéric  Dufresne Hôpital Maisonneuve-Rosemont, Université de Montréal, Department of Infectious Diseases and Medical Microbiology, Montréal, QC, Canada

Contributors

Contributors

xv

Herbert  L.  DuPont, MD Baylor St. Luke’s Medical Center, Department of Research, Houston, TX, USA Program in Infectious Diseases, University of Texas School of Public Health, Houston, TX, USA Kelsey Research Foundation, Houston, TX, USA Baylor College of Medicine, Houston, TX, USA University of Texas School of Medicine Houston, Houston, TX, USA Marlene L. Durand  Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA Department of Medicine, Infectious Disease Unit, Massachusetts General Hospital, Boston, MA, USA Infectious Disease Service, Massachusetts Eye and Ear Infirmary, Boston, MA, USA Thomas  M.  Fishbein Georgetown University Hospital, Transplant Institute, Washington, DC, USA Graeme N. Forrest  Division of Infectious Diseases, Portland VA Medical Center and Oregon Health and Science University, Portland, OR, USA Alison  G.  Freifeld Infectious Diseases Division, University of Nebraska Medical Center, Omaha, NE, USA Benjamin  E.  Gewurz Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine, Boston, MA, USA Raffaele  Girlanda Georgetown University Hospital, Department Transplant Surgery, Washington, DC, USA Chad  R.  Gordon Department of Plastic and Reconstructive Surgery, The Johns Hopkins Hospital, Baltimore, MD, USA David E. Griffith  University of Texas Health Science Center, Tyler, TX, USA Heartland National TB Center, Tyler, TX, USA Chadi A. Hage  Indiana University School of Medicine, Pulmonary-Critical Care, Thoracic Transplantation Program, Methodist Professional Center-2, Indianapolis, IN, USA Morgan  Hakki Oregon Health and Science University, Division of Infectious Diseases, Portland, OR, USA Matthew  M.  Halpert Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA Christopher  N.  Hampton Department of Pathology and Immunology, Baylor College of Medicine, Huffington Center on Aging, Houston, TX, USA Stephen  Harold, MD, MPH  Baylor St. Luke’s Medical Center, Department of Research, Houston, TX, USA Andrés  F.  Henao-Martínez Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, CO, USA Dora Y. Ho  Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA

xvi

Harold W. Horowitz  New University School of Medicine, Division of Infectious Diseases and Immunology, New York, NY, USA Weill Cornell Medicine, New York—Presbyterian—Brooklyn Methodist Hospital, Department of Medicine, Division of Infectious Diseases, Brooklyn, NY, USA Shirish Huprikar  The Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA Kenneth  B.  Hymes Hematology, Coagulation, and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA Sharon Hymes  Department of Dermatology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA Samantha  E.  Jacobs Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA Transplant Infectious Diseases Program, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, Department of Medicine, New York, NY, USA Alexander Z. Jow  Division of Gastroenterology, Mid-Atlantic Kaiser Permanente Medical Group, Springfield, VA, USA Aspasia  Katragkou Transplantation-Oncology Infectious Diseases Program, New  York-­ Presbyterian/Weill Cornell Medical Center, New York, NY, USA 3rd Department of Pediatrics, Aristotle University, Hippokration Hospital, Thessaloniki, Greece Nationwide Children’s Hospital, Department of Pediatric Infectious Diseases, Columbus, OH, USA Carol  A.  Kauffman  University of Michigan Medical School, Infectious Diseases Section, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA Partow Kebriaei  MD Anderson Cancer Center, Department of Stem Cell Transplantation and Cellular Therapy, Houston, TX, USA Vanaja  Konduri  Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA Robert  M.  Kotloff Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA Camille  Nelson  Kotton Transplant and Immunocompromised Host Infectious Diseases, Division of Infectious Diseases, Massachusetts General Hospital, Travelers’ Advice and Immunization Center, Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Carrie L. Kovarik  Departments of Medicine and Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Yeon Joo Lee  Department of Internal Medicine, Infectious Diseases Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, Cornell University, New York, NY, USA Dan Liang  Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA Catherine Liu  Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Washington, DC, USA Ann-Marie Lobo  Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA

Contributors

Contributors

xvii

Bennett Lorber  Section of Infectious Diseases, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA Temple University, Philadelphia, PA, USA Temple University Hospital, Department of Infectious Diseases, Philadelphia, PA, USA Joseph Lowy  NYU Langone Health, NYU Medical School, Department of Medicine, New York, NY, USA Nell S. Lurain  Rush University Medical Center, Department of Immunology/Microbiology, Chicago, IL, USA Johan Maertens  Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, University Hospital Gasthuisberg, K. U. Leuven, Leuven, Belgium Dennis  G.  Maki Section of Infectious Diseases, Department of Medicine, University of Wisconsin-Madison, School of Medicine and Public Health, and the William S.  Middleton Memorial Veterans Hospital, Madison, WI, USA Kieren A. Marr  Johns Hopkins University, Department of Medicine, Baltimore, MD, USA Melanie Maslow  New York University School of Medicine, New York, NY, USA Matthew W. McCarthy  Weill Cornell Medicine, Department of General Internal Medicine, New York, NY, USA Man Yee Merl  Smilow Cancer Hospital at Yale-New Haven Health, Department of Pharmacy, New Haven, CT, USA Jonathan  Merola Department of Surgery, Yale School of Medicine, Yale-New Haven Hospital, New Haven, CT, USA Robert  G.  Micheletti Departments of Medicine and Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Benjamin  A.  Miko  Columbia University Medical Center, Division of Infectious Diseases, Department of Medicine, New York, NY, USA Elizabeth Ann Misch  University of Wisconsin Hospital, Department of Medicine, Division of Allergy and Infectious Disease, Madison, WI, USA University of Wisconsin-Madison, School of Medicine and Public Health, Department of Medicine, Madison, WI, USA Sheila  Mitsuma  Massachusetts General Hospital, Division of Infectious Diseases, Boston, MA, USA Robert M. Mocharla  Division of Gastroenterology, NYU School of Medicine, Department of Internal Medicine, New York, NY, USA B. Sharmila Mohanraj  MedStar Georgetown University Hospital, Department of Infectious Diseases and Travel Medicine, Washington, DC, USA José  G.  Montoya Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA Palo Alto Medical Foundation Toxoplasma Serology Laboratory, National Reference Center for the Study and Diagnosis of Toxoplasmosis, Palo Alto, CA, USA Stanford University Medical Center, Palo Alto, CA, USA Megan K. Morales  University of Maryland School of Medicine, Institute of Human Virology/ Department of Infectious Diseases, Baltimore, MD, USA Scott  W.  Mueller Department of Clinical Pharmacy, University of Colorado Hospital, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA

xviii

Lior Nesher  Infectious Disease Institute, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel Soroka University Medical Center affiliated with Faculty of Health Sciences Ben-Gurion University of the Negev, Infectious Disease Institute, Beer Sheba, Israel Marcio Nucci  University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil Hospital Universitário Clementino Fraga Filho, Department of Internal Medicine – Hematology, Rio de Janeiro, RJ, Brazil Lucy  O’Connor Transplantation-Oncology Infectious Diseases Program, New  York-­ Presbyterian/Weill Cornell Medical Center, New York, NY, USA University of Manchester School of Medicine, Manchester, UK John Papadopoulos  Department of Pharmacy, Division of Pharmacotherapy, NYU Langone Medical Center, New York, NY, USA Genovefa  Papanicolaou Department of Internal Medicine, Infectious Diseases Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, Cornell University, New York, NY, USA Memorial Sloan Kettering Cancer Center, Memorial Hospital, Department of Medicine, New York, NY, USA Marcus  R.  Pereira Department of Medicine – Infectious Diseases, Columbia University Medical Center, New York, NY, USA John R. Perfect  Duke University Medical Center, Departments of Medicine and Pathology, Division of Infectious Diseases and International Health, Durham, NC, USA David S. Perlin  Public Health Research Institute, Rutgers Biomedical and Health Sciences, Rutgers New Jersey Medical School, Newark, NJ, USA Jennifer  A.  Philips  Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA Julie V. Philley  University of Texas Health Science Center at Tyler, Department of Pulmonary and Critical Care Medicine, Tyler, TX, USA Michael Phillips  New University School of Medicine, Division of Infectious Diseases and Immunology, New York, NY, USA Didier Pittet  Infection Control Programme and WHO Collaborating Centre on Patient Safety, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland Michelle Limei Poon  National University Hospital, Department of Hematology Oncology, Singapore, Singapore Cynthia  Portal-Celhay Division of Infectious Diseases, Department of Medicine, NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA Stephanie  M.  Pouch  Division of Infectious Diseases, Emory University, Atlanta, GA, USA Amol  S.  Rangnekar MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC, USA Raymund R. Razonable  Division of Infectious Diseases, Department of Medicine, and the William J. von Liebig Center for Transplantation and Clinical Regeneration, College of Medicine, Mayo Clinic, Rochester, MN, USA

Contributors

Contributors

xix

Emmanuel Roilides  3rd Department of Pediatrics, Hippokration Hospital, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece Kenneth  V.  I.  Rolston  Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Axel Rosengart  Cedars-Sinai Medical Center, Departments of Neurology, Neurosurgery and Biomedical Sciences, Los Angeles, CA, USA Amar  Safdar Clinical Associate Professor of Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, USA Nasia  Safdar Section of Infectious Diseases, Department of Medicine, University of Wisconsin-Madison, School of Medicine and Public Health, and the William S.  Middleton Memorial Veterans Hospital, Madison, WI, USA Michael  J.  Satlin Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA Jennifer L. Saullo  Duke University Medical Center, Department of Medicine, Division of Infectious Diseases and International Health, Durham, NC, USA Joanna M. D. Schaenman  Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Kelly  E.  Schoeppler Department of Pharmacy Services, University of Colorado Health, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA Marco R. Scipione  Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY, USA Brian  Scully Columbia University Medical Center, Division of Infectious Diseases, Department of Medicine, New York, NY, USA Susan K. Seo  Department of Medicine, Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Shmuel  Shoham  Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, MD, USA Amy  Sievers Dana-Farber Cancer Institute, Division of Medical Oncology, Boston, MA, USA Samuel  H.  Sigal  Division of Gastroenterology and Hepatology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA Maria  Simitsopoulou  Research Infectious Disease Laboratory, 3rd Department Pediatrics, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece Lucia Sobrin  Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA Kevin  M.  Soriano Georgetown University Hospital, Department of Infectious Diseases, Washington, DC, USA Brad Spellberg  Los Angeles County+University of Southern California (LAC+USC) Medical Center, Los Angeles, CA, USA Division of Infectious Diseases, Keck School of Medicine at USC, Los Angeles, CA, USA Lynne  Strasfeld Oregon Health and Science University, Division of Infectious Diseases, Portland, OR, USA

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Susanna K. Tan  Stanford University School of Medicine, Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford, CA, USA Yi-Wei Tang  Department of Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, Cornell University, New York, NY, USA Joseph  G.  Timpone Jr. MedStar Georgetown University Hospital, Division of Infectious Diseases and Travel Medicine, Washington, DC, USA Gaurav Trikha  Division of Infectious Diseases, University of Florida College of Medicine, Gainesville, FL, USA University of Florida Health Shands Hospital, Division of Hematology/Oncology, Department of Medicine, Gainesville, FL, USA Nicholas Vander Els  Pulmonary Service, Memorial Sloan- Kettering Cancer Center, New York, NY, USA Pascalis  Vergidis University Hospital of South Manchester, University of Manchester, Department of Medicine, Manchester, UK Jesse J. Waggoner  Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Atlanta, GA, USA Thomas  J.  Walsh Transplantation-Oncology Infectious Diseases Program, New  York-­ Presbyterian/Weill Cornell Medical Center, New York, NY, USA Department of Pediatrics, New York-Presbyterian/Weill Cornell Medical Center, New York, NY, USA Department of Microbiology and Immunology, New York-Presbyterian/Weill Cornell Medical Center, New York, NY, USA Transplant Infectious Diseases Program, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA David  M.  Weinstock  Dana-Farber Cancer Institute, Harvard Medical School, Division of Medical Oncology, Boston, MA, USA L. Joseph Wheat  MiraVista Diagnostics, Indianapolis, IN, USA Kathryn  Whitaker Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Hospital at the University of Pennsylvania, Philadelphia, PA, USA John R. Wingard  University of Florida, Division of Hematology/Oncology, Department of Medicine, Gainesville, FL, USA Belinda  Yen-Lieberman Pathology and Laboratory Medicine Institute, Cleveland Clinic, Department of Laboratory Medicine, Cleveland, OH, USA Jasmine  Zain City of Hope National Medical Center, Department of Hematology/ Hematopoietic Cell Transplantation, Duarte, CA, USA Sara  A.  M.  Zerbel  UnityPoint Health-Meriter, Department of Performance Improvement, Madison, WI, USA Walter  Zingg Infection Control Programme and WHO Collaborating Centre on Patient Safety, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland

Contributors

Part I Principles of Transplantation and Overview of Infectious Diseases

1

Infections in Transplantation: Introduction and Overview Amar Safdar

Transplantation remains a pioneering scientific innovation that has a significant impact on restoring well-being for patients and benefit society as a whole. Blood and marrow hematopoietic stem cells have become accepted and, in some instances, established approach to treat incurable neoplastic diseases and congenital disorders of immune system [1]. Similarly, use of allografts in patients with end-stage organ disease involving the liver, kidneys, intestines, heart, and lungs has provided a possibility for continuation of life and a potential for patients to integrate and resume participation in their communities [2]. Recent advances in limb, integument, and face transplantation underscore the substantial leap forward in restoring normalcy for individuals with devastating and often catastrophic physical encumbrance [3, 4]. In patients undergoing solid organ transplantation, advancement in understanding the complex interplay within various facets of immune response against the transplanted allogeneic tissue that recipients’ immune system fails to recognize as “self” has resulted in encouraging long-term outcomes [5]. These achievements in decoding higher mammalian immunity underscore the recent progress made in development and implementation of refined strategies to harness potentially devastating immune rejection of the implanted solid organ allograft [6]. The antirejection strategies, as expected, involve a delicate balance that favors preservation of a functioning allograft and aims at limit severity of drug-induced suppression of recipients’ immune function, which is crucial for the surveillance against various neoplastic processes; conventional and opportunistic infections.

A. Safdar (*) Clinical Associate Professor of Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, USA e-mail: [email protected]

A similar, albeit an opposing role of undesired immune response comes into play in patients undergoing hematopoietic blood and marrow stem cell transplantation from a foreign donor. The conflict arises from aforementioned disconnect between immune recognition of self versus nonself [7, 8]. These transplanted stem cells install foreign effector immune cells in the recipient, and if remain unabated, the resulting graft-versus-host disease is capable of unleashing potentially ruinous systemic inflammation resulting in irreversible tissue damage and death [7]. The stem cell graft restores immunity and functional marrow in patients in need for myeloablative antineoplastic therapy. Furthermore, it is the foreign, graft-mediated, adaptive cancer immune surveillance that has now been widely recognized as the pivotal feature that sustains cancer in remission following successful allogeneic hematopoietic stem cell transplantation. This feature of stem cell graft-assisted antitumor response is recognized as “graftversus-leukemia or graft-versus-tumor  effect.” Donorderived adaptive antitumor immunity is an important objective of allogeneic stem cell transplantation, especially in patients with hematologic malignancies, and forms the bases for donor lymphocyte infusions to treat cancer recurrences during posttransplant period [9]. As in patients following solid organ transplants, in recipients of allogeneic HSCT, anti-GVHD therapy is assessed and continuously refined to achieve the lowest possible cumulative iatrogenic immune suppression required to prevent or treat GVHD, whereas an earnest attempt is made for preservation of recipients’ immune function such that the risk of conventional and opportunistic infections and malignancies do not overwhelm the projected efficacy and feasibility of these lifesaving procedures. A number of agents have been successfully used for prevention and treatment of graft-versus-host disease and solid organ allograft rejection [8, 10]. Severity of immune dysfunction is in most instance a direct consequence of treatment with these agents that are commonly prescribed

© Springer Science+Business Media, LLC, part of Springer Nature 2019 A. Safdar (ed.), Principles and Practice of Transplant Infectious Diseases, https://doi.org/10.1007/978-1-4939-9034-4_1

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as combination drug regimens. Cyclosporine was the first major breakthrough in this regard; subsequent generation calcineurin inhibitors (CNI) have improved therapeutic index although resultant severe immune suppression and the risk for opportunistic infection like CMV, BK virus, and certain posttransplant cancers question the therapeutic feasibility for agents such as tacrolimus, especially in patients with low risk for allograft-related complications. Serious infections due to cytomegalovirus including viremia and end-organ disease, BK virus viremia, viruria, and BK  virus  allograft nephropathy with risk for potential graft compromise, rare progressive multifocal leukoencephalopathy due to polyomavirus, higher potential for opportunist cancers such as Kaposi’s sarcoma, EBV lymphoproliferative disorders among others, are well-recognized limitations in individuals given tacrolimus for extended duration with doses leading to prolong  high serum drug concentration [11]. Experience with sirolimus, a macrolide xenobiotic that induces potent immune suppression via inhibition of mechanistic target of rapamycin (mTOR; a conserved threonine and serine protein kinase) was associated with lower incidence of CMV infection in solid organ transplant recipients. This protective antiviral effect of mTOR inhibitors against BK virus nephropathy after renal transplantation has not been noted  consistently. Additionally, antitumor properties of mTOR inhibitors may favorably influence the lower incidence and risk for posttransplant malignancies in recipients of solid organ allografts, especially those with a profile that indicates low risk for graft rejection [12]. Monoclonal antibodies against T- and B-cell pathways have also gained prominence, as potential treatment options. Alemtuzumab (Campath) is a monoclonal antibody that targets C52 antigen expressed on all lymphocytes. Treatment with Campath results in profound lymphocyte depletion. The drug-induced immune suppression may last for up to 9  months, although maximum degree of lymphopenia is noted between 8 and 9 weeks after therapy. As part of HSCT preparatory condition regimen, treatment with alemtuzumab was associated with reduced risk for GVHD following allogeneic hematopoietic stem cell transplantation [13]. In kidney transplant recipients, the risk for organ rejection was low in patients given alemtuzumab; however, this benefit was mainly observed in patients that were at a low risk for allograft rejection [14]. Other trials are underway with the aim to explore regimen(s) that may spare CNI (tacrolimus) for the prevention of allograft rejection. Humanized monoclonal antibody rituximab that targets CD20 antigen expressed prominently and selectively  on B lymphocytes forms the cornerstone for treatment of solid organ antibody-mediated renal allograft rejection. It is also

A. Safdar

considered the standard of care for the treatment of posttransplant B-cell lymphoproliferative disorders [15]. Systemic glucocorticoids have maintained relevance in drug cocktails given to prevent and treat solid organ graft rejection and GVHD. Since the early observation enabled addition of corticosteroids to successfully reduce cyclosporine dose that was traditionally needed to prevent rejection of transplanted allograft, this observation was regarded as a major breakthrough and forged the path for preservation of transplanted organs without serious, lifethreatening CNI toxicity. Detailed discussion regarding immunosuppressive agents for prevention and treatment of allograft rejection  is provided in chapters throughout this book. A keen understanding of patients’ underlying immune defect(s) is the knowledge cornerstone, essential for optimizing infection risk stratification, assessing need for preventive, preemptive or empiric antimicrobial therapy. This information serves as an imperative in establishing meaningful patient-centered management and infection prevention paradigm [16, 17]. Table 1.1 provides an outline for such a relationship between underlying immune defects and susceptibility for particular group of pathogens. It is also ­important to note that a combination of unrelated immune defects may overlap. Furthermore, such patients may present with multiple infections concurrently, sequentially, or in close proximity to a primary infection episode, with a variety of conventional and opportunistic microorganisms. An extensive exposure to hospital environment poses risk for transplant recipients to acquire infections that may not respond to conventional antimicrobial drugs. The recent interest in exploring the potential influence of perturbation and reorganization of hosts’ microbial flora or microbiota resulting from extensive exposure to healthcare environment, broad-spectrum antimicrobial drugs among other factors, has yielded greater insight into a field that was largely underappreciated  for decades. Altered orointestinal microbiota has been proposed in limited observational studies to influence the risk for acquiring infection, recurrence of previously resolved infection, suboptimum response to antimicrobial therapy, and importantly, long-term viability of the transplanted allograft [18–20]. The possibility of noninfectious complications and their potential relationship with altered hosts’ microbiota are currently under investigation. An important approach in the assessment of transplant patients lends from the understanding and knowledge of temporal relationship for the risk of infection that may occur during various clinical phases after transplantation procedure (Table 1.2, with Figs. 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6). For example, patients with long-standing chronic GVHD are

1  Infections in Transplantation: Introduction and Overview

5

Table 1.1  Infections in transplant patients in relationship with the underlying immune defects Immune defect Granulocytopenia

Bacteria Staphylococcus aureus

[ANC < 500 cell/ml] Streptococcus pneumoniae Streptococcus gp A, and gp B Enterococci including VREb Coagulase-negative Staphylococcusd Enterobacteriaceae Escherichia coli Klebsiella species Enterobacter spp. Proteus spp. Citrobacter spp. Serratia spp.

Cellular immune defects

Yeasts and dimorphic fungi Candida spp. Candida albicansa

Filamentous molds Hyalohyphomycetes (hyaline or clear wall) Aspergillus fumigatus

Non-albicans Candida spp.   Candida glabratac

Aspergillus niger

  Candida kruseie

Aspergillus terreusf

  Candida parapsilosisg   Candida guilliermondiig Non-Candida yeastsh   Trichosporon asahii   Saprochaete capitataj   Saccharomyces   Magnusiomyces capitatus

Aspergillus nidulans

Viruses Herpes simplex virus type I and II Varicella zoster virus

Parasites

Aspergillus flavus

Non-Aspergillus hyalohyphomycetes   Fusarium spp.i   Paecilomyces Mucormycoses

  Mucorales speciesk Dematiaceous (black or melanin pigmented) molds Nonfermentative   Rhodotorula   Alternaria, Bipolaris, Curvularia, Exserohilum gram-negative bacteria mucilaginosa spp.   Pseudomonas   Wickerhamomyces   Pseudallescheria aeruginosa anomalus boydii   Stenotrophomonas   Pichia kudriavzevii   Scedosporium maltophilia apiospermum   Acinetobacter   Cyberlindnera   Scedosporium species fabianii prolificans   Achromobacter spp.   Kodamaea ohmeri   Lodderomyces elongisporus   Pseudozyma Nocardia asteroides Cryptococcus Aspergillus spp. Human complex neoformans cytomegalovirus Salmonella Endemic mycoses Non-Aspergillus Respiratory viruses typhimurium hyalohyphomycetes Salmonella enteritidis   Histoplasma Pneumocystis jirovecii  Influenza A and capsulatum influenza B Rhodococcus equi   Coccidioides Dematiaceous (black  Respiratory syncytial immitis pigmented wall) molds virus Rhodococcus   Blastomyces Mucormycoses  Parainfluenza type-3 bronchialis dermatitidis Listeria monocytogenes   Paracoccidioides Cryptococcus  Adenovirus brasiliensis neoformans Mycobacterium Endemic mycoses  Human coronavirus tuberculosis HKU1, NL63, OC43 and C229Em Nontuberculous   Histoplasma  Corona virus, SARS, mycobacteria capsulatum MERSo Legionella spp.   Coccidioides immitis  Human metapneumovirusq Yersinia spp.   Blastomyces Varicella dermatitidis Campylobacter jejunir   Paracoccidioides Varicella zoster virus brasiliensis Human herpes virus 6 Parvovirus B19 Hantavirus

Toxoplasma gondii Strongyloides stercoralisl Microsporidium spp. Cryptosporidium Microspora spp. Cyclospora spp. Leishmania donovanin Leishmania infantump

(continued)

6

A. Safdar

Table 1.1 (continued) Immune defect Humoral immune defects

Splenectomy and functional hyposplenism

Mixed immune defects

Bacteria Encapsulated bacteria   Streptococcus pneumoniae   Haemophilus influenzae   Neisseria meningitidis Campylobacter jejuni Encapsulated bacteria   Streptococcus pneumoniae   Haemophilus influenzae   Neisseria meningitidis Capnocytophaga canimorsus Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Klebsiella pneumonia Pseudomonas aeruginosa Acinetobacter spp. Enterobacter spp.

Yeasts and dimorphic fungi

Filamentous molds

Viruses Varicella zoster viruss Echovirus and other enteroviruses

Parasites Giardia lamblia Babesia microti

Giardia lamblia Babesia microti

Pneumocystis jirovecii

Respiratory viruses

Aspergillus spp.

Adenovirus

Candida spp.

Varicella zoster virus

Toxoplasma gondii Strongyloides stercoralis

Cryptococcus neoformans Mucormycoses Endemic mycoses Dematiaceous (black) molds

Stenotrophomonas maltophilia Nocardia asteroides complex Listeria monocytogenes Legionella spp. Campylobacter jejuni Patients with mixed immune defects include recipients of allogeneic hematopoietic stem cell transplant; patients receiving treatment for acute or chronic graft-versus-host disease; acute or chronic solid organ allograft rejection Abbreviations: VRE vancomycin-resistant enterococci, SARS severe acute respiratory syndrome, MERS Middle East respiratory syndrome a In the past two decades, the prevalence of non-albicans invasive candidiasis is seen in excess of Candida albicans infections; the emergence of invasive disease due to Candida auris with limited susceptibility to currently used antifungal drugs is a challenge  b Certain transplant units across the USA have seen a high level of VRE colonization and subsequent risk for invasive disease; these infections are often a surrogate and reflect hosts’ high-risk status c Increasing reports of echinocandin resistance among clinical isolates of C. glabrata is an alarming trend, where this to become more prominent in the future d Among CoNS group of bacteria, an emerging and recently described highly virulent Staphylococcus lugdunensis causes tissue-destructive infections similar to S. aureus with an emphasis on necrotizing and difficult-to-treat endocarditis e Candida krusei is intrinsically nonsusceptible to fluconazole and to some extent itraconazole; these yeasts are uniformly susceptible to the broad-­ spectrum triazoles such as voriconazole, posaconazole, and isavuconazonium sulfate f Aspergillus terreus is the only clinically relevant Aspergillus species that exhibit variable degree of resistance to amphotericin B, thereby increasing the probability of failure to amphotericin-based therapy g Candida parapsilosis and C. guilliermondii have demonstrated less inherent in vitro susceptibility to the echinocandins; alternative antifungal agents are suggested to treat such infections h Non-Candida and non-Cryptococcal yeasts are rare cause of fungemia seen mainly in patients with severe immune dysfunction and those with chronic lung disease i Fusarium spp. infections are now increasingly attributed to food-related intestinal tract colonization and invasive disease during periods of severe immune suppression, such as profound and prolonged neutropenia, especially in patients with extensive orointestinal mucosal disruption; other filamentous fungal pathogens from food are Aspergillus and Mucor spp. Rare organisms linked to food and food products include Lichtheimia, Curvularia, Phoma, Trichoderma, Alternaria, Acremonium, Paecilomyces, Penicillium, Achaetomium, Amesia, Botryotrichum, Chaetomium, Dichotomopilus; Microascus, Scopulariopsis, and Wallemia. Mucor circinelloides was isolated from yogurt samples and presumed to cause illness in >200 consumers

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Table 1.1 (continued) j Geotrichum capitatum is now named Saprochaete capitata k Mucormycoses in transplant recipients remain an uncommon cause of invasive fungal disease, although patients with voriconazole breakthrough mold disease have significantly higher probability of mucormycosis l Strongyloides stercoralis may lead to serious, life-threatening hyperinfection syndrome in patients with marked cellular immune defects following allogeneic allograft transplantation, albeit, this remains a rare complication in patients undergoing transplantation even in the endemic regions m These strains of human coronavirus may cause potentially serious lower respiratory tract disease in the immunocompromised host n L. donovani and L. infantum may lead to serious visceral leishmaniasis in patients with profound cellular immune defects; L. donovani is seen in Africa and Asia o These novel outbreak stains of coronavirus have been observed to cause serious illness in immunosuppressed patients and those with diabetes mellitus, ischemic heart disease, or end-stage kidney disease p L. infantum is seen in Africa, Europe, Mediterranean, Central and South America q Systemic extrapulmonary infection including viral encephalitis along with viral pneumonitis in allogeneic stem cell transplant recipients has been noted to cause devastating and life-threatening illness r The incidence of campylobacter disease in AIDS patients is 40-fold higher than in the general population; patients with humoral and cellular immune defects are considered susceptible; it is important to recognize the serious sequelae such as Guillain-Barre syndrome, and reactive arthritis may follow acute infection episode in a small group of patients s VZV is rarely associated with systemic dissemination in patients with humoral immune defects or even those with mixed immune dysfunctions

Table 1.2  Infections in recipients of allogeneic hematopoietic stem cell transplantation

Pathogens Bacteria

Pretransplant disease or high-risk exposure-related Pre-engraftment during infections neutropenia (0–30 days) Streptococcus pneumoniaea Staphylococcus aureusb

Staphylococcus aureusb Coagulase-negative staphylococcuse

Coagulase-negative staphylococcuse Enterobacteriaceaeg

Enterobacteriaceaeg

  Escherichia coli

  Escherichia coli

  Klebsiella pneumoniae and Klebsiella oxytoca

  Klebsiella pneumoniae and Klebsiella oxytoca Nonfermentative gram-negativesi   Pseudomonas aeruginosa   Stenotrophomonas maltophilia Clostridium difficile-­ associated diarrheaj Mycobacteria M. tuberculosisk M. kansasiil

Nontuberculous mycobacteria  Rapid-growing mycobacteria  Slow-growing mycobacteria

Post-engraftment including acute GVHD (30–100 days) GPB and GNB bacteremiac

Posttransplant including chronic GVHD (>100 days) Encapsulated bacteriad

Listeria monocytogenesf Nocardiosish

GPB and GNB bacteremiac Listeria monocytogenes Nocardiosis

Posttransplant seasonal community-onset infections Community acquired pneumonia Community onset sinusitis Community onset or travel-related enterocolits Community onset urinary tract infection including pyelonephritis Community onset Clostridium difficile-associated diarrhea

Nonfermentative gram-negativesi   Pseudomonas aeruginosa   Stenotrophomonas maltophilia Clostridium difficile-­ associated diarrheaj

Reactivation of latent tuberculosis Relapse of previously treated M. kansasii infection New or relapse MAC infectionm

(continued)

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Table 1.2 (continued)

Pathogens Viruses

Pretransplant disease or high-risk exposure-related infections Herpes simplex type 1 and II Human cytomegalovirusq Varicella zoster virus

Pre-engraftment during neutropenia (0–30 days) Herpes simplex type I and II Varicella zoster virusr Cytomegalovirust Human herpesvirus 6s Adenovirusu

Molds and yeasts

Invasive aspergillosis Endemic mycosis Cryptococcal disease Invasive candidiasis

Parasites

Toxoplasma gondii Strongyloidiasisao Chagas diseaseaq Leishmaniasisar

Post-engraftment including acute GVHD (30–100 days) Cytomegalovirusn

Posttransplant including chronic GVHD (>100 days) Cytomegaloviruso

Human herpesviruss Adenovirusu BK virus cystitisw

Human herpesvirus 6s Adenovirusu Epstein-Barr virus PTLDx Parvovirus B 19z

Epstein-Barr virus PTLDx

Candida fungemiaac Invasive aspergillosisad Invasive aspergillosis and Invasive candidiasisag rare moldsaf Pneumocystis jiroveciiai Zygomycosisaj Fusariosisak Dematiaceous (melanin pigmented) moldsal Cryptococcal diseaseam Toxoplasma gondiian Strongyloidiasisap Chagas disease Leishmaniasis

Posttransplant seasonal community-onset infections Influenza A and Bp Parainfluenza RSVv hMPVy hCoVaa

BK virus cystitisw JC virus PMLab Invasive aspergillosisae Invasive candidiasisah Pneumocystis jirovecii Zygomycosisaj Fusariosisak Dematiaceous (melanin pigmented) moldsal Cryptococcal diseaseam Toxoplasma gondiian Strongyloidiasisap Chagas disease Leishmaniasis

Pneumococcus is the leading cause of community-onset bacterial pneumonia, and patients with hematologic malignancies, especially those with cancer or antineoplastic therapy-related humoral immune dysfunction and various other medical comorbid conditions such as diabetes mellitus, chronic structural lung diseases like emphysema, end-stage kidney disease, and cirrhosis of liver to name a few, are at risk for potentially severe systemic disease b The emergence and global spread of community-acquired methicillin-resistant S. aureus has made empiric use of anti-staphylococcal penicillin’s obsolete c Catheter-related bloodstream infection, extensive healthcare environment exposure and hospital-acquired pathogens, persistent mucositis, orointestinal or cutaneous hyper-acute and acute GVHD, and accelerated iatrogenic immune suppression including need for high-dose corticosteroids are salient factors that promote invasive bacterial infections during this period. Pretransplant colonization due to VRE, MRSA, or MDR GNB including MRD Pseudomonas, ESBL-producing Enterobacteriaceae, and some food-borne fungi such as Fusarium spp., especially in transplant unit located in certain geographic areas, are thought to promote infections due to these pathogens d Hyposplenism after HSCT is a late complication and commonly attributed to late-onset acute GVHD, most frequently noted in patients with chronic GVHD. It is however important to recognize that a number of allogeneic HSCT recipients without clinical diagnosis of GVHD may have functional hyposplenism and are at risk for severe, systemic infection due to encapsulated bacteria e Indwelling prosthetic devices including intravascular access catheters; surgical drains; implanted prosthesis such as heart valves, joints, biliary, bronchial, urinary tract stents; and other various implantable surgical devices promote infections due to CoNS and Candida spp. that commonly colonizes the skin and genitourinary and orointestinal tracts f Listeria bacteremia and meningitis are rare complications in patients receiving TMP-SMX prophylaxis for PCP. The incidence of bacterial meningitis is 30-fold higher in HSCT recipients compared with persons without HSCT. As expected, patients undergoing allograft stem cell transplant are at a significant higher risk compared with those undergoing autologous HSCT (70 vs. 16 per 100 000 patients per year). In HSCT recipients Streptococcus pneumoniae is the most common pathogen associated with bacterial meningitis, Neisseria meningitidis, Streptococcus mitis; listeriosis may be rarely seen g Increasing frequency of multidrug-resistant strains to fluorinated quinolones and regional high prevalence of extended-spectrum beta-lactamases producing GNB including carbapenem-resistant Enterobacteriaceae has seriously curtailed treatment options for such infections. Enterobacteriaceae include Salmonella spp., Escherichia coli, Yersinia pestis, Klebsiella spp., Shigella, Proteus, Enterobacter, Serratia, and Citrobacter h CNS nocardiosis is difficult to distinguish from brain toxoplasmosis, tuberculosis, aspergillosis and other neurotropic clear (hyaline) and black mold infections, and CNS lymphoma i Nonfermentative gram-negatives include Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, Acinetobacter baumannii, other Acinetobacter spp., Alcaligenes and Achromobacter spp., and emerging cases of Sphingomonas paucimobilis. Inherent or acquired drug resistance is a major concern in selection of effective empiric therapy for pathogens in this group, which may either lack the drug target site or produce extended-spectrum hydrolyzing enzymes aginst a variety of commonly used antimicrobials; these bacteria may also exhibit phenotypes with reduced expression of outer membrane porins and/or heightened expression of efflux pumps among other mechanisms for antimicrobial drug resistance j Orointestinal mucositis increases the risk of CDAD and so does exposure to broad-spectrum antimicrobials and possibly antineoplastic chemotherapy-­induced alteration in hosts’ intestinal protective anaerobic microbiota a

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Table 1.2 (continued) k It now considered standard of care to perform interferon-gamma release assays for diagnosis of latent tuberculosis infection; treatment with isoniazid is considered gold standard and should be administered for a minimum of 6 months prior to the transplantation procedure, with the aim to prevent active tuberculosis infection during the post-transplant period. Such infections tend to be more serious and, due to potential drug toxicity and drug-drug interaction, often difficult to treat after allograft transplantation  l M. kansasii leads to clinical disease indistinguishable from M. tuberculosis infection; risk for infection relapse, drug resistance, and infection recalcitrance are reason for longer duration of therapy m In a recent study from South Korea, in 7342 SOT and 1266 HSCT recipients, 22 patients developed NTM after a median 2 years following transplantation. Mycobacterium avium-intracellulare complex was the most common pathogen isolated; nodular bronchiectasis (~80%) was common presentation. A near 70% response to antimicrobial therapy in this group was encouraging. However, disseminated NTM including MAC disease in severely immunosuppressed patients following high-risk allogeneic HSCT may occasionally present as salvage therapy-refractroy recalcitrant bacteremia with high fatality  n Risk of CMV infection is highest in CMV-seronegative recipients in whom allograft is given from a CMV-seropositive donor. Ganciclovir prophylaxis effectively prevents CMV disease in high-risk patients during the first 100 days after allogeneic HSCT o Late CMV disease is associated with high mortality rate nearing 45% and seen 170 median days after HSCT. It is important to recognize that close to 40% of patients that respond to the initial episode of late posttransplant CMV infection will develop a second CMV episode within a median of 11–12 weeks. Three months after HSCT, patients with positive CMV-pp65 antigenemia; post-engraftment severe lymphopenia of less than 100 lymphocytes/mm3, especially those with helper T-cell lymphocytopenia of less than 50 cells/mm3; presence of GVHD; and those with undetectable CMV-specific T-cell responses are at higher risk for late CMV end-organ disease. Furthermore, after 100 days following transplantation, presence of CMV viremia or pp65 antigenemia and severe lymphopenia endorsed by less than 300 lymphocytes/mm3 is considered strong predictors for late CMV disease and death p Most frequently detected viruses in symptomatic HSCT or SOT recipients with URTI are picornaviruses (~40%), such as rhinovirus and enterovirus, whereas coronavirus and influenza are isolated in nearly 20% of such patients, each. Influenza URTIs similar to RSV and unlike parainfluenza virus infections have the potential for progression to the lower respiratory tract. Viral pneumonitis is a serious complication in patients following allogeneic stem cell transplantation. It is important to recognize that hosts’ immune response to influenza infection garners a high IFN-­ gamma state resulting in a transient increased susceptibility for secondary bacterial infections like pneumococcus, S. aureus, and Pseudomonas spp. The resulting superimposed bacterial pneumonia may precipitate life-threatening sepsis and respiratory failure. Furthermore, RTVIs are recognized as fostering enhanced susceptibility for invasive fungal lung disease during early and late transplant periods q Serologic evaluation of the donor and recipient for latent CMV infection is the cornerstone during pretransplant assessment. Dissonance between D+ and R- CMV serology is the most important complicating factors during early and late posttransplant period. Antiviral prophylaxis, preemptive and empiric therapy approaches are based on CMV serologic disparities r It is standard to provide prophylaxis for HSV and VZV during preparatory conditioning regimen and continue during the  early post-HSCT period. Prophylaxis may have to be extended in patients with acute GVHD, cancer recurrence, patients undergoing high-risk transplantation procedure, and those with primary or secondary allograft compromise s HHV-6 high-grade viremia by DNA analysis has been associated with central nervous system (CNS) dysfunction, although viral interstitial/alveolar pneumonitis is not an uncommon disease attributed to HHV6 infection following allogeneic HSCT. HHV6 may also present as limbic encephalitis with subcortical temporal lobe seizure activity presenting as memory loss and insomnia. Febrile partial or complete myelosuppression and/or skin rash should alert the physicians regarding HHV6 as a potential treatable cause of secondary stem cell allograft loss. Viral gastroduodenitis, colitis, and pericarditis are other clinical manifestations attributed to HHV6 infection in this vulnerable population. An association with post-HSCT HHV6 viremia with delayed monocyte and platelet engraftment, increased platelet transfusion requirements, risk for high-grade GVHD, and all-­ cause mortality needs further evaluation t Early CMV low-grade viremia was observed by the use of ultrasensitive nucleic assays, within 3–4 weeks after high-risk allogeneic stem cell graft transplantation u The incidence of adenovirus disease ranges from 3% to as high as 47% in high-risk pediatric allogeneic HSCT recipients. Patients undergoing T-cell-depleted stem cell grafts and those with acute graft-versus-host disease are also at increased risk for severe life-threatening adenovirus disseminated disease, which is a well-recognized complication in patients with persistent peripheral blood lymphocyte counts of 30 days) viral shedding is not uncommon in patients following allogeneic HSCT; RSV is notable RTVI in this regard. The 80 days of median duration of viral shedding may extend to just under a year in some allogeneic transplant recipients. This potential for pronged viral shedding warrants heightened awareness and strict adherence to appropriate precautions to prevent nosocomial RSV transmission to other vulnerable hospitalized patients. In the pediatric HSCT recipients, RSV infection within 60 days after transplant, patients given systemic corticosteroids within a week prior to the onset of RSV infection and the need for assisted mechanical ventilation were significant predictors for subsequent complications and death w The BK virus was first isolated in 1971; after primary childhood infection, persistent BKV infection occurs within renal tubular cells and the urothelium. Viral reactivation in the recipients of kidney and allogeneic HSCT usually presents as allograft nephropathy and hemorrhagic cystitis, respectively. Presently, reduction in drug-induced immune suppression, when possible, and supportive care are the only viable treatment option; direct antiviral drug against BKV remains elusive x EBV influence over B-cell malignant clones may act through different mechanisms of transcriptional regulation and possibly variance in genetic mechanisms that eventually determined viral latency during early EBV infection and EBV-host interaction y The incidence of hMPV infection was similar to the incidence of RSV or parainfluenza virus UTRIs in patients undergoing HSCT. hMPV infections are notable for low risk of progression to the LRT. Serious systemic hMPV disease including viral encephalitis has been reported. Overall, these infections are well-tolerated, albeit hMPV pneumonitis in severely immunosuppressed stem cell allograft recipients may result in serious life-threatening lung disease (continued)

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Table 1.2 (continued) z Parvo B19 infection may present as pure red cell aplasia after allogeneic HSCT aa hCoV similar to hMPV is a common RTV. Serotypes associated with disease in transplant population include hCoV-OC43 followed by NL63, HKU1; 229E is less common. Unlike hMPV, these infections have a higher likelihood for progressing to the LRT, which often presents as subclinical, mild to moderate viral illness. In an observation among HSCT recipients, hCoV infection resulted in a notable number (~20%) of hospitalizations. In concert with hMPV infection, despite presence of severe immune suppression, hCoV-related confirmed deaths in allogeneic HSCT recipients remain less than 5%. Approximately one-third of transplant patients with hCoV infection may have infection due to other RTVs such as human bocavirus (HBoV). HBoV is an uncommon RTV in transplant patients and often (> 80%) seen with other RTVs. HBoV rarely causes LRTI; most infections are well-tolerated despite, transplant-related severe immune suppression ab John Cunningham virus (JCV)-associated progressive multifocal leukoencephalopathy (PML) is an uncommon disease in patients undergoing allogeneic HSCT. In a report from Israel, 20 of 40 patients (24%) with JCV reactivation had persistent viremia after receiving myeloablative and nonmyeloablative pretransplant conditioning. PML was diagnosed in two patients with persistent JCV viremia, 96 and 127  days after HSCT. Advanced age was a significant predictor of JCV reactivation; 70% of these allogeneic HSCT recipients with persistent viral reactivation had died. Identifying high-risk patients with persistent JCV reactivation, especially those with incremental levels of viremia, may benefit from reduced drug-induced immune suppression for prevention of JCV leukoencephalopathy. PML continues to remain a devastating, albeit rare posttransplant infectious complication. Artesunate, an antimalarial drug that showed potent ex vivo activity against HHV-6, however, clinical response to artesunate in HSCT recipients with JCV-PML, has not been encouraging ac Candidemia is seen in patients with severe pre-engraftment neutropenia (absolute neutrophil count 2 weeks) recovery of peripheral blood granulocyte count. Patients receiving high-dose systemic corticosteroids are also at an increased risk. Aspergillus fumigatus remains the most prevalent mold to cause invasive human disease, including in patients undergoing HSCT. Infections caused by Scedosporium and Fusarium spp. are occasionally seen in hematopoietic stem cell allograft recipients and commonly present during the period(s) of severe and prolonged neutropenia ag Routine blood cultures have low sensitivity for diagnosis of fungemia. Carbohydrate biomarker (1, 3)-β-d-glucan has emerged as a useful laboratory test for the diagnosis of invasive yeast and mold disease. Furthermore, it may be used to monitor response to systemic antifungal therapy and infection relapse ah Post-HSCT recovery of antigen-specific T lymphocyte-mediated immune response against CMV and Candida albicans is regarded as critical during the early and the late transplant period. Most patients develop antigen-specific T-cell response early in the transplant period which is derived from clones of both donor and recipient stem cell origin. Reconstitution of immune response via antigen-specific T lymphocytes of recipient origin is weakened in patients with GVHD. Incidence of IC during the 1st year after nonmyeloablative (5%) and myeloablative transplant conditioning is lower than that for IA (14%). Echinocandin nonsusceptible Candida spp. infection has been recently recognized as an emerging challenge in providing care for these highly vulnerable patients ai PCP is a serious OI in transplant patients with severe cellular immune defect(s). Routine anti-PCP prophylaxis breakthrough infections are rare; although in patients receiving aerosolized pentamidine, atypical upper lung PCP may occasionally occur aj Invasive zygomycosis or mucormycosis may occur disproportionally more frequently in patients on voriconazole prophylaxis and those with sinuorbital invasive mold disease. In transplant patients, the overall prevalence is less than 8% among all invasive fungal infections ak Nearly half of the patients with disseminated fusariosis have evidence of fungemia, and close to 80% may exhibit multiple (>10–15) papular skin lesions with a necrotic center that is indistinguishable from ecthyma gangrenosum due to Staphylococcus aureus or disseminated Pseudomonas spp. infection al Dematiaceous or melanin pigmented molds are associated with chronic localized infections and prevalent in certain geographic regions. In transplant patients, disseminated infections may occur; neurotropism is an important feature of these infections, and treatment with older antifungal drugs such as amphotericin B and early generation triazole-based compounds was associated with high rates of treatment failure am The cumulative incidence of CNS infection following HSCT is 20%) in patients given antithymocyte globulin versus those in whom this treatment was not given (180 days after transplantation (Fig. 8.2) [39]. However, polymicrobial infections are not uncommon and may occur simultaneously or sequentially. The prototype of this interaction is the immunomodulatory effect of CMV infection,

A. Katragkou et al. Table 8.2  Risk factors determining the risk of infections in solid organ transplant recipients [3] Pretransplantation factors Young age Underlying disease

Duration and frequency of hospitalizations Palliative surgery before transplantation Complications of end-stage organ disease Malnutrition Environmental exposures (community, hospitals) Travel

Peri-­ transplantation factors Type of organ transplanted Transplant procedure (injury, prolonged time, technical problems) Indwelling medical devices

Posttransplantation factors Net state of immunosuppression  Dose, duration, and temporal sequence of immunosuppressive agents (steroids, calcineurin inhibitors, sirolimus)  Rejection and its treatment (antithymocyte globulin, alemtuzumab, palivizumab)  Host defense defects due to underlying disease  Technical/anatomic abnormalities that compromise the integrity of mucocutaneous barriers  Neutropenia  Metabolic abnormalities (protein-calorie malnutrition, uremia, hyperglycemia)  Viral infections with immunomodulating effect (CMV, EBV, HBV, HCV, HIV) Environmental exposure (community, hospital) Indwelling medical devices

Adapted from Fonseca-Aten and Michaels [3]

which results in immunosuppression and, thereby, promotes hosts’ susceptibility for other opportunistic viral, bacterial, and invasive fungal disease(s) [40, 41].

 arly Phase Infections During 0–30 Days After E Transplantation The net state of immunosuppression at this phase is not great despite the high doses of immunosuppressive therapy. Therefore, opportunistic infections that are caused by pathogens such as Aspergillus, Listeria, and Nocardia are rare. There are three main types of infections during this period: (1) infections present in the recipient before undergoing transplantation, which are exacerbated after the transplantation due to transplant surgery and immunosuppressive drug

8  Infections in Pediatric Transplant Recipients

therapy; (2) donor-derived infections which are usually due to critical or terminal illness, organ harvesting procedure and transport, and donor’s undiagnosed infections such as West Nile virus, HIV, rabies, and among others [42–44] as well as undiagnosed critical care-related bacterial infections such as pneumonia including HAP/VAP, bacteremia, and endovascular infections; and finally (3) infections transmitted perioperatively that could also occur in an immunocompetent patient. The majority of the infections during the early phase after transplantation is of this last variety and determined by the technical integrity of the operation and the post-surgery use of indwelling medical devices. Early graft injuries resulting from tissue ischemia (bile ducts) or reperfusion injury (lungs) may later become foci of liver or lung abscesses [45].

I ntermediate Phase Infections (30–180 Days After Transplantation) The infections occurring in this phase are the result of immunosuppression and the immunomodulatory effects of coinfecting viruses. There are three types of infections during this period: (1) continuation of infections acquired during the previous phase; (2) opportunistic viral infections such as CMV, Epstein-Barr virus (EBV), herpesvirus-6, and other pathogenic viruses like hepatitis B virus and hepatitis C virus and HIV. However, other rare viral pathogens such as polyomavirus BK and adenovirus have also emerged and (3) opportunistic fungal infections due to Pneumocystis jirovecii and Aspergillus fumigatus which usually suggest an environmental source. Additionally, infections due to non-endemic and endemic dimorphic fungi like Cryptococcus spp., Histoplasma, Coccidioides, and Blastomyces are noted during this period. Trypanosoma cruzi and Strongyloides stercoralis may cause potentially devastating disease in SOT recipients during this period; a thorough travel and potential exposure history is crucial for evaluating patients being considered for organ transplantation [3, 46].

 ate-Phase Infections After 6 Months L Following Transplantation There are three types of infections during this period: (1) patients with good transplantation outcome requiring minimal immune suppression and good allograft function, in which no opportunistic viral infections are at risk from community-­acquired respiratory viruses such as influenza, parainfluenza, and respiratory syncytial virus; (2) patients with chronic viral infections that may cause allograft injury such as recipients HCV infection of hepatic allograft, bronchiolitis obliterans in lung transplant recipients, accelerated vasculopathy in heart transplant recipients with CMV infec-

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tion, or a malignant condition such as posttransplantation lymphoproliferative disorder (PTLD) or skin or anogenital cancer; and (3) patients with poor result from transplantation like repeated episodes of acute and chronic allograft injury, excessive immunosuppression, and chronic viral infections. These patients are at risk for opportunistic infections with Listeria monocytogenes or Nocardia species, invasive fungal infections such as zygomycetes and dematiaceous molds, and unusual organisms like Rhodococcus species [3, 45–47].

Diagnosis and Laboratory Findings A careful history and physical examination directed toward identifying possible foci of infection is important as a guide to further management. As surrogate markers able to accurately evaluate the relative risk for each patient for infection do not exist, it is essential that these patients be monitored carefully and receive early intervention for signs or symptoms of an infectious disease. Fever in immunocompromised patients may be the first and only sign of infection [5, 48]. However, one should keep in mind that noninfectious causes such as pyrogenic medications, transfusions of blood products, and drug reactions may also be responsible for a febrile episode. The absence of fever in immunocompromised patients with localizing signs does not exclude the possibility of an ongoing infection. Further, clinical signs and symptoms frequently indicative of an infectious process such as pain, warmth, erythema, and tissue swelling may be blunted or lacking. Patients should be questioned about the presence of any localizing pain or discomfort. Attention on history and physical examination should be focused on areas such as the oropharynx, respiratory tract, perianal area, central venous catheter sites, and any site of recent invasive procedures, as well as the skin and soft tissues. According to the specific phase after transplantation, the diagnostic approach should be guided toward the most frequent pathogens (Figs. 8.1 and 8.2). Blood cultures should be obtained from all lumens of central venous catheters, when present. Volume of blood cultures is the most important factor for detection of circulating bacteria and fungi. Urine cultures should be routinely submitted where feasible. Other cultures should be obtained based on clinical suspicion including stool, cerebrospinal fluid, central line site, or surgical wound. A routine complete blood count and serum chemistry profile could provide evidence of disease from an infectious agent or indicate noninfectious causes of hepatic or renal disease such as GVHD. The diagnosis of a catheter-related versus non-catheter-­ related bacteremia is difficult. Evidence of catheter-related infection as opposed to bacteremia from other sources includes a greater number of colony-forming units per mil-

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liliter of blood from cultures of the central line compared with simultaneous peripheral cultures and positive catheter tip cultures. Another approach is to use differential time to positive blood culture. However, as peripheral blood cultures in pediatric patients are inconvenient and contribute little to increasing the diagnostic yield of bacteremia, their utility is questionable. The volume of blood drawn is the critical determinant for recovery of bacteria during bloodstream infections. Thus, two or three blood cultures through the central venous catheter, one set per each lumen will provide a yield similar to that of central cultures plus peripheral cultures but without the patients’ discomfort and the potential for contamination from cutaneous flora. Nasopharyngeal washes for viral pathogens, including respiratory RSV, parainfluenza, influenza, and adenovirus, are important in patients with concomitant upper respiratory tract infection-like symptoms. Nucleic acid detection assays, such as PCR, are useful for detecting and follow-up of the response to therapy of certain pathogens like herpesviruses and parvovirus B19. The impact of PCR on diagnosis of HSV encephalitis is especially apparent [49–53]. Recent advances in PCR may assist in noninvasive diagnosis of CNS toxoplasmosis and detect Mycoplasma and Chlamydia DNA in BAL samples [54, 55]. Serologic testing is useful for diagnosing toxoplasmosis, bartonellosis, histoplasmosis, and blastomycosis. However, serology tests in transplant recipients are of limited value as these patients are immunosuppressed and a good number of them may have received pooled immunoglobulin therapy. Nevertheless, when PCR is not available, acute and convalescent serum antibody titers against herpesviruses, echoviruses, and the less common arboviruses should be measured. Specific cerebrospinal fluid antibody may be detected in cases of mumps, HSV, or VZV. A chest radiograph should be obtained in all patients with fever and neutropenia. Routine chest radiographs in asymptomatic neutropenic patients may provide an important baseline for future reference. The presence of a pulmonary infiltrate should also prompt consideration for subsequent evaluation by bronchoscopy for a more definitive microbiological diagnosis. Computed tomography scans of the brain, paranasal sinuses, chest, and the abdomen are useful when evaluating patients with invasive fungal disease. Radiologic examination of the sinuses is useful for diagnosis of sinusitis in children older than 1 year of age. Radiographic evaluation with a CT scan is more sensitive than conventional chest radiography and may provide more information regarding the pattern and extent of disease [56]. Specific findings of a “halo” sign, crescent sign, nodular infiltrate, peripheral pleural-­based lung lesions, or wedge-shaped infiltrate are indicative of a possible angioinvasive filamentous fungal disease, including, but not limited to, Aspergillus spp. [57–59]. Flexible fiber-optic bronchoscopy can provide evidence for a

A. Katragkou et al.

specific diagnosis in immunocompromised patients with pneumonia. The yield of bronchoscopy depends on the clinical situation and the extent of prior therapy [60]. Bronchoalveolar lavage (BAL) can yield a specific diagnosis in approximately 80% on cases of PCP, whereas it is significantly less sensitive for detection of invasive fungal infections or bacterial infections in patients who have received prior antibiotic therapy. Ultrasound can be used to diagnose abdominal problems such as typhlitis. The double sandwich ELISA system for detection of galactomannan antigenemia is an important advance in the non-culture diagnosis of invasive aspergillosis among HSCT recipients. Depending upon the patient population, several studies have demonstrated a sensitivity ranging from 50% to 95% and specificity ranging from 87% to 99% for diagnosis of invasive aspergillosis. Additional studies indicate that serial serum galactomannan antigen levels permit therapeutic monitoring and have prognostic implications [61–64]. Coupled with a CT scan that is radiographically compatible with invasive pulmonary aspergillosis in the appropriate host population, a positive serum galactomannan assay establishes a reasonable diagnosis of probable invasive aspergillosis HSCT recipients [65].

Management and  Therapy The initial management of patients with fever and neutropenia after transplantation is similar to that of cancer patients with chemotherapy-induced fever and neutropenia. It is well recognized that bacteremia in the neutropenic host can progress rapidly to septic shock and death making, thus, empirical therapy a therapeutic consensus [66, 67]. Empiric antibiotic therapy should be started after obtaining appropriate samples for culture [68]. When considering a particular empiric antibacterial regimen, the choice should be dictated by the local epidemiology of bacterial infections, antibiotic susceptibility profiles, cost, toxicity, as well as the patient’s surveillance isolates. Hence, an empiric antibiotic regimen must cover a broad-spectrum of bacteria, provide high serum bactericidal drug levels, be stable against the emergence of resistant bacteria, and be nontoxic and simple to administer. Several regimens, usually consisting of a cephalosporin, an aminoglycoside, and extended-spectrum penicillin, have been employed [69–71]. A combination that provides broad coverage to Gram-negative bacteria and Gram-positive cocci would be ceftazidime or cefepime with or without vancomycin. If Pseudomonas aeruginosa is suspected, an aminoglycoside should be added. Once antibiotics have been initiated empirically, a meticulous investigation of the cause of fever is warranted. Other clinical findings indicating the addition of other agents as empirical therapy are described in Table  8.3.

8  Infections in Pediatric Transplant Recipients Table 8.3  Indications for the addition of specific agents in the empirical therapy of the febrile neutropenic child with transplantation [8] Head, eyes, ears, nose, throat Add specific anti-anaerobic agent (clindamycin or Necrotizing or metronidazole) to empirical therapy marginal gingivitis Suspect HSV infection. Culture and begin Vesicular or acyclovir therapy ulcerative lesions Suspect invasive fungal infection with Aspergillus Sinus or Zygomycete; obtain imaging studies and ENT congestion, consultation. Adjust antifungal therapy according tenderness or nasal ulcerative to organism recovered lesions Gastrointestinal tract Retrosternal Suspect candida or herpetic esophagitis, or both. burning pain Add antifungal therapy and, if no response, acyclovir. Bacterial esophagitis also is a possibility. For patients not responding within 48 h, endoscopy should be considered Suspect typhlitis, as well as appendicitis, if pain Acute abdominal pain in right lower quadrant, even in the absence of fever. Add specific anti-anaerobic coverage (e.g., metronidazole to ceftazidime; or substitution of imipenem for ceftazidime) to empirical regimen and monitor closely for need for surgical intervention Evaluate for anal fissures, perianal cellulitis, Perianal tenderness perianal fistulas, or perirectal abscesses. Add specific anti-anaerobic drug to empirical regimen, as indicated, and monitor need for surgical intervention, especially when patient is recovering from neutropenia Respiratory tract Observe carefully, as such lesions may be a New focal consequence of inflammatory response to lesion(s) in previously occult pneumonic process detected in patient recovering from concert with neutrophil recovery neutropenia Invasive pulmonary aspergillosis is the chief New focal concern. Rule out other causes of fungal lesion(s) in pneumonia. Perform BAL or transthoracic needle patient with aspirate with appropriate direct exams and continuing cultures. Add voriconazole or lipid formulation of neutropenia amphotericin B, depending upon findings (do not administer voriconazole and amphotericin B simultaneously) New interstitial Attempt diagnosis by examination of induced pneumonitis sputum or BAL. If patient is symptomatic, begin empirical treatment with trimethoprim-­ sulfamethoxazole, pending procedure. Consider noninfectious causes and need for open-lung biopsy if diagnosis is not established Adapted from Pizzo and Poplack [8]

Guidelines for the management of fever and neutropenia specifically for children with HSCT have recently been published by the International Pediatric Fever and Neutropenia Guideline Panel [68]. Empiric antifungal therapy is recommended for patients who remain persistently granulocytopenic and febrile after 5–7 days of antibiotic therapy without identification of a bac-

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terial cause. Conventional amphotericin B, liposomal amphotericin B, voriconazole, caspofungin, and itraconazole have been well characterized for empirical antifungal therapy for persistent fever in high-risk neutropenic patients. Selection of an agent for empirical antifungal therapy will depend upon the patterns of infection in one’s institution, cost, and the risk for end-organ toxicity (e.g., renal or hepatic dysfunction) [72–76]. For patients who remain neutropenic, antifungal therapy should be continued until the resolution of neutropenia. Persistence or recrudescence of fever should prompt a meticulous investigation for non-fungal infections such as bacterial or viral superinfections or for a fungus that is resistant to initial empirical antifungal coverage like Aspergillus spp., Trichosporon, Fusarium spp., Pseudallescheria boydii, Scedosporium spp., and agents of mucormycosis. Patients who develop a documented fungal infection should be treated with the appropriate antifungal agent (Table  8.4). The indications, dosages, and activity spectrum of the most commonly used antibacterial, antifungal, antiviral, and anti-­pneumocystis agents in pediatric patients are shown in Tables 8.4, 8.5, and 8.6.

Catheter-Associated Bacteremia Removal of chronic indwelling central venous catheters is best determined by the type of organism recovered, the hemodynamic stability of the patient, and the presence of persistent bacteremia, rather than by differences in colony counts suggesting evidence of direct involvement of the catheter (Table  8.7). Removal and replacement of chronic indwelling catheters carry the risk of general anesthesia, pneumothorax, and hemorrhage, particularly in thrombocytopenic patients.

Prevention of Infections The most efficacious and practical intervention to prevent or reduce infections in the immunocompromised host is adherence to strict handwashing practices [77]. Another measure to decrease the acquisition of new organisms is to maintain a cooked diet during periods of granulocytopenia, with avoidance of fresh fruits and vegetables and non-processed dairy products, because these foods are naturally contaminated with Gram-negative bacteria, especially E. coli, K. pneumoniae, and P. aeruginosa [78, 79]. Environmental sources can contribute to fungal especially Aspergillus spp., Fusarium spp., and Zygomycetes and bacterial such as Legionella spp., Pseudomonas spp., and ­ Acinetobacter spp. colonization and infection. In medical cen-

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Table 8.4  Antifungal agents used in children for infections after transplantation

Class Polyenes

Triazoles

Agent Deoxycholate amphotericin B

Lipid formulations (amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B) Fluconazole

Daily dose (maximum) Neonates Infants Route Spectrum (0–30 days) (31 days–1 year) Children (>1–17 years) Empirical therapy: 0.5–1.5 mg/kg Q24h Empirical IV Very broad therapy: antifungal activity including 0.5–1.5 mg/ kg Q24h Candida spp., Aspergillus spp., Documented Documented fungal infections: 1.0– Zygomycetes, 1.5 mg/kg Q24h fungal Cryptococcus infections: neoformans, 1.0–1.5 mg/ Histoplasma kg capsulatum 5 mg/kg Empirical therapy: 3 mg/kg Q24h IV Same spectrum as deoxycholate Q24h Documented fungal infections: 5 mg/kg formulation Q24h (max. dose 10 mg/kg, but no evidence for improved efficacy)

PO, IV

Itraconazole

PO, IV

Voriconazole

PO, IV

Posaconazole

PO

Candida spp., (not C. krusei and not some strains of C. glabrata); C. neoformans, Trichosporon spp. and Coccidioides immitis Aspergillus spp., Candida spp., H. capsulatum, Blastomyces dermatitidis, and C. immitis

12 mg/kg Q24h Treatment: 12 mg/kg Q24h Prophylaxis: 3 mg/kg twice weekly

Unknown

Unknown

3–12 mg/kg Q24h

Life threatening infections: 12 mg/kg/ day Q12h (max 600 mg/day)

Load with 6 mg/kg/day Q12h × 1 day; maintain with 2.5–5 mg/kg/day Q12ha (max 10 mg/kg/day)

Comments Children can generally tolerate higher doses than adults

Significantly less nephrotoxicity with efficacy at least equal to that of deoxycholate amphotericin B

Excellent bioavailability, independent of gastric acidity. Higher dose required in children and infants due to shorter half-life

Absorption erratic but increased with taking drug with meals or by using cyclodextrin formulation. Dosing Q12h preferred in children. TDM recommended 8–16 mg/kg/day Q12h (IV, PO) Loading dose 6 mg/kg Linear Candida spp., Q12h day 1, then 4 mg/ pharmacokinetics in Aspergillus spp., children. Higher kg Q12h IV for Trichosporon dosages may be invasive aspergillus spp. and some necessary in pediatric and serious mold strains of patients to achieve infections; 3 mg/kg Scedosporium comparable adult drug Q12h for serious spp., and exposures. Pediatric candida infections Fusarium spp. suspension is PO, 1–17 years) 25 mg/m2 50 mg/m2 Q24h Load with 70 mg/m2/ Q24h day for 1 day; maintain with 50 mg/m2/day Q24h (max 70 mg)

Comments Dosing should be adjusted for hepatic insufficiency to 35 mg/m2 Q24h

Adapted from Michelow and McCracken [106] Abbreviation: TDM therapeutic drug monitoring a IV formulation for itraconazole is available, but dosage and pharmacokinetics have not been defined in pediatric patients

Table 8.5  Antibacterial agents used in children for infections after transplantation Generic agent name (trade names) Route Spectruma Class Third-generation Ceftazidime IV, Enteric bacteria, some cephalosporin IM Gram-positive aerobes, no anaerobic coverage

Fourth generation Cefepime cephalosporin

IV, IM

Carbapenems

IV, IM

Imipenem-­ cilastatin

Meropenem IV

Extended-­ spectrum penicillins

Piperacillin, IV azlocillin, mezlocillin

Piperacillin-­ IV tazobactam

Daily dose (maximum)

Children (>1– Infants (31 days–1 years) 17 years) Comments Inappropriate for mild infections Only ceftazidime covers Pseudomonas Moderate infections: 90–150 mg/ aeruginosa: 200–300 mg/kg/day kg/day Q8h recommended for (max 6 g/day) serious pseudomonas infection Enteric bacteria, 0–7 days: 50 mg/ Inappropriate for mild infections Active against some Gram-positive aerobes kg Q12h P. aeruginosa, Enterobacter spp., 8–30 days: 50 mg/ Moderate infections: 100– and Serratia spp. kg Q8h 150 mg/kg/day Q8h or Q12h resistant to (max 6 g/day) ceftazidime; broader Gram-positive spectrum Inappropriate Inappropriate for mild infections Stenotrophomonas Most Gram-negative including those Moderate infections: 60–100 mg/ maltophilia and Burkholderia producing betakg/day Q6h cepacia not covered. lactamases and P. (max 4 g/day) IM form not aeruginosa; Gramapproved for positive aerobes, 1– Infants (31 days–1 years) 17 years) Mild infections: 90 mg/kg/day Q8h (max 4 g/day) 8–30 days: 30 mg/ Moderate infections: 120 mg/kg/ kg Q8h day Q6h (max 4 g/day) Neonates (0–30 days) 0–7 days: 30 mg/ kg Q12h

Glycopeptide

Vancomycin PO, IV

Exclusively Gram-positive

Lipopeptide

Daptomycin IV

6 mg/kg Q12h Exclusively Grampositive, including ORSA and susceptible strains of VRE

Oxazolidinone

Linezolid

Exclusively Grampositive, including MRSA, susceptible strains of VRE, and penicillin and cephalosporin resistant S. pneumoniae Exclusively Grampositive, similar to linezolid but spectrum does not include E. faecalis

Streptogramin

PO, IV

Quinupristin/ IV dalfopristin

Inappropriate

0–7 days (unless TBW >2 kg): 10 mg/kg Q12h 8–30 days or TBW >2 kg: 10 mg/kg Q8h Inappropriate

Comments Limited spectrum requires pairing with Gram-positive agent, not cross-reactive with beta lactams so can be used in penicillin or cephalosporin allergic patients Inappropriate for mild infections No need to add Moderate infections: 40–60 mg/ vancomycin routinely for kg Q6h or Q12h empirical coverage (max 3 g/day) for fever and neutropenia 2–5 years 10 mg/ 4 mg/kg/day Data in pediatrics are kg/day Q24h Q24h (based limited at this time 6–11 years 7 mg/ on total body kg/day Q24h weight) 30 mg/kg/day Q8h 30 mg/kg/ Excellent oral day Q8h bioavailability >12 years, 1200 mg/ day Q12h 22.5 mg/kg/day Q8h

Venous irritation should be given via central venous catheter

Adapted from Michelow and McCracken [106]

ters where Aspergillus spp. and Fusarium spp. are a significant problem, special air filtration systems, such as high-­efficiency particulate air filters (HEPA filters) and close attention cleaning bathroom facilities, may be helpful [80, 81]. Total protective isolation is a comprehensive regimen designed to reduce patients’ endogenous microbial burden while preventing the acquisition of new organisms. A sterile environment is created in a clean-air room with constant positive-pressure airflow. It is maintained by an aggressive program of surface decontamination and sterilization of all objects that enter the room and by an intensive regimen to disinfect the patient, including oral nonabsorbable antibiotics, skin antiseptics, antibiotic sprays and ointments, and a low-microbial diet. The total protective environment reduces the number of infections in profoundly granulocytopenic patients. However, a total protective environment is expensive, and because of the improvement in treating established infections, it does not offer a survival advantage to patients.

Total protective isolation is not necessary for the routine care of immunosuppressed patients. Modifications of the approach are used, on occasion, for patients undergoing allogeneic bone marrow transplantation and for patients who are likely to experience periods of 30 or more days of profound neutropenia [82]. In recipients of SOT, the organ donor is frequently the source of various pathogens. To prevent transmissible pathogens from the solid organ donor, the current requirements for donor and recipient screening are provided in Table 8.8 [46, 83].

Antibacterial Prophylaxis The fluoroquinolone antibiotics are attractive for oral prophylaxis because of their bioavailability, tolerability, and broad-spectrum. These agents have been widely used in

8  Infections in Pediatric Transplant Recipients

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Table 8.6  Antiviral and anti-pneumocystis agents used in children for infections after transplantation

Class Anti-herpetic agents

Daily dose (maximum) Neonates Infants Children (0–30 days) (31 days–1 years) (>1–17 years) Empirical therapy: 0–7 days (unless TBW 15–60 mg/kg/day Q8h (IV) 60–80 mg/kg/day Q6-8 h (PO) >2 kg): 40 mg/kg/day HSV: 750 mg/m2/day Q8h or 5 mg/ Q12h kg Q8h 8–30 days or VZV: 1500 mg/m2/day Q8h or 10 mg/kg Q8h TBW >2 kg: 60 mg/kg/day Q8h CMV: 12 mg/ CMV: 10–15 mg/kg/day Q12h for kg/day Q12h 14 days induction, then 5 mg/kg/ day for maintenance/suppression (IV) VZV, HSV: 10 mg/kg/day Q8h (IV) 90 mg/kg/day (PO) Inappropriate CMV treatment: 180 mg/kg/day Q8h for 14 days then 90–120 mg/ kg/day for maintenance/suppression VZV, HSV: 120 mg/kg/day Q8h

Agent Acyclovir

Route Spectruma PO, HSV, VZV IV

Ganciclovir

PO, IV

CMV, HSV, VZV, EBV, HHV-6

Foscarnet

PO, IV

HSV, VZV, CMV (including most acyclovir and ganciclovir resistant strains) Inappropriate Pneumocystis jirovecii (formerly, P. carinii) also is active against many Gram-­ positive and Gram-negative bacteria, including S. maltophilia and B. cepacia P. jirovecii Inappropriate

Trimethoprim-­ PO, Anti-­ pneumocystis sulfamethoxazole IV agents

Pentamidine

IV, IM

Dapsone

PO

P. jirovecii

Atovaquone

PO

P. jirovecii

30 mg/kg/day

Empirical therapy: 8–10 mg of TMP/kg/day UTI prophylaxis: 2 mg of TMP/kg/ day PCP treatment: 15–20 mg of TMP/ kg/day Q12h (IV) PCP prophylaxis: 150 mg of TMP/ m2/day Q12h 3×/week

Comments IV dose for VZV is twice that for HSV Hydration should be ensured when administering high doses

Neutropenia is the major dose-limiting toxicity; not routinely used for HSV, VZV but dose used for CMV is effective for the other herpesviruses Nephrotoxicity is dose-limiting effect; renal function and electrolytes require close monitoring May cause bone marrow suppression in high doses

4 mg/kg/day Q24h (IV) for treatment

Adverse effects include pancreatitis, hypoglycemia, hypocalcemia, infusional hypotension Prophylaxis: 2 mg/kg/day Q24h High incidence of (max. 100 mg/day) hemolytic reactions can also cause methemoglobinemia 45 mg/kg/day 30 mg/kg/day Suspension formulation has better bioavailability Q12h for treatment, Q24h for prophylaxis (max. 1500 mg/day)

Adapted from Michelow and McCracken [106]

adult oncology patients but are not generally used for prophylaxis in children because of concern of cartilage toxicity with long-term exposure. In adults, comparative studies have shown no advantage of the oral quinolones over more traditional regimens of infection prophylaxis, such as trimethoprim-­sulfamethoxazole, for prevention of infection. Moreover, none of the studies of antibacterial prophylaxis has demonstrated a reduction in mortality caused by infection [84, 85].

Antifungal Prophylaxis Fluconazole is FDA-approved for prevention of deeply invasive fungal infections in neutropenic patients and HSCT recipients when the risk of aspergillosis is not high. Randomized, placebo-controlled studies demonstrated that the prophylactic administration of fluconazole to allogeneic HSCT recipients reduced the incidence of both disseminated and mucosal candidiasis [86, 87]. However the shift in the

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Table 8.7  Management of central venous catheters in patients with bacteremia [8] Criteria for central venous line removal 1. Evidence of a local tunnel infection 2. Persistently positive blood cultures 3. Recurrently positive blood cultures with the same pathogen 4. Positive blood cultures for:   Staphylococcus aureus   Candida spp.  Polymicrobial infections  Atypical mycobacteria (e.g., M. fortuitum, M. chelonae, M. abscessus)   Bacillus spp. Adapted from Pizzo and Poplack [8] Table 8.8  Screening requirements for solid organ donors and recipients [46, 83] Pathogen HIV-1 and 2

Donor + −

HTLV-1 and 2

+

Hepatitis B virus

HBsAb+ HBsAg+

Recipient − +

HBcAb IgM+ +

+ or − HBsAb – or + HBsAb – or + +

+

−

+ or − +

+ −

EBV

+ or − +

+ −

Toxoplasma gondii Treponema pallidum CNS viral pathogens (LCMV, rabies, WNV)

+ or − + +

+ − + or −

Hepatitis C virus

CMV

Clinical suspicion of infection

Action required Reject donor Accept donor if HIV well controlled Exclude donor (may be used in life-­ threatening conditions) Accept donor Reject donor Reject donor Accept (by some centers) Decision depends on urgency Accept Accept (high risk for CMV infection) Accept Accept (higher risk for primary EBV infection and PTLD) Accept Accept Accept Reject

Modified from Allen and Green [46] and Hayes-Lattin et al. [82] Abbreviations: PTLD posttransplant lymphoproliferative disease, LCMV lymphocytic choriomeningitis virus, WNV West Nile virus

colonization pattern toward more resistant species, including C. glabrata, Candida krusei, Candida parapsilosis, Aspergillus, and other filamentous spp. fungi, is of concern [88]. More recent studies involving pediatric patients demonstrated that micafungin is superior to fluconazole in prevention of proven and suspected invasive fungal infections in neutropenic HSCT patients [89].

Antiviral Prophylaxis Acyclovir, given orally or intravenously, is effective prophylaxis against reactivation of HSV in seropositive HSCT recipients [90–92]. Intravenous doses ranging from 250 mg/ m2 every 8 h to 5 mg/kg every 12 h, and oral doses of 400 mg given three times daily, are effective in preventing reactivation of HSV in seropositive individuals. Although acyclovir is therapeutically less active against VZV or CMV, ­prophylactic acyclovir given to HSCT recipients may nonetheless decrease the occurrence of zoster and invasive CMV disease during the posttransplant period [93, 94]. Refractory lesions may respond to foscarnet [95]. Ganciclovir prophylaxis can reduce the frequency of invasive CMV disease in HSCT recipients. However, myelosuppressive effects of ganciclovir are problematic for most patients, making it undesirable for routine anti-CMV prophylaxis. Targeting transplant recipients at highest risk for severe CMV disease has yielded the practice of “preemptive” ganciclovir therapy, that is, treatment of patients who have evidence of CMV reactivation in surveillance assays such as CMV antigenemia, or quantitative CMV PCR. This approach has been shown to effectively suppress CMV viremia, when present and, accordingly, appropriate selection of patients reduces universal need for prophylaxis and dramatically reduces the risk for end-organ CMV disease [96, 97].

Pneumocystis Prophylaxis There are several effective regimens for Pneumocystis jirovecii pneumonia prophylaxis. The choice among them often depends on the patient’s tolerance of their various side effects. TMP-SMX, given twice a day for 3 days a week, is considered the first-line regimen [98]. For patients who can tolerate this regimen, protection against PCP is virtually complete [99]. In a number of individuals, presence of skin rash, neutropenia, and gastrointestinal symptoms may limit the routine use of TMP-SMX.  Alternative compounds for prevention of PCP in patients who are intolerant of or refractory to TMP/SMX include dapsone, atovaquone, and aerosolized pentamidine.

Immunization There are no universally accepted recommendations for immunizing children undergoing transplantation. The American Academy of Pediatrics and the CDC regularly publish updated guidelines regarding immunization practices in healthy and transplant pediatric recipients [100, 101] (Table 8.9).

8  Infections in Pediatric Transplant Recipients Table 8.9  Immunizations in patients after hematopoietic stem cell transplantation (HSCT) [102] Vaccine Pneumococcala Haemophilus influenzae type b Tetanus-diphtheria toxoida Inactivated polio Hepatitis B Hepatitis A Measles, mumps, rubella (MMR)a Meningococcal Varicella zoster virusa Influenza

Recommended time after HSCT 12 and 24 months 12, 14, and 24 months 12, 14, and 24 months 12, 14, and 24 months 12, 14, and 24 months Routine administration not recommended 24 months Routine administration not recommended Contraindicated 6 months (yearly lifelong)

Modified from Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation [102] a See text

Children and adolescents before undergoing HSCT or SOT should receive immunizations recommended for their age at least 4 or 2  weeks before the transplantation, respectively. Immunizations can be started 6–12 months after HSCT as long as the patient has no persistent complications (GVHD) and is not receiving immunosuppressive therapy. If the patient is 7 years old, three doses of tetanus and diphtheria toxoid-containing vaccine [including two doses of tetanus and diphtheria (TD) and one dose of adolescent tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap)] should be used [100]. For HSCT recipients who are seronegative to measles and without GVHD or immunosuppression, one dose of MMR vaccine should be given to adolescents and adults and two doses to children at least 24 months after transplantation [100]. Varicella vaccine is contraindicated for HSCT recipients less than 24  months after transplantation. Given the lack of access of immunocompromised patients to the live attenuated varicella vaccine, passive immunoprophylaxis either with varicella zoster immune globulin (VZIG) within 96  h of exposure or regular infusions of gamma globulin is indicated in the high-risk children with no reliable history of varicella. If inadvertent contact occurs between an immunocompromised child and a recent varicella vaccine recipient, administration of VZIG is not recommended as the transmission rate is low and varicella from the Oka strain, albeit unlikely, would be mild and self-limiting. Finally, one should be aware that the vari-

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cella vaccine may not be fully protective against varicella, particularly in an outbreak setting. The 13-valent pneumococcal conjugate vaccine (PCV13) shows good immunogenicity after three doses starting 3–6 months after HSCT. At 12 months after HSCT in children ≥2  years is recommended a dose of pneumococcal polysaccharide vaccine to broaden the serotype coverage given that the patient does not have chronic GVHD.  For patients with chronic GVHD, a fourth dose of PCV13 can be given at 12 months after HSCT [100]. After SOT, DTaP, HIB, hepatitis A, hepatitis B, inactivated influenza and pneumococcal and meningococcal conjugate and polysaccharide vaccines can be administered if indicated. Immunization schedules vary between centers, but most experts recommend waiting at least 6  months after transplantation. Administration of live-virus vaccines such as MMR and varicella is advised in patients who are stable at least 6 months after SOT, who are receiving minimal immunosuppressive agents, and who have not had recent episodes of organ rejection. Household and health-care contacts of HSCT and solid organ transplant recipients should have immunity or be immunized against poliovirus, measles, mumps, varicella, influenza, and hepatitis A [100, 101].

Use of CSFs in Stem Cell Transplantation Recombinant human cytokines and colony-stimulating factors (CSFs) for adjunctive therapy in immunocompromised patients have been an important assistance in attenuating the myelotoxic effects of HSCT. Granulocyte-CSF (G-CSF; filgrastim) and granulocyte-macrophage-CSF (GM-CSF; sargramostim) have undergone extensive evaluation for their potential role in reducing infectious morbidity during periods of severe immunosuppression. However, they should be used judiciously in order to maximize medical benefit, limit potential toxicity, and be cost-effective. The effects of G-CSF and GM-CSF in prevention of infections in neutropenic patients are perhaps best illustrated in the impact of these agents on stem cell mobilization in HSCT donors. Transfusion of peripheral mobilized stem cells has led to a substantial reduction in depth and duration of neutropenia [103–106]. G-CSF and GM-CSF also are used in HSCT recipients as part of most immediate posttransplant regimens for their impact on shortening the duration of neutropenia. The effects on the incidence of fever or documented infections, antibiotic usage, or duration of hospitalization have been more variable and dependent on clinical trial design. Notably, as these cytokines do not augment platelet recovery, thrombocytopenia remains a challenging problem for HSCT recipients.

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WJ.  Epidemiology, outcomes, and costs of invasive aspergilloLancet Infect Dis. 2003;3:79–86. sis in immunocompromised children in the United States, 2000. 33. Hierholzer JC.  Adenoviruses in the immunocompromised host. Pediatrics. 2006;117:e711–6. Clin Microbiol Rev. 1992;5:262–74. 15. Morrison VA, Haake RJ, Weisdorf DJ.  The spectrum of non-­ 34. Runde V, Ross S, Trenschel R, Lagemann E, Basu O, et  al. Candida fungal infections following bone marrow transplantation. Adenoviral infection after allogeneic stem cell transplantation Medicine (Baltimore). 1993;72:78–89. (SCT): report on 130 patients from a single SCT unit involved 16. Fisher BT, Alexander S, Dvorak CC, Zaoutis TE, Zerr DM, et al. in a prospective multi center surveillance study. Bone Marrow Epidemiology and potential preventative measures for viral infecTransplant. 2001;28:51–7. tions in children with malignancy and those undergoing hematopoi 35. Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch etic cell transplantation. Pediatr Blood Cancer. 2012;59:11–5. HH, et al. European guidelines for diagnosis and treatment of ade 17. Wasserman R, August CS, Plotkin SA.  Viral infections in pedinovirus infection in leukemia and stem cell transplantation: sumatric bone marrow transplant patients. Pediatr Infect Dis J. mary of ECIL-4 (2011). Transpl Infect Dis. 2012;14:555–63. 1988;7:109–15. 36. Leung TF, Chik KW, Li CK, Lai H, Shing MM, et al. Incidence, 18. Hale GA, Heslop HE, Krance RA, Brenner MA, Jayawardene D, risk factors and outcome of varicella-zoster virus infection in chilet al. Adenovirus infection after pediatric bone marrow transplantadren after haematopoietic stem cell transplantation. Bone Marrow tion. Bone Marrow Transplant. 1999;23:277–82. Transplant. 2000;25:167–72.

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Part II Clinical Disorders in Transplant Recipients

9

Febrile Neutropenia in Transplant Recipients Lior Nesher and Kenneth V. I. Rolston

Introduction Hematopoietic transplantation has been used to treat many disorders including neoplastic, hematologic, immunologic, and metabolic diseases. Currently, most hematopoietic transplants are performed for the treatment of hematologic malignancies [1]. Hematopoietic cells for transplantation can be collected from various sources including bone marrow, peripheral blood, and umbilical cord blood. Autologous transplants utilize the patient’s own cells, whereas allogeneic transplants utilize cells obtained from a different individual. Syngeneic transplants are between genetically identical twins. Conditioning therapy given prior to hematopoietic transplantation can be myeloablative or non-myeloablative (i.e., reduced intensity) and produces significant neutropenia (absolute neutrophil count [ANC] ≤500 cells/mm3), which is the most common predisposing factor for the development of bacterial and fungal infections during the pre-engraftment phase. Neutropenia is more prolonged in recipients of myeloablative allogeneic transplants than in recipients of non-­myeloablative or autologous transplants. Thus, the frequency and severity of infection in allogeneic transplant recipients are greater than in other transplant subgroups [2–6]. Some patients with hematologic malignancies may have normal or even elevated ANCs but may be at increased risk for infection due to defects in neutrophil function (qualitative neutropenia). These defects include significant reduction in phagocytosis, decreased bacL. Nesher Infectious Disease Institute, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel Soroka University Medical Center affiliated with Faculty of Health Sciences Ben-Gurion University of the Negev, Infectious Disease Institute, Beer Sheba, Israel e-mail: [email protected] K. V. I. Rolston (*) Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]

tericidal and fungicidal activity, decreased production of superoxide anions, and defects in granulocyte locomotion. Myeloablative conditioning regimens also inflict substantial damage to mucosal barriers causing mucositis of the mouth and gastrointestinal tract, resulting in increased risk of infections arising from these sites [7, 8]. Early recognition and aggressive management of infection is critical for the overall survival of hematopoietic transplant recipients, and delays in the administration of appropriate anti-infective therapy are associated with poorer outcomes [9]. Unfortunately, signs and symptoms commonly associated with infection may be blunted in these highly immunosuppressed patients. Often the only manifestation of infection during an episode of neutropenia is fever. This condition is commonly referred to as “febrile neutropenia.” The widely accepted definition of febrile neutropenia is an oral temperature of ≥38.3 °C, or two consecutive readings of >38 °C during a 2 h period, and an absolute neutrophil count of 10–12 days will develop lung infiltrates. These often do not respond to broad-­spectrum antimicrobial therapy and establishing a specific diagnosis in such patients remains a significant challenge [22]. Data regarding other sites of infection are not as robust as those describing BSIs.

unexplained fever 45 - 50% clinically documented infections 20 25% (predominantly respiratory and SSIs) microbiologically documented infections 20- 25% (predominantly bacterial and fungal) non infectious causes of fever 65% of S. aureus in S. aureus CLABSI [43]. Of concern are the increasing rates of methicillin resistance among S. aureus (MRSA) isolates were methicillin-resistant b Approximately 18% of Enterococcus species were vancomycin-­ isolates worldwide. Although MRSA rates as low as resistant enterococci (VRE) 10% are still reported occasionally, many institutions are c VGS – viridans group streptococci – the most common species were S. reporting MRSA rates in the range of 55–60%, making mitis, S. sanguis, and S. salivarius d them more common than methicillin-susceptible isolates. Included groups A, B, C, G, and F Some MRSA isolates have developed tolerance (MBC ≥32 Table 9.3  Spectrum of Gram-negative organisms isolated from febrile times the MIC) or reduced susceptibility to vancomycin neutropenic patients (referred to as the MIC creep), thereby reducing the theraOrganism % Frequency peutic impact of this agent, which until recently has been Escherichia colia 20–45 considered to be the agent of choice for the treatment of 10–20 Klebsiella speciesb Gram-positive infections in neutropenic patients [44, 45]. 15–20 Other Enterobacteriaceaec Alternative agents are being recommended for infections 18–24 Pseudomonas aeruginosad caused by such organisms [46]. 2–5 Stenotrophomonas maltophiliad Alpha-hemolytic streptococci or VGS are major comd 3 months). transplant recipients, and that thrombotic events and HIT The authors note that it has been proposed that the early-­ antibody positivity were not well correlated [72, 73]. Case onset presentation may be due to passive transfer of antibodstudies in renal transplant patients have reported some inci- ies from the donor to the recipient. Those that developed dences of HIT posttransplant and graft-failure related to HIT, late-onset ITP were felt to have developed the antibodies in part related to previous exposure to heparin in hemodialy- independently of their donors [79]. sis [74, 75]. Additionally, studies have reported on development of HIT antibody immunoassays are often sent if a patient alloimmune thrombocytopenic purpura, with antibodies develops thrombocytopenia and has received heparin at any introduced from donors with a history of ITP [79, 80]. One time during the hospitalization. However, the high sensitivity case study described a case where a donor liver was obtained but low specificity of the test results in overdiagnosis of from a donor who had died after a cerebral hemorrhage secheparin-­ induced thrombocytopenia exposes patients to ondary to ITP. The recipient developed ITP within 3 days of unnecessary risks associated with therapeutic anticoagula- transplant and subsequently expired after developing portal tion. Chaturvedi and colleagues examined this phenomenon vein thrombosis. The authors attributed the death to ITP in at Cleveland Clinic and found that utilizing the 4Ts algo- that they were unable to anticoagulate but were providing rithm to first rule out patients at low risk for HIT was a safe, blood products that may have resulted in increased likelireliable, and cost-effective [76]. Therefore, we recommend hood of thrombosis. It is also possible, however, that the that immunoassays for HIT antibodies be utilized only in donor was producing procoagulant antibodies, as approxithose patients whose 4T scores suggest intermediate or high mately 20–25% of patients with ITP also have antiphosphoprobability of heparin-induced thrombocytopenia. lipid antibodies [81, 82]. Based on this event, the authors If a HIT antibody immunoassay is sent once a patient is recommended excluding cadaveric transplants from donors determined to be of intermediate/high risk for HIT, it is whose death is attributed to ITP [80]. important to understand how this test is interpreted. The immunoassay detects the presence of antiplatelet factor 4 (PF4) antibodies in patient serum and is interpreted by opti- Other Etiologies cal density (OD). A higher reported OD correlates to a higher titer of the antibody and is more strongly suggestive of a Particularly in liver transplant patients, thrombocytopenia is diagnosis of HIT. As mentioned previously, ELISAs for HIT often seen prior to transplant, and generally approximately have a high sensitivity (meaning a negative test can rule out 50% of transplant recipients develop worsening thrombocythe diagnosis) but a low specificity, underscoring the need to topenia within 2  weeks following transplant. This acute first confirm a high pretest probability. decrease generally resolves within the 1st month after trans-

10  Cytopenias in Transplant Patients

plant, and if thrombocytopenia persists, another etiology should be sought [79, 83, 84]. Thrombocytopenia following liver transplant can also be attributed to residual portal hypertension or hypersplenism, if either of these conditions persist following transplant. However, it is important to remain vigilant to other causes particularly drug-related and infectious etiologies that could cause a drop in the platelet count. Additionally, while case reports exist of TMA with low ADAMTS13 levels attributed to inhibitors present in the blood [85], this is not a common phenomenon, and etiologies of TMA mentioned previously (infectious and drug-related) would be much more likely.

Treatment In most cases, treatment of the underlying etiology of the thrombocytopenia will result in improvement in platelet counts. That may require antivirals, adjustment of the immunosuppressant regimen, withdrawal of other pharmacologic agents such as heparin, or supportive care. Platelet transfusions may be necessary if bleeding events occur or if additional procedures are necessary, but we do not recommend prophylactic transfusions for maintenance of the platelet count above a specific threshold. TPO receptor agonists, romiplostim and eltrombopag, have been used in management of chronic thrombocytopenia due to ITP and liver disease and are being studied as a supportive medication in stem cell transplantation [86]. There is a case report in the pediatric transplant literature where romiplostim was used in the peri-transplant setting, which resulted in a platelet-transfusion-free liver transplant [87]. However at this time, there is no data to support use of TPO agonists outside of their approved indications following solid organ transplant.

References 1. Vanrenterghem Y, Ponticelli C, Morales JM, et al. Prevalence and management of anemia in renal transplant recipients: a European survey. Am J Transplant. 2003;3:835–45. 2. Yorgin PD, Scandling JD, Belson A, Sanchez J, Alexander SR, Andreoni KA. Late post-transplant anemia in adult renal transplant recipients. Am J Transplant. 2002;2:429–35. 3. Kolonko A, Pinocy-Mandok J, Kocierz M, et al. Anemia and erythrocytosis after kidney transplantation: a 5 year graft function and survival analysis. Transplant Proc. 2009;8:3046–51. 4. Przybylowski P, Malyszko J, Malyszko J.  Anemia is a predic tor of outcome in heart transplant recipients. Transplant Proc. 2009;41:322–3231. 5. Taegtmeyer AB, Rogers P, Breen JB, Barton PJ, Banner NR, Yacoub MH.  The effects of pre- and post-transplant anemia on 1-year survival after cardiac transplantation. J Heart Lung Transplant. 2008;27:394–9.

205 6. Yazer MH, Triulzi DJ.  Immune hemolysis following ABO-­ mismatched stem cell or solid organ transplantation. Curr Opin Hematol. 2007;14:664–70. 7. Audet M, Panaro F, Piardi T, et al. Passenger lymphocyte syndrome and liver transplantation. Clin Dev Immunol. 2009;2008:715769. 8. Shortt J, Westall GP, Roxby D.  A ‘dangerous’ group O donor: severe hemolysis in all recipients of organs from a donor with multiple red cell alloantibodies. Am J Transplant. 2008;8:711–4. 9. Seltsam A, Hell A, Heymann G, Salama A. Donor derived alloantibodies and passenger lymphocyte syndrome in two of four patients who received different organs from the same donor. Transfusion. 2001;41:365–70. 10. Salerno CT, Burdine J, Perry EH, Kshettry VR, Hertz MI, Bolman IIIR. Donor-derived antibodies and hemolysis after ABO-­ compatible but nonidentical heart-lung and lung transplantation. Transplantation. 1998;65:261–4. 11. Panaro F, DeChristopher PJ, Rondelli D. Severe hemolytic anemia due to passenger lymphocytes after living related bowel transplant. Clin Transpl. 2004;18:332–5. 12. Winkelmayer WC, Kewalramani R, Rutstein M, Gabardi S, Vonvisger T, Chandraker A. Pharmacoepidemiology of anemia in kidney transplant recipients. J Am Soc Nephrol. 2004;15:1347–52. 13. Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD. Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: risk factors and implications for mortality. J Am Soc Nephrol. 2006;17:3240–7. 14. Augustine JJ, Knauss TC, Schulak JA, Bodziak KA, Siegel C, Hricik DE.  Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. Am J Transplant. 2004;4:2001–6. 15. Pratap B, Abraham G, Srinivas CN, Bhaskar S.  Post-renal transplant hemolytic uremic syndrome following combination therapy with tacrolimus and everolimus. Saudi J Kidney Dis Transpl. 2007;18:609–12. 16. Go O, Naqvi A, Tan A, Amzuta I, Lenox R. The spectrum of thrombotic thrombocytopenic purpura: a clinicopathologic demonstration of tacrolimus-induced thrombotic thrombocytopenic purpura in a lung transplant patient. South Med J. 2008;101:744–7. 17. Saito M, Satoh S, Kagaya H, et  al. Thrombotic microangiopathy developing in early stage after renal transplantation with a high trough level of tacrolimus. Clin Exp Nephrol. 2008;12:312–5. 18. Maheshwari A, Mishra R, Thuluvath PJ. Post-liver transplant anemia: etiology and management. Liver Transpl. 2004;10:165–73. 19. Nosari A, Marbello L, De Carlis LG, et  al. Bone marrow hypoplasia complicating tacrolimus (FK506) therapy. Int J Hematol. 2004;79:130–2. 20. Engelen W, Verpooten GA, Van der Planken M, Helbert MF, Bosmans JL, De Broe ME. Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients. Clin Nephrol. 2003;60:119–24. 21. Naik PM, Lyon GM 3rd, Ramirez A, et al. Dapsone-induced hemolytic anemia in lung allograft recipients. J Heart Lung Transplant. 2008;27:1198–202. 22. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83:265–73. 23. Dunford LM, Roy DM, Hahn TE, et al. Dapsone-induced methemoglobinemia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12:241–2. 24. Balbi E, Leal CR, Pacheco-Moreira LF, et al. Treatment for recurrent hepatitis C virus infection after liver transplantation. Transplant Proc. 2009;41:891–4. 25. Glanville AR, Scott AI, Morton JM, et al. Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant. 2005;24:2114–9.

206 26. Ar MC, Ozbalak M, Tuzuner N, et  al. Severe bone marrow failure due to valganciclovir overdose after renal transplantation from cadaveric donors: four consecutive cases. Transplant Proc. 2009;41:1648–53. 27. Elimelakh M, Dayton V, Park KS, et al. Red cell aplasia and autoimmune hemolytic anemia following immunosuppression with alemtuzumab, mycophenolate, and daclizumab pancreas transplant recipients. Haematologica. 2007;92:1029–36. 28. Mix TC, Kazmi W, Khan S, et al. Anemia: a continuing problem following kidney transplantation. Am J Transplant. 2003;3:1426–33. 29. Smith EP.  Hematologic disorders after solid organ transplan tation. Am Soc Hematol Am Soc Hematol Educ Program. 2010;2010:281–6. 30. Park JB, Kim DJ, Woo SY, et  al. Clinical implications of quantitative real time-polymerase chain reaction of parvovirus B19  in kidney transplant recipients  – a prospective study. Transpl Int. 2009;22:455–62. 31. Florea AV, Ionescu DN, Melhem MF.  Parvovirus B19 infec tion in the immunocompromised host. Arch Pathol Lab Med. 2007;131:799–804. 32. Shekar K, Hopkins PM, Kermeen FD, Dunning JJ, McNeil KD. Unexplained chronic anemia and leukopenia in lung transplant recipients secondary to parvovirus B19 infection. J Heart Lung Transplant. 2008;27:808–11. 33. Marinella MA.  Hematologic abnormalities following renal transplantation. Int Urol Nephrol. 2010;42:151–64. 34. Parker A, Bowles K, Bradley JA, et  al. Management of post-­ transplant lymphoproliferative disorder in adult solid organ transplant recipients  – BCSH and BTS guidelines. Br J Haematol. 2010;149:693–705. 35. Kato T, Yazawa K, Madono K, Saito J, Hosomi M, Itoh K. Acute graft-vs-host disease in kidney transplantation: case report and review of literature. Transplant Proc. 2009;41:3949–52. 36. Lo MM, Mo JQ, Dixon BP, Czech KA. Disseminated histoplasmosis associated with hemophagocytic lymphohistiocytosis in kidney transplant recipients. Am J Transplant. 2010;10:687–91. 37. Hughes WT, Armstrong D, Bodey GP, et al. Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730–51. 38. Hartmann EL, Gatesman M, Roskopf-Somerville J, Stratta R, Farney A, Sundberg A. Management of leukopenia in kidney and pancreas transplant recipients. Clin Transpl. 2008;22:822–8. 39. Dewit O, Moreels T, Baert F, et al. Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients. Clin Biochem. 2011;44:1062–6. 40. Danesi R, Del Tacca M. Hematologic toxicity of immunosuppressive treatment. Transplant Proc. 2004;36:703–4. 41. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation. 1996;61:1029–37. 42. Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol. 2003;14:2381–6. 43. Fischer SA. Emerging viruses in transplantation: there is more to infection after transplant then CMV and EBV.  Transplantation. 2008;86:1327–39. 44. Thomas LD, Hongo I, Bloch KC, Tang YW, Dummer S.  Human ehrlichiosis in transplant patients. Am J Transplant. 2007;7: 1641–7. 45. Arakawa Y, Matsui A, Sasaki N, Nakayama T. Agranulocytosis and thrombocytopenic purpura following measles infection in a living-­ related orthotopic liver transplantation recipient. Acta Paediatr Jpn. 1997;39:226–9. 46. Wiwanitkit V.  Dengue infection in kidney transplant patients: an appraisal on clinical manifestation. Iran J Kidney Dis. 2010;4:168.

M. Barry et al. 47. Eid AJ, Brown RA, Patel R, Razonable RR. Parvovirus B19 infection after transplantation: a review of 98 cases. Clin Infect Dis. 2006;43:40–8. 48. Karakus S, Arin BE, Arat Z, Karakayali H, Haberal M. Impact of hepatitis serology on development of leukopenia after solid organ transplantation. Transplant Proc. 2008;40:199–201. 49. Razeghi E, Hadadi A, Mansor-Kiaei M, Molavi M, Khashayar P, Pourmand G.  Clinical manifestation, laboratory findings, and the response of treatment in kidney transplant recipients with CMV infection. Transplant Proc. 2007;39:993–6. 50. Simmons P, Kaushansky K, Torok-Storb B.  Mechanisms of cytomegalovirus-­mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells. Proc Natl Acad Sci U S A. 1990;87:1386–90. 51. Kute VB, Vanikar AV, Shah PR, et  al. Post-renal transplant cytomegalovirus infection: study of risk factors. Transplant Proc. 2012;44:706–9. 52. Cooke ME, Potena L, Luikart H, Valantine HA. Peripheral blood leukocyte counts in cytomegalovirus infected heart transplant patients: impact of acute disease versus subclinical infection. Transplantation. 2006;82:1419–24. 53. Rane S, Nada R, Minz M, Sakhuja V, Joshi K.  Spectrum of cytomegalovirus-­induced renal pathology in renal allograft recipients. Transplant Proc. 2012;44:713–6. 54. De Keyzer K, Van Laecke S, Peeters P, Vanholder R.  De novo thrombotic microangiopathy induced by cytomegalovirus infection leading to renal allograft loss. Am J Nephrol. 2010;32:491–6. 55. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Fremeaux-­ Bacchi V, Legendre C.  New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;7:23–35. 56. Ramasubbu K, Mullick T, Koo A, et al. Thrombotic microangiopathy and cytomegalovirus in liver transplant recipients: a case-based review. Transpl Infect Dis. 2003;5:98–103. 57. Hachem RR, Yusen RD, Chakinala MM, Aloush AA, Patterson GA, Trulock EP.  Thrombotic microangiopathy after lung transplantation. Transplantation. 2006;81:57–63. 58. Fischer SA. Emerging viruses in transplantation: there is more to infection after transplant than CMV and EBV.  Transplantation. 2008;86:1327–39. 59. Caires RA, Marques IDB, Repizo LP, et  al. De novo thrombotic microangiopathy after kidney transplantation: clinical features, treatment, and long-term patient and graft survival. Transplant Proc. 2012;44:2388–90. 60. Fouad YM. Chronic hepatitis C-associated thrombocytopenia: aetiology and management. Trop Gastroenterol. 2013;34:58–67. 61. Smith EP. Hematologic disorders after solid organ transplantation. ASH Educ Program Book. 2010;2010:281–6. 62. Devadoss CW, Vijaya VM, Mahesh E, Venkataramana SR, Girish MS. Tacrolimus associated localized thrombotic microangiopathy developing in early stage after renal transplantation. J Clin Diagn Res. 2012;6:1786–8. 63. Boyer NL, Niven A, Edelman J. Tacrolimus-associated thrombotic microangiopathy in a lung transplant recipient. BMJ Case Rep. 2013;2013:bcr2012007351. 64. Nwaba A, MacQuillan G, Adams LA, et  al. Tacrolimus-induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients. Intern Med J. 2013;43:328–33. 65. Fortin MC, Raymond MA, Madore F, et al. Increased risk of thrombotic microangiopathy in patients receiving a cyclosporin-sirolimus combination. Am J Transplant. 2004;4:946–52. 66. Minson Q, Gentry CA.  Analysis of linezolid-associated hema tologic toxicities in a large veterans affairs medical center. Pharmacotherapy. 2010;30:895–903. 67. Bernstein WB, Trotta RF, Rector JT, Tjaden JA, Barile AJ. Mechanisms for linezolid-induced anemia and thrombocytopenia. Ann Pharmacother. 2003;37:517–20.

10  Cytopenias in Transplant Patients 68. El-Khoury J, Fishman JA. Linezolid in the treatment of vancomycin-­ resistant enterococcus faecium in solid organ transplant recipients: report of a multicenter compassionate-use trial. Transpl Infect Dis. 2003;5:121–5. 69. Radunz S, Juntermanns B, Kaiser GM, et  al. Efficacy and safety of linezolid in liver transplant patients. Transpl Infect Dis. 2011;13:353–8. 70. Attassi K, Hershberger E, Alam R, Zervos MJ. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis. 2002;34:695–8. 71. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A.  Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:7. 72. Bachmann R, Bachmann J, Lange J, Nadalin S, Konigsrainer A, Ladurner R. Incidence of heparin-induced thrombocytopenia type II and postoperative recovery of platelet count in liver graft recipients: a retrospective cohort analysis. J Surg Res. 2014;186:429–35. 73. Kaneko J, Sugawara Y, Tamura S, Togashi J, Matsui Y, Makuuchi M.  Heparin-induced thrombocytopenia after liver transplantation. Transplant Proc. 2008;40:1518–21. 74. Dracopoulos S, Vougas V, Kassimatis TI, Theodoridis T, Ali ME, Apostolou T. Heparin-induced thrombocytopenia type II: a serious hazard in preemptive renal transplantation: a case report. Transplant Proc. 2007;39:3481–4. 75. Muzaffar M, Li X, Ratnam S. Successful preemptive renal retransplantation in a patient with previous acute graft loss secondary to HIT type II: a case report and review of literature. Int Urol Nephrol. 2012;44:991–4. 76. Chaturvedi S, Kohli R, McCrae K. Over-testing for heparin induced thrombocytopenia in hospitalized patients. J Thromb Thrombolysis. 2015;40(1):12–6. 77. Lugao Rdos S, Motta MP, de Azevedo MF, et al. Immune thrombocytopenic purpura induced by intestinal tuberculosis in a liver transplant recipient. World J Gastroenterol. 2014;20:8304–8.

207 78. Einollahi B. Renal transplantation and idiopathic thrombocytopenic purpura: two case reports. Transplant Proc. 2009;41:2923. 79. Taylor RM, Bockenstedt P, Su GL, Marrero JA, Pellitier SM, Fontana RJ.  Immune thrombocytopenic Purpura following liver transplantation: a case series and review of the literature. Liver Tranplant. 2006;12:11. 80. Pereboom IT, de Boer MT, Haagsma EB, van der Heide F, Porcelijn L, Lisman T, Porte RJ. Transmission of idiopathic thrombocytopenic purpura during orthotopic liver transplantation. Transplant Int. 2010;23:3. 81. Kim KJ, Baek IW, Yoon CH, Kim WU, Cho CS.  Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies. Br J Haematol. 2013;161: 706–14. 82. Yang YJ, Yun GW, Song IC, et al. Clinical implications of elevated antiphospholipid antibodies in adult patients with primary immune thrombocytopenia. Korean J Intern Med. 2011;26:449–54. 83. Chatzipetrou MA, Tsaroucha AK, Weppler D, et  al. Thrombocytopenia after liver transplantation. Transplantation. 1999;67:702–6. 84. Plevak DJ, Halma GA, Forstrom LA, et al. Thrombocytopenia after liver transplantation. Transplant Proc. 1988;20:630–3. 85. Pham PT, Danovitch GM, Wilkinson AH, et  al. Inhibitors of ADAMTS13: a potential factor in the cause of thrombotic microangiopathy in a renal allograft recipient. Transplantation. 2002;74:1077–80. 86. Liesveld JL, Phillips GL 2nd, Becker M, et  al. A phase 1 trial of eltrombopag in patients undergoing stem cell transplantation after total body irradiation. Biol Blood Marrow Transplant. 2013;19:1745–52. 87. Minowa K, Arai K, Kasahara M, et  al. Romiplostim treatment allows for platelet transfusion-free liver transplantation in pediatric thrombocytopenic patient with primary sclerosing cholangitis. Pediatr Transplant. 2014;18:E212–5.

Infections in Allogeneic Stem Cell Transplantation

11

Marcus R. Pereira, Stephanie M. Pouch, and Brian Scully

Introduction

Underlying Host Disease

Allogeneic hematopoietic stem cell transplantation (allo-­ HSCT) has become a widely used modality of therapy for a variety of malignant and nonmalignant diseases. While many advances have been made in the field, infection remains one of the most severe and frequently encountered complications of HSCT.  In this chapter we review the defects in host defenses and important risk factors predisposing allo-HSCT recipients to infection, the major categories of infection and their time courses following transplantation, and preventive strategies.

Infection risk is very much impacted by the disease for which the patient is being transplanted and also by the presence of preceding infections. Acute leukemia, for example, predisposes to neutropenia and other defects of innate immunity. Profound neutropenia (500 mg/dL, and phytohemagglutinin within 60% of the lower limit of normal [72]. Patients with active GVHD should also receive antibiotic prophylaxis aimed at pneumococcus. Penicillin V usually suffices, but trimethoprim/sulfamethoxazole or dox-

Cytomegalovirus CMV continues to be one of the most important pathogens in this group. It is estimated that about 50% of the population in the United States is latently infected with CMV [75]. In other places in the world, including developing nations, the prevalence is even higher [76, 77]. Prior to widespread use of anti-CMV prophylaxis, approximately 80% of seropositive allo-HSCT recipients developed CMV reactivation, usually in the first 3  months after transplantation [78]. Despite prophylaxis with either ganciclovir or valganciclovir, the incidence of CMV reactivation ranges between 20% and 50%, with episodes increasingly occurring after prophylaxis is finished (late CMV) [79–83]. Approximately 6–18% of allo-HSCT recipients with CMV reactivation develop disease [79, 80, 83]. Clinical manifestations of CMV disease are variable and include interstitial pneumonia, enteritis, hepatitis, retinitis, encephalitis, and a CMV syndrome that includes cytopenia and fevers. CMV-related mortality is on average 40–50%, but can be as high as 86% in cases of severe pneumonia [83]. In addition to its direct end-organ effects, CMV disease is also associated with increased bacterial, fungal, and other viral infections [84]. The classic and most important risk factor for CMV reactivation is the serostatus of the recipient and donor, with a CMV-infected (seropositive) patient receiving a graft from a CMV-­naïve (seronegative) donor considered the highest risk.

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Additional risk factors include total body radiation in the conditioning phase, development of acute and chronic GVHD, T-cell-depleting therapies, steroids at doses greater than 1 mg/kg per day, and the use of mismatched or unrelated donors [78, 79]. Diagnosis of CMV disease remains clinically challenging given the varied and nonspecific presentations. Although PCR analysis of CMV DNA in the serum has become the mainstay of diagnosis, no absolute cutoff in viremia exists for differentiation between infection and disease. The presence of viremia does not automatically indicate disease although studies have shown that the likelihood of disease is high when levels above 10,000 copies/mL are found [85]. Conversely, disease does not always correlate with viremia, especially in cases of gastrointestinal involvement. With the introduction of international units, better studies to correlate disease and viremia will be possible in the future. Intravenous ganciclovir is first-line therapy for CMV disease in allo-HSCT recipients. In non-severe cases, including asymptomatic viremia, oral valganciclovir can be used. Due to toxicities, foscarnet and cidofovir are considered second-­ line drugs and reserved for treatment failure due to GCV resistance or in situations where GCV is not tolerated. It is recommended that continuing treatment for 14–21 days after CMV DNA is no longer detectable in serum, followed by 1–3  months of maintenance therapy [86]. CMV immunoglobulins have been studied and in general are reserved for severe cases, especially pneumonia, or lack of response to antiviral therapy [87]. Recent studies have suggested that CMV-specific T-cell administration can be effective in the prophylaxis and treatment of CMV [88]. Although risk-stratified prophylaxis with oral valganciclovir can be effective, problems with toxicity, especially bone marrow suppression, preclude it from being a standard approach. An alternative approach involves frequent serum CMV PCR monitoring and initiation of treatment if viremia is detected. This preemptive approach is usually more logistically difficult and leads to higher rates of CMV reactivation [51]. An elusive goal for many decades, the search for a vaccine has recently shown promising results around glycoprotein B and phosphoprotein 65 epitopes [89, 90].

Epstein-Barr Virus (EBV) In the United States and worldwide, it is estimated that almost 95% of adults demonstrate past infection with EBV. The spectrum of EBV-related diseases includes asymptomatic viremia, a viral syndrome with fevers and neutropenia, oral hairy leukoplakia, and rarely meningoencephalitis. More importantly, EBV is also associated with 50–70% of cases of PTLD in allo-HSCT recipients [91]. PTLD usually occurs in the first year after transplant and arises when EBV-specific T-lymphocytes are depleted, allowing for unchecked proliferation of donor-derived mono-

M. R. Pereira et al.

clonal or polyclonal B cells [92]. The spectrum of PTLD includes extranodal lymphocyte infiltration to high-grade B-cell lymphoma and varies from an indolent to fulminant presentation. Although the overall incidence of EBV-related PTLD in this population is approximately 1% (up to 2.8% in children), mortality can be as high as 50–90% [93]. Risk factors include age >50; recipients of mismatched, matched unrelated, or T-cell-depleted transplants; acute and chronic GVHD; and use of T-cell-depleting agents such as thymoglobulin and alemtuzumab [92]. Treatment options range from reduced immunosuppression to chemotherapeutic agents such as rituximab or CHOP. Antiviral agents have a limited role in the treatment or prevention of EBV-PTLD. Given that persistent or increasing EBV viremia usually precedes PTLD, preemptive treatment with rituximab may reduce the risk of progression to PTLD [94, 95].

 erpes Simplex Virus (HSV) H More than 50% of US adults are latently infected with HSV-1 [96]. In allo-HSCT recipients who do not received antiviral prophylaxis, the rate of reactivation can be as high as 80% and often occurs earlier, 2–3 weeks post-engraftment, than other herpesviruses [97, 98]. Clinical manifestations most commonly include oral-labial lesions and esophagitis, but can be varied and cause bone marrow suppression, keratitis, pneumonia, hepatitis, as well as meningoencephalitis [99– 104]. HSV-2, on the other hand, is less frequent and is usually involved with perineal lesions only. Recurrent episodes of either HSV-1 or 2 infections may warrant suppressive therapy [51].  aricella Zoster Virus (VZV) V Similar to HSV, reactivation is the most common cause of VZV-related disease after allo-HSCT, occurring in about 16% of patients in the first year after transplant [105]. Since anti-HSV or CMV prophylaxis is effective against VZV, reactivation usually occurs after prophylaxis has stopped, although breakthrough can also occur [105, 106]. GVHD is a major risk factor for VZV reactivation [107]. Clinical manifestations include either classic or multi-dermatomal shingles with lesions usually taking longer to heal that in immunocompetent patients. Disseminated VZV is a rare but severe occurrence, which can involve the lungs, liver, and CNS [108].  uman Herpesvirus (HHV) 6, 7, and 8 H HHV-6 reactivation is common early post allo-HSCT, ranging from 36% to 47% of patients in the first month [109, 110]. The vast majority of cases range from asymptomatic viremia to fevers and transient marrow suppression, but patients can infrequently develop severe disease, including encephalitis, hepatitis, and pneumonitis. Posttransplant acute

11  Infections in Allogeneic Stem Cell Transplantation

limbic encephalitis [111] is a form of CNS disease in allo-­ HSCT recipients that is related to HHV-6 reactivation [112]. In addition to its direct effects, HHV-6 viremia has been found to increase delayed engraftment and GVHD as well as predispose patients to CMV and EBV reactivation [109]. Risk factors for HHV-6 reactivation include cord blood transplantation as well HLA mismatch [113]. Ganciclovir has activity against HHV-6 and is used for treatment [114]. Screening and preventative measures have not been developed. HHV-7 viremia is also a common occurrence, but its association with post-HSCT disease is not well documented at this time. Reports of CNS disease associated with this virus have been reported [115]. HHV-8 can be transmitted to seronegative recipients, but clinical manifestations of viremia are also not well documented at this time, although it may possibly be related to fever, rash, mild hepatitis, and bone marrow aplasia. Unlike solid organ transplantation, cases of Kaposi’s sarcoma are very rare [116].

Adenovirus (ADV) Besides reactivation of latent infection, allo-HSCT recipients are susceptible to transmission of ADV via the stem cell graft as well as primary acquisition of any of the other >50 serotypes. About 12% of allo-HSCT recipients are affected by ADV reactivation, most of which are children under 5 years of age [117]. Reactivation usually occurs between 30 and 90 days posttransplant. Besides young age, risk factors for reactivation include severe GVHD, high-dose steroids, as well as use of unrelated cord blood [74]. In recipients with ADV viremia, approximately 40–50% develop disease, which ranges from a viral syndrome (fever, elevated liver enzymes, and pancytopenia) to pneumonitis, nephropathy, hemorrhagic cystitis, colitis, myocarditis, and CNS disease. Mortality in the setting of ADV disease is estimated to be around 22% [117]. Diagnosis is usually a combination of high clinical suspicion, serum ADV quantitative PCR, and histology. Treatment is not well defined but usually consists of reduced immunosuppression and cidofovir, which has a high incidence of nephrotoxicity [118]. Preventative measures are also not well defined. Respiratory Viruses With continuously improving detection techniques, respiratory viral pathogens have been increasingly recognized as significant sources of morbidity and mortality among recipients of allo-HSCT. These include, among others, influenza [119], parainfluenza [120], RSV [121], human metapneumovirus [122], as well as multiple strains of rhinoviruses, coronaviruses, and bocaviruses [123, 124]. Both community and nosocomial outbreaks are responsible for majority of infec-

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tions, and rates of respiratory viral infections among allo-­ HSCT recipients undergo seasonal variation, much like the general population [125]. Estimates vary, but studies have shown that influenza (both A and B), parainfluenza, and RSV are the most common causes of viral respiratory infections [125]. Risk factors include GVHD, lymphopenia, and the presence of children younger than 12 years of age at home. Diagnosis involves clinical suspicion and RT-PCR. Mortality is variable and is usually associated with complications such as respiratory failure and bacterial or fungal superinfection. Preventative measures include vaccination, hand washing, and isolation measures in the setting of outbreaks. Besides anti-influenza drugs, antiviral therapy for most other respiratory viruses remains largely unproven [119, 120].

Hepatitis B Virus The main risk with hepatitis B virus is reactivation of previously resolved infection, which can occur in up to 20% of cases if prophylaxis is not instituted [126]. Among those who reactivate, liver failure can be a rare complication. It is recommended that both recipients and donors be checked for hepatitis B serologies prior to HSCT and appropriate therapeutic or prophylactic measures taken [127].  olyoma Viruses (BK and JC) P Although more commonly affecting renal transplant recipients, BK virus reactivation has also been described to cause both hemorrhagic cystitis and nephropathy in allo-HSCT recipients [128–131]. JCV-related progressive multifocal leukoencephalopathy (PML) is a rare but well-described complication in allo-HSCT recipients with dismal prognosis [132].

Fungal Infections Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among HSCT recipients. Individuals undergoing allo-HSCT are at higher risk for developing IFIs compared to recipients of autologous grafts, largely owing to delayed engraftment and GVHD. The epidemiology of IFIs in HSCT recipients remains dynamic. Since the 1990s, there has been a decrease in the incidence of invasive candidiasis among HSCT recipients due to the more widespread use of fluconazole prophylaxis; however, IFIs due to Aspergillus and other filamentous molds remain a significant concern.

Candida Candida species commonly inhabit the skin and mucosa of the gastrointestinal tract, and disruption of the integrity of either mucosal barrier can lead to invasive candidiasis. In the

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setting of allo-HSCT, invasive candidiasis typically results from mucositis of the gastrointestinal tract incurred during conditioning. Additional risk factors for invasive candidiasis include HLA mismatch, recipient age, prolonged neutropenia, GVHD, gastrointestinal tract colonization, and CMV disease [133, 134]. In the early 1990s, two large trials demonstrated a significant decrease in candidiasis with the use of fluconazole prophylaxis, and its administration through 75 days posttransplant was later shown to significantly reduce mortality among alloHSCT recipients [135–137]. This prompted the widespread use of fluconazole prophylaxis in the early posttransplant period. More recent data from the Prospective Antifungal Therapy (PATH) Alliance registry, however, reported a 28% and 23% incidence of invasive candidiasis in allo-HSCT recipients from matched-related and matched-­ unrelated donors, respectively [138]. While Candida albicans accounted for over half of all episodes of invasive candidiasis in HSCT recipients in the 1980s, invasive candidiasis caused by azoleresistant Candida species such as C. glabrata and C. krusei has increased since the 1990s, which may reflect the routine use of fluconazole prophylaxis [28–30, 137, 138]. Invasive candidiasis in allo-HSCT recipients most commonly presents as fungemia or hepatosplenic candidiasis. Candidemia occurs in approximately 3% of HSCT recipients and may be accompanied by sepsis, a discreet palpable vasculitic rash, and/or end-organ involvement including but not limited to meningitis, endophthalmitis, and endocarditis [139]. In contrast, hepatosplenic candidiasis, or chronic disseminated candidiasis, results from invasion of Candida species into the portal vasculature with subsequent seeding of the liver and/or spleen during periods of neutropenia. While the exact incidence of hepatosplenic candidiasis remains unknown, one autopsy study identified hepatic candidal infection in 9% of HSCT recipients [140]. Patients typically present with fever and an elevated alkaline phosphatase level following neutrophil recovery. Blood cultures tend to be negative in this setting, but computed tomography of the abdomen demonstrates multiple lesions in the liver and spleen; such lesions decrease in size with recurrent neutropenia, indicating that hepatosplenic candidiasis results from a systemic inflammatory response. Biopsy is required for definitive diagnosis, especially because other IFIs and malignancy can result in a similar clinical syndrome. The diagnosis of invasive candidiasis remains challenging, particularly because conventional blood cultures may only have a sensitivity of 50% in those with deep fungal infection [141]. Newer diagnostic assays, including the beta-­D-­glucan test, which detects beta-glucans in the cell wall of molds and yeasts except zygomycetes and cryptococci, may be valuable in the diagnosis of invasive candidiasis. One recent study demonstrated a sensitivity and specificity of 87.5% and 85.5%, respectively, of this assay. The mannan antigen and antibody and the Cand-Tec Candida antigen assays have

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demonstrated lower sensitivities than the beta-­D-­glucan assay (58.9%, 62.5%, and 13%, respectively) [142]. Given the prevalence of azole-resistant Candida species in neutropenic patients, particularly C. glabrata and C. krusei, management of invasive candidiasis in allo-HSCT recipients should include amphotericin B or an echinocandin such as caspofungin, micafungin, or anidulafungin. Several studies have demonstrated comparable efficacy between both antifungal classes; however, echinocandins have been associated with a more favorable toxicity profile [143, 144]. Voriconazole may be used in situations where additional mold coverage is desired; however, since voriconazole resistance has been seen in 3% of Candida infections in solid organ and HSCT recipients, this agent should not be used unless susceptibility of the isolate is confirmed [145, 146]. As the majority of cases of hepatosplenic candidiasis are caused by C. albicans, clinically stable patients may receive fluconazole. Those who are acutely ill or who have relapsed disease should receive 1–2 weeks of induction with liposomal amphotericin B or an echinocandin followed by fluconazole. Duration of therapy for hepatosplenic candidiasis is dependent upon resolution of visceral lesions, typically 3–6  months. Chronic suppressive therapy may be used in individuals at high risk for recurrence, including those with GVHD [146].

Invasive Mold Infections Aspergillus and other molds are ubiquitous environmental pathogens. HSCT recipients are at high risk of infection with these organisms, which are largely acquired via inhalation of conidia that are inadequately cleared in the setting of immunosuppression. Less common routes of infection include invasion of the gastrointestinal tract or cutaneous inoculation.

Aspergillus Invasive aspergillosis is the most frequent IFI encountered among allo-HSCT recipients. Data from the PATH Alliance demonstrated an incidence of invasive aspergillosis of 53.5% and 59.8% in recipients of matched-related donor and matched-unrelated donor transplants, respectively [138]. While both autologous and allo-HSCT recipients are at risk for the development of invasive aspergillosis, prolonged neutropenia, as well as GVHD, and its treatment contribute to higher incidences of invasive aspergillosis among allo-HSCT recipients [147, 148]. The onset of invasive aspergillosis following HSCT occurs in a bimodal fashion, with the first peak noted within the first 40 days of transplantation [149] and corresponding to the period of neutropenia. The second peak occurs post-­

11  Infections in Allogeneic Stem Cell Transplantation

engraftment (“late period”), typically defined as 41+ days following transplant, and tends to arise in the setting of acute or chronic GVHD [147, 148, 150]. Age >40 has been associated with the development of invasive aspergillosis at any time following transplantation, as have donor and recipient polymorphisms in various Toll-like receptors and genes regulating interleukin-1, interleukin-10 promoter, and plasminogen [147, 151–155]. Specifically, donor haplotype 1363T/1063G, which contains two cosegregated single nucleotide polymorphisms in the Toll-like receptor 4 gene, has been associated with the development of invasive aspergillosis [151]. Single nucleotide polymorphisms in the chemokine ligand 10 (CXCL-10) gene have also been demonstrated to reduce dendritic cell CXCL-10 expression when exposed to Aspergillus germlings; these polymorphisms have also been associated with invasive aspergillosis following allo-HSCT [154]. Hematologic malignancies other than chronic myelogenous leukemia in the chronic phase, as well as aplastic anemia, myelodysplastic syndrome, mismatched donor, the use of cord blood, summer season, lack of laminar air flow, and local building construction, have been identified as risk factors for invasive aspergillosis in the early posttransplant period. The risk of invasive aspergillosis in the late posttransplant period increases in the setting of underlying multiple myeloma, use of T-cell-­ depleted or CD34-selected stem cell products, neutropenia, lymphopenia, use of corticosteroids, CMV disease, respiratory virus infection, and GVHD [147, 148]. GVHD and CMV disease are the major risk factors for the development of invasive aspergillosis >6  months after transplantation [148]. The contribution of GVHD to the risk of invasive aspergillosis is highlighted by the fact that conditioning regimens do not appear to impact the incidence of this invasive fungal infection. While the period of neutropenia is shorter and the incidence of early invasive aspergillosis is less in non-myeloablative HSCT recipients, this group remains at highest risk in the late posttransplant period in conjunction with GVHD [12, 156–158]. Aspergillus fumigatus is the most commonly isolated species associated with invasive aspergillosis in allogeneic HSCT recipients; infections with A. niger, A. flavus, and A. terreus are less frequently encountered [147, 159]. The lungs represent the most commonly involved site of infection, though patients may develop sinusitis, CNS disease, and tracheobronchitis. Clinical presentation may be variable, but frequently includes fever, cough, chest pain, hemoptysis, and/or respiratory failure, and the presence of these symptoms should prompt CT of the chest. Lung lesions, with surrounding ground-glass halos, nodular infiltrates, and cavitations, are highly suggestive of pulmonary aspergillosis; however, radiographic findings can be variable in allo-­HSCT recipients with concomitant GVHD and include focal infiltrates and/or bronchopneumonia [160]. Given the lack of specificity of symptoms and radiographic findings, prompt microbiologic

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diagnosis via bronchoscopy should be pursued. Diagnosis of invasive aspergillosis may also be facilitated with use of the Aspergillus galactomannan assay, which employs a doublesandwich enzyme immunoassay to detect the galactomannan component of the Aspergillus cell wall. While the sensitivity of the serum galactomannan assay has varied between studies, it has proven clinically useful for the diagnosis of invasive aspergillosis and monitoring of clinical response during therapy [161, 162]. The galactomannan assay on bronchoalveolar lavage fluid in patients with hematologic malignancies and HSCT recipients has demonstrated higher sensitivity than bronchoalveolar lavage culture, cytology, and the serum galactomannan assay [163]. Important caveats for the use of galactomannan testing include false negative results in individuals receiving concomitant antifungals, false positive results in children and patients receiving beta-lactams, particularly piperacillin-tazobactam, and cross-reactivity with plasmalyte [164–166]. The beta-D-­glucan test, which detects beta-glucans in the cell wall of molds and yeasts except zygomycetes and cryptococci, may also be a valuable adjunctive screening test for invasive aspergillosis particularly in conjunction with the galactomannan assay, though the performance characteristics of the beta-D-glucan assay in the HSCT population have not yet been evaluated. Empiric therapy for suspected invasive aspergillosis should include a mold-active azole or amphotericin B. The use of an echinocandin can also be entertained, though these agents are fungistatic, rather than fungicidal. Once the diagnosis of invasive aspergillosis has been confirmed, primary therapy should include voriconazole in most patients, as this agent has been associated with improved clinical outcomes and survival rates and less toxicity compared with amphotericin B [167, 168]. Voriconazole is also the preferred therapy for Aspergillus tracheobronchitis [168]. Combination therapy with an echinocandin and either amphotericin B or a mold-active azole may be more efficacious than voriconazole alone, however, particularly for salvage therapy [169, 170]. The duration of therapy in allogeneic HSCT recipients should be prolonged and continue at least until immunosuppressives, particularly corticosteroids, are completed. Prevention of invasive aspergillosis in allogeneic HSCT recipients should include the use of high-efficiency particulate air (HEPA) filtration and/or laminar flow rooms during the pre-engraftment period. In addition, two recent studies have suggested that voriconazole may be appropriate secondary prophylaxis prior to HSCT in patients with previous IA [171, 172].

Other Molds Mucor and Rhizopus species are the most commonly encountered zygomycetes in clinical practice, with an incidence of 8.5% and 5.9% in recipients of matched-related and matched-­

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unrelated allo-HSCT, respectively [138]. Infection with these organisms results in mucormycosis, which can occur in the late posttransplant period and causes devastating sino-­ orbital, CNS, and gastrointestinal disease, as well as cutaneous lesions and fasciitis. Among HSCT recipients, risk factors for zygomycosis include HLA mismatch, prolonged neutropenia, corticosteroid use, iron overload, and GVHD [173, 174]. Additionally, several studies have noted increasing numbers of zygomycosis cases among patients receiving voriconazole as either prophylaxis or treatment of invasive aspergillosis [32, 111, 175]. Whether this reflects azole-­ related selective pressure remains unknown. Fusarium species are environmental organisms, which cause infrequent but severe invasive fungal infection in HSCT recipients. Cases of fusariosis among HSCT recipients have been linked to contamination of central venous catheters and hospital water supply [176, 177]. Risk factors for fusariosis include underlying multiple myeloma and HLA mismatch. As with invasive aspergillosis, the onset of fusariosis occurs in a bimodal fashion; infection in the early posttransplant period is associated with prolonged neutropenia, and late infection is associated with T-cell depletion, corticosteroid use, and GVHD.  Infection with Fusarium species can mimic invasive aspergillosis; however, patients with fusariosis are more likely to have positive blood cultures and multiple papular or ulcerated skin lesions compared to patients with invasive aspergillosis [176, 178]. Scedosporium apiospermum and Scedosporium prolificans have also been isolated in HSCT recipients; their disease spectrum is similar to invasive aspergillosis. Risk factors for Scedosporium infection include prolonged neutropenia and GVHD [159, 179, 180].

Miscellaneous Infections Pneumocystis Jirovecii (PJP) Due to effective prophylaxis, PCP has become a rare event among allo-HSCT recipients with retrospective studies showing incidence rates from 1.3% to 2.5% [181, 182]. PCP is usually a late occurrence, and risk factors include treatment for GVHD or cessation of PCP prophylaxis [183]. Despite effective treatment, mortality can be high if infection occurs early after transplant [184].

Toxoplasmosis The majority of cases of toxoplasmosis in allo-HSCT recipients are due to reactivation of latent infection. In the United States, the incidence of toxoplasmosis has been reported to be as low as 0.25% [185], reflecting a low seroprevalence in the population [186]. In regions of the world with a higher seroprevalence, incidence rates of toxoplasmosis are predictably higher [187]. Disease usually occurs in the first 6 months after

M. R. Pereira et al.

transplantation [185, 186]. Besides seropositivity, the main risk factor for reactivation is intensification of immunosuppression due to GVHD [186]. The most common clinical presentation is encephalitis, which usually presents with focal neurological deficits. Extra-CNS forms of toxoplasmosis include pneumonitis, chorioretinitis, and myocarditis. Diagnosis of toxoplasmosis in any of the above manifestations requires a high clinical suspicion. A toxoplasma PCR can be obtained in serum and tissue such as CSF and vitreous fluid [188, 189]. First-line treatment includes extensive treatment with pyrimethamine and sulfadiazine. Despite best efforts mortality in allo-HSCT recipients remains high [185, 190]. Prophylaxis is usually accomplished with trimethoprim/sulfamethoxazole [191].

Strongyloides Strongyloides stercoralis can latently infect auto-HSCT recipients who previously lived or visited endemic areas (tropical and subtropical region worldwide), even many decades earlier. In the setting of immunosuppression, the parasite’s life cycle is accelerated and cause hyperinfection and disseminated disease [192]. Clinical manifestations include intestinal obstruction, respiratory failure including alveolar hemorrhage, bacterial sepsis, or meningitis [193]. Because of delays in diagnosis, infections can be devastating and carry high mortality. Patients from endemic areas should be serologically screened and treated with ivermectin prior transplant [193].

Preventative Strategies Like solid organ transplant recipients, allo-HSCT recipients can benefit from measures aimed to prevent infectious complications in the posttransplant period. These can include infection control practices in hospitals and outpatient clinics as well as guidelines for the prevention of opportunistic infections. The CDC/IDSA and ASBMT have published extensive evidence-based infection control guidelines that include specific practices regarding room ventilation, isolation and barrier precautions, cleaning, hand hygiene, equipment disinfection, plants, patient skin and oral care, prevention of intravascular catheter-related infections, construction and renovations, as well as healthcare workers [194]. In terms of specific infections, guidelines from the CDC were published in 2000. Because many of these organisms not only involve reactivation of latent infection in the recipient but can also be donor-derived, both donors and recipients should be universally tested for CMV, EBV, HIV I/II, HTLV I/II (although this is not done in all centers), hepatitis B and C, syphilis, and M. tuberculosis (in donor only if from endemic country). Additionally, all recipients should be tested for HSV I/II, VZV, and Toxoplasma. Potential donors and recipients

11  Infections in Allogeneic Stem Cell Transplantation Table 11.2  Pretransplant screening in candidate allo-HSCT donors and recipients Donor screening Standard CMV IgG EBV VCA IgG VZV IgG HIV Ab and NAT HTLV I//II Ab Hepatitis B surface Ag and core Ab Hepatitis C Ab, NAT

Recipient screening CMV IgG EBV VCA IgG HSV I/II IgG VZV IgG HIV Ab and NAT HTLV I/II Ab

Table 11.3  Recommended and optional vaccination of allo-HSCT recipients [195]

Comments on use after allo-HSCT 3–4 doses, a fourth dose with PPSV23a may be beneficial 3 doses, DTaP preferred over Tdap

3 doses

1 dose, follow country recommendations for general population Inactivated polio 3 doses Recombinant 3 doses, follow country hepatitis B recommendations for general population Inactivated Yearly influenza 1–2 doses, all children and Measles, mumps, rubella measles seronegative adults, not recommended if active GVHD or (live) on immunosuppression Optional Hepatitis A Follow country recommendations for general population

Table 11.3 (continued) Varicella (Varivax, live)

Human papillomavirus Yellow fever (live)

Hepatitis B surface Ag and core Ab Syphilis screening (RPR) Hepatitis C Ab, NAT Syphilis screening (RPR) Latent Tb screening (PPD or IGRA) Optional (if risk factors are present) Hepatitis B NAT Hepatitis B NAT West Nile virus Ab West Nile virus Ab Toxoplasma Ab Toxoplasma Ab Strongyloides Ab Strongyloides Ab Trypanosoma cruzi Trypanosoma cruzi Leishmania Ab/PCR Coccidioides Ab Babesia Ab Histoplasma Ab Rickettsia Ab Brucella Ab Coxiella burnetii Ab

Vaccine Recommended Pneumococcal conjugate (PCV) Tetanus, diphtheria, acellular pertussis Haemophilus influenzae conjugate Meningococcal conjugate

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Time post-HSCT to initiate vaccine

Rabies

Tick-borne encephalitis Japanese B encephalitis

Limited data regarding safety and efficacy. Not recommended if active GVHD or on immunosuppression Follow country recommendations for general population Limited data regarding safety and efficacy. The risk-benefit balance may favor use of the vaccine in patients residing in or traveling to endemic areas Appropriate for use in HCT recipients with potential occupational exposures to rabies. Postexposure administration of rabies vaccine with human rabies Ig can be administered any time after HCT, as indicated According to local policy in endemic areas According to local policy when residing in or travelling to endemic areas

>24 months

No data >24 months

12–24 months

No data No data

Adapted and printed by permission from Macmillan Publishers Ltd.: Nature Publishing Group, Bone Marrow Transplantation, Vaccination of hematopoietic cell transplant recipients, Ljungman P, Cordonnier C, Einsele H, Englund J, Machado CM, et  al.; Center for International Blood and Marrow Transplant Research; National Marrow Donor Program; European Blood and Marrow Transplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Disease Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Diseases Canada; Centers for Disease Control and Prevention Vol. 44/No. 8, pages 521–526, © 2009 Contraindicated vaccines: BCG (live), oral polio (live), intranasal live influenza, cholera (live), typhoid (live and IM), Rotavirus, zoster vaccine (Zostavax, live) a PPV23: 23-valent pneumococcal vaccine

3–6 months 6–12 months

6–12 months

6–12 months

6–12 months 6–12 months

4–6 months >24 months

12 months

should also be tested for Strongyloides and Trypanosoma cruzi if they have epidemiologic risks. Patients with evidence of syphilis, Strongyloides, or latent tuberculosis infection should be treated in the pretransplant period (see Table 11.2). Vaccinations are an important component of disease prevention. Because of predictable decline in antibody titers posttransplant, it is recommended that recipients be revaccinated in the post-engraftment at the appropriate time (see Table 11.3) [195]. Prophylaxis in the posttransplant period is usually aimed at the most common and predictable organisms. A discussion of strategies to prevent CMV is beyond the scope of this chapter but includes either preemptive treatment in cases of CMV viremia or universal prophylaxis for those at risk for CMV reactivation. Recipients not at risk for CMV should receive acyclovir for HSV prophylaxis. PCP and Toxoplasma prophylaxis is accomplished with sulfamethoxazole/trimethoprim for 6–13 months, although this practice varies when taking into consideration the myelosuppressive effects of

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this drug combination. Dapsone, atovaquone, and pentamidine are alternatives for PCP prophylaxis. Of those, only atovaquone has activity against Toxoplasma as well. Many centers also institute bacterial and fungal prophylaxis in the peri-transplant period until neutropenia resolves.

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Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation

12

Jasmine Zain, Merav Bar, and Amar Safdar

Introduction Hematopoietic stem cell transplantation (HSCT) is performed to provide long-term cures for patients with advanced hematological malignancies and other nonmalignant disorders. However, transplantation procedures can result in complications that can affect any organ system in the body. Many factors may contribute toward these complications including direct effects of old and newer modalities in transplant conditioning, severe and prolong  pancytopenia, immunosuppressive antineoplastic drugs, graft-versus-host disease (GVHD), and infections, especially opportunistic viral, bacterial, and fungal infections. Factors that may help elucidate complications related to  pretransplant conditioning include the following: (1) the incidence of complications appears to be similar between autologous and allogeneic stem cell transplants, (2) complication occurs less frequently in the setting of reduced-intensity conditioning (RIC), and (3) complications associated with radiation therapy (XRT) and total body irradiation (TBI) are mostly abrogated when  nonradiation-­based preparatory  regimen  is administered. The differences between the risk for various complications among autologous and allogeneic stem cell graft recipients may not only represent toxicity from the conditioning regimen; patients undergoing allograft transplantation are also given immunosuppressive drugs for prevention J. Zain Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA e-mail: [email protected] M. Bar Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA e-mail: [email protected] A. Safdar (*) Clinical Associate Professor of Medicine, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, USA e-mail: [email protected]

and treatment of acute and/or chronic GVHD. Introduction of RIC may further assist in elucidating complications arising from  drugs used  for prevention and treatment of GVHD during the post-transplant period. Adults undergoing cord blood stem cell transplantation experience prolonged periods of pancytopenia, thereby placing such patients at an increased risk for infection and hemorrhagic complications. In this chapter a focused discussion includes systemic toxicities related with various preparatory regimens among adult patients undergoing stem cell transplantation based on aforementioned principles is presented [1, 2]. Where possible, the authors intend to identify effects of GVHD and/or underlying immune suppression that may have contributed toward various systemic complications.

Conditioning Regimens Preparatory conditioning regimens given prior to HSCT have two main functions: (1) to provide tumor cytoreduction and (2), in allogeneic HSCT, to suppress hosts’ immune response against the allograft and to  prevent early graft rejection. Traditionally, preparatory regimens consist of high-dose chemotherapy and/or chemotherapy plus total body irradiation (TBI) with the objective for near-total eradication of cancer. However, high-dose, myeloablative conditioning regimens are associated with significant systemic toxicity including pancytopenia, injury to internal organs and skin. The regimen-related toxicity (RRT) poses  a major obstacle in achieving successful transplant outcome. Modifications in traditional myeloablative conditioning include  reduced-­ intensity conditioning regimens (RIC). Patients undergoing RIC are given lower doses of chemotherapy, and containment of cancer in the recipients mainly relies upon the donor graft-mediated anticancer cellular immune response known as “graft-versus-tumor” (GVT) or “graft-versus-leukemia” effect. RIC transplants are better tolerated and may be offered to older patients, patients with medical comorbidities, or “heavily pretreated patients” in whom multiple courses of

© Springer Science+Business Media, LLC, part of Springer Nature 2019 A. Safdar (ed.), Principles and Practice of Transplant Infectious Diseases, https://doi.org/10.1007/978-1-4939-9034-4_12

227

200 mg/m2

20 mg/kg given over 4 days, steady-state PKs over 4 days more predictable of toxicity than actual dose 1135 mg/m2

Melphalan

Busulfan

25–60 mg/kg or 2400 mg/m2 150–165 mg/m2 delivered over 96 h as a CI

725–750 mg/m2

Etoposide Doxorubicin

Paclitaxel Bortezomib Bendamustine Fludarabine Clofarabine Ifosfamide

TBI

Cytarabine

1600–2400 mg/m2

Carboplatin

36 gm/m2 for 4–12 doses at 12 h intervals 10–16 Gy

18–20 mg/m2

300 mg/m2

Cisplatin

1,3-bis (2-chloroethyl)- 900–1200 mg/m2 1-­nitrosourea (BCNU)

Thiotepa

Known MTD 200 mg/kg

Agent Cyclophosphamide

Ovarian failure, infertility, and azoospermia

Chronic DLT CHF

Mechanism of injury Direct myocardial toxicity due to leakage of drug from damaged endothelium; and renal tubular injury

GI toxicity includes severe mucositis; hepatic and Growth retardation, pulmonary toxicity chronic pulmonary insufficiency, secondary malignancies, and cataracts

Renal, and urinary bladder toxicity; neurotoxicity may present as somnolence, lethargy, confusion, and seizures Neurotoxicity, particularly cerebellar

Neurologic toxicity

CNS toxicity including somnolence, confusion and coma; oral and esophageal mucositis, enterocolitis, liver toxicity and SOS, acute dermatitis manifested as desquamating dermatitis; interstitial pneumonitis and cardiac toxicity Depletion of pulmonary Pulmonary toxicity, SOS, hypotension, glutathione reductase  myocardial ischemia, renal toxicity, and encephalopathy Renal dysfunction including electrolyte wasting; ototoxicity and high-frequency hearing loss; peripheral neuropathy; nausea and vomiting Liver toxicity, mucositis, peripheral neuropathy, ototoxicity, nephrotoxicity Mucositis, GI toxicity Secondary leukemias Secondary malignancies Cardiac toxicity (cumulative for doses above 350–400 mg/m2, this may be lower in patients with existing cardiac risk factors), orointestional mucositis resulting in stomatitis, diarrhea, and typhlitis Peripheral neuropathy, and mucositis Secondary malignancies Peripheral neuropathy

Acute DLT Nausea, hemorrhagic myocarditis, acute CHF, SIADH, Cardiac arrhythmias, hemorrhagic cystitis resulting from secretion of active drug metabolites into the bladder Mucositis, GI toxicity, SOS, diffuse pulmonary alveolitis, and SIADH SOS, neurotoxicity characterized by seizure; mucositis, radiation recall and pulmonary fibrosis, and gonadal toxicity

Table 12.1  Toxicities of common agents used in HSCT conditioning regimens

Shielding of internal organs; targeted delivery of radiation like total marrow irradiation or total lymphoid irradiation

Mesna infusion

Treatment Supportive care, use of Mesna to prevent hemorrhagic cystitis, and bladder irrigation

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12  Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation

antineoplastic therapy have been given for the treatment of recurring or relapsed cancer; in the past such patients were considered high risk for  traditional myeloablative HSCT. Recent advances in targeted antineoplastic drugs like radioimmunotherapy, proteasome inhibitor, and monoclonal antibodies are being incoorporated in preparatory regimens with the intent to minimize systemic toxicity. Table 12.1 provides an outline of adverse events associated with commonly used modalities for conditioning given in preparation for stem cell transplantation.

Orointestinal Complications Damage to  the mucosa of orointestinal tract is  common in patients undergoing  HSCT.  The ensuing mucositis may be severe after myeloablative stem cell allograft transplantation. It is important to note that mucosal damage resulting from conditioning regimens can overlap with orointestinal acute GVHD and enterocolitis due to opportunistic cytomegalovirus or adenovirus infection. Therefore, it is essential to thoroughly evaluate the patients, especially if symptoms appear more than  2  weeks post-transplantation. Following are the common presentations of orointestinal toxicities among patients undergoing HSCT.

Emesis and Anorexia Most conditioning regimens are associated with emesis and anorexia [3, 4]. The pathogenesis of chemotherapy-induced emesis includes direct drug-induced stimulation of central vomiting center and local injury to cell lining of the orointestinal tract. Nausea and vomiting in such cases can last for up to 3 weeks after transplant procedure [5]. The main process during days 1-10 following transplantion is  damage to the mucosal lining, resulting in systemic translocation of bacteria and bacterial endotoxins, triggering various aspects of innate immune response that includes  acute-phase protein, and local  release of  proinflammatory cytokines. Cytokines such as interleukin-1, interleukin- 6, and tumor necrosis factor alpha via systemic circulation penetrate the blood-brain barrier suppressed brain regulation of appetite  may result in devestating  anorexia. Conditioning-induced anorexia is prominent during the first 3 weeks after transplantation.

Mucositis Oral mucositis is a common transplant-related complication, usually seen during the first 2–3 weeks after HSCT. Mucositis may affect up to 80% of transplant recipients and frequently  associated with myeloablative regimens  that include

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radiation [6]. Mucositis occurs in phases starting with erythema and atrophy progressing to ulceration and the  final, healing phase. Mucositis is common with cytarabine, etoposide, highdose melphalan, and treatement with multiple alkylating agents [7, 8]. Preexisting periodontal disease and prior radiation to the head and neck area increase the risk for mucositis. Chemotherapy-induced symptomatic mucositis usually starts 5–10 days after initiation of the conditioning and may take up to 3 weeks to heal. The healing phase can be delayed if additional factors like  methotrexate used as GVHD prophylaxis, bacterial and fungal infections, and in patients with recrudescence of oral HSV infection. Morbidity and risk of death due  to  mucositis include severe  oral pain and dysphagia with marked decline in oral calorie intake, recurrent bleeding, superimposed viral (HSV), bacterial and fungal (Candida) infections, edema of the upper airway, and airway obstruction. The extent and severity of oral mucositis correlates with the risk for infection, prolonged hospital stay, and hospital mortality [9]. Treatment is usually supportive and includes analgesia, oral rinsing solutions, and parenteral nutrition. Severe mucosal swelling and upper airway edema may  require  endotracheal intubation to secure patients' airway. Prevention strategies are  developed to minimize the risk for mucositis. Palifermin, a recombinant human keratinocyte growth factor, it was approved by FDA for prevention of mucositis in patients undergoing autologous and allogeneic HSCT. Preclinical data in mice showed protective effects of palifermin against chemotherapy and radiation-induced mucositis [10–12] and led to clinical trials [13, 14]. Phase III study in patients following  autologous transplants after TBI conditioning  demonstrated a decreased incidence and duration of grade III–IV mucositis. Goldberg et al. conducted a retrospective study in 251 patients undergoing allogeneic HSCT, 154 of whom received palifermin during peritransplant period. In all patients, treatment with palifermin significantly reduced the number of days needed for  (1) total parenteral nutrition (TPN; 13 vs. 16 days; P = 0.006), (2) patient-controlled analgesia (PCA; 6 vs. 10 days; P = 0.023), and length of hospitalization (32 vs. 37 days; P = 0.014). However, the effect of palifermin was only significant in patients who received TBI; this benefit was not evident in patients given busulfan-based conditioning [15]. Injury to mucosal barrier may also result in diarrhea, gastrointestinal bleeding, susceptibility to infections, and risk of  death [16, 17]. Typhilitis is a  particularly serious complication.  Cecal edema, mucosal friability, and mucosal ulceration, accompanied with fever, abdomonal pain, and diarrhea are salient features; polymicrobial infections may reasult in severe sepsis [3]. The pathophysiology of neutropenic typhlitis is not fully understood; it is hypothesized that  an acute mucosal injury caused by cytotoxic drugs  serves as a trigger, followed by secondary infection of the bowel wall, progressing to systemic infection and sepsis with increased risk for bowel perforation [18]. Typhlitis may progress rapidly and

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mortality rate of up to 20% may be seen in high-risk patients. High index of suspicion, early diagnosis and timely institution of aggressive medical therapy that includes  complete bowel rest, broad-spectrum antimicrobials, elecrolyte,  mineral, and  intravascular homeostasis  among other supportive measures is essential for improve outcome [19].

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are radiation and specific chemotherapy agents used in high doses particularly cytoxan (Cy) and busulfan (Bu). Combination regimens with chemotherapy and TBI has shown a correlation between cytoxan and TBI dose. The incidence of SOS after conditioning regimens that include cyclophosphamide at a dose of 120 mg/kg plus TBI greater than 14 Gy can be as high as 50% [24]; however, the incidence of SOS can be minimized with reduced-intensity regiDiarrhea mens [28]. In the past, gemtuzumab ozogamicin exposure was associated with the risk of SOS in patients undergoing Diarrhea is seen in nearly  half of patients receiving high-­ myeloablative allogeneic HSCT [29]. Additional risk factors dose chemotherapy and radiation-based conditioning as a for SOS include: (1) variations in the metabolism of cycloresult of mucosal damage, which  usually resolves within phosphamide and other chemotherapy drugs  [30, 31]; (2) 3  weeks after transplantation [4, 20]. Patients with  other underlying fibroinflammatory liver diseases [32], and (3) complications such as superimposed  infections or concomitant use of drugs during and after conditioning therGVHD involving the orointestinal tract, the duration of diar- apy that either affect the metabolism of cytotoxic drugs such rhea my be prolonged. Preparatory regimen with radiation, as triazole-based antifungals, or cause concomitant liver alkylating agents, cytarabine, high-dose melphalan, or busul- injury like sirolimus (Table  12.1). During the 1990s, the fan frequently result in  diarrheal illness. Radiation- or overall incidence of SOS at Fred Hutchinson Cancer chemotherapy-­induced diarrhea is classified as osmotic or Research Center was 38% with 7% of the patients  having secretory diarrhea [21, 22]. The underlying processes include severe disease after cyclophosphamide and TBI preparatory (1) damage to the intestinal mucosa and crypts resulting in regimen.  A  favorable reduction (12% with 2% severe disreduced chloride absorption causing an osmotic load, (2) ease) was noted after oral busulfan plus cyclophosphamide alteration in gut motility with reduced transit time  due to combination  was introduced [31, 33]. There has been an direct effect of chemotherapy, and (3) mucositis resulting in appreciable  decline in the frequency and severity of SOS decreased water absorption. Additionally, chemotherapy and during  the past decade  and probably represent  (1) lower radiation change the composition of the native intestinal doses of TBI being used, (2) replacement of cyclophosphamicrobiota, which may also contributes to diarrhea follow- mide with fludarabine, (3) conditioning regimens that do not ing HSCT;  intestinal yeast overgrowth may play a role in contain either cyclophosphamide or high-­dose TBI, and (4) some patients. Organisms that may cause diarrhea in stem therapeutic drug monitoring that allows individualized doscell transplant recipients  include infection due to  exotoxin ing of chemotherapeutic drugs adjusted for  variabilproducing Clostridium difficile and, less commonly, tissue-­ ity of drug metabolism [24]. Prevention of severe sinusoidal invasive disease due to C. perfringens, and C. septicum.  It is liver injury begins with an assessment of patients risk due to important to recognize that enterocolitis due to opportunistic underlying liver disease (Table 12.2) and tailoring appropriviral infections such as CMV, and adenovirus are difficult to ate conditioning regimen for select group of at-risk patients distinguish clinically from other causes of diarrheal illness in [25, 31, 34]. There are no satisfactory treatments for SOS; such patients.  however complete recovery from SOS occurs in more than 70% of patients with supportive care, that include management of sodium and water balance, preservation of renal Conditioning-Induced Liver Complications blood flow, and paracenteses, as needed. Patients with poor prognosis are recognized by a steep rise in total serum biliHepatic complications are a major cause of morbidity and rubin level, increase body weight, serum ALT level of greater mortality following HSCT.  The frequency and severity of than 750 U/L, portal pressure greater than 20 mm Hg, develliver complications however,  have declined in the recent opment of portal vein thrombosis, and development of years [23]. Hepatotoxicity due to pre-transplant condition- multi-­organ failure [24]. However, liver failure is an uncoming is usually seen within the first 3 weeks after transplants mon cause of death in patients with SOS; most patients die [24]. Sinusoidal obstruction syndrome (SOS) or  veno-­ from secondary renal and cardiopulmonary failure, or both occlusive disease (VOD) is the main complication. [26, 35]. Treatment with defibrotide, a compound porcine Treatment-induced  damage to the endothelial cells in the oligodeoxyribonucleotides with procoagulant and fibrinohepatic sinusoids clinically  presents as tender hepatomeg- lytic properties may ameliorate SOS disease in select group aly, fluid retention, weight gain, and elevated serum biliru- of  patients [36, 37]. Recent observation that octerotide bin level [25–27]. SOS is a direct manifestation of ­prophylaxis may reduce the incidence of SOS after HSCT conditioning-­related hepatotoxicity. The major risk factors was interesting and needs further evaluation [38].

12  Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation Table 12.2  Risk factors for SOS in patients undergoing HSCT [24]

Liver diseases at baseline Inflammatory diseases  Chronic hepatitis B or C  Nonalcoholic steatohepatitis  Alcoholic hepatitis

Fibrotic diseases  Cirrhosis  Lobular fibrosis  Extramedullary hematopoiesis with sinusoidal fibrosis Cholestatic disorders  Jaundice caused by intrahepatic cholestasis Past history  Prior SOS from conventional chemotherapy  Recent exposure to gemtuzumab ozogamicin  Prior liver irradiation  Prior myeloablative hematopoietic cell transplant

Concomitant drugs during conditioning therapy Itraconazole Sirolimus (rapamycin)

Specific conditioning regimens Cyclophosphamide-­based  CY 120 mg/kg plus TBI (greater risk with higher TBI dosing)  BCV (BCNU + CY + Norethisterone VP-16)  BU + CY (greater risk without therapeutic drug monitoring of BU) Melphalan-based  BU + MEL + thiotepa  BU + MEL

Other regimens  BU + TBI (greater risk with higher TBI dosing)

Gemtuzumab ozogamicincontaining myeloablative regimens High-dose radiolabeled antibody myeloablative regimens

Reprinted and adapted from McDonald [24], with permission from John Wiley and Sons

Conditioning-Induced Renal Complications Acute Renal Failure Acute kidney injury (AKI) is a common complication in patients undergoing HSCT, and usually seen within the first 3  months after transplantation [39]. The  incidence, timing and severity is different among patients following myeloablative versus RIC preparatory regimen, thereby emphasizing differential nephrotoxic potential of conditioning regimens. In 1989 Zager et al. reported that 53% of patients who underwent myeloablative HSCT developed AKI after a mean 14 days post-transplantation [40]. Since then several studies have evaluated renal injury in patients undergoing myeloablative transplantation [35, 41–48]. First 3 months after transplantation is when most episodes of AKI are observed; the incidence range between 21% and 73% after myeloablative allogeneic transplants; it is 12–19% for patients undergoing

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autologous stem cell graft transplantation. The cause of AKI include: (1) direct renal toxicity from  cytotoxic drugs; (2) indirect damage sustained  from  intense conditioning regimens, i.e., patients with SOS; (3) GVHD via cytokine- and immune-related kidney injury; (4) nephrotoxicity from calcineurin inhibitors such as cyclosporine and tacrolimus; (5) dehydration and other conditions with depletion of intravascular volume; and (6) opportunistic CMV, or adenovirus  infections that  may  involve the  kidneys. Myeloablative conditioning is an independent risk factor for the development of AKI [43]. Severe AKI was shown to be more frequent in patients undergoing myeloablative HSCT compared with those treated with RIC [41, 43, 44, 46, 49, 50]. Several studies have evaluated the incidence and time of occurrence of AKI in patients given  RIC and  ranges from 29% to 56%; most cases are  observed during the 2nd month after transplantation [42, 43, 46, 49–55]. Factors shown to increase the risk of AKI in RIC transplant recipients include, requirement for  mechanical ventilation [50], previous autologous SCT, preexisting chronic kidney disease (CKD) [56, 57], acute GVHD, CMV reactivation [49], incomplete HLA-­ matched stem cell allograft  transplantation, presence of sepsis [55], methotrexate given for GVHD prophylaxis, three or more antineoplastic treatments before transplantation, and patients with preexisting diabetes mellitus [54].

Chronic Renal Failure AKI in the early post-transplant period  is a risk factor for CKD. In a retrospective study, 158 adults received myeloablative allogeneic HSCT [58], proteinuria was noted in 23% of patients; prevalence of stage 3 or stage 4 CKD was 17%. Initiation of chronic renal replacement therapy or kidney transplantation for end-stage kidney disease was performed in 4% after an average 11 years following transplantation. In this study, presence of AKI after transplant was significantly associated with the risk for severe CKD (≥ stage 3). Another large study included 1,635 adult and pediatric patients who underwent myeloablative or RIC HSCT at the Fred Hutchinson Cancer Research Center between 1991 and 2002 [59]. A total of 23% developed CKD at a median of 191 (range, 131–516) days after transplantation. Presence of AKI was a prominent risk for  CKD in the late transplant period [59]. Lack of resolution of structural and functional renal  abnormalities back  to the  baseline after AKI episode  and persistence of  reduced renal  reserves predicted the risk for CKD [60, 61]. AKI after transplant was associated with a higher risk for hypertension, which further increased the risk for CKD [62]. RIC regimen did not reduce the incidence of CKD.  In an  another retrospective study, the risk for CKD was 55% at 6 months, 50% at 9 months, and 45% at 12 months after RIC transplants [63]. Overall, 66%

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of the patients developed CKD within 1 year following RIC transplantation. AKI during the first 3  months following transplantation was associated with the  risk for CKD. Hingorani et al. reported albuminuria (ACR >30 mg/gm and proteinuria as >300 mg per day) on day 100 was associated with greater risk of CKD 1 year after HSCT; they also found that overt albuminuria was associated with an increase risk of non-cancer relapse death, and reduced 1 year post-transplant survival [64].

plantation [68–70]. However, despite recovery of the innate cell counts, some of the cell functions may not recover fully for months after transplantation [65]. NK cells reach normal levels within 3 months after transplantation and regain their ability to destroy  malignant cells early in the post-transplant period [71, 72]. Additional events like GVHD, opportunistic viral  infections  such as CMV, and medications particularly high-dose systemic corticosteroids may further dampen prospects of immune recovery.

I mmune System Complications and Immune Reconstitution

Adaptive Immunity

Conditioning regimens are designed to suppress  hosts’ immune response  in order to allow the donor hematopoietic stem cells to establish stable engraftment. After HSCT, there is a prolonged period of immune deficiency affecting both the innate and the adaptive component of immune system thereby  enhancing hosts'  vulnerability  to a variety of infections and other complications. Several factors contribute to immune deficiency state  after HSCT, including: advance  age, preparative regimen  like  myeloablative vs RIC;  source of stem cell graft  such as bone marrow, vs.  G-CSF-mobilized peripheral  blood stem cells, or stem cells derived from umbilical cord blood; graft manipulation, donor-recipient human leukocyte antigen (HLA) and non-­ HLA (minor) antigen mismatch; drug-induced immune suppression, and presence of acute or chronic GVHD [65].

Innate Immunity Epithelial barriers are an important  component of innate immune defense that are compromised on account of chemotherapy and/or radiation-induced mucositis or mucosal disruption resulting from acute or chronic GVHD.  Direct injury  to epithelial cells and  cell-cell  junctions  or desmosomes facilitate systemic  translocation of pathogens and microbial byproducts  through the skin  intergumentary system, respiratory, orointestinal, and genitourinary tracts. The epithelial barriers often recover quickly after transplant, however, presence of secretory acellular antimicrobial components such as cationic peptides, lyzosome, secretory immunoglobulins  may remain subnormal for  a potentially extended duration, especially in patients with GVHD [66, 67]. Cells of the innate immunity, including neutrophils, natural killer (NK) cells, monocytes, macrophages, and dendritic cells including antigen-presenting cells (APCs), are destroyed by the conditioning regimen in patients undergoing  autologous and allogeneic HSCT.  Various classes of immune cells originating from the hematopoietic progenitor cells start the process of recovery within weeks after trans-

Myeloablative preparatory conditioning regimens comprises of agents that have myeloablative capacity resulting in destruction of hosts’ adaptive immune system. Restitution and recovery of  adaptive immune response in recipients after  allogeneic stem cell grafts transplantoriginates from mature lymphoid cells from the donor derived effecter immune cells. The newly engrafted stem cells differentiate into common lymphoid progenitors (CLP) a common precursor to both T and B lymphocytes. If T-cell depletion methods are not used, the graft also contains antigen-specific T cells and naïve T cells that undergo peripheral expansion outside the thymus; lacking capacity for  self-recognition. The proliferation, maturation, and differentiation of the donor-derived T cells into a diverse immune repertoire are dependent on adequate thymic function in  recipients and controlled by the expression of surface molecules on thymic stromal cells and cytokines secreted by these important regulatory  cells [73]. Immune regulatroy  thymic activity is a complex process; dependent upon the patient age and prior treatments at the time of transplantation. Chemotherapy and radiation before HSCT and as preparatory conditioning regimen results in  thymic dysfunction causing  delayed T-cell immune reconstitution [74]. B cells derived from the common lymphoid progenitors undergo differentiation in the bone marrow, and the number of B cells usually returns to normal levels within 1–2  months after HSCT; however, serum immunoglobulin levels may remain  subnormal for several months after transplantation [75]. The maturation process of B cells is dependent on the interactions with antigen-­specific T lymphocytes. Therefore, defects in T-cell maturation due to inadequate thymic function or ongoing iatrogenic  immunosuppression may also adversely ­ affects  B-cell maturation and B-cell  function. Plasma cells are relatively resistant to chemotherapy and irradiation; studies have shown that persistence of antibody producing residual plasma cells of hosts origin may linger for a year after HSCT [76, 77]. However, a durable source of antibody production requires both antigen-specific donor T cells and mature B donor-derived lymphocytes. RIC regimens are immunosuppressive rather than immunoablative, and the

12  Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation

immunological outcome in RIC transplant recipients’ depends upon the degree of elimination of the residual recipients’ immune system following  donor-derived T lymphocytes  repopulation and functional recovery. The immune reconstitution after RIC HSCT is not significantly different from the immune reconstitution after myeloablative HSCT, although this occurs early after RIC transplants compared with patients undergoing myeloablative HSCT [78]. In most cases, T lymphocytes are all  from donor origin within 3–4  months after RIC transplantation [79]. In patients following autologous HSCT, the number and function of NK cells return to normal as early as day 14 after transplantation; the quantitative and functional B-cell recovery may be delayed up to 18  months after HSCT, and T-cell subsets’ (CD3, CD4, and CD8) recovery does not return to normal for a year or in some cases longer after transplant procedure [80]. The prolonged immunodeficiency state after allogeneic HSCT results in significant morbidity due to potentially life-­ threatening bacterial, viral, fungal and protozoal infections, this may also have a negative influence on the much desired  graft-versus-tumor effect [81]. Since the immune reconstitution process after autologous HSCT is more rapid, opportunistic infections are not as common in patients undergoing these procedures [78].

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Anticonvulsant prophylaxis is recommended when these medications are being administered. Oral phenytoin and levetiracetam are commonly used for this purpose, and it is imperative that a therapeutic level of the anticonvulsant be achieved before chemotherapy is commenced. Other agents associated with acute CNS toxicity include ifosfamide as part of high-dose ICE regimens that may result in seizures, confusion, mutism, disordered sensorium, and even comma. Ifosfamide neurotoxicity results due to the accumulation of chloroacetaldehyde, a chloral hydrate-like compound which is an important metabolite of the drug. There is no prophylaxis, but methylene blue has been used to treat neurological toxicity in select cases [85]. High-dose mechlorethamine used with TBI and fludarabine is also associated with encephalopathy; fludarabine-associated encephalopathy may present late in some patients. High-dose cytarabine used in BEAM and other conditioning regimens given for lymphoproliferative disorders is associated with cerebellar symptoms in over 10% of cases; permanent Purkinje fiber damage observed in nearly 3% of cases [86]. This can also result in seizures and transient encephalopathy. High-dose Ara-C can cause peripheral neuropathy and demyelinating polyneuropathy similar to Guillain-Barre syndrome [87]. Cisplatin and VP-16 are associated with a delayed axonal neuropathy that develops approximately 2 months after the administration of these drugs, and recovery is gradual and protracted [88]. Cisplatin neurotoxicity involves large sensory fibers resulting in a deficit in proprioception with preserved tactile and Neurologic Complications pain sensations without motor deficits. It correlates with Conditioning regimens can lead to both short- and long-term cumulative toxicity with symptoms usually occurring at neurologic complications in patients undergoing HSCT.  In doses of 300–600 mg/m2. Other problems include ototoxicaddition, patient may experience neurological symptoms due ity that involves high-frequency hearing loss, and ultimately to neurotoxicity from  immunosuppressive drugs or infec- speech frequency hearing loss may occur with continued tions that directly or indirectly affect the nervous system. Up drug exposure. Cisplatin has also been reported to result in to 3% of patients will have neurological complications after CNS toxicity including Lhermitte phenomenon, which is autologous transplants; whereas 44% after allogeneic trans- presented as cortical blindness and seizures [89]. By contrast plants may experience these complications [82, 83]. VP-16 and paclitaxel neuropathies affect all sensory fibers. Manifestations can include paresthesia and sensory disturbances of the distal extremities; cases of motor and autoNeurologic Toxicity nomic neuropathy have also been described. Prior exposure to other neurotoxic agents like vincristine can exacerbate Direct neurotoxic effects of specific chemotherapeutic agent such symptoms. High-dose paclitaxel at a minimum dose of and radiation can result in acute encephalopathy, and new-­ 625  mg/m2 used in some conditioning regimens for solid onset  seizures,  as well as long-term complications such tumors is associated with a high incidence of peripheral senas  peripheral neuropathy and cognitive impairment may sory neuropathy within 5 days after the drug is given [90]. adversly impact patients' quality of life. Among the common High-dose methotrexate (5 gm/m2) may be associated with chemotherapeutic agents used in conditioning, busulfan and transient leukoencephalopathy [91], while the use of intracarmustine (BCNU) are most likely to cause seizures as they thecal methotrexate can rarely result in hemiparesis. A readily cross the blood-brain barrier. About 10% of patients delayed onset chronic leukoencephalopathy may result in receiving high-dose busulfan, defined as 4 mg/kg for 4 days, patients  after intrathecal MTX and whole brain radiation will experience generalized seizures [84]. BCNU typically [92]. Neurologic signs develop within 4–5  months after used in conditioning regimens for lymphoma and Hodgkin’s transplantation and progress to dysarthria, ataxia, dysphasia, disease may result in seizures at doses of 300  mg/m2. spasticity, upper motor neuron weakness, spasticity, seizures,

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confusion, and eventually death. The combination of TBI and amphotericin B has also been reported to lead to a similar leukoencephalopathy. Intrathecal cytarabine and the depot version are associated with a predictable aseptic meningitis due to meningeal irritation. Concomitant use of steroids either given intrathecally or systemically may ameliorate symptoms [86]. Some of the newer agents that are being used in conditioning regimens like bortezomib may cause peripheral neuropathy [93]. This is usually reversible with dose modification or discontinuation of the drug.

Central Nervous System Infections Conditioning regimens lead to a period of pancytopenia and immune suppression that increases the risk for infections involving the CNS. Most of these present in the immediate post-transplant period, and late infections can also occur in patients with prolonged immunosuppression due to GVHD or graft dysfunction. The incidence of CNS infections is 5% in allogeneic transplants and as high as 8–15% in autopsy series [94]. The presenting symptoms are altered mental status, delirium, and altered sensorium. Meningeal signs or focal neurologic deficits are less common. Workup should include imaging studies and spinal fluid examination once intracranial mass lesion(s) with potential for herniation is ruled out. Aspergillosis was the most common infection accounting for 30–50% of CNS infections [94]. The newer mold-active triazole drugs like voriconazole have better CNS penetration as compared to other antifungals and currently recommended for the treatment of  CNS aspergillosis. Systemic candidiasis in patients with fungemia can result in CNS involvements in nearly 3% of cases; seen in up to 15% in autopsy series [95]. Protozoal infections that include Toxoplasmosis gondii CNS disease mostly noted in the early post-transplant period, especially if patients, in whom prophylaxis with trimethoprim-sulfamethoxazole was deferred [94]. Bacterial infections are less common in the era of aggressive antibacterial prophylaxis and routine antimicrobial therapy for suscepted or porven infections. However, cases of meningitis due to Listeria monocytogenes, penicillinnonsusceptible Streptococcus pneumoniae, and Stomatococcus mucilaginous have been reported in patients after allogeneic and autologous stem cell transplants; these infections are usually seen during the early post-transplant period. However, in  patients with chronic GVHD, such infections may present late after HSCT. CNS mycobacterial infections are rare in patients undergoing HSCT [94]. CMV reactivation is a common and serious complication after allograft  transplants. Unlike patients with HIV/AIDS, CMV chorioretinitis is seldom seen in patients following HSCT for reasons still not well understood [96]. Similarly,

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herpes simplex encephalitis is rare in post-­transplant setting despite up to 80% of seropositive patients may experience high-level viral reactivation after undergoing stem cell transplantation.  There are few reports in literature; the presentation and findings in HSCT recipients are mostly diffuse brain involvement that is not limited to the temporal lobe. EEG shows periodic lateralized epileptiform discharges characteristic of herpetic encephalitis and may precede before radiolographic  changes become evident [96]. Activation of VZV mainly as mucocutaneous disease is seen 4–5  months after transplantation; viral encephalitis may seldom occur. Postherpetic neuralgias can develop in up to 25% of patients despite antiviral therapy and secondary prophylaxis. Cranial nerves can be involved resulting in symptoms of facial palsy, hearing loss, and unusual features like arm weakness from cervical neuralgia or a neurogenic bladder from the involvement of lumbosacral plexus [97]. Adenovirus and other herpes viruses like Epstein-Barr virus or human herpesvirus 6 can cause fatal meningoencephalitis during the periods of pancytopenia and severe cellular immunosuppression. Progressive multifocal leukoencephalopathy (PML)  caused by JC virus is a rare complication that may present late after allogeneic transplantation and even rare among patients in whom autologous stem cell transplantation was performed years prior to PML presentation [98, 99].

Vascular Complications In the early post-transplant period following myeloablative conditioning, patients are typically pancytopenic for nearly 2  weeks and are at risk for intracranial bleeding due to severe thrombocytopenia. Subdural hematoma may occur, whereas intracerebral hemorrhage is often fatal. Subdural hematomas are the most common form of intracranial hemorrhage in this group of patients; clinical presentation includes  mental status changes without acute localizing neurologic signs [100, 101]. Treatment requires maintenance of platelet count of greater than 75,000/mm3, correction of any coagulation abnormalities, and surgical treatment, as necessary [102]. The clinical presentation for intracerebral hemorrhage reported in up to 3% of allogeneic transplant recipients may present with an acute localizing neurologic event accompanied by decreased sensorium. Fatal transtentorial herniation may occur if not recognized and treated promptly with surgical decompression. Cerebellar bleeds may present with more subtle signs of gait abnormalities and nystagmus, which can progress to changes in sensorium. Ischemic strokes can also occur in the early  post-­ transplant period. These can arise from thrombotic emboli in patients with infectious and noninfectious endocarditis or a hypercoagulable state resulting from disseminated intravas-

12  Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation

cular coagulation in patients with multi-organ failure (MOF) or severe sepsis [103, 104]. Rare cases of vasospasm associated with the infusion of cryopreserved stem cells have been reported [105]. Intracranial infections and meningitis can lead to endarteritis, resulting in an ischemic events; a compication occasionally seen in patients with CNS aspergillosis. Sinusoidal infections either bacterial or fungal may extend into the carotid artery and the venous cavernous sinus causing vascular compromise and stroke. Conditioning chemotherapy can lead to endothelial damage, which may  be exacerbated by calcineurin inhibitors. The hypercoagulable state and non-bacterial thrombotic endocarditis carries a high  risk for stroke.  Thrombotic microangiopathy seen in 5–15% of stem cell transplant patients can also cause acute mental status changes. The presence of fragmented RBCs, elevated LDH, and renal insufficiency are the classic features. Treatment consists of discontinuation of calcineurin inhibitors, infusion of cryoprecipitate poor plasma, or plasmapheresis [104].

Metabolic Encephalopathy Acute metabolic complications after conditioning regimens can lead to acute mental status changes that present as altered sensorium. The leading causes include sepsis, use of sedatives and other neurotrophic medications, hypoxia from various respiratory complications; uremia and liver failure [106]. Multi-organ failure (MOF) is a significant cause of mortality in patients undergoing transplantation. Severe CNS dysfunction is a salient feature of this syndrome, which is thought to reflect an excessive  systemic inflammatory response. Prolonged critical care unit stay in transplant patients may result in critical care polyneuropathy that is thought to occur due to impaired blood flow to the peripheral nerves [107]. Vasogenic edema with characteristic radiologic findings has been associated with the use of calcineurin inhibitors. Radiation-based conditioning regimens and the use of highdose chemotherapy may contribute to the breakdown of blood-brain barrier resulting in the release of endothelin and other vasoactive peptides that may trigger vascular and neurological changes well documented with calcineurin inhibitors [108].

Delayed Neurologic Complications Intensive chemotherapy and radiation are  well-recognized cause for  chronic neurologic sequelae. Ongoing immunosuppression, GVHD, and infections may beother contributing factors. Both the central and peripheral nervous system may be involved; In general, the neurologic complications are less frequent among recipients of autologous stem cell

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graft compared with those undergoing allogeneic transplants. Leukoencephalopathy can arise in the setting of aggressive intrathecal chemotherapy in combination with cranial irradiation with  TBI dose  of 1800–2400  cGY or higher. This is an irreversible complication and can leave a patient in a permanent vegetative state. Adequate shielding of cranium  and judicious use of intrathecal chemotherapy has reduced the risk for this devastating complication [109]. Vasculitic changes in the CNS as well as peripheral neuropathy have been described in the setting of GVHD.  Cognitive impairment, memory dysfunction, and shortened attention span are  reported in patients, particularly children after  stem cell transplantation; these CNS complications may or may not be directly attributed to preparatory pre-transplant conditioning  particularly patients receiving cranial irradiation [110, 111]. Radiation-induced neurocognitive impairment due to brain irradiation in patients with CNS lymphoma  or leukemia, presents as  a biphasic illness;  a subacute transient decline that  peaks around 4 months and a late irreversible neurocognitive dysfunction that becomes evident several months to years after brain irradiation was given [112].

Cardiovascular System Cardiac complications occur at a rate of 2–28% despite aggressive pre-transplant screening and implementation of  reduced-intensity conditioning  regimens.  They are  an increasing problem as stem cell transplants are being offered to older patients. Congestive heart failure, and  arrhythmias  are common;  pericardial effusions, and rarely,  infectious or noninfectious endocarditis may be seen [113].

Acute Cardiac Complications High-dose cyclophosphamide, prior history of anthracycline use, chest and  mediastinal radiation are risk factors for CHF.  This is exacerbated in patients with  pancytopenias, particularly severe  anemia, fluid overload, and renal dysfunction. Cyclophosphamide can result in cardiac toxicity within 3 weeks following administration. This occurs at doses above 150  mg/kg. Besides CHF, it can also cause pericardial effusion and cardiac tamponade. Pathophysiology of cyclophosphamide-related cardiac injury is related to endothelial damage resulting in extravasation of active drug metabolites into the myocardium causing direct cellular injury by severe depletion of cardiac thiol stores. Fractionated cyclophosphamide can reduce the incidence of cardiac injury. The risk of cardiac toxicity is increased by concomitant administration of cytarabine or mitoxantrone [114]. Melphalan and fludarabine, commonly

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used for reduced-intensity conditioning, are associated with a 2–14% incidence of cardiac toxicity in the acute setting [115]. Pancytopenia, particularly  severe neutropenia  following pre-­ transplant  conditioning can lead to infections, which may present as pericarditis with pericardial effusions, and less commonly,  endocarditis with or without valvular dysfunction. Cardiac arrhythmias can also be a manifestation of acute cardiac injury associated with conditioning regimens. Rituximab, cyclophosphamide, and melphalan are the most common agents associated with cardiac arrhythmias [116].

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Infections

Severe neutropenia following high-dose conditioning regimens substantially increases the risk for acute pulmonary infections. Pneumonia is the leading cause of death after HSCT. In the first 30 days, patients are most susceptible to bacterial pneumonia with an incidence up to 15%. Myeloablative conditioning regimens are more likely to cause bacterial pneumonia compared with reduced-intensity regimens. Atypical clinical presentation and absence of consolidation on CXR is not uncommon in neutropenic patients with penumonia. Bacterial pneumonia can be a rapidly progressive illness resulting in acute respiratory failure and death. Therefore, high-index of suspicion is of paraDelayed Cardiac Complications mount importance in managing patients during pre-engraftment neutropenia, in particular those with fever without localizing Several antineoplastic  agents that are part of pre-­ sign(s) of infection. transplant conditioning can result in long-term cardiac comRespiratory viral infections due to respiratory syncytial plications. Late effects consist of arrhythmias, congestive virus, influenza, parainfluenza, and adenovirus can lead to heart failure, myocardial infarction, hypertension, angina, debilitating acute illness in the early post-transplant period pericarditis, and valvular heart disease. In a study of 248 and in patients with GVHD-related  prolonge immunosuppatients with chronic myeloid leukemia, the incidence of pression [122, 123]. CMV reactivation and viral pneumonitis delayed cardiac complications was 33% compared with age-­ among other CMV manifestations of systemic disease are controlled general population, and the degree of cardiac usually seen after engraftment, herald by recovery in periphimpairment was greater after unrelated donor stem cell trans- eral blood cell count usually between day 30 and day  100 plants (48%) as compared with 29% in related donor HSCT after transplantation. This is related to the ongoing immunoand 18% in patients following autologous transplants [117]. suppression in the post-transplant period rather than condiOther than direct cardiotoxicity from chemotherapeutic tioning regimen-associated complication; furthermore, CMV agents, GVHD appears to be a major factor associated with end-organ disease is rarely seen in patients following autolocardiovascular complications. There is an increased inci- gous stem cell transplants [124]. dence of coronary artery disease in survivors of stem cell Prolonged neutropenia, and continued immunosupprestransplantation due to the delayed effects of chest radiation, sion increases the risk for  invasive fungal disease (IFD); hyperlipidemia associated with calcineurin inhibitor therapy, aspergillosis mostly involve lungs and less frequently paracorticosteroid use, endocrine dysfunctions, physical inactiv- nasal sinuses with the  risk for intraorbital and  intracranial ity, and overall physical deconditioning. Vascular sequelae of extension. These neurotropic filamentous fungi may cause the seldom seen infective and non-infective endocarditis can intracranial infection via hemtogenous seeding. In recipients lead to permanent valvular dysfunction; it is important ot of  cord blood stem cells, the incidence of invasive fungal note that sudden, severe aortic valve regurgitation is a life-­ infections is highest  among adults undergoing allogenic threatneing cardiac emergency [118]. HSCT; which in most part is a reflection of delayed hematopoietic engraftment and therefore, extended duration of ­neutropenia [125]. Chronic GVHD and drug-induced cellular  immune suppression also places the patient at risk for Pulmonary Complications invasive fungal disease. Dyspnea and cough are usually presIn nearly 60% of transplant recipients, pulmonary complica- ent. CT scan of chest should be obtained early and findings tions are expected and may result in 30% of deaths attributed such as pulmonary nodules with the classic "Halo sign" indito non-(cancer) relapse mortality (NRM) [119]. Pulmonary cating hemorrhage in the adjoining lung tissue that tends to complications after transplant may have various causes such disapper after first week of infection; dense areas of consolias infections, direct effects of the drugs or radition used in dation in peripheral lung, near pleura, or thick wall cavitapre-transplant  conditioning, non-cardiogenic  pulmonary tion with seldom seen “air crescent sign” are highly edema, fluid overload  states, diffuse alveolar hemorrhage, suggestive of pulmonary IFD. Hyphae seen in bronchoalveoand idiopathic pneumonia syndrome, as well as late obstruc- lar lavage samples have a positive predictive value of 80%; tive and restrictive lung disease each with unique clinical and however it has low sensitivity. Voriconazole and other mold-­ diagnostic features. GVHD also affects the respiratory active triazole drugs such as posaconazole and ­isavuconazonium sulfate have replaced amphotericin B as tract [120, 121].

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the gold standard of therapy for most cases of pulmonary fungal disease. Echinocandins and lipid formulations of amphotericin B may still be used in select cases. The incidence of Pneumocystis jirovecii pneumonia was up to 15% in patients undergoing transplantation. Routine prophylaxis with  trimethoprim-­sulfamethoxazole has almost  eliminated this serious fungal lung disease in the susceptible population. BAL is the diagnostic procedure of choice, with a yield of nearly 90%. Treatment consists of high-dose trimethoprim-­ sulfamethoxazole; corticosteroids are reserved  for patients with severe hypoxemia.

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Late-Onset Pulmonary Complications

Late complications affecting the airways and lungs are seen in 7–26% of patients undergoing HSCT; common causes are  lung  infections, TBI-based conditioning  regimen, and GVHD [131, 132]. Mucositis due to aggressive preparatory conditioning  reduces mucociliary clearance and mucous retention  in the respiratory tract. Chronic  inflammation ensues, alveoli and pulmonary interstitium are both affected, recurring or perisstent  hemorrhage, and  edema  promotes fibrosis resulting in chronic obstructive and/or restrictive lung disease. High-dose regimens containing carmustine Idiopathic Pneumonia Syndrome are known to cause  delayed pulmonary syndrome seen Also known as interstitial pneumonia, is an acute pulmonary approximately 10  weeks after transplantation.  Symptoms syndrome with widespread alveolar injury, with multilobar consist of dyspnea, nonproductive  cough, and fever. PFT infiltrates, increased alveolar to arterial oxygen gradient, and show a mild restrictive defect although severe defect in lung restrictive pulmonary dys function in the absence of infec- diffusion capacity becomes evident. Radiographic presentation or cardiogenic lung  disease. The histopathologic find- tion  comprises of scattered  diffuse ground-glass infiltrates. ings consist of interstitial pneumonitis; diffuse alveolar Patients respond to corticosteroids; however, progressive damage; cryptogenic organizing pneumonia (COP), for- respiratory failure and death may occur in nearly 8% of merly bronchiolitis obliterans organizing pneumonia patients [133, 134]. (BOOP); and lymphocytic bronchitis. The incidence is Bronchiolitis obliterans is seen as a late complication and 3–15% and associated with high-dose conditioning regimens often associated with chronic GVHD.  Methotrexate and compared to RIC; suggesting  toxicity from  pre-transplant respiratory viral infections within first 100 days after transpreparatory regimen as a contributing factor. The incidence plants increases the risk of bronchiolitis obliterans.  Some is also higher in patients who undergo allogeneic transplan- patients may progress to obstructive lung disease and respitation compared with  patients given  autologous stem cell ratory failure [135]. grafts [126]. Symptoms occur early in the post-transplant Late idiopathic pulmonary syndrome (IPS) defined as a period, usually within the first 100 days and are fairly typical noninfectious interstitial pneumonitis may occur in 6–18% for pneumonia such as dyspnea, fever, hypoxemia, and of HSCT recipients between 3 and 24  months after transmostly non-productive  cough. Infections  need to  be ruled plantation. It is characterized by thickening of the interstitial out, and treatment consists of high-dose corticosteroids. This space with a cellular infiltrate, accumulation of  fluid, and condition may rapidly progress to respiratory failure requir- fibrotic tissue. Radiographic studies show diffuse pulmonary ing assisted mechanical ventilation [121, 127]. COP is usu- infiltrates, and the symptoms consist of progressive dyspnea, ally seen as a complication of GVHD within the first hypoxemia, and fevers. High-dose radiotherapy and GVHD 1–3 months after HSCT. Pathologically it consists of small are the risk factors associated with this complication. airway injury and interstitial inflammation with granulation Treatment includes high-dose corticosteroid therapy plugs in the small airways. Patients with COP respond to [136–138]. high-dose  steroids; however,  long-term respiratory compliPatients undergoing HSCT are at increased risk for seccations in such patients are not uncommon. ondary malignancies including lung cancer, head and neck Diffuse alveolar hemorrhage (DAH) is  seen in 5% of cancers that are usually seen 2  years after transplantation. HSCT recipients. The  characteristic features include  fever, Total body irradiation during preparatory  conditioning  is a cough, and respiratory compromise during  the early post-­ well-described risk factor. transplant period usually within the first 30  days. Diffuse ground-glass infiltrates are suggestive, by no means diagnostic. Diagnosis requires progressively bloodier return of BAL Hematologic Complications aliquots and 20% or more blood-laden macrophages. Patients may need mechanical ventilation, and treatment consists of Myeloablative conditioning regimens are designed to corticosteroids given in high doses such as 125 or 250 mg of erode marrow function completely; recovery of the resulmethylprednisolone every 6  h for 4–5  days followed by a tant pancytopenia requires successful engraftment, which gradual tapering steriod dose schedule. Mortality is high, up is an amalgam of variables such as stem cell graft source to 60% at 6 months. Risk factors for DAH include high-dose i.e.,  autologous vs. allogeneic; dose of nucleated  stem conditioning regimen, total body irradiation, renal insuffi- cells;  marrow-derived vs. PBSC  vs.  cord blood-derved; ciency, older age, and previous history of GVHD [128–130]. donor factors i.e., related vs. unrelated; ABO blood type,

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major,  and minor HLA antigen compatibility. RIC is designed to creat a hosts’  milieu  of  immune  suppression rather than myelosuppression. Therefore, as expected RIC is associated with low systemic and myelotoxicity. The duration of pancytopenia is  shorter and conceivably less infectious, and non-­infections complications, including the need for transfusions. Conditioning regimens are associated with hemolytic complications secondary to thrombotic microangiopathy (TM); a Coombs’ negative hemolysis associated with RBC fragmentation, thrombocytopenia; renal and neurologic abnormalities [139, 140]. The incidence varies from 1% in autologous transplants and up to 70% in small series of patients following allogeneic transplants particularly where tacrolimus and sirolimus was used for GVHD prophylaxis [141, 142]. RIC is associated with 15–23% incidence of TM, with the highest risk in patients with  prior myeloablative transplant ( or equale to 20 Gy. At the standard doses of 12 Gy used in TBI, the damage to the hypopituitary axis is minimal, however, concomitant or prior use of systemic and intrathecal chemotherapy may lower this threshold particularly in patients given highdose methotrexate [151].

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Growth Hormone Dysfunction Children undergoing HSCT are highly susceptible; the incidence of short stature may  range from 4–60% and correlates with young age at the time of transplantation. TBI and cranial irradiation are the strongest predictors for growth retardation due to: skeletal dysplasia of the spine by direct effects of chemotherapy and irradiation, radiation-induced hypopituitarism, hypothyroidism, and possibly precocious puberty resulting in early closure of bone epiphysis. In addition, use of glucocorticoids can blunt the secretion of growth hormone (GH), and direct effects of Bu and Cy on the epiphyseal growth plate may also contribute to growth retardation in children given radiation sparing preparatory regimen [152, 153]. In adults, there are no clearly recognizable syndromes associated with GH deficiency. However, GH deficiency may be associated with lean body mass and muscule wasting  and increased body fat; cardiovascular adverse events and reduced bone mineral density [154].

Bone Metabolism and Osteoporosis Patients undergoing  HSCT exhibit  bone loss particularly within the first 6  months [155, 156]. Typically, 5–15% bone  loss is  expected in  lumbar spine and femoral neck within the 1st year after  HSCT; osteopenia is noted in 50–60% and osteoporosis in 20% of stem cell transplant recipients [157]. The pathogenesis of bone loss in is multifactorial. Prolonged use of glucocorticoids, alterations in calcium and magnesium homeostasis in patients given calcineurin inhibitors contribute to bone loss [158, 159]. It is prudent to be aware of this complication, assess bone density by DEXA scans at regular intervals, and replenish  calcium, vitamin D; and bisphosphonate therapy as indicated.

Thyroid Dysfunction Thyroid dysfunction is seen  2–56%, and effects  both autologous and allogeneic stem cell graft recipients [160, 161]. Conditioning regimen is thought to  play a role, as expected, radiation-based conditioning would elicit direct damage to the thyroid tissue and to the hypothalamus and pituitary gland. The incidence of thyroid dysfunction after single dose irradiation is higher  (23–73%) compared with  10–28% seen with fractionated dose therapy  [162]. Similarly, patients undergoing  allogeneic vs. autologous HSCT have higer risk for thyroid dysfunction as a result of immunosuppressive drugs  [163, 164]. In the post-transplant period, thyroid dysfunction presents as euthyroid sick syndrome (ETS), hypothyroidism, autoimmune disease, or a thyroid nodule.

12  Complications Arising from Preparatory Conditioning Regimens for Stem Cell Transplantation

ETS is the most common thyroid dysfunction observed during  first 3  months following  HSCT.  It  is characterized by low free T3 and free T4 and a normal or low TSH; and  regarded as an indicator for  poor overall  prognosis. Hypothyroidism is a common long-term thyroid complication after transplantation,  with a  cumulative incidence of 48% after 5 years and 67% after 8 years; however, median time to diagnosis is 4 years post-HSCT.  Single-dose TBI  carries higher risk for hypothyroidism  (50%) compared with fractionated TBI (15%). The incidence of hypothyroidism is lower (11%) in patients given non-radiation conditioning. In this case the mechanism appears to be related to the effects of chemotherapy on the cytokines that control thyroid function; in addition GVHD may elicit thyroid dysfunction via immune/inflammatory pathway [163, 165, 166]. The incidence of thyroid nodules is higher in patients undergoing HSCT (27%) compared with the general population (4%)  [162]. Although most patients with thyroid nodules have no symptoms, although 5–10% may be malignant, therefore, rigorous evaluation should be performed  at the time of initial  diagnosis  and follow up. Patients, particularly children undergoing HSCT, have an increased risk for thyroid cancers compared with the general population, with an overall incidence of 0.2%. Radiation  (TBI)-associated relative risk for nodules and thyroid malignancies is estimated between  0.6–14.9 and 3.6, respectively [167, 168].

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exposure to radiation as part of the conditioning regimen, and development of moderate-to-severe chronic GVHD.  However, risk factors for solid tumors differed by the type of tumor. Radiation was found to be a major factor for non-squamous cell carcinoma (SCC), especially among patients who had survived 5  years or longer  after transplant.  Whereas, chronic GVHD was associated with an increased risk for SCC, during both early and late post-­ transplant period [170]. The overall risk for secondary solid tumor was twofold higher  in  patients in whom  radiation was  a  part of pre-transplant  conditioning compared with  patients given radiation sparing prepartory regimen. The increased solid tumor risk with radiation was most significant for patients younger than 10 years of age at the time of transplantation and remained high up to the age of 30 years. Patients 30 years and older at the time of transplant did not display higher risk for secondary solid organ malignancies despite receiving TBI conditioning. The risks of secondary solid organ  malignancies in  nonradiation-­based HSCT  conditioning, with busulfan-­ cyclophosphamide was evlauted in 4,318 patients [171]. The cumulative incidence of solid cancers was 0.8% after 5 years and 2% after 10 years following transplantation. HSCT recipients had 1.4× higher rate of solid organ  cancer compared with age- and gender-matched general population. Lung cancer  was common, followed by breast cancer; significantly elevated risk was also observed for tumors involving the oral cavity, esophagus, soft tissue, and brain. On multivariate analysis, old age, lower performance status at time of transplantation, and chronic GVHD were important predictors for Secondary Malignancies After HCT such cancers [171]. It is hypothesized that busulfan can cause Secondary malignancies are a rare and usually late complica- pulmonary injury and fibrosis [172]; exposure to alkylator tion; total body irradiation and chronic GVHD appears to be chemotherapy and particularly in patients with history of smoking increases the risk for lung cancer [173]. There the strongest risk factors [169]. might have been a synergistic carcinogenic effect of smoking and busulfan-cyclophosphamide lung cancer  in non-TBI HSCT study [170, 171, 174–177]. Solid Tumors The pathophysiology of secondary solid organ malignanSecondary solid cancer following HSCT was performed by cies after allogeneic HSCT is not well understood and most the Center for International Blood and Marrow Transplant likely a culmination of number of factors. Differences in type Research (CIBMTR) [170]. Risk factors for solid cancers in of malignancies related with  TBI exposure versus busulfana multi-institutional cohort of 28,874 allogeneic transplant cyclophosphamide preparatory therapy or chronic GVHD sugrecipients, who underwent myeloablative transplanta- gest divergent carcinogensis pathways. Radiation may increase tion  was assessed. Approximately 70% had received TBI-­ the risk of post-transplant malignancies by inhibiting DNA based conditioning. New solid tumors were reported in 153 repair mechanisms resulting  in gene ­translocation and gene transplant recipients, with a  cumulative incidence of 1% instability due to  breaks in  double-strand DNA.  Chronic after 10 years, 2.2% after 15 years, and 3.3% 20 years after GVHD and prolong exposure to immunosuppressive transplantation. In this study, transplant recipients developed drugs  likely increase the risk for  secondary malignancies by solid organ malignancies twice the rate of age- and gender-­ inhibiting cancer-protecting immunologic defense mechamatched general  population. Risk  for tumors involving  the nisms; for example, increased incidence of SCC involving oral cavity, liver, thyroid, bone, soft tissue, melanoma, brain female genital tract or head and neck cancer due to infection and CNS were prominent. Risk for invasive solid tumor can- with human papilloma virus is related with chronic GVHD and cers was strongly related with  age at time of transplant, prolonged immunosuppressive therapy [170, 171, 177–179].

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Post-Transplant Lymphoproliferative Disorder

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possible is the main treatment strategy. Additional therapeutic options include rituximab, chemotherapy, antiviral therPost-transplant lymphoproliferative disorder (PTLD) is a apy, cytokine therapy, adoptive immunotherapy, surgery, and serious  complication in patients undergoing  solid organ radiation [202, 204]. Given the heterogeneity of PTLD, surtransplants (SOT) and allogeneic HSCT. PTLD is a hetero- vival is variable with an overall median survival range geneous group of lymphoproliferative diseases with a wide-­ between ~1.5 and 8 years [180]. Mortality rate may be high spectrum of underlying  pathology and clinical (70–90%) in patients following high-risk allogeneic HSCT manifestations that range from benign lymphoid hyperplasia [185]. to aggressive lymphoma [180]. The incidence of PTLD is 1–10% after SOT and 0.5–1% after HSCT [181–185]. Most SOT-related PTLD is of host origin [186], whereas PTLD in Secondary Myelodysplastic Syndrome allogeneic HSCT recipients is predominately of donor origin and Leukemia [187]. The highest  risk for PTLD is in patients with drug-­ induced severe immune suppression for prevention and treat- Recipient-Derived Myelodysplastic Syndrome ment of solid organ  allograft rejection;  rate between 10% and Acute Myelogenous Leukemia and 25% are observed in SOT subgroup that require  high Treatment-related myelodysplastic syndrome (MDS) and doses of  antirejection therapy  that is commonly  given for acute myelogenous leukemia (AML) may occur after autoloa prolong duration after heart, lung, and multivisceral trans- gous HSCT. Up to 10% of patients with lymphoma treated plants [181, 182, 188].  The incidence rates are lower (1% with either conventional or high-dose antineoplastic therapy, and 5%) after kidney and  liver transplantation, as these and those after autologous stem cell transplants may develop patients in most cases, do not require intense drug-induced treatment-related MDS or AML within 10 years after the priimmunosuppressive state [184, 188]. An estimated 50–70% mary therapy [205, 206]. Main risk factors are prior exposure of all PLTD cases are associated with EBV infection [189– to alkylating agents and the purine nucleotide analog 191], the risk is higher in  EBV-negative recipient like fludarabine, and TBI as part of the preparatory regimen given allograft from EBV-positive donor [190, 192]. [205, 206]. Cases of treatment-related MDS/AML have been In HSCT recipients, the main risk  factors for  PTLD reported in patients who were treated with radioimmunotherare  T-cell depletion (TCD), and HLA mismatch, unrelated apy; however the possible contribution of radioimmunotherdonor graft transplants. Severity of GVHD, and transplanta- apy to the risk for  secondary malignancies is still unclear tion for primary immune deficiency disorders are additional since most patients had been previously treated with alkylatcontributing factors [185, 187, 193]. The median time from ing agents [207]. The pathogenesis  of alkylating drug and transplantation for PTLD in SOT patients varies from 30 to TBI-induced MDS/AML is a result of chromosomal damage 72  months [183, 189, 194–197]. Among HSCT recipients, of hematopoietic precursors; possibly other yet PTLD has a more rapid onset with a median time between 4 unknown tumor promoting external elements and unrecogand 6 months after transplantation [185, 187, 198]. nized hosts’ genetic haecceity may also play a role. The neoThe incidence of EBV-negative PTLD is 10–20%; it usu- plastic transformation of the hematopoietic stem cells is a ally occurs late and responds poorly to treatment [169, 196, multiple step process, which is most likely initiated by 197]. PTLD have a diverse clinical presentation based on prior exposure to cytotoxic drugs and accelerated by high-­ location and the degree an  organ is  involved. Presenting dose chemo- and radiation therapy used in transplant condisymptoms include fever, lymphadenopathy, weight loss, tioning. Therefore, patients undergoing autologous HSCT anorexia, fatigue, sepsis-like syndrome, and multi-organ should be carefully evaluated for pre-transplantation risk(s) dysfunction. Extra-nodal involvement is relatively common; for  secondary MDS/AML, and selection of  conditioning sites such as the gastrointestinal tract, lung, skin, bone mar- regimen must be tailored accordingly. row, and central nervous system are frequently affected [183, 189, 194, 197, 199, 200]. PTLD in patients after HSCT usu- Donor-Derived MDS and AML ally has an aggressive course with extensive  disseminated In the allogeneic setting, secondary MDS and AML after disease, involving multiple organs [201]. Prognostic factors HSCT are thought to occur as a result of oncogenic transassociated with poor  survival include older age, elevated formation of the apparently normal donor hematopoietic LDH, presence of B symptoms, multi-organ involvement, stem cells exposed to a foreign environment [208]. Donor-­ decreased performance status, advanced stage of the disease, derived MDS/AML is a rare complication after HSCT, and involvement of the allograft in solid organ recipients, >1 its incidence has been reported between 0.12% and 5% extra-nodal sites, and CNS or bone marrow involvement [208–210]. Alteration of the bone marrow microenviron[202, 203]. At present there is no consensus on standard ment following allogeneic stem cell transplantation resulttreatment for PTLD; reduction in immune suppression, when ing from  high -doses cytotoxic and immunosuppressive

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drugs may influence normal hematopoietic progenitor cells to undergo  leukemic transformation  via a complex mechanism(s) that may involve  interaction between donor  hematopoietic progenitor cells, and  recipients’ unique stromal cells and signalling milieu, influence of growth factors, selective impact via cytokines and chemokine dysregulation, among others [208]. In large survey conducted by  European Group for Blood and Marrow Transplantation (EBMT), 14 donor-derived leukemia were reported among 10,489 allogeneic HSCT recipients. The median time to onset was 17  months, with a range of 4–164  months  after transplantation. No specific risk factors, such as  type of  conditioning  regimen, donor graft manipulation, or type and degree of recipients’  immune suppression were identified [209]. It is important to differentiate secondary leukemia after allogenic transplant from relapse of the original disease, which is an important cause of death in patients undergoing allogeneic stem cell transplantation [211]. The current understanding of secondary malignancies after HSCT is based on studies that evaluated mainly patients who  have  received myeloablative conditioning. Less is known about the repertoire and risks for secondary malignancies after reduced-intensity HSCT recipients; long-term follow up studies are needed to assess post-transplant cancer risk this population.

Conclusion HSCT is an effective life-saving treatment modality  for many hematologic malignancies and a growing number of  nonmalignant hematologic and autoimmune disorders. However, as discussed in the aforementioned text, there are a number of  short- and long-term complications associated with preparatory regimens given prior to transplantation. In this chapter, we have enumerated  common and less frequently noted complications attributed to various conditioning regimens used to achieve cytoreduction, antitumor effect, myeloablation, and immunosuppression. Additional complications and toxicities may occur as a result of GVHD, opportunistic infections, and disruption in various aspects of hosts' immune response. Whenever the transplant procedure is performed, a life is at risk, and the question of risk vs. benefit needs to be discussed in great detail with the patient along with quality of life issues and reasonable  expectations in near and far post-transplant period. The goal always is  to minimize transplant-related risks, which can be achieved with better understanding of such complications. As we move forward into the era of targeted and molecular biologics, it remains imperative that feasiability of new agents with better therapeutic index and safety profiles be incorporated in next generation preparatory regimens with the aim to

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reduce the burden of complications and achieve  sustained cancer  remission  following  hematopoietic stem cell transplantation. 

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Intravascular Catheter and Implantable Device Infections in Transplant Patients

13

Nasia Safdar, Cybele Lara R. Abad, and Dennis G. Maki

Introduction The use of intravascular devices for administration of drugs, fluids, blood products, and nutritional support is essential to medical care. Unfortunately, these intravascular devices have a significant potential to produce iatrogenic disease, especially bloodstream infection originating from colonization of the device used for access or from contamination of the infusate administered through the device [1–4]. Over two-­thirds of all healthcare-associated bacteremia originate from devices used for vascular access [5]. Patients with hematologic malignancies undergoing stem cell transplantation (SCT), who have inherently compromised immune function because of their malignancy and are further incapacitated due to the preparative regimen or graft-versus-host disease (GVHD), are particularly prone to device-related infections [6]. Every year more than five million central venous catheters (CVC) are inserted in the United States [7]. More than 250,000 intravascular catheter-related bloodstream infections (IVDR BSI) occur annually with an associated mortality of 12–25% [7]. A recent meta-analysis found mortality to be significantly increased in intensive care unit (ICU) patients who had IVDR BSI compared with those without IVDR BSI (odds ratio [OR], 1.96; 95%  confidence interval [CI], 1.25–3.09) (Fig.  13.1) [8]. Each episode of IVDR BSI significantly increases hospital length of stay, and the added healthcare costs range from $4,000 to $56,000 per episode [9–11]. Probably more than any other healthcare-associated infection, IVDR BSI is preventable [5, 12–15]. N. Safdar (*) · D. G. Maki Section of Infectious Diseases, Department of Medicine, University of Wisconsin-Madison, School of Medicine and Public Health, and the William S. Middleton Memorial Veterans Hospital, Madison, WI, USA e-mail: [email protected]; [email protected] C. L. R. Abad Section of Infectious Diseases, Department of Medicine, University of the Philippines Manila, Philippine General Hospital, Manila, Philippines

This chapter focuses on the epidemiology and prevention of IVDR BSI in transplant patients. Given the paucity of data specific to the transplant population, we extrapolate from studies in other populations, particularly the critically ill and patients with cancer. The first step to preserve vascular access is a highly effective institutional program for prevention of IVDR BSI.  In recent years, a large volume of high-quality research studies have delineated key measures for prevention, and IVDR BSI rates in the ICU have declined markedly in most institutions [13, 16–27]. However, despite adherence to best practices, IVDR BSI continues to pose formidable challenges, especially in solid organ and stem cell transplant patients [28].

Pathogenesis of IVDR BSI There are two major sources of IVDR BSI: (1) colonization of the IVD, or device-related infection, and (2) contamination of the fluid administered through the device, or infusate-­ related infection [29]. Contaminated infusate is the cause of most epidemic intravascular device-related BSI [4, 30]; in contrast, catheter-related infections are responsible for most endemic device-related BSI. A major route of BSI in transplant patients may be translocation of gut and oral flora into the bloodstream as a result of mucositis, called mucosal barrier injury-related BSI. These infections may be mistakenly classified as IVDR BSI if the patient has an IVD in place at the time of positive blood culture. Understanding the pathogenesis of IVDR BSI is fundamental to devising effective strategies for prevention and treatment of these infections; however, relatively few published studies have determined the mechanism of IVDR colonization and infection using sophisticated molecular techniques to prove or disprove potential routes of infection [31–37]. In order for microorganisms to cause catheter-related infection, they must first gain access to the extraluminal or intraluminal surface of the device where they can adhere

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250 Review: Comparision: Outcome:

N. Safdar et al. Impact of catheter-related bloodstream infections on the mortalty of critically ill patients: a meta-analysis 01 Mortality 01 In-hospital mortality (all studies)

Study or sub-category

CR-BSI n/N

Control n/N

23/55 21/41 49/176 77/142 10/26 5/9 11/49 20/38

12/55 301/1091 82/315 42/142 7/26 93/251 17/49 20/75

12.04 14.64 17.37 16.44 8.62 7.27 11.38 12.25

2.58 [1.12, 5.93] 2.76 [1.47, 5.16] 1.10 [0.72, 1.66] 2.82 [1.73, 4.60] 1.70 [0.53, 5.48] 4.67 [1.21, 18.00] 0.54 [0.22, 1.33] 3.06 [1.35, 6.92]

Total (95% CI) 536 2004 Total events: 216 (CR-BSI), 534 (Control) Test for heterogeneity: Chiz = 21.63, df = 7 (P = 0.003), Iz = 67.6% Test for overall effect: Z = 2.91 (P = 0.004)

100.00

1.96 [1.25, 3.09]

Higuera Warren Blot Rosenthal Renaud Dimick Rello Soufir

OR (random) 95% CI

Weight %

OR (random) 95% CI

0.01 0.1 1 10 100 Favors survival vs favors mortality

Fig. 13.1  Attributable mortality of IVDR BSI in critically ill patients [8]. (Reprinted from Siempos et  al. [8], © 2009, http://journals.lww. com/ccmjournal/Abstract/2009/07000/Impact_of_catheter_related_ Fig. 13.2  Potential sources of infection of a percutaneous IVD: the contiguous skin flora, contamination of the catheter hub and lumen, contamination of infusate, and hematogenous colonization of the IVD from distant, unrelated sites of infection [42]. (Reprinted from Crnich and Maki [42], by permission of Oxford University Press)

bloodstream_infections.22.aspx, with permission from Wolters Kluwer Health, Inc.)

Contaminated catheter hub

Skin organisms Endogenous Skin flora Extrinsic HCW hands Contaminated disinfectant

Endogenous Skin flora Extrinsic HCW hands

Contaminated infusate Extrinsic Fluid Medication Intrinsic Manufacturer

Skin Fibrin sheath, thrombus Vein

Hematogenous from distant infection

and become incorporated into a biofilm that allows sustained colonization and ultimately hematogenous dissemination [38]. Microorganisms gain access to the implanted IVD by one of three mechanisms: (1) skin organisms invade the percutaneous tract, probably facilitated by capillary action [39], at the time of insertion or in the days following; (2) microorganisms contaminate the catheter hub and lumen when the catheter is inserted over a percutaneous guidewire or later manipulated [40]; or (3)  organisms are carried hematogenously to the implanted IVD from remote sources of local infection, such as a pneumonia [41] or from gut or mouth translocation due to inflammation or mucositis (Fig. 13.2) [42].

With short-term IVDs that are in place  0.05) [88]. Although these results are promising, a larger trial powered to show equivalence or

Maximal Barrier Precautions

Insertion Site According to the HICPAC Guideline, the preferred site for insertion of non-tunneled CVCs in adult patients is the subclavian vein (rating 1B) [7]. However, the subclavian site is typically avoided in hemodialysis patients and patients with advanced kidney disease to avoid stenosis (1A). The femoral site has been reported to be associated with higher rates of catheter colonization as well as an  increased risk of deep vein thrombosis compared to cephalad sites in adults [7, 43, 91–93]. In an RCT with uncuffed CVCs comparing femoral with subclavian sites, catheters inserted in a femoral site were associated with a higher incidence of infectious complications (19.8% vs 4.5%; p 2 calendar days) of an Catheter-­ intravascular device associated BSI Primary BSI and at least one of the following: positive Catheter-­ related BSI semiquantitative culture of the catheter (>15 CFU/ catheter segment) with the same organism; [4] positive quantitative culture of the catheter (>103 CFU/catheter segment) with the same organism; [7] quantitative blood cultures obtained from the catheter and a peripheral vein with a ≥5: 1 ratio (catheter versus peripheral vein); [5] or differential time to positivity >2h of blood cultures simultaneously obtained from the catheter and a peripheral vein [6] BSI bloodstream infection, CFU colony-forming unit

the hospital setting are due to healthcare-associated BSI [14]. Of these, most are primary and associated with central catheter use [15]. Most surveillance systems today, such as the United States National Healthcare Safety Network (NHSN), the German Krankenhaus Infektions Surveillance System (KISS), or the International Nosocomial Infection Control Consortium (INICC), focus on catheter-associated, laboratory-­confirmed, primary BSI (CLABSI), with rates

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274

W. Zingg and D. Pittet

Table 15.2  Infective endocarditis: modified Duke criteria Major criteria Blood culture positive for IE  Typical microorganisms consistent with IE from 2 separate blood cultures:    Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus    Community-acquired enterococci in the absence of a primary focus  Microorganisms consistent with IE from persistently positive blood cultures, defined as follows:    At least 2 positive cultures of blood samples obtained >12 h apart    All of 3 or a majority of >4 separate cultures of blood (with first and last sample obtained at least 1 h apart)  Single positive blood culture for Coxiella burnetii or IgG antibody titer >1: 800 Evidence of endocardial involvement Echocardiogram 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 first 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  Abscess  New partial dehiscence of prosthetic valve New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor criteria Predisposition, predisposing heart condition, or injection 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’s nodes, Roth’s spots, and rheumatoid factor Microbiological evidence: positive blood culture, but does not meet a major criterion as noted abovea or serological evidence of active infection with an organism consistent with IE Echocardiographic minor criteria eliminated Definite infective endocarditis Pathologic criteria 1. Microorganisms demonstrated by culture or histologic examination of a vegetation, a vegetation that has embolized or an intracardiac abscess specimen 2. Pathologic lesions; vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis Clinical criteria 1. 2 major criteria 2. 1 major criterion and 3 minor criteria 3. 5 minor criteria Possible infective endocarditis 1. 1 major criterion and 1 minor criterion 2. 3 minor criteria Rejected 1. Firm alternate diagnosis explaining evidence of infective endocarditis 2. Resolution of infective endocarditis syndrome with antibiotic therapy for 50% mortality Nonspecific constitutional symptoms, dissemination to multiple organs (skin, most common clinical manifestation)

Subcutaneous nodules, ulcerating nodules, cellulitis mimic

Generalized wasting, fever, cough with disseminated disease

Widespread nodules, sinus tracts, ulcers, abscesses, cellulitis

Speciation is essential to guide management

22  Skin and Soft Tissue Infection in Transplant Recipients

387

Table 22.1 (continued) Organism Viruses Herpes simplex

Common cutaneous presentations

Atypical presentations

Complications and prognosis

Vesicles or punched-out erosions; periorificial ulcer or crust with a scalloped/polycyclic border

Dissemination with pneumonitis, hepatitis, pancreatitis, esophagitis, retinitis, encephalitis, adrenal necrosis

Varicella zoster

Dermatomal, disseminated

Cytomegalovirus

Rare cutaneous infection

Ulcers of the oral mucosa, herpetic geometric glossitis, linear fissures in body folds, exophytic granulation tissue (herpes vegetans), Kaposi varicelliform eruption Zoster sine herpete, recurrent primary varicella, chronic hyperkeratotic crusted plaques and punched-out ulcers Chronic anogenital ulcers with sharp borders; can occur elsewhere on skin, oral mucosa; rare morbilliform exanthem Erythematous morbilliform exanthem similar to acute graft-versus-host disease Extensive, numerous, exuberant, recalcitrant; may become large, confluent Giant molluscum: verrucous, lobulated nodules; viral folliculitis mimicking tinea barbae; recalcitrant and resistant, chronic

Human herpes virus 6 Exanthem subitum in infants

Human papillomavirus

Verrucous papules or plaques

Molluscum contagiosum

Small white dome-shaped umbilicated papules

Subcutaneous and deep mycoses Aspergillus Purpuric plaques with black or purple necrotic centers; sites of inoculation or dissemination, of which it may be a presenting sign Fusarium Painful red macules or papules evolving into violaceous, necrotic pustules, ulcers, or eschars; inoculation or dissemination Scedosporium/Pseuda Ulcerated dusky nodules, tender llescheria pustules, necrotic bullae; inoculation or dissemination Mucormycosis/ zygomycosis

Hyalohyphomycosis

Phaeohyphomycosis

Candida

Cryptococcus

Coccidioides

Rhinocerebral disease most common; nasal discharge, black nasal mucosa, palatal infarction, necrotic facial lesions Erythematous macules, necrotic, painful papules and nodules, vesiculopustules, cellulitis at portal of entry Inoculation injury with prolonged incubation period; nodule or abscess Local infection versus erythematous, purpuric papules with pale, necrotic, or pustular centers in disseminated disease Molluscum-like umbilicated or crusted papules, cellulitis, subcutaneous nodules, ulcers Reactive erythema nodosum

Pneumonitis, meningoencephalitis, hepatitis; abdominal pain with hyponatremia and SIADH Gastrointestinal ulceration, hepatitis, pneumonitis, myelosuppression

Fever, pneumonitis, bone marrow suppression, encephalitis Warts develop in 80% of transplant patients; can be locally destructive Differentiate from disseminated cryptococcosis and histoplasmosis, which can appear molluscoid

Most common opportunistic fungal infection s/p SCT; consider aggressive surgical management of solitary lesions; high mortality in dissemination Widespread cutaneous lesions more Acral bullae, flaccid umbilicated common than in aspergillosis (75–90% pustules, sporotrichoid nodules, vs 10%); sinopulmonary, fungemia; localized abscess dissemination almost uniformly fatal Suppurative nodules with spread along More than half present with disseminated cutaneous lymphatics disease; around 60% die; blood cultures frequently positive; S. prolificans almost uniformly resistant Rhinocerebral, pulmonary, GI, CNS, and Erythematous papule or plaque disseminated disease; involved area may develops into purpuric, hemorrhagic far exceed what is visible clinically; ulcer or necrotic eschar; “bull’s-eye 80–100% mortality infarct” Fusarium, Paecilomyces, Acremonium, Mycetoma with tumefaction and Trichoderma, Scopulariopsis, draining sinuses (Acremonium), Trichosporon; fungemia common and onychomycosis with necrotic mortality high; high-level resistance periungual cellulitis (Scopulariopsis) Phialophora, Fonseca, Cladosporium, Suppuration, sinus tract formation, Exophiala, Alternaria, Scedosporium; ulceration; scaly/verrucous plaques; surgical debridement if possible dissemination from the skin is rare Subcutaneous nodules, folliculitis, and Second most common fungal infection in cellulitic plaques SCT; skin lesions in 10% of dissemination; endophthalmitis, liver/ spleen infection; high mortality Skin lesions can present months before Skin lesions in 10–15% with dissemination; meningeal/ craniobulbar signs of dissemination; isolated skin signs plus skin lesions lesions rare; can get necrotizing cellulitis, fasciitis Verrucous or crusted papules, plaques, Fever, cough, sweats; skin, meningeal, abscesses, cellulitis, ulcers bone, and joint disease

Erythematous to violaceous plaques with pustules, subcutaneous nodules, cellulitic plaques

(continued)

388

R. G. Micheletti and C. L. Kovarik

Table 22.1 (continued) Organism Blastomyces

Histoplasma

Sporothrix

Superficial mycoses Trichophyton Microsporum Epidermophyton

Common cutaneous presentations Annular plaque with atrophic center and verrucous edges, pustules, and lymphatic spread Reactive erythema nodosum; macules, papules, necrotic papules, pustules in dissemination Fixed cutaneous (20%) or lymphocutaneous (70%); painless ulcerated papule/nodule at inoculation site

Atypical presentations Ulceration and pustulosis, disseminated papulopustules and subcutaneous nodules Morbilliform eruption, ulcers, panniculitis, cellulitis, verrucous or vegetative plaques Rare extracutaneous and disseminated disease; widely distributed ulcerated papules or plaques, crusted nodules, necrotic ulcers

Complications and prognosis Most blasto in immunocompetent; more severe (29–40% mortality) in immunosuppressed; bone, GU, CNS Fever, respiratory symptoms, weight loss, hepatosplenomegaly, bone marrow suppression Bone and joints most often involved in dissemination (80%); skin lesions usually a presenting sign

Erythematous or violaceous papules, Annular pruritic scaling plaques with serpiginous borders typical of pustules, nodules, deep abscesses, draining nodules, or ulcers; can mimic tinea corporis folliculitis, lupus, rosacea

Rare invasive infection occurs at sites of chronic superficial dermatophytosis

Protozoa Trypanosoma

Tender subcutaneous nodules

Leishmania

Beefy ulcers at inoculation site

Toxoplasma

Rare cutaneous infection

Reactivation with immunosuppression or transmission via infected organ Reactivation or transmission via infected organ; visceral disease most common form in transplant patients Reactivation or transmission via infected organ; fever, CNS, lungs

Acanthamoeba

Rare cutaneous infection

Strongyloides

Larva currens (migratory pruritic serpiginous plaques)

Painful erythematous, indurated plaques mimicking cellulitis Rare erythematous or brown macules and papules due to dissemination; may be a presenting sign of visceral disease Disseminated erythematous papules resembling acute graft versus host disease Numerous firm, purulent papulonodules develop into nonhealing crusted ulcers Hyperinfection syndrome with pathognomonic thumbprint purpura on abdomen, flanks, thighs May mimic severe seborrheic dermatitis or psoriasis; can result in erythroderma, involvement of whole body surface

Bacterial superinfection can occur; highly contagious, significant infection control issue

Infestations Crusted scabies

Widespread thick, crusted, yellow-brown plaques with predilection for body folds

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22  Skin and Soft Tissue Infection in Transplant Recipients 281. Glover R, Young L, Goltz RW.  Norwegian scabies in acquired immunodeficiency syndrome: report of a case resulting in death from associated sepsis. J Am Acad Dermatol. 1987;16:396–9. 282. Hulbert TV, Larsen RA. Hyperkeratotic (Norwegian) scabies with gram-negative bacterium as the initial presentation of AIDS. Clin Infect Dis. 1992;14:1164–5. 283. Bonomo RA, Jacobs M, Jacobs G, et al. Norwegian scabies and a toxic shock syndrome toxin 1-producing strain of Staphylococcus aureus endocarditis in a patient with trisomy 21. Clin Infect Dis. 1998;27:645–6. 284. Grossman ME, Fox LP, Kovarik C, Rosenbach M. Gram-negative bacteria. In: Grossman ME, Fox LP, Kovarik C, Rosenbach M, editors. Cutaneous manifestations of infection in the immunocompromised host. 2nd ed. New York: Springer; 2012. 285. Grossman ME, Fox LP, Kovarik C, Rosenbach M. Mycobacteria. In: Grossman ME, Fox LP, Kovarik C, Rosenbach M, editors.

395 Cutaneous manifestations of infection in the immunocompromised host. 2nd ed. New York: Springer; 2012. 286. Grossman ME, Fox LP, Kovarik C, Rosenbach M.  Viruses. In: Grossman ME, Fox LP, Kovarik C, Rosenbach M, editors. Cutaneous manifestations of infection in the immunocompromised host. 2nd ed. New York: Springer; 2012. 287. Grossman ME, Fox LP, Kovarik C, Rosenbach M. Subcutaneous and deep mycoses. In: Grossman ME, Fox LP, Kovarik C, Rosenbach M, editors. Cutaneous manifestations of infection in the immunocompromised host. 2nd ed. New  York: Springer; 2012. 288. Grossman ME, Fox LP, Kovarik C, Rosenbach M.  Protozoa. In: Grossman ME, Fox LP, Kovarik C, Rosenbach M, editors. Cutaneous manifestations of infection in the immunocompromised host. 2nd ed. New York: Springer; 2012.

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Ana Ciurea and Sharon Hymes

Introduction Many cutaneous conditions may mimic infectious processes. The ability to diagnose non-infectious skin eruptions, especially in cancer patients, is oftentimes challenging. Using the morphology of the primary skin lesion as a starting point, this section will review the clinical presentation, physical examination, and diagnostic work-up of many of these conditions. This should help the clinician generate a differential diagnosis when evaluating cutaneous lesions in immunosuppressed patients.

Section 1: Pustular Lesions Pustules are purulent collections which can be solitary or widespread. Not all the pustular processes in the skin are due to infection; pustular psoriasis is one of the non-infectious examples. They may be mistaken for bacterial, fungal, or superinfected herpetic infections.

undermined border surrounding a purulent necrotic base (Fig.  23.1). Culture-negative pulmonary infiltrates are the most common extracutaneous site of disease [1]. PG is associated with a dysregulation of the immune system, in particular altered neutrophil chemotaxis in reaction to various precipitating causes such as inflammatory bowel diseases [2, 3]. Many conditions can be confused with the early pustular stage: folliculitis, furunculosis, carbuncles, and streptococcal gangrene. The ulcerative stage must be differentiated from cutaneous amebiasis, cryptococcosis, blastomycosis, sporotrichosis, and atypical mycobacterial infections [4–6]. PG has a tendency to recur and it usually heals with scarring. Behcet’s syndrome is a chronic relapsing, idiopathic, multisystem disease of recurrent aphthous ulcers, genital ulcers, and uveitis (Fig. 23.2). The cause is unknown; however, current research points toward an autoimmune etiology following exposure to an infectious agent which includes herpes simplex virus, Streptococcus and Staphylococcus species, and Escherichia coli. It has been suggested that the heat shock proteins (HSPs) found in higher concentrations in

Reactive Neutrophilic Dermatoses Reactive neutrophilic dermatoses are a spectrum of diseases mediated by neutrophils manifested by systemic complaints in association with an underlying disease such as inflammatory bowel disorders or internal malignancies.

 ifferential Diagnosis: Bacterial, Fungal, D and Viral Infections Pyoderma gangrenosum is an uncommon idiopathic ulcerative skin disorder that often is associated with systemic diseases. The ulcerations are distinctive: an irregular, boggy,

A. Ciurea (*) · S. Hymes Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]; [email protected]

Fig. 23.1  Pyoderma gangrenosum. Painful neck ulceration with an elevated dusky undermined border and fibrinous base

© Springer Science+Business Media, LLC, part of Springer Nature 2019 A. Safdar (ed.), Principles and Practice of Transplant Infectious Diseases, https://doi.org/10.1007/978-1-4939-9034-4_23

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Fig. 23.2  Behcet’s disease. Oral ulcerations

skin lesions and oral aphthae can induce antibody production that cross-react with streptococcal species that are usually found in the mouth [7]. An acneiform papulopustular eruption may be seen on the face, neck, and trunk. The aphthous lesions begin as vesicles and/or pustules and tend to heal with scar formation. Tender, erythematous, recurrent nodules that resemble erythema nodosum are common on the extremities in women. Extragenital ulcerations, if present, are very specific for Behcet’s disease [8]. Various treatment regimens have demonstrated benefit including systemic corticosteroids, colchicine, azathioprine, dapsone, interferon-alfa, and infliximab. The disease can be confused with herpetic gingivostomatitis and syphilis. Acute neutrophilic febrile dermatosis (Sweet’s syndrome) is a distinct entity characterized by one or more edematous red, tender, spontaneously painful plaques predominantly on the upper body, accompanied by fever, peripheral leukocytosis, and a variety of constitutional symptoms (Fig. 23.3). It is thought to be a hypersensitivity reaction of unknown cause characterized by infiltration of neutrophils in the skin. It has been associated with various carcinomas and hematopoietic malignancies especially acute myelogenous leukemia (AML) [9]. It responds dramatically to systemic corticosteroids and may resolve with treatment of the underlying disease [9, 10]. Ulcers and bullae are more common in malignancy-­associated disease than in other forms. These lesions may be extensive and are generally hard to treat [11]. Sweet’s syndrome must be differentiated from erysipelas, cellulitis, arthropod bites, herpetic infections, and drug eruptions. Bowel bypass syndrome is a constellation of medical complications secondary to intestinal bypass surgery for the treatment of morbid obesity, consisting of fever, asymmetrical polyarthritis, tenosynovitis, sterile skin pustules, mucous membrane ulcerations, retinal vasculitis, and thrombophlebitis [12]. The syndrome is presumed to result from the deposition of circulating immune complexes containing bacterial antigens derived from overgrowth in the bypassed loop of the bowel [13]. Surgical excision of the blind loop or revision of the

Fig. 23.3  Sweet’s syndrome. Erythematous, edematous plaques on the dorsal hand and fingers in a patient with acute myelogenous leukemia

bowel bypass cures bowel bypass syndrome. The disease may resemble gonococcal sepsis, infectious panniculitis, pyoderma gangrenosum, Behcet’s syndrome, and Sweet’s syndrome.

 cute Generalized Exanthematous Pustulosis A (AGEP)  ifferential Diagnosis: Bacterial, Viral, or Fungal D Infections AGEP is a neutrophilic dermatosis characterized by acute-­ onset monoform, sterile, nonfollicular 1–2-mm pustules on a background of erythema secondary to drug administration, most commonly antibiotics. The lesions have a predilection for the face and intertriginous areas (Fig. 23.4). The eruption is accompanied by fever which can occur several days prior or the same day as the eruption. Widespread desquamation occurs after a few days. Neutrophilia and eosinophilia are commonly seen [14]. The precise mechanism of the disease is unknown. It is suggested that neutrophil-activating cytokines released by drug-specific T lymphocytes (IL-3, IL-8, and G-CSF) are potent triggers for blood neutrophilia and accumulation of neutrophils within the lesions [14]. It is characterized by fever which can occur several days prior to the eruption followed by the onset of classic lesions on the face or intertriginous areas. The withdrawal of the responsible drug is the mainstay of treatment in conjunction with topical corticosteroids [15].

Acneiform Hypersensitivity Drug Eruptions  ifferential Diagnosis: Bacterial and Fungal D Folliculitis Acneiform eruptions are characterized by pruritic inflammatory papules or pustules localized primarily on areas with a

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Fig. 23.4  Acute generalized exanthematous pustulosis. Affected individuals show large areas of erythroderma topped with small nonfollicular sterile pustules

399

Fig. 23.6  EGFR inhibitor-associated alopecia. Scalp inflammatory papules and scarring alopecia

treated with systemic corticosteroids. Isoniazid, as well as chemotherapeutic agents including cyclosporine, azathioprine, and sirolimus, may induce acneiform drug eruptions [16, 17]. Cutaneous adverse events associated with epidermal growth factor inhibitors (EGFR) include pustular skin eruptions usually on the scalp, neck, chest, and back along with paronychia, xerosis, and alopecia (Fig. 23.6). Although the exact mechanism of the development of the rash is not completely understood, the inhibitor therapy disrupts the EGFR function by inducing terminal differentiation and apoptosis in the stratum corneum and hair follicles. Patients are often managed symptomatically or by adjusting the dose of the targeted therapy [18]. It is important to promptly identify and treat the adverse events during therapy with EGFR inhibitors to avoid drug suspension. The infectious diseases that enter the differential diagnosis of acneiform drug eruptions are folliculitis, measles, rubeola, rubella, and syphilis.

Eosinophilic Folliculitis

Fig. 23.5  Acneiform drug eruption due to EGFR inhibitor erlotinib. Follicular pustules, located on the skin of the face and trunk in patient with metastatic lung cancer

large number of pilosebaceous units: face, neck, chest, and upper back, sparing the palmar or plantar surfaces (Fig. 23.5). In contrast to acne vulgaris, comedones are absent in acneiform eruptions. The eruption is common in cancer patients

 ifferential Diagnosis: Bacterial and Fungal D Folliculitis Eosinophilic folliculitis is an uncommon recurrent eosinophilic infiltration of hair follicles manifested by pruritic papules and pustules associated with soft tissue edema seen most commonly on the head, neck, and trunk mostly in immunosuppressed patients [19, 20] (Fig.  23.7). Eosinophilic folliculitis has been classified as an AIDS-defining illness [19]. Although the exact etiology is unknown, an autoimmune reaction against sebocytes or sebum component and an abnormal T-cell immune response to a follicular antigen, such as caused by Demodex species, may be responsible for the eruption [19]. Topical corticosteroids are the mainstay of treatment for eosinophilic folliculitis. Highly active antiretroviral therapy along with isotretinoin therapy is

400

Fig. 23.7  Eosinophilic folliculitis. Crops of sterile papules and pustules on the face

A. Ciurea and S. Hymes

Fig. 23.8  Transient acantholytic dermatosis or Grover’s disease. This is an acquired condition that presents with pruritic vesicles and erosions on the upper trunk, most often in men

beneficial for eosinophilic folliculitis in the setting of HIV disease [21]. Clinically, it resembles bacterial folliculitis and candidiasis.

Grover’s Disease  ifferential Diagnosis: Bacterial and Fungal D Folliculitis and Allergic Drug Eruptions Also known as transient acantholytic dermatosis, this condition is benign, self-limited, exacerbated by heat and sweating, characterized by a sparse eruption of inflammatory papules, and fragile vesicles that erode. It is limited to the chest and upper abdomen, and it can be confused with bacterial folliculitis, herpes simplex and zoster infections, scabies, and syphilis (Fig. 23.8). Viral and bacterial pathogens have been proposed, but no causative role has been established. Potent topical corticosteroids are effective in diminishing inflammation and in controlling pruritus associated with transient acantholytic dermatosis.

Miliaria Rubra  ifferential Diagnosis: Bacterial and Fungal D Folliculitis Miliaria rubra is a common anhidrotic disorder in which an obstruction of the sweat duct occurs in the deeper level of the epidermis characterized by minute erythematous macules with a punctate vesicle usually centrally located. The lesions can be seen to be extrafollicular, in contrast to the pustules of folliculitis (Fig.  23.9). It is the only type of miliaria in which the symptom of pruritus is experienced [22]. It occurs primarily at sites of occlusion such as the back of febrile,

Fig. 23.9  Miliaria rubra. Multiple erythematous pinpoint macules and papules, especially prominent on the occluded surface of the back

ill patients. Resident bacteria, such as Staphylococcus epidermidis and Staphylococcus aureus, may play a role in the pathogenesis of miliaria [23].

Neutrophilic Eccrine Hidradenitis  ifferential Diagnosis: Cellulitis D Also known as toxic erythema of chemotherapy, neutrophilic eccrine hidradenitis is a skin condition observed in the setting of AML treated with cytarabine and has been reported in persons with various neoplastic and non-neoplastic conditions and otherwise healthy individuals [24]. It is characterized by solitary or multiple, red and purpuric, macules,

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Fig. 23.10  Neutrophilic eccrine hidradenitis. Facial erythematous, indurated plaques

papules, nodules, or plaques most frequently located on the trunk or extremities (Fig. 23.10). The plaques are often tender. Neutrophilic eccrine hidradenitis can simulate orbital and facial cellulitis [24, 25]. Anthracyclines, antimetabolites, taxanes, vinca alkaloids, mitotic inhibitors, and granulocyte colony-stimulating factors may induce this disorder [26].

Section 2: Papulosquamous Lesions

Fig. 23.11  Stasis dermatitis. Post-inflammatory hyperpigmentation over the medial malleolus on the background of varicose veins

Dermatitis Dermatitis also known as eczema reflects an inflammatory skin reaction due to exposure to irritants, drugs, and other unknown triggers. It often presents as scaly erythematous plaques and patches, not uncommonly secondarily infected. 90% will be culture positive for Staphylococcus aureus [27].

 ifferential Diagnosis: Superficial Fungal D Infection and Cellulitis Stasis dermatitis presents as erythema and light-brown pigmentation on the lower extremities, especially above malleolus, associated with eczematous dermatitis (Fig.  23.11). It is a cutaneous marker for venous insufficiency and often mistaken for cellulitis. When chronic venous insufficiency is present, patients may present with marked woody induration in a stocking distribution associated with dyspigmentation, termed “lipodermatosclerosis.” Pityriasis alba is a form of dermatitis frequently atopic in origin, characterized by slightly scaly hypopigmented patches on the cheeks, upper arms, and trunk in children (Fig.  23.12). Potassium hydroxide examination of the fine white scale can rule out superficial cutaneous dermatophyte infection.

Drug eruptions mimic various dermatoses and the morphology includes exanthem (morbilliform), papulosquamous, urticaria, vasculitis, and erythema nodosum. It should be suspected in any patient taking medication who developed a symmetric cutaneous eruption (Fig.  23.13). Chemotherapeutic agents such as busulfan and gentifinib are common causes for intertriginous drug eruption which can be confused with dermatophyte or yeast infection [28, 29]. Acute radiation dermatitis commonly occurs following local radiation therapy for various malignancies, with more than 90% of the patients experiencing erythema and more than 30% experiencing moist desquamation [30] (Fig. 23.14). Intense inflammatory reaction may result in a breakdown of the skin’s barrier function and accompanying bacterial colonization, with organisms like Staphylococcus aureus [31, 32].

Psoriasis  ifferential Diagnosis: Superficial Fungal D Infection Psoriasis is a complex multisystem inflammatory disorder of unknown etiology showing wide variation in severity and

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Fig. 23.12 Pityriasis alba. Circumscribed scaly hypopigmented lesions on the face Fig. 23.14  Acute radiation dermatitis. Extensive erythema and crusting with geographic borders defined by the radiation field

ular apparatus, is considered a disturbance of keratinization with predilection for the ears, trunk, neck, and extremities. Clinical features include discrete follicular-based reddish papules on the hands dorsum and diffuse palmar exfoliation (Fig. 23.16). Confluent scaly, salmon-colored plaques may appear on the trunk within islands of normal skin. A skin biopsy is mandatory to distinguish this from psoriasis and fungal infection and a search for occult malignancy should be considered if the presentation is atypical or in older patients.

Fig. 23.13  Drug eruption. Morbilliform macules and papules on the abdomen resulting from cefepime

distribution of skin lesions. The most common skin manifestations are erythematous macules, papules, and plaques with thick silvery scale that follow an irregular chronic course marked by remissions and exacerbations of unpredictable onset and duration (Fig. 23.15). Although no region is exempt from involvement, psoriasis has a predilection for the scalp, elbows, and knees [33]. Psoriasis plaques can be mistaken for cutaneous tinea corporis or secondary syphilis.

Pityriasis Rubra Pilaris  ifferential Diagnosis: Superficial Fungal D Infection Pityriasis rubra pilaris, a rare scaly, erythematous skin condition of unknown etiology with a preference for the follic-

Pityriasis Rosea  ifferential Diagnosis: Superficial Fungal D Infection and Syphilis This is an acute self-limited, clinically distinctive exanthematous eruption of unknown etiology more commonly seen in adolescents and young adults. A mild prodrome manifested by malaise, fatigue, headache, and sore throat precedes the skin eruption with a few days. The earliest change is the “herald patch,” a solitary, oval, or annular plaque on the trunk, arms, and thighs, followed by eruptive erythematous, flat plaques measuring 0.5–1.5  cm in diameter (Fig. 23.17). The clinical features and course of pityriasis rosea strongly suggest a viral etiology; however, no single virus has been proven to cause the disease. The widespread lesions of secondary syphilis and tinea versicolor may resemble pityriasis rosea [34]. Tinea corporis can be confused with the herald patch seen earlier during the course of the disease.

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Fig. 23.17  Pityriasis rosea. Truncal involvement with larger plaques and predominantly round patches with peripheral scale

Fig. 23.15  Psoriasis vulgaris. Typical plaques of psoriasis with thick, white scaly overlying erythema

Fig. 23.18 Cutaneous T-cell lymphoma. Hyperpigmented scaly patches with minimal scaling

Fig. 23.16 Pityriasis rubra pilaris. Symmetric, diffuse, scaly erythema

Cutaneous T-Cell Lymphoma  ifferential Diagnosis: Superficial Fungal D Infection Cutaneous T-cell lymphoma, a class of non-Hodgkin lymphoma, is characterized by infiltration of the skin by clonal

malignant T-cells and has many clinical variants, but the classic subtype is characterized by sharply demarcated plaques, uniform in color, ranging from an erythematous to a violaceous hue (Fig. 23.18). The clinical features, histomorphology, and cytomorphology of the lesions are diagnostic clues, and demonstration of a dominant T-cell clone in skin biopsy specimens constitutes an additional diagnostic test to distinguish CTCL from inflammatory dermatoses. The early stage is typically nonspecific and is often misdiagnosed as eczema, psoriasis and superficial fungal infection.

Section 3: Purpuric and Petechial Lesions Purpura is the multifocal extravasation of blood into the skin or mucous membranes manifested by distinctive red macules a few millimeters in size. Petechiae are superficial, pin-

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Fig. 23.19  Leukocytoclastic vasculitis. Multiple purpuric papules in a patient with drug-induced hypersensitivity vasculitis

head-­sized hemorrhagic macules, bright red at first, seen in the dependent areas. Petechiae most often imply a disorder of platelets.

Leukocytoclastic Vasculitis  ifferential Diagnosis: Bacterial and Fungal D Infection Leukocytoclastic vasculitis (LCV) represents a hypersensitivity reaction secondary to immune complex deposition, other autoantibodies, inflammatory mediators, and local factors that involve the endothelial cells. Palpable purpura is the clinical prototype of LCV in which the vascular insult is at the level of arterioles and postcapillary venules. Lesions appear in crops, ranging from 1 to 2 mm in size, and have a predilection for dependent parts. Palpable purpura is generally asymptomatic, but in severe cases (with erosions, bullae, and hemorrhagic vesicles) patients may experience pruritus, edema, and burning [35] (Fig. 23.19). It can be mistaken for systemic bacterial infections including candidiasis and meningococcemia. Skin biopsy reveals the presence of vascular and perivascular infiltration of polymorphonuclear leukocytes with formation of nuclear dust (leukocytoclasis), extravasation of erythrocytes, and fibrinoid necrosis of the vessel walls.

Superficial Thrombophlebitis  ifferential Diagnosis: Cellulitis D An inflammatory reaction in which clotting appears on the wall of an inflamed vein in patients with idiopathic venous stasis, prolonged bed rest, local injury to endothelium by trauma, and superficial thrombophlebitis presents with erythema, edema,

Fig. 23.20  Superficial thrombophlebitis. Erythema and edema along the leg vein

and tenderness in the affected limb (Fig. 23.20). This needs to be distinguished from cellulitis which is a nonnecrotizing inflammation of the skin and subcutaneous tissues.

Calciphylaxis  ifferential Diagnosis: Cellulitis, Ecthyma D Gangrenosum, and Bacterial and Deep Fungal Infections This is a highly morbid syndrome characterized by painful ischemic tissue necrosis primarily on fingers, legs, and thighs surrounded by livedo reticularis in patients with chronic renal insufficiency and hyperparathyroidism [36]. Lesions of calciphylaxis typically develop suddenly and progress rapidly. The clinical manifestations of calciphylaxis are similar to those of a significant number of other disorders, including among others cellulitis, necrotizing fasciitis, ecthyma gangrenosum, vibrio vulnificus infection, cholesterol embolization, warfarin necrosis, cryoglobulinemia, and vasculitis [37, 38] (Fig. 23.21).

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cancer patients. It must be distinguished from the eruption of Rocky Mountain spotted fever (RMSF), a tick-borne disease caused by the organism Rickettsia rickettsii. The hallmark of RMSF is a petechial eruption beginning on the palms of the hands and soles of the feet [39].

Disseminated Intravascular Coagulation

Fig. 23.21  Calciphylaxis. Deep skin necrosis and non-healing ulcer

 ifferential Diagnosis: Bacterial and Fungal D Sepsis Disseminated intravascular coagulation may produce a clinical picture varying from a severe and rapidly fatal disorder (purpura fulminans) to a relatively minor disorder. Varying combinations of bleeding, thromboembolism, and hemolytic anemia are superimposed on the clinical picture caused by primary disorders which include, among others, extensive tissue damage, severe infections, and malignant diseases. The normal inhibitory mechanisms of clotting are overcome so that there is intravenous coagulation, followed by consumption and depletion of platelets and plasma clotting factors. In the most severe cases onset is sudden with fever and a very extensive, symmetrical purpura of the extremities but also on the ears, nose, and lips (Fig. 23.23). Lesser changes include petechiae, purpuric papules, hemorrhagic bullae, and acral cyanosis. Treatment includes that appropriate for the underlying condition, treatment of shock, and replacement therapy as indicated.

Section 4: Lesions of the Adipose Tissue Fig. 23.22  Petechiae. Pinpoint, monoform red macules on the lower legs

Petechiae  ifferential Diagnosis: Rickettsial, Bacterial, D and Fungal Infection Petechiae are small purpuric lesions up to 2  mm in size often occurring in crops due to extravasation of red blood cells into the skin. The purpura is not palpable, in contrast to palpable and sometimes tender purpura observed in patients with vasculitis. It tends to form in areas of increased venous pressure, such as the legs (Fig. 23.22). The etiology is multifactorial and includes among others thrombocytopenia, defective platelet function, increased intravascular venous pressure, vitamin C deficiency, and localized trauma or pressure. Purpura is often seen at intravenous injection sites in

 ifferential Diagnosis: Bacterial, Deep Fungal, D and Mycobacterial Infections and Cellulitis Panniculitis is an inflammation occurring within the adipose tissue. It can occur in the septae, lobules, or both. It is often associated with a variety of systemic diseases and clinical syndromes and it often presents as red-to-violaceous nodules and plaques that have a predilection for lower extremities.

Nodular Vasculitis Nodular vasculitis also called erythema induratum is a vasculitis of the muscular arteries of the deep dermis and fat that result in secondary lobular panniculitis. It occurs in middle-­ aged women who develop painful, reddish-blue, variably tender nodules and plaques over the lower extremities, especially the calves (Fig. 23.24). A severe small-vessel vasculitis is seen on histologic examination. Nodular panniculitis may be idiopathic but is most commonly due to infections such as tuberculosis and occasionally histoplasmosis,

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Fig. 23.23  Disseminated intravascular coagulation. Extensive skin necrosis with hemorrhagic bullae

Fig. 23.25  Pancreatic panniculitis. Faint erythematous tender plaques on the lower extremities

Cold Panniculitis Cold panniculitis is an acute, nodular eruption usually limited to areas exposed to the cold. Cold panniculitis results from a cold injury to the adipose tissue. It is more common in women. The eruptive phase usually begins 48  h (range, 6–72  h) after a cold injury to exposed or poorly protected areas. The lesions should be distinguished from cellulitis and deep fungal or mycobacterial infections. Fig. 23.24  Nodular vasculitis. Tender blue-reddish nodules on the lower legs

HIV, and hepatitis C [40–42]. Painful, indurated red plaques located on the extremities resembling erythema induratum have been reported in patients with chronic myelogenic leukemia undergoing treatment with imatinib [43] and dasatinib [44]. The differential diagnosis of nodular vasculitis includes erythema nodosum, granulomatous vasculitis, and miscellaneous forms of panniculitis.

Pancreatic Panniculitis Pancreatic panniculitis, acute pancreatitis, and pancreatic tumors may cause fat necrosis of the pancreas and of the subcutaneous tissue. The clinical picture consists of raised, erythematous nodules, 1–3 cm in size, located on the upper and lower extremities (Fig. 23.25). The pathogenic mechanisms underlying the various features of pancreatic panniculitis are unclear. The histopathology of pancreatic panniculitis is pathognomonic, characterized by ghost adipocytes that are necrotic,

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Fig. 23.26  Erythema nodosum. Tender red oval nodules on the extensor aspect of the legs

anucleate and contain basophilic material within the cytoplasm indicating dystrophic calcification from the saponification of fat [45]. The exact mechanism is unknown, but it is believed that lipase plays a strong pathogenic role for subcutaneous fat necrosis. The Schmid’s triad of panniculitis, polyarthritis, and eosinophilia portends very poor prognosis in a patient with pancreatic carcinoma.

 eptal Panniculitis (Erythema Nodosum) S Septal panniculitis (erythema nodosum) is the most common form of inflammatory panniculitis manifested by erythematous, tender nodules on anterior shins, thighs, and lateral aspects of the lower legs and occasionally on the face, accompanied by fever, chills, arthralgias, and leukocytosis (Fig. 23.26). It results from an immunologic reaction triggered by drugs; benign and malignant systemic illness; bacterial, fungal, and viral infections; pregnancy; and medications including oral contraceptives. Circulating immune complexes have not been found in idiopathic and uncomplicated cases but demonstrated in patients with inflammatory bowel disease [46]. It resolves without scarring in 4–6 weeks.  clerosing Panniculitis (Lipodermatosclerosis) S Sclerosing panniculitis (lipodermatosclerosis) is a disease process that clinically appears as painful indurated erythematous hyperpigmented plaques and nodules on the lower extremities in middle-aged women. The underlying fibrosis and lobular atrophy give the impression of an inverted champagne bottle with a hard, wood-like appearance which becomes circumferential in well-developed lesions (Fig.  23.27). Occasionally there is overlying ulceration or crusting. Lipodermatosclerosis (LDS) is believed to

Fig. 23.27  Lipodermatosclerosis. Chronic inflammation and fibrosis of the skin surrounding the entire lower legs

be associated with chronic venous insufficiency. Abnormal fibrinolysis, an excessive proteolytic activity by matrix metalloproteinase, and the upregulation of an inflammatory response by interleukin-8 are thought to be the causes for this condition [47, 48].

Traumatic Panniculitis Traumatic panniculitis represents a localized reaction of the subcutaneous tissue following minor trauma. It is most frequently seen in obese women. The lesions consist of indurated, inflamed nodules that undergo necrosis. When localized to the breast, they may clinically simulate a carcinoma or infectious mastitis. Traumatic panniculitis is usually a self-limiting disorder and requires only symptomatic treatment.

Section 5: Vesiculobullous Lesions A vesicle is a fluid-filled blister less than 0.5  cm in its greatest dimension, while bullae is greater than 0.5  cm. Vesiculobullous lesions may be solitary, grouped, or annular and either localized or widespread in distribution. The etiology of these lesions varies, and valuable clues may be found in the patient’s history, clinical presentation, and skin biopsy. From an infectious disease specialist’s viewpoint, blistering lesions are often caused by herpetic eruptions or infectious pathogens which produce skin necrosis. However, a variety of non-infectious vesiculobullous lesions may occur in the transplant setting and are reviewed in this section.

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Fig. 23.28  Allergic contact dermatitis. Characterized by well-defined plaques of vesiculopapules overlying erythema and edema. Oozing and secondary infection are common

Acute Dermatitis  ifferential Diagnosis: Viral Infections D and Impetigo The vesiculobullous eruption associated with acute dermatitis is caused by inter- and intracellular edema in the epidermis, also called spongiosis. The patient may be aware of a preceding irritant or allergen applied to the skin, including surgical preparations, topical antibiotics, or tape. Allergic contact dermatitis may be linear or geometric, corresponding to the application of the precipitating agent (Fig. 23.28). As the blisters rupture, a superficial crust forms, which may be mistaken for impetigo. It is not unusual for the dermatitis to become secondarily infected, especially in the immunosuppressed transplant patient. On occasion, non-infectious vesicular lesions may appear distant to the site of the original dermatitis, a phenomenon known as autosensitization dermatitis. This should be distinguished from a disseminated herpetic process.

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Fig. 23.29  Mechanical blister. Flat bullae on the toe dorsum secondary to trauma

Mechanical Blisters  ifferential Diagnosis: Cellulitis and Ecthyma D These painful blisters occur in areas of high friction or pressure, which causes epidermal necrosis. The surrounding erythematous rim may mimic cellulitis. Mechanical blisters are also precipitated by burns, extravasations of toxic substances, or vesicants. Hemorrhagic bullae may occur at sites of injections in patients with thrombocytopenia or capillary fragility (Fig. 23.29).

Coma Blister

 ifferential Diagnosis: Cellulitis and Ecthyma D Skin blisters at sites of pressure and associated with underlying sweat gland necrosis were reported in comatose patients with carbon monoxide intoxication as early as 1812 [50]. Also called barbiturate or neurologic blisters, these lesions are at times associated with surrounding erythema that may look like cellulitis. While barbiturates Diabetic Blisters are the most frequently reported causative agent [51, 52], similar findings have been reported with other medicaDifferential Diagnosis: Viral Infection tions including tricyclic antidepressants [53] and benzoand Cellulitis diazepines [54]. Coma blisters have been associated with Also known as bullosis diabeticorum [49], this condition is central nervous system disorders [55], hypoglycemia [56], characterized by the spontaneous appearance of intraepi- and diabetic ketoacidosis [57]. The ­etiology is multifactodermal or subepidermal, clear, tense bullae on the non-­ rial, but in some cases, a direct toxic drug effect has been erythematous skin of diabetic patients. These blisters are implicated, perhaps via drug excretion through the eccrine most often found on the lower extremities and are minimally glands. The bullae may appear as early as 1 h after acute symptomatic. The pathogenesis may be related to diabetic intoxication and usually resolve in 2–4  weeks. They may angiopathy or trauma, and this condition should be distin- be clear or hemorrhagic and should be distinguished from guished from infectious cellulitis. ecthyma or cellulitis.

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Miliaria Crystallina  ifferential Diagnosis: Herpes Infection D Miliaria crystallina, also known as sudamina, occurs in the setting of profuse sweating and epidermal occlusion. It is characterized by 1–2-mm asymptomatic vesicles on a non-­inflammatory base, which are easily “wiped away” with pressure. As opposed to grouped herpetic vesicles on a more erythematous base, miliaria crystallina appears on occluded skin, with no underlying erythema (Fig. 23.30).

Edema and Lymphedema Blisters  ifferential Diagnosis: Cellulitis D Large dependent bullae may develop in the setting of peripheral edema, anasarca, and lymphedema, especially if the onset of swelling is acute. Although these bullae are usually found on normal-appearing skin, underlying stasis changes may make it difficult to distinguish from bullous cellulitis. Initially, the blisters are tense and clear but may become hemorrhagic or superinfected. Treatment is directed at minimizing the underlying edema.

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ing drug exposure but within 30 min–24 h after re-challenge. The eruption is characterized by erythema, sometimes the formation of bullae, and often characteristic residual “slate-­ grey” pigmentation as the lesion resolves. Findings suggest that fixed drug eruptions are a form of classic delayed-type hypersensitivity mediated by CD8+ cells [58], although mast cells may play a role [59]. When located on the genitalia the blisters may look like acute herpes simplex infection and, on other sites, cellulitis. Widespread bullous drug reactions have varying etiologies and pathologic features. Certain medications may produce immune-mediated blistering, characterized by the deposition of IgA at the dermal-­epidermal junction. This is of special interest to infectious disease specialists as it has been reported with antibiotics like trimethoprim-sulfamethoxazole, penicillin, metronidazole, and rifampicin [60].

Bullous Graft Versus Host Disease

 ifferential Diagnosis: Viral Infection D and Cellulitis Allogeneic hematopoietic stem cell transplantation is widely used for the treatment of hematologic malignancies, bone marrow failure syndromes, and immunodeficiency. The skin is commonly affected in patients who Bullous Drug Eruptions develop graft-versus-host disease (GVHD). Grade 4 acute GVHD of the skin is characterized by a generalized exfoDifferential Diagnosis: Viral Infections, Ecthyma, liative dermatitis, ulcerative dermatitis, and bullae [61] and Cellulitis that may be mistaken for disseminated viral infection Bullous drug reactions may be localized or widespread. (Fig. 23.31). In these cases, the damage at the epidermalWhen localized and recurrent at the same site after drug re-­ dermal junction is severe enough to allow the dermis to challenge, they are referred to as fixed drug eruptions. Fixed separate from the epidermis. Bullae may also appear in drug eruptions initially appear within 2  weeks of the incit- the setting of scleroderma-like GVHD changes [62, 63].

Fig. 23.30  Miliaria crystallina. Clear, thin-walled vesicles occurring in crops on otherwise normal-appearing skin

Fig. 23.31  Bullous graft-versus-host disease. Tense bulla and vesicles on the ear in patient with diffuse erythema of the head and neck

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Although the pathogenesis is unknown, these cases show significant fibrosis and dermal edema [64, 65].

 orphyria Cutanea Tarda (PCT) P and Pseudoporphyria Cutanea Tarda  ifferential Diagnosis: Viral and Bacterial D Infections Porphyria cutanea tarda (PCT) is a group of familial and acquired disorders characterized by deficiency in the activity of uroporphyrinogen decarboxylase, an enzyme key in heme synthesis. In the transplant setting, this may be precipitated by exposure to environmental agent such as excess iron [66], coexisting conditions that affect the liver, and infection agents including hepatitis C [67] and HIV [68]. Patients exhibit skin fragility and blistering, especially in sun-exposed areas, as well as hypertrichosis, scleroderma-like changes, milia (small white cysts), and dystrophic calcification (Fig. 23.32). Pseudoporphyria mimics the findings of PCT without demonstrable porphyrin abnormalities. It has been reported in the setting of chronic renal failure and dialysis [69], as well with medications like beta-lactam antibiotics [70], ciprofloxacin [71], voriconazole [72], and tetracycline [73].

Autoimmune Bullous Diseases  ifferential Diagnosis: Viral Infection, Cellulitis, D and Scabies This broad category of diseases is characterized as immune-­mediated blistering of the skin. Bullous pemphigoid presents with tense skin blisters, urticarial (hive-like)

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lesions, and variable mucosal involvement. It is characterized by autoantibodies located in the hemidesmosomal complex of the basement membrane zone. It may occur de novo, with other autoimmune diseases, or occasionally with malignancies. Some antibiotics implicated in pathogenesis include amoxicillin [74], cephalexin [75], and ciprofloxacin [76]. The clinical presentation of tense blisters associated with urticaria may be mistaken for cellulitis. Pemphigus presents on the skin and mucous membranes with intraepidermal flaccid bullae. It is divided into three forms: vulgaris; foliaceus; and paraneoplastic. Patients with pemphigus vulgaris develop painful mucosal erosions and skin lesions, which may resemble a herpetic process. Patients with pemphigus foliaceus develop extensive crusted erosions, easily confused with cutaneous infection (Fig.  23.33). Paraneoplastic pemphigus is associated with underlying neoplasms, and characterized by severe stomatitis, often mistaken for herpetic stomatitis. The lesions on the skin are polymorphous and may resemble lichen planus or erythema multiforme. (These patients may also develop lung involvement characterized by bronchiolitis obliterans [77]). Antibiotics are implicated in the pathogenesis of pemphigus vulgaris, including ampicillin, penicillin, cefadroxil, and rifampicin [60, 78]. In these cases, the eruption usually starts a few weeks after starting the medication. The diagnosis of pemphigus is made by performing a skin biopsy, which demonstrates an intraepidermal vesicle with acantholysis ­(separation between epidermal cells). Direct immunofluorescence of peri-lesional skin demonstrates IgG and/or C3 binding to the intercellular cement or keratinocyte cell surface [79]. Dermatitis herpetiformis, a cutaneous manifestation of

Fig. 23.32  Porphyria cutanea tarda. Vesicles and bullae on light-­ exposed cutaneous surfaces, especially the dorsal aspects of the Fig. 23.33  Pemphigus vulgaris. Painful scalp erosions with underlyhands ing erythema

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Fig. 23.35  Urticaria. Transient, well-circumscribed erythematous dermal plaques on the trunk Fig. 23.34  Dermatitis herpetiformis. Grouped, symmetric, and pruritic papules on the elbow

gluten-­sensitive enteropathy, is characterized by pruritic, tiny vesicles easily reminiscent of scabies or herpes infections. These are most commonly found on the elbows, back buttocks, and knees (Fig. 23.34). The biopsy shows neutrophils in the dermal papillae and granular deposits of IgA.  The eruption may be worsened by ingestion or application of iodide [80].

Bullous Insect Bite Reaction  ifferential Diagnosis: Ecthyma, Viral Infection, D and Cellulitis Insect bite reactions may produce varying degrees of erythema and are less commonly vesicles, bullae, and necrosis. Exaggerated bite reactions have been reported in the setting of chronic lymphocytic leukemia as well as other hematoproliferative disorders and human immunodeficiency virus infections [81, 82]. Many patients have no recollection of the bite.

Section 6: Erythematous Lesions Injury, infection, vascular reactivity, and inflammation may cause erythema of the skin. Most of the conditions discussed in this section produce blanchable erythema, that is, resolution of the erythema with pressure. So-called reactive erythema is a cutaneous response to an underlying systemic process, which may be infectious, malignant, or drug related. The primary lesions are red plaques that may be annular, transient, or fixed.

Fig. 23.36 Tinea corporis. An expanding, erythematous annular plaque

Urticaria  ifferential Diagnosis: Cellulitis and Superficial D Fungal Infections Urticaria, commonly referred to as hives or wheals, are well-­ demarcated, smooth, dermal plaques that may become confluent and demonstrate a variable degree of pruritus. When associated with significant edema and warmth, they are mistaken for cellulitis (Fig. 23.35) and when annular in configuration, for tinea corporis (Fig.  23.36). Because they result from transient dermal edema, they tend to change in size and shape and are rarely present in the same spot for more than 48 h. When persistent, a biopsy may demonstrate urticarial vasculitis, characterized by small vessel destruction. Angioedema presents with deep and painful swelling, without urticaria. Transplant patients may be at increased risk

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of angiotensin-converting enzyme (ACE)-associated angioedema because of the effects of immunosuppressants on the activity of circulating dipeptidyl peptidase IV (DPPIV) [83].

 rythema Multiforme (EM)/Stevens-Johnson E Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN)  ifferential Diagnosis: Disseminated Viral, D Bacterial, or Fungal Infections At the onset, erythema multiforme presents as erythematous macules and plaques on the extensor surfaces of the limbs and on the palms and soles. Other infectious etiologies for palm and sole lesions including rickettsia, spirochetes, or viruses should be considered. The classic target or iris lesion is characterized by a dusky center, red border, and surrounding pallor (Fig. 23.37). If enough epidermal apoptosis is present, the center may appear bullous, hemorrhagic, or necrotic, suggestive of ecthyma or embolic infection. SJS may be complicated by significant mucous membrane involvement of the lips, buccal mucosa palate, conjunctivae, urethra, and vagina. TEN is a life-threatening condition characterized by detachment of the epidermis from the dermis (Fig. 23.38). The differential diagnosis includes staphylococcal scalded skin syndrome (SSSS). However, SSSS causes a more superficial subcorneal skin split that can readily be distinguished by skin biopsy. EM, SJS, and TEN are associated with many different etiologies. Infectious agents are important precipitating factors in children and young adults [84], whereas drug reactions and malignancy are more important in adults [85, 86]. Herpes simplex, mycoplasma pneumonia, Coxasackie B-5, influenza type A, and echo viruses have all been implicated in pathogenesis [87].

Fig. 23.37  Erythema multiforme. Round lesions in which concentric rings with color variation are present

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Gyrate Erythema  ifferential Diagnosis: Superficial Fungal, D Bacterial, or Rickettsial Infections A gyrate erythema is characterized by polycyclic erythematous plaques. In the case of erythema annulare centrifugum, the lesions slowly expand, disappear over weeks, and are replaced by new annular lesions (Fig.  23.39). Some cases are associated with dermatophyte infections, but the lesions themselves do not contain fungus. This condition is rarely associated with internal malignancy, and the clinical presentation may mimic secondary syphilis, dermatophytosis, Hansen’s disease or erythema migrans, and the gyrate erythema associated with Lyme disease. Necrolytic migratory erythema, associated with glucagon-­ secreting tumors of the pancreas, is a gyrate erythema that

Fig. 23.38  Toxic epidermal necrolysis. Extensive erosions and sloughing of skin resembling wrinkled, wet tissue paper

Fig. 23.39  Gyrate erythema. Slowly expanding annular lesions and palpable scaly erythematous borders

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Fig. 23.40  Granuloma annulare. Annular, dusky-red, nonscaly plaques on the trunk

Fig. 23.41  Squamous cell carcinoma. Large, sun-induced, keratotic, non-ulcerated nodule on the arm

occurs in periorificial, flexural, and acral areas. The eruption may resemble chronic mucocutaneous candidiasis, severe seborrheic dermatitis, or acrodermatitis enteropathica associated with zinc deficiency. It has also been associated with hepatitis C [88].

Section 8: Hair and Scalp Lesions

Granuloma Annulare  ifferential Diagnosis: Superficial Fungal D Infection This granulomatous process presents with annular and serpiginous plaques with no significant scale (Fig.  23.40). In some studies, GA has been associated with diabetes mellitus [89], but many cases are idiopathic. The lesions may be confused with a superficial fungal infection.

 ection 7: Ulcerative Lesions and Skin S Tumors  ifferential Diagnosis: Bacterial, Fungal, D Mycobacterial, or Parasitic Infections Organ transplantation markedly increases the risk of developing non-melanoma skin cancers, the most common of which are squamous cell carcinoma followed by basal cell carcinoma [90] (Fig. 23.41). Compared to the biologic behavior in non-immunosuppressed individuals, the squamous cell carcinomas tend to be more aggressive, with a higher risk of invasion of surrounding structures as well as metastasis [91, 92]. Kaposi’s sarcoma and Merkel cell carcinomas occur with increased frequency [90]. In organ transplant patients with chronic ulcerations, it may be prudent to biopsy for bacterial, fungal, and acid-fast culture as well as for histopathology.

Transplant patients may present with inflammatory lesions of the scalp and alopecia as a result of bacterial and fungal infections. This section will review some of the non-­ infectious etiologies of hair and scalp lesions.

Tumors  ifferential Diagnosis: Bacterial and Deep Fungal D Infections The incidence of squamous cell and basal cell carcinomas of the skin increase with the duration of immunosuppressive therapy in transplant recipients and affect at least 50% of Caucasian transplant patients [93]. Approximately 80% of tumors develop on the head [94] with associated ulceration, crusting, and erosions. Early on, these crusted lesions may be mistaken for bacterial or fungal infections, delaying the diagnosis. Some of these tumors resemble warts and, in fact, human papillomaviruses may be cocarcinogenic [95]. Patients post-organ transplantation may also be at a higher risk for melanoma [96], Kaposi’s sarcoma [97], and Merkel cell carcinoma [98].

Plaques and Pustules  ifferential Diagnosis: Bacterial and Fungal D Infections While erythematous plaques and pustules on the scalp may be caused by dermatophyte and bacterial infections, this is also a common presentation of scalp psoriasis. The characteristic well-demarcated, scaly plaques may be studded with

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Fig. 23.42  Dissecting cellulitis of the scalp. Painful cutaneous nodules and patchy alopecia

sterile pustules; the latter may be precipitated by systemic corticosteroid withdrawal or taper. Dissecting cellulitis of the scalp, also called perifolliculitis capitis abscedens et suffodiens, produces boggy and fluctuant scalp nodules with interconnecting sinus tracts and sterile, purulent discharge (Fig. 23.42). This disorder often responds better to retinoids than antibiotics [99]. Other common causes of sterile pustules and inflammation on the scalp include acne keloidalis or inflamed cysts.

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A. Ciurea and S. Hymes 6. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol. 1996;34(3):395–409; quiz 410–2. 7. Emmi L, Brugnolo F, Salvati G, et al. Immunopathological aspects of Behcet’s disease. Clin Exp Rheumatol. 1995;13(6):687–91. 8. Alpsoy E, Zouboulis CC, Ehrlich GE.  Mucocutaneous lesions of Behcet’s disease. Yonsei Med J. 2007;48(4):573–85. 9. Cohen PR, Kurzrock R.  Sweet’s syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42(10):761–78. 10. von den Driesch P.  Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol. 1994;31(4):535–56. 11. Cohen PR, Kurzrock R. Sweet’s syndrome: a neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol. 2000;18(3):265–82. 12. Kennedy C.  The spectrum of inflammatory skin disease fol lowing jejuno-ileal bypass for morbid obesity. Br J Dernatol. 1981;105(4):425–35. 13. Ely P. The bowel bypass syndrome: a response to bacterial peptidoglycans. J Am Acad Dermatol. 1980;2(6):473–87. 14. Revuz J, Valeyrie-Allanore L.  Drug reactions. In: Bolognia J, Lorizzo JL, Rapini RP, Callen JP, Horn TD, Mancini AJ, et al., editors. Dermatology. Mosby: Elsevier; 2008. p. 301–20. 15. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127(9):1333–8. 16. Ramdial PK, Naidoo DK.  Drug-induced cutaneous pathology. J Clin Pathol. 2009;62(60):493–504. 17. James WD.  Clinical practice. Acne. N Engl J Med. 2005;352(14):1463–72. 18. Wnorowski AM, de Souza A, Chachoua A, Cohen DE. The management of EGFR inhibitor adverse events: a case series and treatment paradigm. Int J Dermatol. 2012;51(2):223–32. 19. Nervi SJ, Schwartz RA, Dmochowski M.  Eosinophilic pus tular folliculitis: a 40 year retrospect. J Am Acad Dermatol. 2006;55(2):285–9. 20. Fraser SJ, Benton EC, Roddie PH, Krajewski AS, Goodlad JR.  Eosinophilic folliculitis: an important differential diagnosis after allogeneic bone-marrow transplant. Clin Exp Dermatol. 2009;34(3):369–71. 21. Fukamachi S, Kabashima K, Sugita K, Kobayashi M, Tokura Y. Therapeutic effectiveness of various treatments for eosinophilic pustular folliculitis. Acta Derm Venereol. 2009;89(2):155–9. 22. Wenzel FG, Horn TD.  Nonneoplastic disorders of the eccrine glands. J Am Acad Dermatol. 1998;38(1):1–17. 23. Mowad CM, McGinley KJ, Foglia A, Leyden JJ. The role of extracellular polysaccharide substance produced by Staphylococcus epidermidis in miliaria. J Am Acad Dermatol. 1995;33(5. Pt 1):729–33. 24. Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59(3):524–9. 25. Cohen PR. Neutrophilic dermatoses occurring in oncology patients. Int J Dermatol. 2007;46(1):106–11. 26. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol. 2002;14(2):212–6. 27. Kim BS, Kim WJ, Ko HC, Kim MB, Kim DW, Kim JM. Features of Staphylococcus aureus colonization in patients with nummular eczema. Br J Dermatol. 2013;168(3):658–60. 28. Lin SS, Tsai TH, Yang HH. Rare cutaneous side-effect of gefitinib masquerading as superficial dermatophytosis. Clin Exp Dermatol. 2009;34(4):528–30. 29. Wolf R, Oumeish OY, Parish LC.  Intertriginous eruption. Clin Dermatol. 2011;29(2):173–9. 30. Pignol JP, Olivotto I, Rakovitch E, et al. A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol. 2008;26(13):2085–92.

23  Cutaneous Lesions that Mimic Infection in Transplant Patients 31. Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol. 2006;54(1):28–46. 32. Hill A, Hanson M, Bogle MA, Duvic M.  Severe radiation dermatitis is related to Staphylococcus aureus. Am J Clin Oncol. 2004;27(4):361–3. 33. Johnson MA, Armstrong AW.  Clinical and histologic diagnos tic guidelines for psoriasis: a critical review. Clin Rev Allergy Immunol. 2013;44(2):166–72. 34. Drago F, Broccolo F, Rebora A. Pityriasis rosea: an update with a critical appraisal of its possible herpesviral etiology. J Am Acad Dermatol. 2009;61(2):303–18. 35. Blanco R, Martínez-Taboada VM, Rodríguez-Valverde V, García-­ Fuentes M. Cutaneous vasculitis in children and adults. Associated diseases and etiologic factors in 303 patients. Medicine (Baltimore). 1998;77(6):403–18. (review). 36. Wilmer WA, Magro CM.  Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15(3): 172–86. 37. Fischer AH, Morris DJ.  Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol. 1995;26:1055. 38. Hussein MR, Ali HO, Abdulwahed SR, Argoby Y, Tobeigei FH. Calciphylaxis cutis: a case report and review of literature. Exp Mol Pathol. 2009;86(2):134–5. 39. Buckingham SC, Marshall GS, Schutze GE, et al. Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children. J Pediatr. 2007;150(2):180–4, 184.e1. 40. Winkelmann RK.  Panniculitis in connective tissue disease. Arch Dermatol. 1983;119:336. 41. Friedman PC, Husain S, Grossman ME.  Nodular tuberculid in a patient with HIV.  J Am Acad Dermatol. 2005;53(2. Suppl 1):S154–6. 42. Fernandes SS, Carvalho J, Leite S, Afonso M, Pinto J, Veloso R, et al. Erythema induratum and chronic hepatitis C infection. J Clin Virol. 2009;44(4):333–6. 43. Ugurel S, Lahaye T, Hildenbrand R, Glorer E, Reiter A, Hochhaus A, et al. Panniculitis in a patient with chronic myelogenous leukaemia treated with imatinib. Br J Dermatol. 2003;149(3):678–9. 44. Assouline S, Laneuville P, Gambacorti-Passerini C.  Panniculitis during dasatinib therapy for imatinib-resistant chronic myelogenous leukemia. N Engl J Med. 2006;354(24):2623. 45. Ball NJ, Adams SP, Marx LH, et  al. Possible origin ofpancreatic fat necrosis as a septal panniculitis. J Am Acad Dermatol. 1996;34:362–4. 46. Nguyen GC, Torres EA, Regueiro M, et  al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort. Am J Gastroenterol. 2006;101(5):1012–23. 47. Miteva M, Romanelli P, Kirsner RS.  Lipodermatosclerosis. Dermatol Ther. 2010;23:375–88. 48. Herouy Y, May AE, Pornschlegel G, Stetter C, Grenz H, Preissner KT, et al. Lipodermatosclerosis is characterized by elevated expression and activation on matrix metalloproteinases: implications for venous ulcer formation. J Invest Dermatol. 1998;111:822–7. 49. Cantwell AR Jr, Martz W. Idiopathic bullae in diabetics. Bullosis diabeticorum. Arch Dermatol. 1967;96:42–4. 50. Larrey D.  Memoires de Chirurgie Militaire et Campagnes. Paris: Smith and Buisson; 1812. 51. Groschel D, Gerstein AR, Rosenbaum JM. Skin lesions as a diagnostic aid in barbiturate poisoning. N Engl J Med. 1970;283:409–10. 52. Wenzel FG, Horn TD.  Nonneoplastic disorders of the eccrine glands. J Am Acad Dermatol. 1998;38:1–17. quiz 8–20. 53. Herschthal D, Robinson MJ. Blisters of the skin in coma induced by amitriptyline and clorazepate dipotassium. Report of a case with underlying sweat gland necrosis. Arch Dermatol. 1979;115:499.

415 54. Varma AJ, Fisher BK, Sarin MK.  Diazepam-induced coma with bullae and eccrine sweat gland necrosis. Arch Intern Med. 1977;137:1207–10. 55. Judge TG, Nisbet NH. Trophoneurotic blisters in elderly hemiplegics. Lancet. 1967;1:811–2. 56. Raymond LW. “Barbiturate blisters” in a case of severe hypoglycaemic coma. Lancet. 1972;2:764. 57. Mehregan DR, Daoud M, Rogers RS 3rd. Coma blisters in a patient with diabetic ketoacidosis. J Am Acad Dermatol. 1992;27: 269–70. 58. Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316–21. 59. Teraki Y, Moriya N, Shiohara T. Drug-induced expression of intercellular adhesion molecule-1 on lesional keratinocytes in fixed drug eruption. Am J Pathol. 1994;145:550–60. 60. Ramdial PK, Naidoo DK.  Drug-induced cutaneous pathology. J Clin Pathol. 2009;62:493–504. 61. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8. 62. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease: part I. Pathogenesis and clinical manifestations of graft-versus-host disease. J Am Acad Dermatol. 2012;66:515 e1–e18. 63. Schauder CS, Hymes SR, Rapini RP, Zipf TF.  Vesicular graft-­ versus-­host disease. Int J Dermatol. 1992;31:509–10. 64. Moreno JC, Valverde F, Martinez F, Velez A, Torres A, Fanego J, et al. Bullous scleroderma-like changes in chronic graft-versus-host disease. J Eur Acad Dermatol Venereol. 2003;17:200–3. 65. Hymes SR, Farmer ER, Burns WH, Morison WL, Tutschka PJ, Walters LL, et al. Bullous sclerodermalike changes in chronic graft-­ vs-­host disease. Arch Dermatol. 1985;121:1189–92. 66. McLaren GD, Muir WA, Kellermeyer RW. Iron overload disorders: natural history, pathogenesis, diagnosis, and therapy. Crit Rev Clin Lab Sci. 1983;19:205–66. 67. Daoud MS, Gibson LE, Daoud S, el-Azhary RA. Chronic hepatitis C and skin diseases: a review. Mayo Clin Proc. 1995;70:559–64. 68. Hogan D, Card RT, Ghadially R, McSheffrey JB, Lane P. Human immunodeficiency virus infection and porphyria cutanea tarda. J Am Acad Dermatol. 1989;20:17–20. 69. Green JJ, Manders SM.  Pseudoporphyria. J Am Acad Dermatol. 2001;44:100–8. 70. Phung TL, Pipkin CA, Tahan SR, Chiu DS. Beta-lactam antibiotic-­ induced pseudoporphyria. J Am Acad Dermatol. 2004;51:S80–2. 71. Degiovanni CV, Darley CR.  Pseudoporphyria occurring during a course of ciprofloxacin. Clin Exp Dermatol. 2008;33:109–10. 72. Kwong WT, Hsu S. Pseudoporphyria associated with voriconazole. J Drugs Dermatol. 2007;6:1042–4. 73. Epstein JH, Seibert JS. Porphyria-like cutaneous changes induced by tetracycline hydrochloride photosensitization. Arch Dermatol. 1976;112:661–6. 74. Alcalay J, David M, Ingber A, Hazaz B, Sandbank M. Bullous pemphigoid mimicking bullous erythema multiforme: an untoward side effect of penicillins. J Am Acad Dermatol. 1988;18:345–9. 75. Czechowicz RT, Reid CM, Warren LJ, Weightman W, Whitehead FJ.  Bullous pemphigoid induced by cephalexin. Australas J Dermatol. 2001;42:132–5. 76. Kimyai-Asadi A, Usman A, Nousari HC.  Ciprofloxacin-induced bullous pemphigoid. J Am Acad Dermatol. 2000;42:847. 77. Nousari HC, Deterding R, Wojtczack H, Aho S, Uitto J, Hashimoto T, et  al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. 1999;340:1406–10. 78. Brenner S, Bialy-Golan A, Ruocco V.  Drug-induced pemphigus. Clin Dermatol. 1998;16:393–7. 79. Yeh SW, Ahmed B, Sami N. Razzaque Ahmed A. Blistering disorders: diagnosis and treatment. Dermatol Ther. 2003;16:214–23.

416 80. Blenkinsopp WK, Haffenden GP, Fry L, Leonard JN. Histology of linear IgA disease, dermatitis herpetiformis, and bullous pemphigoid. Am J Dermatopathol. 1983;5:547–54. 81. Rosen LB, Frank BL, Rywlin AM. A characteristic vesiculobullous eruption in patients with chronic lymphocytic leukemia. J Am Acad Dermatol. 1986;15:943–50. 82. Ajithkumar K, George S, Babu PG. Abnormal insect bite reactions: a manifestation of immunosuppression of HIV infection? Indian J Dermatol Venereol Leprol. 2001;67:72–4. 83. Byrd JB, Woodard-Grice A, Stone E, Lucisano A, Schaefer H, Yu C, et  al. Association of angiotensin-converting enzyme inhibitor-­ associated angioedema with transplant and immunosuppressant use. Allergy. 2010;65:1381–7. 84. Choy AC, Yarnold PR, Brown JE, Kayaloglou GT, Greenberger PA, Patterson R. Virus induced erythema multiforme and Stevens-­ Johnson syndrome. Allergy Proc. 1995;16:157–61. 85. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138:1019–24. 86. Hazin R, Ibrahimi OA, Hazin MI, Kimyai-Asadi A.  Stevens-­ Johnson syndrome: pathogenesis, diagnosis, and management. Ann Med. 2008;40:129–38. 87. French LE, Prins C.  Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. In: Bolognia J, Rapini R, editors. Dermatology. St. Louis, MO: Mosby Elsevier; 2008. p. 288. 88. Geria AN, Holcomb KZ, Scheinfeld NS. Necrolytic acral erythema: a review of the literature. Cutis. 2009;83:309–14. 89. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol. 1989;20:39–47.

A. Ciurea and S. Hymes 90. Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II.  Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:263–79. quiz 80 91. Lott DG, Manz R, Koch C, Lorenz RR.  Aggressive behavior of nonmelanotic skin cancers in solid organ transplant recipients. Transplantation. 2010;90:683–7. 92. Bangash HK, Colegio OR.  Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13(3):354–76. 93. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91. 94. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, et  al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33: 222–9. 95. Euvrard S, Chardonnet Y, Pouteil-Noble C, Kanitakis J, Chignol MC, Thivolet J, et al. Association of skin malignancies with various and multiple carcinogenic and noncarcinogenic human papillomaviruses in renal transplant recipients. Cancer. 1993;72:2198–206. 96. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer. 2005;104:1962–7. 97. Vajdic CM, van Leeuwen MT.  Cancer incidence and risk factors after solid organ transplantation. Int J Cancer. 2009;125:1747–54. 98. Miller DD, Cowen EW, Nguyen JC, McCalmont TH, Fox LP.  Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity. Arch Dermatol. 2010;146(3):300–4. 99. Scerri L, Williams HC, Allen BR. Dissecting cellulitis of the scalp: response to isotretinoin. Br J Dermatol. 1996;134:1105–8.

Part III Etiologic Agents in Infectious Diseases

Staphylococcus, Streptococcus, and Enterococcus

24

Amar Safdar and Donald Armstrong

Introduction

patients with chronic GVHD, which promotes the likelihood for serious, invasive pneumococcal disease and infections Gram-positive bacterial (GPB) infections are an important due to other encapsulated microorganisms [2–4]. cause of serious illness in patients undergoing transplantaInfection prevalance varies among patients undergotion [1]. In recipients of hematopoietic stem cell transplanta- ing solid organ transplantation (SOT), in most part the risk is tion (HSCT), GPB are by far the most common bacterial a reflection upon the transplanted organ allograft and surgipathogens isolated. A relative  decline in infections due to cal procedure(s) involved. Deceased donor allograft-derived Gram-negative bacteria (GNB) has been attributed to a vari- and organ perfusion fluid (PF)-associated GPB infections are ety of factors: (1) frequently used antimicrobial prophylaxis a potential source for such infections. The risk of invasive with an emphasis on prevention of systemic infections result- bacterial infections reflects  a proclivity for GPB in this ing from these microorgansisms; (2) a rise in drug-­ group, and mostly  related to surgical procedures that are resistance  among disease-casuing  GPB due to extensive often  long and difficult.  Prolonged tissue hypoperfusion, exposure to healthcare environment and frequent use of posttransplant allograft ischemia, and retransplantation probroad-spectrum antibiotics that are often given as preventive cedures further increases the risk for bacterial infections. or empiric therapy; (3) the necessity for maintenance of vas- Furthermore, surgical drain(s) that are left in place for a long cular access results in retention of intravascular devices for duration; external biliary tract drains like percutaneous tranextended duration; (4) orointestinal mucositis associated shepatic biliary catheter;  percutaneous nephrostomy cathewith conventional preparatory regimens in patients undergo- ter, chest tube, and thoracic drains to name a few, promote ing allogeneic stem cell transplantation; (5) the presence of risk for hospital-acquired bacterial infections; among such severe pre-engraftment neutropenia that may result in pro- infections,  GPB are common pathogens encountered. tracted courses of recovery in certain high-risk trans- Postsurgical wound infections including wound dehiscence plant  groups, such as adults following  conventional cord or other early complications following transplant surgery blood stem cell transplantation; (6) the emergence and wide- such as the development of primary or secondary hematoma spread distribution of community-acquired methicillin-­ or persistent seroma in the deep surgical bed may provide a resistant Staphylococcus aureus (CA-MRSA) colonization nidus for bacterial infection; GPB are also prominent in such and subsequent  risk for  invasive disease; (7) acute and post -surgical complications. It is important to note that colochronic graft-versus-host disease (GVHD) involving the skin nization with MRSA and vancomycin-resistant enterococci and orointestinal tract; and (8) hyposplenism noted in (VRE) poses a substantial burden due to a more noticeable  risk for subsequent invasive bacterial disease and the risk for potential allograft compromise [5, 6]. A. Safdar (*) Presence of extended-use intravascular access devices Clinical Associate Professor of Medicine, Texas Tech University that are crucial  in patients undergoing transplantation  for Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, USA supportive care that includes and not limited to fluid, electroe-mail: [email protected] lyte and mineral supplimentation,  hyperalimentation, renal D. Armstrong replacement therapy, plasma exchanges, blood and blood Infectious Disease Service, Memorial Sloan-Kettering Cancer product transfusions, and administration of antibiotics Center, New York, NY, USA among other medications needed to be given parenterally. Cornell University Medical College (ret), New York, NY, USA These intravascular acess devices  serve as a direct  conduit Infectious Disease Society of America, Albuquerque, NM, USA between skin and blood vessels thereby promoting the risk © Springer Science+Business Media, LLC, part of Springer Nature 2019 A. Safdar (ed.), Principles and Practice of Transplant Infectious Diseases, https://doi.org/10.1007/978-1-4939-9034-4_24

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for bloodstream infections (BSIs). Skin commensals such as coagulase-negative staphylococci (CoNS) and Corynebacterium jeikeium are a well-recognized cause of catheter-related bloodstream infection (CR-BSI). Similar to HSCT recipients, patients undergoing SOT are also susceptible to serious invasive disease due to CA-MRSA. Allograft rejection and need for intensified drug-induced immune suppression further promote the risk for invasive disease due to conventional and opportunistic bacterial pathogens. In this regard, Staphylococcus aureus, viridans streptococci, and Enterococcus spp. are important pathogens [7–10]. Genetic susceptibility for GPB infections may be further accentuated in patients undergoing allograft transplantation. Minor genetic alternations such as single-nucleotide polymorphisms (SNPs) in the essential components of innate immune signaling pathways may become unmasked following trnspantation procedure and are thought to increase hosts’  susceptibility for infections. Toll-like receptor 2 (TLR2) is an immune sensor for the components of GPB cell wall. Genetic alterations in the TLR2 gene may render this important pattern recognition receptor with impaired function, thereby enhanced susceptibility for GPB infections in such individuals. In a cohort of 694 liver transplant recipients, it was interesting to note that patients with TLR2 R753Q SNP (an amino acid substitution of arginine for glutamine at position 753) had similar frequency of GPB infections compared with those individuals without this TLR2 SNP. However, the presence of TLR2 R753Q SNP was identified in patients with higher rates of infection recurrence (28% vs. 12%, P  =  0.07) and initial infection  presentation with septic shock was significatly higher in subjects with this TLR2 mutation (11% vs. 1%, P = 0.04) versus those without. Important to note that presence of TLR2 R753Q SNP did not result in higher infection-related deaths among liver transplant recipients in this report [11]. Further studies are underway to assess clinical relevance for this and other genetic minor aberrations that may unmask minor immune dysfunction against commonly encountered pathogens, especially in individuals  following  allograft transplantation. 

Staphylococcus Species Staphylococci are the predominant GPB with the ability to cause serious illness in patients undergoing transplantation [12, 13]. Staphylococci can be divided into two main classes based on their ability to coagulate rabbit plasma. Staphylococcus aureus being coagulase positive and all other Staphylococcus species are referred to as coagulase-negative staphylococci (CoNS). Infections due to S. aureus may present as simple cellulitis or bacteremia versus a  disseminated disease that features involvement of various organ systems. Patients with

A. Safdar and D. Armstrong

disseminated S. aureus infection usually present as life-­ threatening illness with sepsis or severe sepsis and even in non-transplant immunocompetent patients such infections may progress, in short order, to cause multiorgan dysfunction, disseminated intravascular coagulation, hemodynamic collapse and death. Probablity of severe illness is emphasized in transplant recipients with compromised immune defenses and compounded by dysregulation of hosts’ immune-inflammatory response. The potential to cause pneumonia, endovascular and prosthetic device infections is an important ability of S. aureus and to a lesser extent by species belonging to the CoNS group. In general, infections due to CoNS are less severe, which is a reflection of low inherent virulence of these bacteria to cause disease in humans [14, 15].

Staphylococcus aureus Epidemiology and Pathogenesis S. aureus is a common commensal that can be isolated from 10% to 40% of individuals residing in various communities  [16]. S. aureus has been well-established as a leading cause of both community-onset and nosocomial infections. Prior to the year 2000, a vast majority of MRSA infections were related directly, or indirectly, to the exposure to healthcare environment. S. aureus infections acquired in the community, almost exclusively were  methicillin-susceptible strains of S. aureus (MSSA) [17]. The emergence and global spread of CA-MRSA have resulted in an increased prevalence of these pathogens among the general population and those undergoing transplantation procedures. MRSA colonization has been regarded as an important risk factor among HSCT recipients, and a precursor for subsequent invasive staphylococcal disease [18]. The risk for such infections now extends beyond healthcare exposure and must be entertained when assessing the possibility of illness due to staphylococci  in the transplant population [19]. Most invasive S. aureus diseases in transplant recipients  occur when mechanical defenses are breached, for example, due to break in the skin barrier resulting from catheter placement or bypassing upper airway defenses following  insertion of an endotracheal tube [20]. The main  risk factors include severe neutropenia, GVHD, allograft rejection, solid allograft  retransplantation, treatment with systemic corticosteroids, and complicated allograft transplant surgery. Staphylococcus aureus infections are also encountered in a high frequency among patients requiring prolonged intensive care unit stay, mechanical assisted ventilatory support, renal replacement therapy, and those with severe preengraftment neutropenia. Diabetic patients with persistent  hyperglycemia-induced neutrophil and macrophage dysfunction are also at risk for potentially severe staphylococcal disease [21, 22].

24  Staphylococcus, Streptococcus, and Enterococcus

HSCT Recipients A recent study from Europe in 15,181 neutropenic HSCT patients assessed 2,388 episodes of BSI.  The annual incidence of BSI in this population was 16%; 62% had undergone allogeneic and 38% autologous stem cell graft transplants [23]. The authors noted an increase in enterococcal BSI from 2% in 2002 to 3% in 2014 (P  3) ß-D-glucan tests are not reliable for the detection of cryptococcus and should not be used for diagnosis of and monitoring cryptococcosis. Several stains are used to identify cryptococcus in biopsy samples and other clinical specimens. Traditionally, India ink preparation was used as a readily available tool for the rapid diagnosis of cryptococcal infection. Cryptococcus species are yeasts, measuring 5–10 μm in diameter, that contain a polysaccharide capsule that appears as clear halo or space in specimens treated with India ink stain. The sensitivity of India ink preparation is only in the 50% in patients with cryptococcal meningitis in the non-AIDS population [49]. Alcian blue stains are also used and may provide better specificity for cryptococcus infection. Mucicarmine staining will stain the cryptococcal capsule to rose or burgundy color [49]. Gram stain usually shows poorly stained Gram-positive yeast, while Gomori methenamine silver (GMS) fungal stain may demonstrate the narrow-based budding oval yeast of cryptococcus in tissue specimens [49].

 reatment of Cryptococcal Disease T in Transplant Recipients Treatment of cryptococcal disease in transplant recipients entails the use of antifungal drugs and reduction in pharmacologic immunosuppression. The antifungal drugs that are recommended for the treatment of cryptococcal disease in transplant recipients are amphotericin B products, preferably lipid formulations, flucytosine, and fluconazole (Table 35.2) [10, 50]. Voriconazole, itraconazole, and posaconazole are also active against cryptococcus, but they offer no additional benefit compared to fluconazole and have higher potential for drug-drug interactions, especially drugs used for prevention of graft rejection and prevention and treatment of GVDH [5, 43]. The basis of the treatment recommendations in transplant recipients is extrapolated from retrospective studies in SOT recipients and from clinical trials performed in patients with AIDS [10, 50]. There are no randomized, prospective clinical treatment trials in transplant recipients with cryptococcosis. Antifungal susceptibility testing is not generally recommended in cryptococcosis, unless there is persistent infection and relapsed infection or the infection is due to C. gattii, which may sometimes be associated with high minimum

35  Cryptococcus Infections in Transplant Recipients

595

Table 35.2  Treatment of cryptococcosis in transplant recipients Therapy Asymptomatic pulmonary disease Mild to moderate isolated pulmonary disease All other cases, including CNS disease, severe pulmonary disease, and disseminated disease Induction therapy  (a) Preferred therapy

 (b) Alternative therapy

Consolidation therapy Maintenance therapy

Drug and dose Fluconazole, 400 mg per day Fluconazole, 400 mg per day

Duration 6–12 months

Liposomal amphotericin B, 3–4 mg/kg per day; or amphotericin B lipid complex, 5 mg/kg per day, plus flucytosine, 100 mg/ kg per day Liposomal amphotericin B, 3–4 mg/kg per day, or amphotericin B lipid complex, 5 mg/kg per day Fluconazole, 400–800 mg per day Fluconazole, 200–400 mg per day

Minimum of 2 weeks

6–12 months

Minimum of 4–6 weeks

8 weeks 6–12 months

inhibitory concentration to fluconazole [51–53]. In vitro resistance to amphotericin B and fluconazole among cryptococcal isolates is very uncommon [53]. With the exception of mild-to-moderate pulmonary cryptococcosis, all other cryptococcal diseases in transplant recipients should be treated using induction therapy with fungicidal liposomal amphotericin B (3–4 mg/kg per day) or amphotericin B lipid complex (5  mg/kg per day) and flucytosine (100 mg/kg per day) for a total of 14 days (Table 35.2) [10, 50]. This combination therapy should be used to treat patients with CNS disease, disseminated disease, or severe respiratory disease. Lipid formulations of amphotericin B are preferred over amphotericin B deoxycholate, as it confers survival benefit and is less nephrotoxic, especially in transplant patients who are already receiving several nephrotoxic medications [54]. Mortality at 90  days is lower in SOT patients with cryptococcosis treated with lipid formulation compared to the deoxycholate formulation of amphotericin B [54]. Flucytosine is an essential component of induction therapy. The lack of flucytosine use and its use for 25 mmHg should have therapeutic lumbar punctures to reduce the intracranial pressure to 6  mg/dL, and alkaline phosphatase >5-fold normal values; ballooning hepatocytes, sinusoidal fibrosis, cholestasis, and a low level of tissue inflammation despite bile duct proliferation on liver biopsy were prominent histologic features of FCH in this setting [129, 130]. High viral load, older recipient age, non-­Caucasian race, female gender, insulin resistance and diabetes mellitus, high-dose corticosteroid treatment for acute cellular graft rejection, donor age greater than 55 years, and HIV coinfection were significant risk factors for more severe HCV recurrence following liver transplantation.

Hepatitis C and Non-liver Transplantation Kidney Transplantation Hepatitis C and End-Stage Kidney Disease Chronic hepatitis C is common in the kidney transplant population, with the prevalence of HCV seropositivity ranging from 7% to 40% in developed countries [131–133]. Several factors account for this high prevalence. Firstly, HCV is a possible factor in the development of the renal disease. Chronic HCV infection may induce a mixed cryoglobulinemia and a systemic vasculitis, leading to glomerulonephritis and renal failure [134–136]. Chronic HCV infection is also associated with a high rate of insulin resistance and type 2 diabetes mellitus [137]. In addition, de novo acquisition of hepatitis C among patients on hemodialysis occurs with high frequency. In patients receiving routine hemodialysis,

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47  Impacts and Challenges of Advanced Diagnostic Assays for Transplant Infectious Diseases 2007;46(5):535–7. Intravesikale Cidofovir--Instillationstherapie bei Polyomavirus-assoziierter hamorrhagischer Zystitis nach Knochenmarktransplantation. ger. 262. Wong AS, Chan KH, Cheng VC, Yuen KY, Kwong YL, Leung AY.  Relationship of pretransplantation polyoma BK virus serologic findings and BK viral reactivation after hematopoietic stem cell transplantation. Clin Infect Dis. 2007;44(6):830–7. 263. Lee YJ, Palomino-Guilen P, Babady NE, Lamson DM, St George K, Tang YW, et al. Disseminated adenovirus infection in cancer patients presenting with focal pulmonary consolidation. J Clin Microbiol. 2014;52(1):350–3. 264. Rustia E, Violago L, Jin Z, Foca MD, Kahn JM, Arnold S, et al. Risk factors and utility of a risk-based algorithm for monitoring cytomegalovirus, Epstein-Barr virus, and adenovirus infections in pediatric recipients after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(9):1646–53. 265. Sive JI, Thomson KJ, Morris EC, Ward KN, Peggs KS. Adenoviremia has limited clinical impact in the majority of patients following alemtuzumab-based allogeneic stem cell transplantation in adults. Clin Infect Dis. 2012;55(10):1362–70. 266. Flomenberg P, Babbitt J, Drobyski WR, Ash RC, Carrigan DR, Sedmak GV, et  al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis. 1994;169(4):775–81. 267. Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, et al. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007;9(2):108–13. 268. Howard DS, Phillips IG, Reece DE, Munn RK, Henslee-Downey J, Pittard M, et  al. Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999;29(6):1494–501. 269. Lynch JP 3rd, Kajon AE.  Adenovirus: epidemiology, global spread of novel serotypes, and advances in treatment and prevention. Sem Resp Crit Care Med. 2016;37(4):586–602. 270. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA.  Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. 1996;88(10):4063–71. 271. Zaia JA. Prevention of cytomegalovirus disease in hematopoietic stem cell transplantation. Clin Infect Dis. 2002;35(8):999–1004. 272. Lindemans CA, Leen AM, Boelens JJ.  How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. 2010;116(25):5476–85. 273. Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch HH, Cordonnier C, Ljungman P, Fourth European Conference on Infections in Leukemia. European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 (2011). Transpl Infect Dis. 2012;14(6):555–63. 274. Williams KM, Agwu AL, Dabb AA, Higman MA, Loeb DM, Valsamakis A, et  al. A clinical algorithm identifies high risk pediatric oncology and bone marrow transplant patients likely to benefit from treatment of adenoviral infection. J Pediatr Hematol Oncol. 2009;31(11):825–31. 275. Zaia J, Baden L, Boeckh MJ, Chakrabarti S, Einsele H, Ljungman P, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant. 2009;44(8):471–82. 276. Ohrmalm L, Lindblom A, Omar H, Norbeck O, Gustafson I, Lewensohn-Fuchs I, et al. Evaluation of a surveillance strategy for early detection of adenovirus by PCR of peripheral blood in hematopoietic SCT recipients: incidence and outcome. Bone Marrow Transplant. 2011;46(2):267–72. 277. Ganzenmueller T, Buchholz S, Harste G, Dammann E, Trenschel R, Heim A. High lethality of human adenovirus disease in adult

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818 with foscarnet sodium for high-risk patients after hematopoietic SCT. Bone Marrow Transplant. 2011;46(6):863–9. 293. Milano F, Campbell AP, Guthrie KA, Kuypers J, Englund JA, Corey L, et  al. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088–94. 294. Campbell AP, Chien JW, Kuypers J, Englund JA, Wald A, Guthrie KA, et al. Respiratory virus pneumonia after hematopoietic cell transplantation (HCT): associations between viral load in bronchoalveolar lavage samples, viral RNA detection in serum samples, and clinical outcomes of HCT. J Infect Dis. 2010;201(9):1404–13. 295. Seo S, Renaud C, Kuypers JM, Chiu CY, Huang ML, Samayoa E, et al. Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies. Blood. 2015;125(24):3789–97. 296. Waghmare A, Pergam SA, Jerome KR, Englund JA, Boeckh M, Kuypers J. Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients. Blood. 2015;125(11):1724–9. 297. Dokos C, Masjosthusmann K, Rellensmann G, Werner C, Schuler-­ Luttmann S, Muller KM, et  al. Fatal human metapneumovirus infection following allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2013;15(3):E97–E101. 298. Englund JA, Boeckh M, Kuypers J, Nichols WG, Hackman RC, Morrow RA, et al. Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Int Med. 2006;144(5):344–9. 299. Schenk T, Strahm B, Kontny U, Hufnagel M, Neumann-Haefelin D, Falcone V.  Disseminated bocavirus infection after stem cell transplant. Emerg Infect Dis. 2007;13(9):1425–7. 300. Kuypers J, Campbell AP, Guthrie KA, Wright NL, Englund JA, Corey L, et al. WU and KI polyomaviruses in respiratory samples from allogeneic hematopoietic cell transplant recipients. Emerg Infect Dis. 2012;18(10):1580–8. 301. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, et al. The impact of culture isolation of aspergillus species: a hospital-based survey of aspergillosis. Clin Infect Dis. 2001;33(11):1824–33. 302. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997;175(6):1459–66. 303. Tarrand JJ, Lichterfeld M, Warraich I, Luna M, Han XY, May GS, et al. Diagnosis of invasive septate mold infections. A correlation

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Diagnosis of Systemic Fungal Diseases

48

Simon Frédéric Dufresne, Kieren A. Marr, and Shmuel Shoham

Introduction Rapid and accurate diagnosis of invasive fungal infections (IFI) is critical to the care of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Such infections are a by-product of immunosuppression and carry substantial morbidity and mortality. Improved diagnostic approaches and new and safer broad-spectrum antifungal agents have revolutionized treatment in these patients. This chapter will review the major diagnostic tools and their role in patients with suspected fungal infections. Diagnosis will be approached from the laboratory perspective, with an overview of methods used in clinical laboratories. Major organisms will then be presented separately, incorporating relevant clinical aspects that guide diagnostic approach.

 verview of Diagnostic Laboratory Methods O in Clinical Mycology General Principles Until recently diagnosis centered upon detection of fungi from clinical samples using traditional staining and culture techniques, with nucleic acid and antibody-based assays playing a supportive role. The testing paradigm

S. F. Dufresne (*) University of Montreal, Maisonneuve-Rosemont Hospital, Department of Medicine, Division of Infectious Diseases and Clinical Microbiology, Montréal, QC, Canada e-mail: [email protected] K. A. Marr · S. Shoham Johns Hopkins University School of Medicine, Department of Medicine, Division of Infectious Diseases, Baltimore, MD, USA e-mail: [email protected]; [email protected]

is shifting, with nonculture tests moving to the fore. Such assays are increasingly used as primary methods of diagnosis in a variety of invasive mycoses, including aspergillosis, candidiasis, cryptococcosis, and histoplasmosis [1–3]. Traditional and newer diagnostic approaches are complementary, and multiple tests are frequently employed simultaneously. The major diagnostic modalities are (A) microscopic examination of biological specimens, including direct microscopy, cytopathology and histopathology; (B) culture followed by speciation using morphological, biochemical, and/or molecular methods and antifungal susceptibility testing; (C) serodiagnosis, antigen or antibody detection; and (D) nucleic acid amplification techniques (NAAT). The relative contributions of these methods for diagnosis of systemic fungal diseases are presented in Table 48.1.

Histopathology Microscopic examination of thin-sectioned ­formalin-fixed paraffin-embedded tissue (histopathology) is generally sensitive and can provide definitive proof of infection when tissue invasion is seen. Major limitations are the requirement for an invasive procedure and the effort required for specimen preparation and processing. As for direct microscopy and cytopathology, unique morphological features can be used to differentiate hyalohyphomycosis (hyaline, septate, acute-angle branching hyphae), phaeohyphomycosis (darkly pigmented, septate hyphae), and mucormycosis (hyaline, non-septate, large ribbon-like, right-angle branching hyphae) and to identify Cryptococcus neoformans/gattii, Pneumocystis jiroveci, and the endemic fungi to the genus or species level. In addition, histopathology can demonstrate host responses, such as patterns of inflammation and tissue damage. For example, the asteroid bodies (Splendore-­Hoeppli reaction) are associated with several fungal infections, including sporotrichosis [4].

© Springer Science+Business Media, LLC, part of Springer Nature 2019 A. Safdar (ed.), Principles and Practice of Transplant Infectious Diseases, https://doi.org/10.1007/978-1-4939-9034-4_48

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Table 48.1  Relative contribution of different diagnostic modalities for detection of invasive fungi

Organisms Aspergillus Other filamentous fungia Candida Cryptococcus Pneumocystis Endemic

Histopathology ++ ++ + + + +++

Direct microscopy/cytopathology ++ ++ ++ ++ +++ ++

Culture ++ ++ +++ +++ − +++

Antigen detection +++ − + +++ ++ +++

NAAT ++ + + + ++ +

Host immune response Humoral Cellular + − + − + − − − − − ++ −

–: not useful or available +: rarely contributive; important limitations with regard to safety, availability, or performance (including lack of clinical data) ++: sometimes contributive; some limitations with regard to safety, availability, or performance +++: often contributive; considered standard method for diagnosis a Includes Fusarium species, Scedosporium species, Mucorales, dematiaceous fungi, and others

Modern histopathology relies on a combination of dyes with immunological and molecular techniques. Most fungi can be observed with hematoxylin-eosin (H&E), but ­specialized stains such as GMS and periodic acid-Schiff (PAS) are preferred and facilitate visualization of certain fungal structures. Certain stains are useful for specific fungi. For example, Giemsa is helpful for identifying P. jiroveci trophic forms, mucicarmine for Cryptococcus spp. (stains capsule), and Fontana-­ Masson for dematiaceous molds (stains melanin). When fungal structures are observed in tissue, formalin-fixed paraffin-­embedded specimens can be analyzed further with immunohistochemistry [5] and in situ hybridization [6–8] to facilitate identification. Furthermore, DNA can be extracted from paraffin-embedded tissue, allowing nucleic acid amplification and sequencing [9–11]. This procedure may prove extremely useful when fungal elements are visualized in tissue, but concomitant culture is negative or not available.

Direct Microscopy and cytopathology Microscopic examination of clinical samples is an extremely valuable tool. Despite lacking sensitivity, it is relatively simple, rapid, and reasonably specific. Visualization of fungal structures by direct microscopy serves three main purposes: 1) primary detection of a fungal pathogen in the sampled body site, 2) identification of the fungal pathogen based on morphological features (it reliably distinguishes major fungal groups such as yeasts, hyphomycetes and Mucorales, and even various species including Pneumocystis jirovecii, Coccidioides immitis/posadasii, Blastomyces dermatitidis and Paracoccidioidesbrasiliensis), and 3) interpretation of positive cultures, by helping determine whether growth from non-sterile specimens is clinically significant. Direct microscopy involves fresh specimens, which can be either directly mounted using saline alone

(plain preparation), or stained with a dye that facilitates fungal visualization (with or without prior smear fixation). Common stains are the chitin-binding fluorescent dye calcofluor white (CFW), India ink, toluidine blue and immunofluorescent stains using P. jirovecii-directed antibodies. Cytopathology refers to examination of fixed free cells, usually obtained from liquid specimens such as bronchoalveolar lavage and pleural fluid. Solid tissues may also be sampled using fine-needle aspiration. Several stains are then used to visualize fungal elements, including Grocott-Gomori’s methenamine silver (GMS) and Giemsa. Accurate microscopic examination relies on the experience and skills of the operator.

Culture Culture is a cornerstone of fungal diagnostics. It is generally more sensitive than microscopy alone and facilitates fungal identification and antimicrobial susceptibility testing. Major limitations include suboptimal sensitivity, prolonged turnaround time, and biosafety issues. The significance of a positive culture depends upon the site from which the specimen was obtained, the organism isolated, and the clinical scenario. Growth from a normally sterile site is indicative of invasive infection. Isolation of certain pathogens (e.g., Cryptococcus neoformans, C. gattii, the endemic fungi) from any body site is virtually synonymous with disease. Conversely, recovery of Candida, Aspergillus, Scedosporium, Mucorales, and dematiaceous fungi from sites that are not normally sterile does not necessarily indicate infection and requires careful consideration of both the host and clinical context. The initial steps involved in fungal culture are specimen collection and inoculation on media. Specimen quality is critical for optimal fungal recovery and to minimize contamination. Table 48.2 summarizes adequate specimens for recovery of different fungi.

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Table 48.2  Adequate specimens for culture of pathogenic fungi Organisms Aspergillus Other filamentous fungi Candida Cryptococcus Endemic

Bone Blood marrow + − +a − +++ +++ +++b

− − +++

Respiratory CSF secretions + ++ + ++

Urine Skin ++ − ++ −

++ + +++ ++ ++ ++

++ +++ ++

++ ++ ++

CSF cerebrospinal fluid –: virtually never recovered from this site +: may be recovered, but generally considered colonization or contamination, or yield is very low ++: may be recovered only if site is clinically infected +++: may be recovered in invasive disease and can be done even if site is not clinically infected or infection is not apparently disseminated a Except for Fusarium spp. (+++) b For H. capsulatum, using lysis-centrifugation methods or mycological media blood culture bottles for continuous monitoring blood culture systems; low yield for Coccidioides spp. (+)

In general, tissue and fluids are preferred over swabs. Volume should be ≥2  ml for cerebrospinal fluid and as much as possible for other sterile fluids. Most specimens should be transported to the laboratory as soon as possible, and some (e.g., corneal scrapings, prostatic fluids) require direct inoculation. Fungal culture media such as Sabouraud dextrose agar (SDA), inhibitory mold agar (IMA), brain-heart infusion (BHI) agar, and malt extract agar usually contain antimicrobial agents to prevent overgrowth by competing microbiota [12–14]. Many fungi grow within a few days, but some, including Histoplasma capsulatum, may need up to 6  weeks. Few studies have directly compared the yield of different media in a clinical setting. IMA was recently shown to recover more isolates than SDA in cultures of specimens from various sites, including yeasts and hyaline hyphomycetes and Mucorales [15]. For recovery from the blood, modern aerobic bottles in continuously monitored blood culture systems are adequate for yeasts and Fusarium. Special lytic mycological media bottles or the lysis-centrifugation procedure may be preferable for fastidious fungi such as Histoplasma capsulatum [16, 17]. Once an isolate is grown, identification is typically achieved using standard procedures. Macroscopic and microscopic morphology remain the mainstay of mold identification. Several vegetable-based or poor media (e.g., potato dextrose agar, Czapek-Dox agar, tap water agar) enhance conidiation and/or pigment production of some fungi and facilitate identification. Simple biochemical tests are also commonly used for yeasts. Other techniques include thermotolerance, nutritional requirements, and conversion assays for thermally dimorphic

fungi [12, 18]. Molecular methods, such as simple hybridization [19] and genomic DNA sequencing [20], are increasingly used, especially when a higher taxonomic resolution is needed. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry is emerging as a powerful tool for identification [21–24]. With the exception of some saprophytic filamentous fungi, identification should be made to the species level. Because many species have well established and predictable susceptibility patterns, identifying the species can have important prognostic and treatment implications. Biosafety of laboratory personnel is a concern when culturing fungi, especially the thermally dimorphic fungi. Biosafety level 3 (BSL-3) practices, containment equipment, and appropriate facilities are required for handling sporulating mold-form cultures of B. dermatitidis, C. immitis/posadasii, and H. capsulatum [25]. Coccidioides poses a particular threat to laboratory workers [26]. This fungus can grow rapidly on bacterial primary isolation plates, and clinicians should alert the microbiology laboratory when infection with one of these organisms is suspected.

Antigen Detection Assays that detect fungal antigens now assume an important role in the evaluation of patients with suspected invasive mycoses and are indispensible aids for diagnosing cryptococcosis, histoplasmosis, and aspergillosis. Their role in candidiasis, pneumocystosis, and other fungal infections is evolving. Favorable aspects of antigen detection assays include rapidity, ease of performance, and potential for diagnosing infections early in the disease course. Sensitivity and specificity remain a concern. Considerations of their pros and cons are important in developing preemptive strategies and point-of-care fungal antigen testing. Various commercially available assays detect polysaccharides released from the cryptococcal capsule and cell walls of Histoplasma and Aspergillus and Candida. Suitable samples include serum, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) fluid, urine, and other body fluids. Methodologies include latex agglutination (LA), enzyme immunoassays (EIA), and lateral-flow immunochromatographic assays (LFIA). Performance characteristics vary by kit, organism, specimen, clinical context, and cutoff used. A summary of commercially available assays is presented in Table 48.3. (1-->3) β-D-glucan (BG) is an important fungal marker. This polysaccharide cell wall component is found in many fungi, with the notable exceptions of Cryptococcus spp. and the Mucorales, making it an almost “panfungal” marker.

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Table 48.3  Commercial assays for detection of fungal antigens

Assay (manufacturer) Cryptococcus neoformans/gattii CALAS®: Cryptococcal antigen latex agglutination system (Meridian Bioscience Inc.) Latex-Cryptococcus antigen detection system (Immuno-­Mycologics Inc.) Remel™ Cryptococcal antigen test kit (Thermo Fisher Scientific, Inc.) ALPHA cryptococcal antigen EIA (Immuno-­Mycologics, Inc.) Premier® Cryptococcal antigen (Meridian Bioscience Inc.) CrAg lateral-flow assay (Immuno-­Mycologics Inc.) Histoplasma capsulatum ALPHA Histoplasma antigen EIA (Immuno-­Mycologics Inc.) MVista® Histoplasma capsulatum quantitative antigen EIA (MiraVista Diagnostics) Blastomyces dermatitidis MVista® Blastomyces dermatitidis quantitative antigen EIA (MiraVista Diagnostics) Coccidioides immitis/posadasii MVista® Coccidioides quantitative antigen EIA (MiraVista Diagnostics) Candida albicans Platelia™ Candida Ag Plus Aspergillus fumigatus Platelia™ Aspergillus Ag

Method

Antigen detected

Approved or most studied specimens FDA-­approved (other specimens with clinical data) kit

LA

GXM

Yes

Serum, CSF

LA

GXM

Yes

Serum, CSF

LA

GXM

Yes

Serum, CSF

ELISA

GXM

Yes

Serum, CSF

ELISA

GXM

Yes

Serum, CSF

LFIA

GXM

Yes

Serum, plasma, CSF (urine)

ELISA

N/A

Yes

Urine

ELISA

GM

No

Urine, Serum (BALF, CSF)

ELISA

GM

No

Urine, serum (BALF, CSF)

ELISA

GM

No

Urine, serum (BALF, CSF)

ELISA

M

No

Serum

ELISA

GM

Yes

Serum, BALF (urine, CSF)

LA latex agglutination, ELISA enzyme-linked immunosorbent assay, LFIA lateral-flow immunochromatographic assay, GXM glucuronoxylomannan, GM galactomannan, M mannan, CSF cerebrospinal fluid, BALF bronchoalveolar lavage fluid, normally sterile body fluids

Serum BG measurement has been mostly studied for diagnosis of aspergillosis, candidiasis, and, more recently, pneumocystosis. Four commercial assays are currently marketed, but only Fungitell® (Associates of Cape Cod) is available in the United States and Canada.

 ucleic Acid Amplification Techniques N NAATs are characterized by high analytical sensitivity and specificity and may allow reliable fungal identification directly from clinical samples, independently of culture. These assays are rapid (especially real-time PCR) and amenable to automation. However, discriminating infection from colonization or environmental contamination, especially when analyzing specimens from non-normally sterile sites, can be difficult. The reliability of these tests is impacted by fungal concentration, ease of DNA extraction (typically difficult for fungi), specimen type, and clinical scenario.

Most effort has focused on Aspergillus spp., Candida spp., and Pneumocystis jirovecii, but NAATs have been developed for most pathogenic fungi. Some target specific genera or species, while others are “panfungal,” targeting universal sequences in the fungal genome [27]. Suitable samples include whole blood, serum, plasma, BALF, sputum, CSF, and tissue. Techniques include PCR, semi-nested PCR, nested PCR, PCR-ELISA, nucleic acid sequence-­ based amplification (NASBA), and real-time PCR. Novel technologies include PCR coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) [28–30], PCR coupled with surface-enhanced Raman scattering (PCR-SERS) [31], and PCR with magnetic resonance [32]. For now, NAATs are not part of standard diagnostic definitions of IFI [33], although many experts advocate for their inclusion [34]. Many centers use “home-brewed” fun-

48  Diagnosis of Systemic Fungal Diseases

gal NAATs, and standardization and reproducibility of the assays are areas of ongoing efforts. The recent development of commercial assays will likely pave the way to wider availability and routine use.

Host Response Another approach to fungal diagnosis is by measurement of antifungal host responses. This includes serology for detection of specific antibodies (humoral immunity) and detection of specific cell-mediated immunity. Serological methods include immunoprecipitation, complement fixation (CF), immunodiffusion (ID), counterimmunoelectrophoresis (CIE), and EIA. Cell-mediated immunity can be tested in vivo or ex vivo, with hypersensitivity skin testing and enzyme-linked immunoblot (ELISPOT) assay, respectively. While providing useful information, limitations of host response assays are that they may lack sensitivity in immunocompromised patients and may not be able to differentiate from active, quiescent, or past infection. Clinically, serology is most commonly used for coccidioidomycosis and h­ istoplasmosis, and the tests are generally performed at reference laboratories.

Diagnosis by Organisms Aspergillus  linical Syndromes and Diagnostic Approach C Invasive aspergillosis (IA) is a disease of immunocompromised patients. At highest risk are patients with profound quantitative and/or qualitative neutrophil abnormalities. Major risk factors include hematological malignancies and their treatment, allogeneic hematopoietic stem cell transplantation (HSCT), receipt of corticosteroid-based therapy (e.g., solid organ transplant recipients and patients with graft-versus-host disease), advanced HIV, and chronic granulomatous disease. Aspergillus fumigatus is the leading species involved, followed by A. flavus, A. niger, and A. terreus [35–40]. The most common sites of infection are the respiratory tract and sinuses. However, almost any organ can be involved with hematogenous seeding and continuous spread or due to inoculation at non-respiratory sites (e.g., skin, ears). The most common presentations include airway and sinus disease, which may manifest as antibacterial-refractory undifferentiated fever in the setting of prolonged and profound neutropenia. Given the wide spectrum of clinical disease, IA is included in the differential diagnosis of many pathogenic processes in susceptible hosts [40, 41].

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The typical diagnostic approach includes pulmonary imaging followed by microbiological testing. For example, an HSCT recipient with fever, neutropenia, and lung abnormalities on computed tomography (CT) scan may have respiratory samples evaluated by direct microscopy, culture, galactomannan antigen detection, and possibly NAAT while simultaneously having blood tested for circulating biomarkers (GM, BG, DNA). With regard to respiratory sample, fiber-optic bronchoscopy with BAL is generally helpful and safe [42]. In HSCT recipients, the procedure may have a higher diagnostic yield and improve outcome when performed early after presentation [43]. Transbronchial biopsies are riskier, thereby limiting their utility in HSCT recipients [44]. In some high-risk populations, a preemptive approach is favored. In this setting, surveillance assays are performed regularly and trigger antifungal treatment upon positivity. Among allogeneic HSCT recipients (along with other high-­ risk hematologic patients), this strategy reduces antifungal consumption without affecting survival [45–49]. A recent meta-analysis suggested that a combination of GM and NAATs provides optimal performance, and aspergillosis is extremely unlikely when both biomarkers are negative [50]. Importantly, surveillance GM and PCR testing is not recommended for patients receiving anti-mold prophylaxis, in which context the very low prevalence of IA leads to a poor positive predictive value [51, 52]. In lung transplant recipients, limited data suggest that a culture-based preemptive strategy may reduce the occurrence of IA [53].

Laboratory Detection Visualization of fungal structures by microscopy provides rapid and definitive evidence of infection when the sample is obtained from a normally sterile site. When the source is from a non-sterile site (e.g., respiratory secretions), results should be interpreted more cautiously. Aspergillus species appear in vivo as narrow (3–6 μm), septate hyphae with dichotomous 45° branching. The hyphae are hyaline after staining and usually indistinguishable from other hyalohyphomycetes [18]. Conidia are not typically seen in  vivo, except in lesions with air-tissue interface, and in infections caused by A. terreus, in which vegetative conidia (aleurioconidia) can be observed along the hyphae [54, 55]. Culture is an important diagnostic modality but may remain negative even with positive stains. This may be due to disruption of delicate fungal structures during acquisition, transport, and processing of the specimen prior to inoculation onto fungal media. Moreover, host-adapted hyphae growing in a microaerophilic environment may not be fit for usual laboratory conditions [56]. It is extremely rare to

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grow Aspergillus from blood cultures and such growth often represents a laboratory contaminant [57, 58]. Aspergillus isolates that do grow in culture can generally be identified further by simple phenotypic characteristics such as macroscopic and microscopic morphology (morphotyping) and thermotolerance. Occasionally, dysgonic isolates may grow as nonsporulating molds (i.e., sterile mycelium), which prevent identification through morphotyping. Such isolates may be mistaken as environmental contaminants or colonizers [59–61], but simple laboratory procedures can avoid such misidentification [62]. Some species (e.g., A. fumigatus, A. terreus, and A. calidoustus) are now recognized as complexes (sections) comprising groups of genetically and biologically distinct species [63], which may have differing susceptibility patterns and clinical presentations [64–67]. Species-level identification is best achieved by molecular methods (e.g., PCR-RFLP [68] and sequencing [69]), although thermotolerance at 50 °C allows definitive identification of A. fumigatus sensu stricto within the section Fumigati [70]. Internal transcribed spacer (ITS), beta-tubulin (BenA), and calmodulin (CaM) are standard gene targets for sequence-based identification. Galactomannan (GM) testing has assumed an increasingly important role. This antigen is released by the growing Aspergillus hyphae and detected using the FDA-cleared double-­sandwich ELISA Platelia™ Aspergillus Ag (Bio-Rad Laboratories Inc., Marnes-la-Coquette, France) [71–73]. An Optical Density Index (ODI) value of ≥0.5 is considered positive for serum [74]. With this cutoff, overall sensitivity and specificity for probable and proven IA are approximately 70–80% and 80–90%, respectively [75, 76], but vary according to clinical setting (diagnosis of active disease versus surveillance), use of concomitant anti-mold prophylaxis, number of tests performed, and patient population. Cross-­reactivity can be seen with Penicillium spp., Fusarium spp., and Histoplasma capsulatum [77–80]. Treatment with piperacillin-­tazobactam was a cause of false positivity [81– 86], but this problem has almost disappeared [87–89]. GM can be used on a range of fluids including BALF, urine, and CSF [90]. When using an ODI cutoff of ≥0.5, the sensitivity and specificity of BALF GM are ~90% [91, 92], although some have reported much lower performances and GM alone cannot distinguish airway colonization from invasive disease [93]. Baseline GM indices and GM dynamics can be used as prognostic and treatment response markers [94, 95]. Assays targeting other antigens and using the lateral-flow technology are in development and could be useful as point-of-care tests [96–100]. Serum BG testing is another important diagnostic approach. The sensitivity and specificity of serum BG for aspergillosis are in the mid 70–80% range, although data from transplant recipient populations are very limited [101– 105]. Of note, circulating BG is not specific for Aspergillus

S. F. Dufresne et al.

and false positives due to a range of non-fungal causes are not uncommon. Tests of antifungal host immune responses have a limited role for diagnosis of IA. In immunocompromised hosts anti-­ Aspergillus antibody titers do not correlate well with invasive infection [35], but may be useful for identifying patients at higher risk for developing invasive infection following HSCT [106–108]. Multiple NAATs have been developed for A. fumigatus and are used at some centers. Earlier generation assays were largely “home brewed,” lacked standardization, and exhibited variable performance characteristics [109–116]. Efforts at standardizing NAATs have been made [52, 117–120] and several commercially available assays have emerged. The LightCycler® SeptiFast (Roche Diagnostics) test detects 25 bacterial and fungal pathogens from whole blood samples, including A. fumigatus. Limited clinical data is available for hematological and solid organ transplant patients [121–124]. The MycAssay™ Aspergillus (Trinity Biotech) is a real-time PCR assay targeting the 18S rRNA gene and that evaluated for BALF, serum, and tissue samples [125– 130]. The AsperGenius® (PathoNostics) is a multiplex real-time PCR assay detecting multiple Aspergillus species (A. fumigatus, A. terreus, and other Aspergillus species) along with major cyp51a mutations associated with azole resistance (TR34/L98H, T289A, and Y121F) and has been studied in both BALF and serum samples [34, 131–133]. The RenDx Fungiplex assay (Renishaw Diagnostics) uses the PCR-­surface-­enhanced Raman scattering (PCR-SERS) technology and detects four Aspergillus species (A. fumigatus, A. flavus, A. niger, and A. terreus) [31]. Finally, the MycoGENIE® Aspergillus fumigatus kit (Ademtech) is designed to detect A. fumigatus and the TR34/L98H mutation from various clinical samples (biopsies, respiratory tract samples, and sera), although no clinical performance data is available to this date. None of these assays have FDA clearance for use as in vitro diagnostics. Overall, clinical data on commercial Aspergillus NAATs remain scarce, but available studies have yielded encouraging results. Collectively, NAATs are thought to perform at least as well as the galactomannan antigen and many advocate for their inclusion within standard definitions [34].

Non-Aspergillus Opportunistic Molds  linical Syndromes and Diagnostic Approach C The Mucorales, Fusarium, Scedosporium/Pseudallescheria, and to a lesser extent the dematiaceous molds are the most important non-Aspergillus filamentous pathogens in organ transplant recipients [36, 37, 134, 135]. Infections may be limited to the lung or skin or involve multiple sites including the CNS, bones and joints, and the eyes [136]. They

48  Diagnosis of Systemic Fungal Diseases

are usually included with Aspergillus species in differential diagnosis of relevant clinical syndromes, and the diagnostic approach is similar, albeit with less reliance on circulating biomarkers and more on traditional diagnostic methods.

Laboratory Detection In stained specimens, the hyphae of Mucorales fungi appear as broad, ribbon-like, and twisted with rare septa and irregular branching. Dematiaceous fungi appear darker on H&E and generally show moniliform (bead-like) hyphae along with large vesicular swellings. The dematiaceous molds are highlighted by the melanin-specific Fontana-Masson stain. Fusarium, Scedosporium, and Aspergillus appear very similar on microscopy of stained tissue and are difficult to differentiate from each other (collectively referred to as hyalohyphomycetes) [18]. Tissue should not be homogenized aggressively (with a mechanical tissue homogenizer or using a mortar and pestle) prior to culturing, as this may reduce the organism’s viability. This is particularly critical for Mucorales. Mucorales are inhibited by cycloheximide contained in some selective media. Malt extract agar may increase primary isolation of the Mucorales from clinical samples [12]. Fusarium and to a lesser extent Scedosporium species may grow in blood cultures [137]. Growth from a non-sterile site does not necessarily indicate infection and must be evaluated in the context of the clinical scenario and direct staining results [138]. Identification to the species level and susceptibility testing can be very helpful for many non-Aspergillus molds. There is only a limited role for serologic and NAATbased techniques in non-Aspergillus mold infections. With the exception of the Mucorales, serum BG may be detected in such infections. Some Fusarium antigens cross-react with the GM-EIA [78]. Detection of Mucorales-specific T cells has shown promise as an adjunct to diagnosis of mucormycosis [139]. Innovative NAATs, including panfungal assays, have been developed but are limited to specialized laboratories [27, 140]. There are currently no commercial NAAT assays targeting those pathogens.

Candida  linical Syndromes and Diagnostic Approach C Candida species are normal commensals of the gut, skin, and female genital tract. Clinical manifestations can range from benign superficial infections to life-threatening deepseated disease. The most common species are C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. Manifestations of superficial infection include thrush, esophagitis, intertrigo, and vulvovaginitis. Invasive candidiasis (IC) occurs when Candida gain access to deeper tissues, usually from an enteric or cutaneous source, with possible hematog-

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enous dissemination to distant organs such as the liver, spleen, kidneys, lungs, heart, eyes, and skin. Candidemia is the most recognized form of IC and occurs with or without clinical evidence of deep-seated candidiasis. Conversely, deep-seated candidiasis is often not associated with candidemia [141]. It the SOT population, IC is mostly seen as a typical nosocomial infection, related to postoperative care, occurring during the weeks following transplantation in non-­neutropenic hosts. Infection of the allograft itself, or at the site of surgery, is often found with concomitant bacterial infection [37, 39]. Conversely, most IC episodes after HSCT arise during or shortly after neutropenia, and the gut is the main source [38, 142].

Laboratory Detection Microscopic examination may be useful for diagnosis of IC.  Suitable stains include Gram stain, CFW, GMS, and PAS. Microscopically, most Candida species appear as oval-­ shaped 3–6 μm budding yeast cells with pseudohyphae and hyphae when invading tissue. Distinctively, C. glabrata produce smaller blastoconidia (2–5 μm) and do not form hyphae [18]. Results from non-normally sterile sites need to be interpreted cautiously, and histopathology is critical for distinguishing invasive disease from colonization. Growth from a sterile body site, including blood, remains the principal means for diagnosis. Candida spp. are non-­ fastidious, fast-growing organisms that can be recovered on most routine media. Traditionally, Candida spp. were best cultured from blood by using a lysis-centrifugation method [143–147], but continuous monitoring blood culture systems (mycological media bottles or regular aerobic bottles) are as effective [16, 148, 149]. Regardless of the method, blood cultures are relatively insensitive because many IC forms do not have circulating viable organisms (candidemia) [141]. For instance, only about 10% of patients with candida endophthalmitis or chronic disseminated candidiasis (also called hepatosplenic candidiasis) have positive blood cultures [150, 151]. Identification of Candida to the species level following growth on primary culture is important for invasive infection. Methods include microscopic morphology (germ tube test and Dalmau method), biochemical tests, chromogenic media, and peptide nucleic acid fluorescence in situ hybridization (PNA FISH) [152–154]. MALDI-TOF is routinely used in many laboratories [23, 155–157] and can be performed directly from positive blood culture bottles [158]. Nonculture-based techniques are important adjuncts. The most developed of these is serum BG measurement. Many fungi including Candida produce BG. A cutoff of 60–80 pg/ml suggests invasive disease. Sensitivity and specificity are typically in the ~80% range [102]. False-positive results may be seen in a variety of circumstances including severe burns, extensive gauze packing, various blood products, renal replacement therapy with cellulose containing membranes, and infection with

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Pseudomonas aeruginosa [159–161]. Accuracy is highest with candidemia, as compared to other forms of invasive candidiasis. The role of serial BG to guide early antifungal therapy in high-risk patients is unclear. There is a paucity of data evaluating BG-based preemptive therapy in the transplant population [104]. Controlled studies in high-risk intensive care unit patients have failed to demonstrate benefits over prophylaxis or empiric strategies [162–164]. Other biomarkers include mannan antigen (Platelia™ Candida Ag Plus, Bio-Rad Laboratories), anti-mannan antibody (Platelia™ Candida Ab Plus, Bio-Rad Laboratories), and the Candida albicans germ tube antibody (CAGTA) (invasive candidiasis (CAGTA) VirClia® IgG Monotest, Vircell), but clinical data are limited and the assays are not commercialized in North America [165–171]. Numerous NAATs have been developed for detection of Candida spp. directly from clinical specimens [172]. Until recently, standardization and clinical data was insufficient to support widespread use. A few commercial NAAT assays are currently available. The LightCycler® SeptiFast (Roche Diagnostics) detects five different Candida species (C. albicans, C. tropicalis, C. parapsilosis, C. krusei, and C. glabrata), while the RenDx Fungiplex assay (Renishaw Diagnostics) targets three additional species (C. guilliermondii, C. lusitaniae, and C. dubliniensis) [31], from blood samples. Neither is currently available in North America and the data from transplant recipients is scanty [31, 123, 173]. The T2Candida® Panel (T2 Biosystems) uses a novel approach for diagnosis of invasive candidiasis from whole blood samples. This FDA-cleared test uses the T2Dx® instrument to extract and amplify Candida DNA (internal transcribed spacer 2) and then detects it via agglomeration of supermagnetic particles (attached to species-specific probes) and T2 magnetic resonance (T2MR) measurement. This technology exhibits high analytical sensitivity with limit of detection of 1 CFU/mL for C. tropicalis and C. krusei, 2 CFU/mL for C. albicans and C. glabrata, and 3 CFU/mL for C. parapsilosis [32]. The assay has a specificity of 99.4%, sensitivity of 91.1%, and negative predictive value reaching 99.5% (in a population with 5% prevalence of candidemia) [174]. Because of this high negative predictive value, the assay may serve to limit antifungal therapy in a low-to-­moderate risk population, especially if coupled with an antimicrobial stewardship program. The cost-effectiveness of the test remains unclear based on model-derived analyses and should be assessed in prospective comparative trials [175, 176].

Cryptococcus  linical Syndromes and Diagnostic Approach C Cryptococcosis is caused by the ubiquitous Cryptococcus neoformans (serotypes A, D, and AD) and the more geographically confined C. gattii (serotypes B and C). Both encompass multiple phylogenetically distinct species, and some

S. F. Dufresne et al.

propose renaming them as “C. neoformans species complex” and “C. gattii species complex” [177]. Cryptococcosis is a major problem in patients with advanced HIV/AIDS but also affects other immunocompromised hosts such as SOT recipients. It is rare in HSCT recipients [36, 38, 39, 135, 178–180]. Primary infection occurs in the lungs, but CNS and disseminated diseases are common [181]. Virtually any organ can become infected including the skin, eyes, lymph nodes, and prostate. The latter can serve as a sanctuary for this yeast. It is important to maintain a high clinical suspicion for cryptococcosis in immunocompromised patients. CNS, pulmonary, cutaneous, and lymph node abnormalities in an appropriate host should raise the possibility of this infection. Sometimes subtle neuropsychiatric symptoms or fever alone may be the only clues. Therefore, cryptococcal antigen testing is frequently done in transplant patients when an infection is considered. When cryptococcal infection is confirmed at any site in a transplant recipient, investigation of the CNS is recommended [182, 183].

Laboratory Detection Cryptococcus can be observed directly in infected tissue and body fluids, including CSF, lung tissue, lower respiratory secretions, skin, and urine. Histopathology is sometimes required and is most helpful for skin biopsies. In clinical specimens, microscopic examination reveals GMS-positive round to oval yeasts, with a single narrow-base budding. Size may vary significantly (2–20 um for regular cells; up to 50–100 um for Titan cells), even within a microscopic field. The organism can be visualized with GMS, H&E, and even Gram staining. The thick polysaccharide capsule is a major feature and can be visualized with mucicarmine dye (for FFPE tissue). Occasionally, acapsular strains are encountered. Fontana-Masson, which stains melanin, is useful in such situations [18]. Visualization of the yeast cells in CSF with the India ink preparation is rapid but lacks sensitivity, especially in non-HIV/AIDS patients in whom the organism burden is lower [184]. Growth in culture is an important part of the diagnostic evaluation. Cryptococcus spp. can grow on most primary isolation media in 36–72  h but sometimes require longer incubation. Blood, CSF, respiratory specimens, and urine [185, 186] are all appropriate materials for culture. Identification is straightforward using standard biochemical tests. Differentiating between C. neoformans and C. gattii may have important clinical and therapeutic implications. This can be achieved using L-canavanine glycine bromothymol blue (CGB) agar, MALDI-TOF, or molecular methods [187–192], but most clinical laboratories do not currently distinguish between the two species. The importance of the capsular polysaccharide antigen (glucuronoxylomannan, GXM) for diagnosis cannot be overstated. It has been used for diagnosis of cryptococcosis for more than half a century [193]. Suitable fluids include

48  Diagnosis of Systemic Fungal Diseases

serum, CSF, BALF, and urine. Various immunoassays (e.g., LA, ELISA, lateral flow) have been developed and commercialized for this purpose [194–200]. Pretreatment of serum samples with pronase improves sensitivity and specificity of the LA-based tests [201]. Cross-reactivity with Trichosporon has been reported, but this is uncommon [202]. Conversely, serum antigen may not be detected in primary pulmonary cryptococcosis [203, 204]. A next-generation lateral-flow immunoassay for point-of-care diagnosis is now available. This test can be applied to a range of specimens including CSF, serum, and urine and compares favorably to other assays [200, 205–207]. Probably because of the high performance of antigen detection, NAATs for Cryptococcus detection directly from clinical specimens contribute only marginally to the diagnostic arsenal [208, 209].

Pneumocystis  linical Syndromes and Diagnostic Approach C Pneumocystis jirovecii is a human-specific fungal pathogen that colonizes both immunocompetent and immunocompromised hosts. In patients with defects in cell-mediated immunity, mostly in the context of advanced HIV/AIDS or transplantation, it can cause severe pneumonia. Mortality is especially high among non-HIV-infected patients. Extrapulmonary sites are rarely involved (e.g., lymph nodes, liver, spleen, bone marrow) [210, 211]. When Pneumocystis pneumonia (PCP) is suspected, respiratory tract specimens (e.g., sputum, induced sputum, BALF, lung tissue) should be obtained for microbiological testing. Serum beta-D-glucan (BG) is increasingly used as a noninvasive diagnostic test for PCP. Laboratory Detection Pneumocystis jirovecii is not routinely cultivatable (achieved by one laboratory using a complex cellular culture system [212]); hence diagnosis is via culture-independent methods including microscopy, BG, and NAATs. Definitive diagnosis is achieved by microscopic evidence of infection. In vivo, two different forms can be observed: cystic and trophic. This nomenclature is a relic of its former (obsolete) classification as a parasite. Giemsa stains the trophic form, while CFW, GMS, and toluidine blue are useful for visualization of the cyst form. The cysts are 4–7 μm and display one or two dark dots on their surface. The cysts have an oval (intact) or crescent (collapsed) shape and often form aggregates in a foamy substance [18]. Monoclonal antibodies are available in commercial kits for direct or indirect immunofluorescence [213–215]. The sensitivity of immunofluorescence-­aided microscopy is superior to other stains [215, 216]. For microscopic methods, sensitivity of BALF is superior to that of less invasive specimens [216–221]. Generally, microscopy lacks sensitivity when compared to

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other methods. Immunofluorescence was reported to detect as few as a third of positive samples as determined by PCR [222]. However, as discussed below, some PCR-­positive/ microscopy-negative samples represent Pneumocystis colonization; sensitivity of microscopy for actual Pneumocystis pneumonia is estimated at 55–60% [223, 224]. This is particularly relevant for non-AIDS patients, in whom the fungal burden is generally lower [224, 225]. Consequently, in transplant recipients with suspected PCP, negative microscopic examination of BALF cannot rule out PCP. Polysaccharide detection (BG) is an important adjunct for PCP diagnosis. BG serum levels correlate well with fungal burden [223, 226, 227]. Most studies have reported serum BG detection to be >90% sensitive [102, 228]. In contrast with microscopic methods, BG accuracy for PCP is not affected by HIV status [102, 228]. BG results must be interpreted with caution as the assay is not specific, but in the appropriate context, it is a good screening test, and a negative result is reassuring for absence of PCP. Multiple NAATs using respiratory samples have been developed. Many are “in-house” assays, but several commercial kits are available, including the Pneumocystis jirovecii PCR kit (Bio-Evolution) [229–231], the AmpliSens® Pneumocystis jirovecii (carinii)-FRT PCR kit (InterLabService) [229], the PneumoGenius® (PathoNostics) [231], and the MycAssay™ Pneumocystis (Trinity Biotech) [126, 222, 229, 232]. The latter has been the most extensively studied. None are FDA-cleared. Most P. jirovecii NAATs are real-time PCR assays targeting the multicopy mitochondrial large subunit ribosomal RNA gene (mtLSU). The PneumoGenius® allows detection of two mutations in the dihydropteroate synthase (DHPS) domain of the FAS gene that confer resistance to sulfa drugs. As a general rule, PCR assays are extremely sensitive with a limit of detection 100 times lower than microscopic methods [233]. This difference is due to the methods’ intrinsic analytical sensitivities and because NAATs detect both trophozoites and cysts, while microscopic methods are unreliable for trophozoites [233]. Sensitivity is virtually 100%, but the assay cannot clearly distinguish between infection and colonization with clinical false positivity ranging from 6% to 17% [126, 229, 232]. Efforts to establish a fungal load cutoff that would discriminate pneumonia from colonization have proved difficult [223, 230, 231, 234, 235]. Compared with microscopy, NAATs’ sensitivity is more homogenous across different types of respiratory samples [229]. Serum DNA level correlates with pulmonary fungal burden [227], but is detectable only in high-burden infections and hence adds little to other diagnostic methods. NAAT testing can be applied to nasopharyngeal aspirates where sensitivity is slightly better than BALF microscopy, but less than BALF NAAT [236, 237]. Overall, microscopic methods suffer from a low sensitivity in transplant recipients, while NAATs are very sensitive

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but also detect colonization. Blood BG testing could offer the best trade-off between sensitivity and specificity and is noninvasive. NAAT performed on a noninvasive respiratory sample such as nasopharyngeal aspirate may also become a useful tool for PCP diagnosis, but more data is needed.

S. F. Dufresne et al.

the fungus should be done in strict adherence to biosafety requirements [25]. Confirmation of H. capsulatum can be attained by the exoantigens method and by nucleic acid probes (AccuProbe® Histoplasma capsulatum Culture Identification Test, Gen-Probe®) [243] and PCR followed by sequencing [244]. Antigen testing is important for evaluation of dissemiGeographically Limited/Endemic Fungi nated histoplasmosis. For histoplasmosis after solid organ transplantation, antigenuria is the most common positive test Histoplasmosis (93% of cases in one study) [245]. The Histoplasma polysaccharide antigen (HPA), which is a galactomannan [246], is Clinical Syndromes and Diagnostic Approach found in serum, urine, and BALF during infection. Detection Histoplasma capsulatum is associated with a range of clini- of HPA is achieved mainly via the MVista® Histoplasma cal manifestations including asymptomatic infection (most capsulatum quantitative antigen EIA (MiraVista Diagnostics, common), acute and chronic pulmonary histoplasmo- MVD). This test was first developed as a radioimmunoassis, and progressive disseminated histoplasmosis (PDH). say [247] and subsequently evolved over four generations of Disease may be due to reactivation or new infection [238]. ELISAs [246, 248–250]. In certain circumstances, sensitivity Immunocompromised patients, such as SOT recipients, are can exceed 90% and tends to be highest with disseminated particularly prone to PDH, which can take on a chronic-­ disease and when the test is performed on urine [239, 245, subacute to fulminant course [239]. Most infections become 246, 251–253]. Addition of EDTA-heat pretreatment for disclinically apparent within 12–18 months after transplantation sociation of immune complexes has further improved sensibut may sometimes present much later [240, 241]. Typical sites tivity [250]. The level of antigenuria correlates with severity of infection are organs of the reticuloendothelial system (RES) of disease [254], and low-positive HPA results should be and the lungs. Other sites include the gastrointestinal tract interpreted carefully considering the host, clinical presen(mucosa), genitourinary tract, adrenal glands, and skin. CNS tation, and complementary tests [255–257]. Detection of disease is uncommon, even with disseminated infection [239]. HPA on BALF may complement antigenemia and antigenBecause of its protean manifestations, histoplasmosis is often uria [258]. Cross-reactivity may be seen with other endemic part of the differential diagnosis of many clinical syndromes mycoses, particularly blastomycosis and paracoccidioiin SOT recipients, including various respiratory, hepatic, and domycosis [246]. The ALPHA Histoplasma antigen EIA febrile illnesses. When PDH is suspected in a transplant recip- (Immuno-­Mycologics) was approved by the FDA in 2011 ient, noninvasive assays such as antigen detection and blood and remains the only commercially available kit for HPA culture are usually performed first. Additionally, samples from detection. Similar to the MVD test, it is a sandwich ELISA almost any clinically infected sites can be used for histopa- utilizing polyclonal rabbit antibodies. This assay may be less thology, culture, and/or antigen detection. sensitive than the MVD test, albeit proper clinical evaluation and comparison by independent laboratories have not Laboratory Detection been performed [259–265]. More sensitive second-generaBlood, bone marrow, lymph nodes, BALF, lung tissue, and tion reagents, based on a monoclonal antibody, are still less occasionally CSF are important sources of specimens for sensitive than the MVD test and are neither commercially staining and culture. On microscopy, the organism appears available nor FDA-cleared at this time [266–268]. Of note, as small (2–4 μm) yeast cells with single narrow-base bud- the HPA can be detected by the Platelia™ Aspergillus EIA, ding and a pseudocapsule. Histoplasma capsulatum var. but at a lower magnitude [80, 269]. This can be particularly duboisii is much larger (8–15  μm) with thick-walled bud- useful in areas where specific HPA assays are unavailable ding. Yeast forms can be visualized extracellularly or within [79, 270]. While BG may be detectable during histoplasmomonocytes [18]. The latter can sometimes be seen in periph- sis [271, 272], it is not routinely used in this setting. eral blood smear or a buffy coat preparation with Wright or Serology is mainly performed using either CF or ID [1, Giemsa staining [242]. 238]. Generally, serology lacks both sensitivity and specificH. capsulatum can be grown using rich media such as ity. Low sensitivity is particularly problematic in immunobrain-heart infusion (BHI) agar and incubated for at least compromised hosts. The two tests are complementary with 4 weeks [14]. Recovery in blood cultures is facilitated when ID being less sensitive, but more specific than CF. Combining a lysis-centrifugation system or an automated system with both techniques may increase sensitivity. In CF, antigen mycological blood culture bottles is used [16, 17, 148, 149]. extracts from the yeast and mold phases of the organism In ambient temperature H. capsulatum grows as a mold on are used separately (the culture filtrate of the mold phase is solid media. Once grown in this form, any manipulation of histoplasmin). Results are reported as antibody titers against

48  Diagnosis of Systemic Fungal Diseases

each of the antigen preparations. A titer ≥1:32 is suggestive of infection (recent of remote), while a fourfold increase in titers between acute and convalescent sera is diagnostic for recent infection. ID is a qualitative method that detects two antibodies, the H- and M-precipitins, which bind the H and M antigens, respectively (both are glycoproteins contained in histoplasmin). In the ID test an M band in seen in both acute and chronic forms, whereas the H band is encountered less commonly, usually in chronic or severe infections. The M band may persist for years even after complete resolution of the infection. Serology is best for mild-to-moderate acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, pericarditis, and acute rheumatologic forms. It is less useful for progressive disseminated histoplasmosis [238]. Several in-house NAATs have been developed for detection of H. capsulatum from clinical samples [209, 273–278], but their use remains marginal.

Coccidioidomycosis Clinical Syndromes and Diagnostic Approach Coccidioidomycosis is caused by C. immitis and C. posadasii. The majority of infections are either asymptomatic or mild and self-limited. The lungs are the most commonly affected organs. Disseminated disease can involve extrapulmonary sites including bones, joints, skin, and CNS [279]. Organ transplant recipients are at increased risk for more severe and disseminated disease [280]. Microbial investigation for coccidioidomycosis can be undertaken in the context of compatible clinical disease or as part of pre-­immunosuppression serology-based preemptive strategy [281, 282]. Laboratory Detection Suitable samples for testing include respiratory secretions, CSF, and material from almost any site of infection (e.g., bones, joints, skin, bone marrow, and urine). On microscopy, spherules that range from 10 to 100 μm and typically contain 2–5  μm endoconidia (endospores) can be seen [18]. Visualization of spherules filled with endoconidia is diagnostic, while empty spherules are strongly suggestive of coccidioidomycosis [283]. Endoconidia-containing spherules may resemble Prototheca or Rhinosporidium sporangia, but size helps distinguish between those organisms. Endoconidia can also be seen alone, in which case they may be confused with Histoplasma, Cryptococcus, or Candida yeast cells. Tissue preparations, stained with fungi-specific dyes (e.g., CFW, GMS, PAS), facilitate detection of the fungal structures. Coccidioides grows well on a variety of fungal and bacterial media (e.g., sheep blood agar and BCYE) [283]. The incubation period for initial growth is 3–5 days (range 2–16  days), at which point another ~10  days are needed for the colonies to reach maturity. Yield from CSF is poor

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but can be improved with a large volume sample (>10 mL) [284]. Growth in blood culture is uncommon and more likely to be detected with lysis-centrifugation and the continuously monitored blood culture systems [285, 286]. In culture, Coccidioides grows as a filamentous fungus with arthroconidia, which appear as alternating barrel-shaped structures and are highly infectious. Because this appearance can be mistaken for the nonpathogenic environmental mold Malbranchea, at least one confirmatory test is required for definitive identification [18]. This is usually accomplished with the exoantigen assay, DNA-rRNA hybridization using commercial probes (AccuProbe® Coccidioides immitis Culture Identification Test, Gen-Probe®) [19], or with in-­house PCR-based methods [287]. Older confirmatory tests such as the conversion assay (to yeast form) and animal inoculation for in  vivo production of spherules are too cumbersome for widespread use. Because the arthroconidia are highly infectious, any manipulation of suspected or confirmed isolates should be done in strict adherence to biosafety regulations [25, 288]. Detection of specific anti-Coccidioides antibodies is helpful for diagnosis. Suitable specimens include serum and CSF.  The traditional methods are tube precipitation and complement fixation. The former detects mainly an IgM antibody directed against a heat-stable antigen, often referred to as “TP” antibody or “precipitin” and “TP” antigen, respectively. The latter involves predominantly an IgG antibody specific to a heat-labile antigen, respectively, called “CF” antibody and “CF” or “F” antigen [1, 283, 289]. Both assays have been adapted to the immunodiffusion format. Because they could detect the same antibodies as TP and CF, they were named “immunodiffusion TP” (IDTP) and “immunodiffusion CF” (IDCF), a nomenclature that might be confusing [289]. These assays use heated or unheated coccidioidin (mycelial-phase broth culture filtrate) as antigen, although purified or recombinant antigens have also been studied [1]. EIAs detecting both IgM and IgG have been developed for serum and CSF [290–294]. The Premier® Coccidioides EIA test has been the most extensively studied. The CF assay is quantitative (titers), while ID and EIA are qualitative or semiquantitative. TP antibody (IgM) is detected early during acute infection and disappears after a few months, while the CF antibody (IgG) appears later and lasts for a longer time. IgM antibody may persist in chronic pulmonary forms, while IgG titers correlate with the extent of disease. As seen for Histoplasma serology, traditional methods (CF and ID) may lack sensitivity in immunocompromised hosts [289]. However, they are considered highly specific [293]. EIA is considered more sensitive but less specific than traditional methods (especially for IgM); hence many still recommend confirmation of EIA-positive results with ID or CF [283, 284]. From a limited number of cases, sen-

830

S. F. Dufresne et al.

a Primary testing

Transplant recipient with pneumonia

Clinical & Epidemiological evaluation

Severe disease Highly IC host

(see figure 1B)

Blood GM (serum) BG (serum) CrAg (serum) Regular BC Sputum* Direct microscopy Culture

No etiology

Clinical syndrome Host status Geography

Endemic fungi suspected

Blood AG detection (serum, plasma) Giemsa (Buffy coat) Fungal BC** Urine AG detection Bone marrow Histopathology Culture***

Pneumocystis suspected

Extrapulmonary disease

According to site, consider: Cutaneous lesion biopsy Lumbar puncture Other fluid aspiration/tissue biopsy

Consider: Fiberoptic bronchoscopy with BAL Lung biopsy (TNB, VATS, OLB)

Fluid/tissue

BALF, CSF, other fluids Direct microscopy Culture AG detection Fungal NAAT Tissue Histopathology Culture Fungal NAAT

Fig. 48.1 (a) Diagnostic approach to suspected fungal pneumonia in transplant recipients. *Only if productive cough. **Mycological media bottles for continuous monitoring systems or lysis-centrifugation method. ***Using the same mycological media bottles as for blood. Legends: GM = galactomannane (Aspergillus); BG = beta-­D-­glucan; CrAg = cryptococcal antigen; BC = blood culture; IC = immunocompromised; AG = antigen; BALF = bronchoalveolar lavage fluid; TNB

= transthoracic needle biopsy; VATS = video-assisted thoracoscopy; OLB = open lung biopsy; NAAT = nucleic acid amplification test. (b) Clinical and epidemiological clues for etiology of fungal pneumoniaa. a List not exhaustive. *Includes organ donor origin for SOT recipients. Legend: BMT = bone marrow transplant; SOT = solid organ transplant; RES = reticuloendothelial system; CNS = central nervous system

sitivity of the recently developed MVista® Coccidioides Antibody IgG IgM EIA was reported to be unaffected by the immune status of the host [294]. Antigen and NAAT assays for Coccidioides are in various stages of development. These include a Coccidioides antigen that may be detected in serum or urine, which showed a sensitivity of 50–70% in severe disease [295, 296]. PCR-based methods for detection of Coccidioides DNA directly from clinical samples have also been described, but more work is needed before these can be widely used in clinical practice [297–299].

In Practice: The Clinician Perspective From the practitioner standpoint, clinical presentation usually drives investigation, and hence a syndromic approach prevails. Figure  48.1 illustrates a stepwise diagnostic process for the investigation of fungal etiologies in a transplant recipient presenting with pulmonary infiltrates, a very common encounter in this population. This schematic representation is not meant as a formal guideline, but as an example of how different diagnostic tools might be used in a particular clinical context.

48  Diagnosis of Systemic Fungal Diseases

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b Clinical s yndrome RES

CNS

Skin

Diffuse lung infiltrate

Histoplasma

Cryptococcus Aspergillus Coccidioides

Fusarium, Aspergillus Blastomyces, Histoplasma Cryptococcus

Pneumocystis Histoplasma, Blastomyces

Host BMT (early)

BMT (late)

SOT

Aspergillus Other molds (Fusarium)

Aspergillus Other molds (Mucorales) Pneumocystis

Aspergillus Other molds Crytococcus Endemic fungi

Geography* Southwest

Ohio & Mississipi River Valleys

Pacific Northwest

Coccidioides

Histoplasma Blastomyces

Cryptococcus gattii

Fig. 48.1  (continued)

Conclusion

References

The epidemiology of fungal infections has changed rapidly over the last decades, an evolution largely driven by advances in transplantation. In response, the growing threat posed by fungi has led to a dramatic improvement in the antifungal arsenal. Equally important has been the ongoing development of powerful tools that facilitate early and accurate diagnosis of fungal infections. While tremendous progress has been made with regard to assay technology and analytical performance, major challenges remain. Widespread use of promising diagnostic tests has been limited by the complexity of the assays, costs related to infrastructure and reagents, and lack of standardization. Therefore, important future avenues in assay development include further advances in point-of-care technologies and automation, as well as commercialization. Finally, assays are commonly compared with one another using banked samples, but there is relative paucity of prospective data defining real clinical performance and usefulness. Further clinical evaluation of assays is needed, and this will be eased by standardization and accessibility, essential attributes for conducting large multicenter efforts.

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Acknowledgments This work was partly supported by the National Institute of Health grant K24 (AI085118, to K.A.M.).

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S. F. Dufresne et al. 284. Brandt ME, Gomez BL, Warnock DW. Histoplasma, Blastomyces, Coccidioides, and other dimorphic fungi causing systemic mycoses. In: Versalovic J, editor. Manual of clinical microbiology. 2. 10th ed. Washington, DC: ASM Press; 2011. p. 1902–18. 285. Rempe S, Sachdev MS, Bhakta R, Pineda-Roman M, Vaz A, Carlson RW. Coccidioides immitis fungemia: clinical features and survival in 33 adult patients. Heart Lung. 2007;36(1):64–71. 286. Keckich DW, Blair JE, Vikram HR.  Coccidioides fungemia in six patients, with a review of the literature. Mycopathologia. 2010;170(2):107–15. 287. Sheff KW, York ER, Driebe EM, Barker BM, Rounsley SD, Waddell VG, et al. Development of a rapid, cost-effective TaqMan Real-Time PCR Assay for identification and differentiation of Coccidioides immitis and Coccidioides posadasii. Med Mycol. 2010;48(3):466–9. 288. Warnock DW. Coccidioides species as potential agents of bioterrorism. Future Microbiol. 2007;2(3):277–83. 289. Pappagianis D, Zimmer BL.  Serology of coccidioidomycosis. Clin Microbiol Rev. 1990;3(3):247–68. 290. Kaufman L, Sekhon AS, Moledina N, Jalbert M, Pappagianis D. Comparative evaluation of commercial Premier EIA and microimmunodiffusion and complement fixation tests for Coccidioides immitis antibodies. J Clin Microbiol. 1995;33(3):618–9. 291. Martins TB, Jaskowski TD, Mouritsen CL, Hill HR. Comparison of commercially available enzyme immunoassay with traditional serological tests for detection of antibodies to Coccidioides immitis. J Clin Microbiol. 1995;33(4):940–3. 292. Zartarian M, Peterson EM, de la Maza LM. Detection of antibodies to Coccidioides immitis by enzyme immunoassay. Am J Clin Pathol. 1997;107(2):148–53. 293. Lindsley MD, Ahn Y, McCotter O, Gade L, Hurst SF, Brandt ME, et  al. Evaluation of the specificity of two enzyme immunoassays for Coccidioidomycosis by using Sera from a region of Endemicity and a region of Nonendemicity. Clin Vaccine Immunol. 2015;22(10):1090–5. 294. Malo J, Holbrook E, Zangeneh T, Strawter C, Oren E, Robey I, et  al. Enhanced antibody detection and diagnosis of Coccidioidomycosis with the MiraVista IgG and IgM detection enzyme immunoassay. J Clin Microbiol. 2017;55(3):893–901. 295. Durkin M, Connolly P, Kuberski T, Myers R, Kubak BM, Bruckner D, et al. Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay. Clin Infect Dis. 2008;47(8):e69–73. 296. Durkin M, Estok L, Hospenthal D, Crum-Cianflone N, Swartzentruber S, Hackett E, et  al. Detection of Coccidioides antigenemia following dissociation of immune complexes. Clin Vaccine Immunol. 2009;16(10):1453–6. 297. Binnicker MJ, Buckwalter SP, Eisberner JJ, Stewart RA, McCullough AE, Wohlfiel SL, et  al. Detection of Coccidioides species in clinical specimens by real-time PCR. J Clin Microbiol. 2007;45(1):173–8. 298. de Aguiar CR, Nogueira Brilhante RS, Gadelha Rocha MF, Araujo Moura FE, Pires de Camargo Z, Costa Sidrim JJ. Rapid diagnosis of coccidioidomycosis by nested PCR assay of sputum. Clin Microbiol Infect. 2007;13(4):449–51. 299. Vucicevic D, Blair JE, Binnicker MJ, McCullough AE, Kusne S, Vikram HR, et  al. The utility of Coccidioides polymerase chain reaction testing in the clinical setting. Mycopathologia. 2010;170(5):345–51.

49

Viral Diagnostics Robin K. Avery and Belinda Yen-Lieberman

Background and Introduction Advances in diagnostic testing for transplant-related infections, particularly molecular viral diagnostic assays, constitute one of the most notable changes in transplant infectious disease over the last two decades [1, 2]. This chapter discusses recent developments in diagnostics for cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK virus (BKV), community respiratory viruses (CRVs), parvovirus, hepatitis viruses, HIV, and other viral agents of importance in solid organ and hematopoietic stem cell transplantation. The recent debate regarding the extent of nucleic acid amplification (NAT) testing for HIV, HBV, and HCV in proposed transplant donors is reviewed [3]. Different uses for molecular viral tests in the transplant recipient are discussed, ranging from facilitation of antiviral preventive strategies to determination of length of therapy for active infections. The advantages and disadvantages of single vs. multiplex assays are explored [2]. Challenges in this field include interlaboratory variation [4], management of false-positive and discordant test results, and need for consensus on which patients should receive which testing, at what intervals, and for what period of time. Despite these challenges, molecular viral diagnostics have clearly contributed significantly to the reduction of infectious morbidity, by enabling early diagnosis and intervention, resulting in such notable examples as the reduction in severe CMV disease [5, 6] and in kidney allograft loss due to BKV [7]. Future clinical trials in the field of transplantation should incorporate accepted definitions of infection and practices of viral monitoring for transplant-­associated viruses [8]. R. K. Avery (*) Division of Infectious Disease, Johns Hopkins, Baltimore, MD, USA e-mail: [email protected] B. Yen-Lieberman Pathology and Laboratory Medicine Institute, Cleveland Clinic, Department of Laboratory Medicine, Cleveland, OH, USA e-mail: [email protected]

 eneral Considerations, Definitions, G and Uses of Viral Diagnostic Tests The term “serology” or “serologic test” refers in general to an assay which detects an antibody to a specific pathogen, usually IgG or IgM. A panel of serologic tests is performed on both donor and recipient prior to transplantation. The results may be used to disqualify a prospective donor or to restrict the use of the donor to a specific subgroup of recipients or more commonly may be used for risk stratification and posttransplant management for particular infections (e.g., the donor-seropositive, recipient-seronegative or D+/Rgroup which is the subgroup at the highest risk for both CMV and EBV, respectively, in solid organ transplantation) [9]. Serologies are of limited value in diagnosing active infections in the posttransplant patient, since immunosuppressed patients may not mount an IgM response even in the setting of an active infection and some recipients with de novo posttransplant hypogammaglobulinemia have globally low IgG levels [10]. IgG serology remains positive for life, and pathogen-specific IgG titers do not usually correlate with the activity of infection, so obtaining an IgG level (for CMV or EBV, among others) is not generally helpful in diagnosing an acute illness in a transplant recipient (an exception is when the clinician wants to know if a previously seronegative patient has seroconverted, which might have prognostic value, for example, in predicting ongoing risk for recurrences of CMV viremia) [11]. Antigen-based testing, such as the pp65 antigenemia test for CMV, does have a potential role in posttransplant recipients, as this is a direct detection of the virus and not a reflection of the patient’s immune response to the virus [12, 13]. However, in most cases, antigen detection is semiquantitative and does not provide an exact viral load to follow over time. In addition, some antigen tests (such as the pp65 antigenemia test for CMV) decay with time, and thus lose sensitivity, if the sample is mailed into a central laboratory or if there is a delay between obtaining the blood sample and laboratory performance of the test.

© Springer Science+Business Media, LLC, part of Springer Nature 2019 A. Safdar (ed.), Principles and Practice of Transplant Infectious Diseases, https://doi.org/10.1007/978-1-4939-9034-4_49

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Table 49.1  Molecular tests for selected transplant-related viruses Test Name Qiagen Artus CMV RGQ Abbott RealTime CMV Roche CMV [19] RealStar qCMV (Altona) CMV Qiagen Artus EBV RealStar EBV qPCR (Altona)___ Qiagen BKV RealStar BKV (Altona)

Method Real-time PCR Real-time PCR Real-time PCR; CAP/CTM Real-time PCR

Dynamic range at Copies/ml 159 IU/ml–1.0 × 107 IU/ml 31.21 IU/ml–156 × 106 IU/ml 137 IU/ml–1 × 106 IU/ml 150 IU/ml–1 × 106 IU/ml

Sensitivity 96.6% 95–97% 97.5–98.0% 100%

Specificity 100% 99% 100% 100%

Test Status IVD IVD IVD ASR

Real-time PCR Real-time PCR Real-time PCR Real-time PCR

500–5.0 × 106 IU/ml 500–10,000,000 copies/ml 500–5.0 × 106 copies/ml 300–100,000,000 copies/ml

95–97% 94.5% 95–97% 100%

99% 98.1% 99% 100%

ASR ASR ASR ASR

ASR analyte-specific reagents, IVD in vitro diagnostic test (FDA-cleared)

Molecular testing has revolutionized viral diagnosis in transplantation [14–16]. Molecular diagnostic tests are generally highly sensitive assays that directly detect the virus’ genetic material such as DNA or RNA (depending on the type of virus) and can be qualitative or quantitative. There are a variety of methodologies, including polymerase chain reaction (PCR) technologies, hybrid capture assay, nucleic acid sequence-based amplification (NASBA), transcription-­ mediated amplification (TMA), and others [1, 2, 17, 18]. Performance characteristics of some of these tests in comparative studies are shown in Table  49.1. Testing may be monoplex (a single pathogen tested at one time) or multiplex (which refers to several or many pathogens tested in one sample). The advantages and disadvantages of each strategy are discussed below. The uses of molecular diagnostic assays are many. Most commonly these tests are performed on whole blood or plasma (and may be referred to as the blood “viral load”) when quantifying the virus, although other relevant samples may be tested, such as urine in the case of BK virus or a nasopharyngeal swab or bronchoalveolar lavage fluid in the case of respiratory viruses. A list of potential uses for quantitative molecular diagnostic tests is shown in Table 49.2. The most common uses are in preemptive therapy or screening for viral infection prior to symptoms, in diagnosis of an acute infectious syndrome, and in monitoring for blood viral clearance to help determine the duration of therapy for an infection episode. An even newer set of diagnostic tests is currently under development, namely, pathogen-specific assays of cellular immune function. Of these, the one in widest use so far is the interferon-gamma release assay (IGRA) for tuberculosis (QuantiFERON-TB Gold in-tube, Cellestis/Qiagen Inc., Germantown, Maryland) [20]. This assay is specific for Mycobacterium tuberculosis and avoids false-positive results due to BCG vaccination, as with the tuberculin skin test [20]. Similar assays for CMV and BKV have been an area of intense research interest. Recent results suggest that measurement of CMV-specific immune function is useful in risk stratification of high-risk organ transplant recipients [21] and

Table 49.2  Potential uses for quantitative molecular diagnostic tests Screening of living or deceased prospective organ donors Diagnosis of an acute infectious syndrome Preemptive therapy or monitoring/screening for viral infection Prediction of severity of disease (quantitative viral load) Monitoring for resolution of infection and guidance for duration of therapy Monitoring for recurrence of infection after completion of therapy Determining the success of viral suppression or secondary prophylaxis Clues to the presence of antiviral resistance (rise in viral load or failure to decrease on therapy) Genotypic antiviral resistance testing (e.g., UL97 or UL54 mutations in CMV)

in hematopoietic stem cell transplant recipients [22]. It is likely that these tests will be more commonly used in the future in transplant virology, with an eye to devising personalized prevention programs using assessments of individual patients’ pathogen-specific immunity. However, testing for virus-specific cell-mediated immunity has not yet become widely performed at the time of this writing, so the current chapter will focus mainly on molecular diagnostic testing.

Cytomegalovirus CMV remains one of the most common viruses to reactivate in the posttransplant patient. In the early years of transplantation, diagnosis of CMV infection relied on detection of viral growth in tissue culture, which was laborious and could take several weeks for a positive result to be obtained, particularly if the samples have low viral load. The advent of shell-vial centrifugation culture methodology shortened the turnaround time from 4–5 days to 48 h, but this test was less sensitive at lower viral loads and did not provide quantitative results [13]. The pp65 antigenemia test was then devised, and multiple studies have validated its utility in posttransplant monitoring and as a basis for preemptive therapy [12, 13, 23]. The pp65 antigenemia test detects CMV-infected white blood cells in peripheral blood using a

49  Viral Diagnostics

fluorescent assay which requires the laboratory technician to visually scan the slide and to report the number of positive (infected) cells per unit of area. It is thus a semiquantitative test. Although this does give some idea of the magnitude of the viral load, it is not as definitive in viral load measurement as quantitative molecular tests, which are usually expressed as DNA copies/ml or, most recently, in international units. The pp65 antigenemia assay is laborintensive for the laboratory and thus may be problematic for transplant centers with very high volumes of tests. In addition, the results decay after obtaining the blood sample, so it is less suitable for mailing in to a central laboratory from patients who live a long distance away from the transplant center. Molecular diagnostic tests for CMV have largely supplanted previous tests at many centers. Their quantification of the blood viral load, ease of handling high volumes of samples, and lack of decay with time if properly handled make the CMV DNA by PCR a useful choice for a transplant center with high volumes of samples and/or patients outside the immediate area. Quantitative viral loads often correspond to severity of disease, although interlaboratory variation has hampered the attempt to describe universal cutoff values for clinical categories and decision-making [4, 24, 25]. In solid organ transplant recipients, tissue-invasive CMV episodes generally have the highest viral loads (e.g., >50,000–100,000 copies/ml); asymptomatic viremia has the lowest viral loads (e.g., 11% and was DFA alone when the prevalence was  MIC—The percentage of the dosage interval in which the concentration of the antimicrobial exceeds the MIC of the organism determines bacterial inhibition. This is also referred to as time-dependent activity in select antimicrobials. • Cmax:MIC ratio—Bacterial inhibition is related to high concentrations of antimicrobial at the site of action. This is also referred to as concentration-dependent activity in select antimicrobials. • AUC:MIC ratio—The total amount of drug exposure determines bacterial inhibition. This is a combination of time-­dependent and concentration-dependent activity. Not to be lost among an array of PK/PD characteristics of multiple medications is critical attention to the transplant patient. History is important and a thorough assessment of current patient status even more so. The state of vital organ function can strongly influence the disposition of many medications. Laboratory tests in conjunction with measurement

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and assessment of vital signs for renal, hepatic, pulmonary, gastrointestinal, and neurologic function should help aid the clinician charged with dosing antimicrobials as well as other medications.

Special Populations Critical Illness Despite recent advances leading to improved short-term survival rates in the SOT population, this patient population is at high risk for critical illness. In both the early post-surgery phase and long-term maintenance phase, sepsis and related septic shock are common causes of death [8]. Long-term immunosuppression may modify or mask clinical features of systemic inflammatory response syndrome in patients with sepsis. What is clear is the benefit of early effective antibiotics in SOT recipients with septic shock [9, 10]. The choice of antibiotics used should relate to the local patterns of bacterial susceptibility, patients’ clinical presentation, and risk probability of infection, not to mention that patients with severe immune dysfunction are prone to multiple infections that may occur concurrently. Appropriate dosing of antibiotics in critical illness requires knowledge of the pathophysiology of sepsis; understanding of the patient’s clinical status and current therapies such as fluid resuscitation status and renal replacement therapy, among others; as well as the PK/PD of the antibiotic being given. Septic shock initially causes circulatory disruption due to vasodilatation and increased permeability of the microvascular endothelium [11]. Coupled with fluid resuscitation, these factors relate to an increased Vd of antibiotics, particularly hydrophilic antibiotics since the extracellular water compartment expands. Lipophilic antibiotics may be affected but to a lesser magnitude since adipose tissue remains unchanged. Beta-lactams, for example, are generally considered hydrophilic. A brief summary of the hydrophilic and lipophilic tendencies of antibiotics can be found in Table 51.1. A systematic review of beta-­lactam pharmacokinetics in critical illness revealed an increased Vd for all studied beta-lactams compared to healthy volunteers [12]. Although this difference may be in part related to increased total body weight, it is important to note that standard renal dose adjustments may not result in effective concentrations of antibiotic after the first dose. Therefore, a full or loading dose should be given prior to dose adjustment for changes in clearance [13, 14]. Increased Vd typically causes a prolonged half-life, and renal dysfunction is common in septic shock; however, some critically ill populations show increased renal blood flow,

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Table 51.1  General classification of hydrophilic and lipophilic antibiotics [14, 16] Hydrophilic β-Lactams Aminoglycosides Glycopeptides (vancomycin) Lipopeptide (daptomycin)

Lipoglycopeptide (telavancin) Oxazolidinone (linezolid) Polymyxin (colistin)

Lipophilic Fluoroquinolones (levofloxacin, ciprofloxacin) Macrolides (azithromycin, clarithromycin) Lincosamide (clindamycin) Tetracyclines (including doxycycline, minocycline, tigecycline) Rifamycin (rifampin)

and calculations of creatinine clearance may underestimate predicted drug clearance [15]. In the case of time-dependent killing bactericidal agents such as beta-lactams, the percentage of time the drug concentration is above the minimum inhibitory concentration (MIC) of the bacteria is crucial. Target ranges from 40% to 100% of the time above MIC for effective drug dosing and depends upon the beta-lactam drug used [14]. Given the wide therapeutic index of most betalactams and lack of available therapeutic drug monitoring, authors’ preference is to dose at the higher or more frequent range whenever possible or reasonable to avoid marginally therapeutic underdosing. Continuous and extended infusions of beta-lactams may have benefit as they optimize the pharmacokinetic and pharmacodynamics by virtue of lower peak and higher trough concentrations. At this time, data on clinical outcomes is mixed and lacks rigorous prospective trials. Although intriguing, routine use of continuous or extended infusion beta-lactam antibiotics should be weighed against potential intravenous line access issues, and care should be taken to ensure delays in initial adequate systemic concentrations are not introduced by implementing a protocol for continuous or extended drug infusion. Aminoglycosides are also considered hydrophilic. Unlike beta-lactams, the bactericidal activity of aminoglycosides is related to peak concentrations such as Cmax:MIC or AUC:MIC ratio. With once-daily dosing, an optimal peak to MIC ratio of 8–10:1 is often targeted [17]. Changes in Vd are again important to consider. Initial doses of 7  mg/ kg of gentamicin or tobramycin [18] and 15–20  mg/kg of amikacin are typically recommended for once-daily dosing regimens; however, the patient populations used to validate these dosing regimens often excluded critically ill patients with altered Vd. Furthermore, higher doses of concentrationdependent antibiotics may be required to reach optimum peak concentrations in the critically ill patients [19–21]. Therapeutic drug monitoring is recommended and doses are adjusted to maintain adequate peak concentrations while extending the dosing interval to minimize trough concentrations. Renal toxicity with aminoglycosides is well-­described.

In an attempt to minimize renal injury, trough concentrations of undetectable or   MIC for efficacy.

Cystic Fibrosis Cystic fibrosis (CF) is the third most common diagnosis category leading to lung transplant in the USA [57]. When infection and inflammation lead to bronchiectasis and, ultimately, end-stage pulmonary disease in patients with CF, lung transplantation offers a survival benefit for most patients [72]. With few exception, the presence of multidrug-resistant pathogens pretransplant is generally not considered a contraindication to lung transplantation [73]. However, in the setting of posttransplant immunosuppression, infections remain

51  Pharmacokinetics and Pharmacodynamics of Antibiotics in Transplant Patients

a major source of complications and declining pulmonary graft function following lung transplantation. Additionally, the transplanted lung lacks innervation, resulting in suboptimum cough reflex and adequate clearance of respiratory secretions [74]. Patients with CF undergoing lung transplantation require perioperative antibiotics with a special attention paid to selecting antimicrobials active against the organism(s) the patient may be colonized with or had infectious episodes with prior to transplant. Frequent courses of antibiotics are also likely to be necessary during the posttransplant period. Consideration of antimicrobial PK/PD parameters is paramount for achieving optimum drug concentrations, especially at the infection site(s), and improved drug efficacy to treat often serious and life-threatening infections in this unique patient population. The extent of drug absorption may be diminished in patients with CF secondary to reduced gastric acid secretion and bile acid malabsorption [75, 76]. While studies in patients with CF have failed to consistently demonstrate a clinically significant decrease in the AUC of orally administered antimicrobials, a reduced Cmax has been observed for some antimicrobial agents [77–82]. There are no PK studies to date which evaluate the impact of CF on the rate and extent of antimicrobial absorption following lung transplantation, although studies of antirejection medications have demonstrated higher oral dosage requirements in the CF population when compared to those without CF [83, 84]. In general, CF patients prior to transplantation have an increased Vd secondary to higher lean muscle mass per kilogram of body weight [85–87]. Hepatic dysfunction is a common complication of CF, but despite this, the CF population appears to have enhanced metabolism of many drugs [88]. Some of the CYP enzymes have demonstrated increased activity in patients with CF such as CYP1A2 and CYP2C8, whereas others like CYP2C9 and CYP3A4 appear to be unaffected [87–91]. The renal clearance of many drugs is also enhanced in patients with CF, although the mechanism for this enhancement is unclear [73, 92, 93]. Data for Vd, CL, t1/2, and AUC of antimicrobials in CF patients following lung transplantation is less than adequate [94, 95]. In one retrospective study, tobramycin PK was evaluated in eight patients with CF before and after bilateral lung transplantation [95]. The investigators found no difference in AUC or Vd pretransplant versus posttransplant. CL decreased and t1/2 increased from pretransplant values during the immediate postoperative period; however, only a significant difference in t1/2 remained in the patients who received tobramycin ≥6 weeks posttransplant. The investigators noted a large interpatient variability in these PK parameters and recommended that they be reexamined during each tobramycin course following lung transplantation. Taken together, these data suggest that antimicrobial dose requirements in patients with CF may not only differ

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from non-CF counterparts but may also diverge from pretransplant parameters after patients have undergone lung transplantation. Some potential explanations for these alterations include medication-associated organ dysfunction, drug interactions and changes in fluid, and patients’ nutritional status. An individualized approach to antimicrobial dosing is required, one that takes into account the patient’s organ function, body composition, and overall severity of illness; TDM should also be utilized when available.

Obesity Historically, obesity has been considered a relative contraindication for SOT due to increased perioperative morbidity and mortality. While it does appear that obese patients are at an increased risk of surgical site infection, the benefits of transplantation outweigh the risks of surgical complications in many clinical situations among patients with obesity and end-organ disease [96–100]. Moreover, a survival benefit has been demonstrated in obese patients in whom kidney and liver transplants were undertaken compared with similar patients in whom transplantation was deferred due to obesity [101, 102]. Organ transplants are being performed in increasing numbers in such patients, and this trend is likely to continue given the continued rise in the prevalence of obesity nationally [103]. Moreover, the prevalence of obesity after undergoing organ transplantation is also on the rise. Nearly one-third of liver transplant recipients with a normal pretransplant body mass index (BMI) were noted to have BMI in obesity range after undergoing orthotropic liver transplantation [104, 105]. The development of posttransplant obesity has been linked to universal prednisone use and near-universal use of calcineurin inhibitors (CNIs), especially cyclosporine for prevention and treatment of allograft rejection [106, 107]. When treating infections in such patients, consideration for changes in the antimicrobial PK is critical for achieving adequate serum concentrations while minimizing drug toxicity. Absorption of drugs remains essentially unchanged; however, an increased volume of adipose tissue results in an increased Vd and CL for many antimicrobial agents [108, 109]. The impact of obesity on a drug’s Vd will vary based on the characteristics of the drug molecule; for example, hydrophilic molecules are less likely to be distributed into the adipose tissue (Table 51.1). The effect of obesity on hepatic metabolism is largely unknown; obese patients are known to have an increased GFR. This phenomenon has been attributed to the enlarged glomeruli observed in obese versus nonobese patients [110]. In fact, organs from obese kidney donors demonstrate a significantly higher GFR compared to renal grafts harvested from nonobese donors [110]. Estimating CrCl in obese patients presents a challenge to clinicians; transplant

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care teams should include experienced PharmDs. CrCl based on total body weight (TBW) in obese patients results in an overestimated renal clearance, whereas ideal body weight (IBW) tends to underestimate CrCl [111, 112]. Adjusted body weight (ABW) appears to closely correlate with CrCl in this population (ABW = IBW + correction factor x [TBW – IBW]). A correction factor of 0.4 is commonly used. The modification of diet in renal disease (MDRD) equation is an attractive option because it does not include body weight as a variable; it should be noted that this formula has not been rigorously tested for drug dose adjustments in obese patients [113]. It is interesting to note that Vd and CL differences have not significantly influenced antimicrobial drug elimination rates, possibly because elimination rate constant (ke) = Vd/Cl, which offset one another. Nonetheless, TDM should be used to help guide therapy in this patient population when possible. The majority of studies for evaluating vancomycin PK in obese subjects suggest that Vd is increased compared to nonobese patients. It is generally recommended that vancomycin be dosed at 15–20 mg/kg using TBW [114, 115]. Vancomycin CL is also increased in obese patients; TDM of serum vancomycin trough levels should be monitored [114, 115]. For highly hydrophilic drugs, such as the aminoglycosides, it is generally recommended that doses be based on an ABW. For the ­aminoglycosides, a correction factor of 0.4 is generally recommended [116, 117]. Studies of the fluoroquinolones have produced variable results precluding any specific dosage recommendations; dosing at the higher end of the therapeutic range has been suggested [109]. Beta-lactam antibiotics display hydrophilic properties and have limited distribution into adipose tissue [109]. Nonetheless, higher doses of beta-lactam antibiotics may be required to achieve adequate concentrations, especially in adult transplant patients with extreme obesity. In a study, 2 g of cefazolin was required in obese patients undergoing bariatric surgery to obtain comparable tissue concentrations to 1 g cefazolin dose in nonobese patients [118]. This is reflected in the current antibiotic surgical prophylaxis guidelines as 3 g of cefazolin dose is recommended for patients weighing greater than 120 kg [119]. Authors recommend TBW be used to determine daptomycin dose [120], and for linezolid, IBW can be considered [121–123]. Further studies are required to assess and validate optimum antibiotic dosing in this patient population.

 ntibiotic Drug Interactions in Solid Organ A Transplantation  harmacokinetic Alterations of Calcineurin P Inhibitors and Proliferation Signal Inhibitors by Antibiotics The majority of recognized pharmacokinetic drug interactions with antimicrobial medications in SOT occur with CNIs such

K. E. Schoeppler et al.

as cyclosporine, tacrolimus, and proliferation signal inhibitors (PSIs) like everolimus and sirolimus. This is mainly due to their reliance on CYP450 isoenzymes and transport proteins for clearance and due to TDM is routinely performed for these drugs in transplant recipients. It is important to note that pharmacokinetic alterations via CYP450 and ABC transporters do not only relate to changes in drug clearance, but also impact oral drug bioavailability. Differences in the magnitude of pharmacokinetic alterations due to concomitant use of antibiotic and CNIs or PSIs are a common occurrence in this population with specific treatment requirements. In general, TDM is strongly recommended when patients receiving CNIs or PSIs are initiated on or discontinued from medications with either inhibitory and/or induction effects on CYP3A and/or ABC transporters (such as P-gp) [124, 125]. Tables 51.3 and 51.4 provide a summary of interactions between antibiotics and antirejection agents. It should be noted that inherent variability among patients makes prediction for the extent of these interactions difficult; therefore, close TDM is required. In the event of difficult-to-manage drug-drug interactions, an alternative agent should be used. Specific interactions requiring empiric dose adjustment are important to recognize. For example, when initiating the CYP3A inhibitors erythromycin or clarithromycin, CNI trough concentrations would be expected to increase 1.6- to sixfold necessitating an empiric dose reduction of 35–50% of the original dose and potentially more based on TDM [126, 127]. Accordingly, dose reductions of 50% for sirolimus and 25% for everolimus should be considered when initiating erythromycin or clarithromycin [128–130]. Once the offending agent is discontinued, dose increases are warranted based on TDM as enzyme and protein inhibition wanes. For the more commonly used azalide, azithromycin, recommendations are less clear. TDM is warranted as reports of increased CNI and, to a lesser extent, PSI concentrations with azithromycin have been reported, but not to the magnitude of the aforementioned macrolides [125, 131–133]. In contrast to enzyme inhibition, the antituberculosis agent rifampin is a potent enzyme inducer responsible for decreasing CNI concentrations by 6- to 15-fold and decreased PSI concentrations by two to fivefold due to reduced bioavailability and heightened enzymatic clearance [134–137]. Whenever possible, an alternative to rifampin should be used as it has been implicated in graft rejection resulting in irreparable graft damage due to subtherapeutic CNI levels. If the combination cannot be avoided, cyclosporine doses may be increased by 1–2 mg/kg/day with three-times-daily dosing and adjusted according to TDM [135]. Specific recommendations for the management of tacrolimus, sirolimus, and everolimus are lacking, but dose adjustments should be expected based on TDM [125]. Rifabutin, a possible substitute for rifampin, may also interact with CNIs and PSIs, albeit to a lesser magnitude [138, 139].

51  Pharmacokinetics and Pharmacodynamics of Antibiotics in Transplant Patients

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Table 51.3  Definitions of onset of action, magnitude of effect, and relative strength of evidence for immunosuppressant drug interactions [124] Onset of action Rapid PCK effect is demonstrated within 24 h of co-administration Delayed PCK effect will not be demonstrated until the interacting drug is administered for a period of days or weeks Magnitude of effect Major Effects are life-threatening, capable of permanent damage, or rejection Moderate May cause a detriment in clinical status, additional treatment, hospitalization, or extension of stay Minor Effects may be mild; consequences may be bothersome or noticeable; additional treatment not required; no sign of effect upon therapeutic outcomes Relative strength of evidence Established Proven to occur in well-controlled studies Altered pharmacologic effect has been demonstrated in well-controlled trials OR PCK effect has been demonstrated in well-controlled human studies. An altered pharmacologic response is expected based upon the magnitude of the kinetic effect, or clinical observations support the occurrence of the interaction Probable Very likely, but not proven clinically A PCK interaction has been demonstrated in well-controlled studies. Based on the magnitude of the kinetic changes and the known plasma level-response relationship of the affected drug, an altered pharmacologic response will probably occur OR When controlled human experimentation is impractical, well-designed animal experiments confirm an interaction which is suggested by multiple case reports or uncontrolled studies Suspected May occur; some good data, but needs further study A PCK interaction has been demonstrated in well-controlled studies Although an altered pharmacologic response might be expected to occur based on the magnitude of the kinetic change, no firm conclusion can be drawn since a plasma level-response relationship has not been established for the affected drug OR An altered pharmacologic response has been reported in multiple case reports or repeated uncontrolled clinical studies Possible Could occur, but data are very limited Although a PCK interaction has been demonstrated, the kinetic changes are of such magnitude that it is not possible to predict if an altered response will occur OR The evidence is divided as to whether an interaction exists OR An altered pharmacologic response is suggested by limited data Used with permission from Page et al. [124]; http://circ.ahajournals.org/content/111/2/230; https://doi.org/10.1161/01.CIR.0000151805.86933.35, with permission from Wolters Kluwer Health, Inc. PCK pharmacokinetic

Noteworthy is the fact that cyclosporine and, to a lesser extent, tacrolimus also inhibit the CYP450 isoenzymes and P-gp. However, there is a paucity of published data implicating elevated antibiotic concentrations due to decreased elimination or increased bioavailability with cyclosporine. Cyclosporine has been shown to increase serum concentrations of tacrolimus, everolimus, and sirolimus when given together. Midazolam and statins eliminated via the liver follow similarly metabolized medications resulting in higher drug exposures, although the significance will vary depending on the therapeutic index of the medication [7, 140, 141].

Pharmacokinetic Alterations of Antimetabolites by Antibiotics Antibiotic pharmacokinetic interactions have been described for the antimetabolites as well. For example, mycophenolic acid (MPA) has a complex metabolic pathway. Briefly, MPA systemic clearance predominately involves glucuronida-

tion via uridine diphosphate-glucuronosyltransferase (UGT) 1A9  in the liver to its major metabolite, 7-O-glucuronide MPA (MPAG). MPAG is a substrate for multidrug resistanceassociated protein 2 (MRP2), which is responsible for biliary excretion of MPAG into the intestinal tract. Once in the colon, MPAG is de-glucuronidated by ß-glucuronidase-producing bacteria and reabsorbed as MPA.  This enterohepatic recirculation is significant and can account for 10–60% of total MPA exposure, often noted in pharmacokinetic monitoring as a second peak of MPA concentration between 6 and 12 h of mycophenolic mofetil (MMF) administration. In addition, UGT 2B7 is responsible for a minor but active metabolite acyl-glucuronide MPA (AcMPAG). Urinary excretion of glucuronidated metabolites eventually accounts for the ultimate elimination of MPA, where MRP2 may play a role in active tubular secretion [7, 142, 143]. Pharmacokinetic analysis of MPA is assessed by calculating an area under the curve (AUC) profile to account for the total drug exposure and enterohepatic recirculation. Antibiotics such as metronidazole, norfloxacin, and the combination of metronidazole and norfloxacin have

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Table 51.4  Documented pharmacokinetic interactions between antibiotic agents with calcineurin inhibitors and proliferation signal inhibitors [125] Drug CSA/ TAC

Interaction drug (specific CNI studied) Beta-lactams Cephalosporins Ceftriaxone (CSA) Carbapenems Imipenem-cilastatin (CSA) Penicillins Ticarcillin (CSA) Nafcillin (CSA) Fluoroquinolones Ciprofloxacin (CSA)

Level of Magnitude evidence

Effect

Onset

Increased CSA exposure

Delayed Moderate

Possible

Monitor CSA/TAC concentrations closely for 1–2 weeks

Increased/decreased CSA exposure

Delayed Moderate

Possible

Monitor CSA/TAC concentrations closely for 1–2 weeks

Increased CSA exposure Decreased CSA exposure

Delayed Moderate Delayed Moderate

Possible Possible

Monitor CSA/TAC concentrations closely for 1–2 weeks Monitor CSA/TAC concentrations closely for 1–2 weeks

Increased CSA exposure

Delayed Moderate

Possible

Levofloxacin (CSA, TAC) Increased CSA/TAC exposure Delayed Minimal Macrolides/azolides Macrolides Erythromycin (CSA, Increase CSA/TAC exposure Rapid Moderate TAC) with subsequent renal, hepatic, and neurologic Clarithromycin (CSA, Rapid Moderate toxicity TAC)

Possible

Monitor CSA/TAC concentrations closely for 1–2 weeks; consider alternative fluoroquinolone Not clinically significant

Erythromycin (EVER, SIR) Clarithromycin (SIR)

Established Reduce dose of SIR to 50% and EVER to 75% of original dose. Monitor SIR/EVER concentrations closely Established Reduce dose of SIR to 50% of original dose. Monitor SIR/ EVER concentrations closely

Increased EVER/SIR exposure Increased SIR

Azalides Azithromycin (CSA, Increased CSA/TAC exposure TAC) Azithromycin (EVER) Increased EVER exposure Antianerobic/antiparasitic agents Metronidazole (CSA, Increased CSA/TAC exposure TAC) Rifamycins Rifampin (CSA, TAC) Decreased CSA/TAC exposure

Rifabutin (CSA, TAC) Rifampin (SIR, EVER)

Rapid

Moderate

Rapid

Moderate

Sulfonamides/sulfonamide combinations Sulfadimidine/ Decreased CSA exposure trimethoprim (CSA) Sulfadiazine (CSA, TAC) Miscellaneous agents Quinupristin/dalfopristin Increased CSA exposure (CSA)

Probable

Possible

Monitor CSA/TAC concentrations closely for 1–2 weeks

?

Possible

Monitor SIR/EVER concentrations closely

Delayed Moderate

Possible

Monitor CSA/TAC concentrations closely for 1–2 weeks

Rapid

Established Monitor CSA/TAC concentrations closely for 2 weeks; consider use of alternative antimycobacterial agent^, for TAC increase dose accordingly, for CSA increase dose 1–2 mg/ kg/day with three times a day dosing Possible Monitor CSA/TAC concentration for up to 25 days after beginning rifabutin therapy and after discontinuation Established Avoid combination; consider use of alternative antimycobacterial agent^. If unavoidable, monitor SIR/ EVER concentrations closely for 1–2 weeks, and adjust dose accordingly

Rapid

Minimal

Major

Major

Delayed Major

Possible

?

Moderate

Possible

Delayed Moderate

Possible

Chloramphenicol (CSA, TAC) Clindamycin (CSA)

Increased CSA/TAC exposure Rapid

Telithromycin Tigecycline (CSA)

Increase CSA/TAC exposure ? Increased CSA Rapid

Reduced CSA exposure

Monitor CSA/TAC concentrations closely for 3 weeks and decrease CSA/TAC dose to 50–65% of original dose

Delayed Moderate

Delayed Moderate Decreased SIR/EVER exposure

Probable

Management #

Moderate

Delayed Moderate Moderate Moderate

Suspected Possible Possible Possible

Monitor CSA/TAC concentrations closely for the first 4 days

Monitor CSA/TAC concentrations closely for the first 2–3 days; consider linezolid, daptomycin, or telavancin as an alternative Monitor CSA/TAC concentrations daily for the first week; reduce initial CSA/TAC dose to 75% of original dose Monitor CSA/TAC concentrations closely for the first 4 weeks Monitor CSA/TAC concentrations closely Monitor CSA/TAC concentrations for the first 1–2 days; may need to reduce CSA dose to 50%

Reprinted from Page et al. [125], © 2011, with permission from Elsevier CSA cyclosporine, (CSA) reported with CSA, EVER everolimus, (EVER) reported with EVER, SIR sirolimus, (SIR), reported with SIR, TAC tacrolimus, (TAC) reported with TAC, ? unknown, ^ includes pyrazinamide, streptomycin, amikacin, ofloxacin, # the frequency in obtaining immunosuppressant concentrations may vary depending on a patient’s clinical stability, time from transplant, or rejection history. Recommendations are based on published literature and varied magnitude of interactions frequently occurs; therefore, individualizing a monitoring plan is always appropriate

51  Pharmacokinetics and Pharmacodynamics of Antibiotics in Transplant Patients

been shown to decrease MPA 48-h AUC on average 10, 19, and 33%, respectively. To a similar magnitude, they decrease MPAG 48-h AUC [144]. The disruption of colonic and intestinal Gram-negative aerobic and anaerobic flora that produce ß-glucuronidase likely decreases enterohepatic recirculation leading to reduced drug and metabolite exposure. Similarly, pre-dose or trough MPA levels were significantly reduced from baseline in a group of renal transplant recipients that received either ciprofloxacin or amoxicillin/clavulanic acid on average by 47% between days 3 and 7 of therapy and trended to recover near baseline trough levels after 3 days following discontinuation of the antibiotics [145]. Given the complex pharmacokinetic profile, the utility of a single pre-dose MPA level is questionable, and the extent of reduced MPA AUC is not known, but the proof of an altered pharmacokinetic profile remains. It is likely that other antibiotics with the potential to disrupt the colonic normal flora may reduce enterohepatic recirculation, although this has not been specifically studied. Rifampin has also been shown to decrease MPA exposure by both increased clearance via UGT induction and possibly inhibition of enterohepatic recirculation. A pharmacokinetic trial assessing the effect of rifampin on MPA concentrations after MMF administration showed a 17.5% reduced average 12-h MPA AUC from the baseline. Metabolite exposure measured by 12-h AUC increased by 34.4 and 193% for MPAG and AcMPAG, respectively [146]. This study showed a much lower magnitude of interaction compared to the reported MPA dose-adjusted 221% increase in 12-h AUC following rifampin discontinuation and a washout period first described by the same investigators [147]. Similarly, in pediatric liver transplant patients, 2 receiving rifampin with MMF had a four- to fivefold higher total clearance of drug from plasma ratio (CL/F) as assessed by 12-h AUC compared to 13 who did not receive rifampin. In this study, target 12-h AUCs were not attained despite dose adjustments [148]. As a whole, literature supports the existence of significant antibiotic-MPA interactions, but with a wide magnitude of variability. Further, MPA TDM is controversial and resource-intensive. At this time, it is unclear how such interactions should be monitored and managed. Broad-spectrum Gram-negative aerobic and anaerobic antimicrobials need judicious use, early de-escalation, or discontinuation when feasible, especially in the SOT recipients. In high-risk individuals, MPA AUCs may be calculated and monitored; however, evidence of improved outcomes with such an approach is currently lacking [7].

 harmacokinetic Alterations of Corticosteroids P by Antibiotics Prednisone and methylprednisolone are two structurally similar and commonly used synthetic corticosteroids.

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However, these compounds differ greatly from a pharmacological perspective. Prednisone is an inactive prodrug that must be converted to the active moiety, prednisolone. Methylprednisolone is active but more susceptible to pharmacokinetic drug-drug interactions due to a methyl group at the 6α position. Corticosteroids undergo CYP3A-dependent 6β-hydroxylation which puts them at risk of interactions with other drugs [149]. Corticosteroids have also been shown to change MRP2 and P-gp activity [140]. Despite ubiquitous use in early transplantation and throughout medicine, data describing pharmacokinetic drug interactions with antibiotics are rare. Macrolides have long been considered to be “steroid-sparing” perhaps due to P-gp and CYP3A4 inhibition in addition to their anti-inflammatory effects. In asthmatics, erythromycin was shown to decrease intravenous methylprednisolone clearance by 46% [150]. Similarly, clarithromycin was shown to decrease oral methylprednisolone clearance by 65%. Interestingly, prednisolone pharmacokinetics following oral prednisone was not significantly altered by clarithromycin [151]. Thus, using an equivalent dose of prednisone or prednisolone may obviate the potential interaction with CYP3A4 inhibitors including some azole antifungal agents [125]. Rifampin has been shown to increase cortisol and prednisolone metabolism resulting in therapeutic failure of the anti-­inflammatory effect when added to methylprednisolone. Prednisolone AUC was reduced by 66%, clearance increased by more than 200%, and half-life decreased by 40–60% in the presence of rifampin, reported in various clinical scenarios [152]. Although not specifically studied, a similar if not greater pharmacokinetic interaction would be expected with methylprednisolone. A doubling of the prednisolone dose may be needed to retain therapeutic efficacy. This interaction should be avoided, or rifabutin, a less potent enzyme inducer, may be substituted when possible [125, 153].

Pharmacodynamic Interactions of Immunosuppressive Agents with Antibiotics Pharmacodynamic interactions between CNIs, PSIs, antimetabolites, corticosteroids, and antibiotics may also occur. Due to the nature of these interactions and lack of reporting, the magnitude and incidence frequently go under-recognized. For example, tacrolimus has been reported to prolong the cardiac QT interval in a concentration-dependent manner and has been associated with torsades de pointes, usually when given with other drugs with the potential for QT interval prolongation [154, 155]. It would be expected that antibiotics that also prolong the QT interval would have an additive effect on QT interval aberration. Some of these drugs include, but are not limited to, the antimalarial chloroquine, macrolides, the fluoroquinolones, and trimethoprim/sulfamethoxazole (TMP/

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SMX) [156]. Often, these interactions go unrecognized and frequently may be accompanied by the addition of other drugs that have the potential for QT prolongation before a cardiac arrhythmia is noticed. Therefore, the true incidence and clinical significance of such interactions are not known. If the combination is given in a hospital setting, QT monitoring may be employed to assess for severity of cardiac toxicity. However, it is controversial whether monitoring needs to routinely take place. The use of these medications with tacrolimus should be weighed against potential risks and alternatives on a per patient basis. For example, TMP/SMX should not be withheld in transplant patients receiving tacrolimus given the weak evidence and risk of torsades de pointes compared to the benefit for the prevention and treatment of Pneumocystis jirovecii pneumonia. In contrast, treatment alternatives to TMP/SMX or linezolid may be considered for cancer patients with severe neutropenia or for those undergoing HSCT if clinical equipoise with an alternative exists to minimize the potential drug-induced myelosuppression. Similarly, the addition of an aminoglycoside to a CNI may result in a higher incidence of acute kidney injury due to additive nephrotoxic effects. As with most pharmacodynamics interactions, the true prevalence and impact of nephrotoxicity are not well established; however, such interactions with cyclosporine are well-described [157]. This is of particular concern given the increased incidence of resistant Gram-negative bacterial infections and increasing limited treatment options for transplant patients with multidrugresistant bacteria infections. The use of this combination will primarily be in hospitalized patients; therefore, close monitoring of renal function as well as any needed adjustments to CNI and aminoglycoside concentrations may minimize the potential for toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided whenever possible with patients being treated with CNI. Renal toxicity due to afferent arterial constriction with CNIs may be potentiated further with repeated NSAID use. Another example of a potential PD interaction is the use of imipenem/cilastatin with a CNI. Both CNIs and imipenem have been associated with seizures. However, clinical data describing an increased risk of seizure with the often-used combination compared to monotherapy of either drugs is lacking [158]. Nevertheless, whenever using this combination, an assessment of seizure risk should be considered. In summary, pharmacokinetic interactions with antibiotics and CNIs or PSIs are frequently made apparent by TDM and can be managed by dose adjustments when the interaction is unavoidable. For immunosuppressive agents without readily identifiable target ranges or available TDM, empiric dose adjustments and heightened awareness of monitoring for toxicities and keen assessment of the allograft rejection

K. E. Schoeppler et al.

are the only available strategies that clinicians can use to manage drug interactions with these agents. Further studies are needed to elucidate the role of dose-adjusted AUC monitoring in such patients. Pharmacokinetic interactions with corticosteroids are more often than not ignored and any resultant side effects treated palliatively. Overlapping drug effects of various immunosuppressive agents such as CNIs, PSIs, antimetabolites, or corticosteroids and antibiotics may indicate a pharmacodynamic interaction. Often dynamic interactions are a result of additive side effects and may lead to unanticipated toxicities. Because of the complexity of the interaction, patient variability, and inability to measure biochemical indicators of the interaction, the true incidence, magnitude, and clinical significance for many PD interactions remain elusive. However, they are important to consider within a clinical context when developing an antimicrobial therapeutic plan for patients undergoing transplantation. Frequently, these potential PD interactions are appropriately managed if considered and carefully monitored without requiring antibiotic substitutions.

Aerosolized Delivery of Antimicrobials Direct delivery of antibiotics via aerosolization is an appealing method of drug delivery in transplant recipients with tracheobronchial and lung infections. This method of drug delivery avoids delays in drug delivery to the site of infection and also bypasses first-pass metabolism in the liver. Systemic exposure to the drug is minimized, which helps limit systemic drug toxicity. Aerosolized delivery of antibiotics avoids PD drug interactions associated with systemic antibiotic therapy, including the additive nephrotoxicity of aminoglycosides in combinations with the CNIs. Still, this method of drug delivery is associated with significant increases in time for drug administration, cost, and adverse respiratory effects. Furthermore, distribution of inhaled antibiotic in the lungs is not necessarily homogenous; careful consideration of PK factors affecting aerosolized medication delivery is warranted. The partial size of the molecule delivered via inhalation is the mass aerodynamic diameter (MMAD). The MMAD is important for ensuring delivery to the lower respiratory tract; the ideal MMAD of a particle undergoing aerosolization is 1–5 um [159–161]. Drug particles having MMAD >5 um are more likely to be deposited in the oropharynx and swallowed. Particles with an MMAD  > L642, T643, L644, L646, R647, and D648 > P649 [51]. In PK-PD studies involving Fks1-Ser645 substitutions, micafungin even in high doses was insufficient to elicit an antifungal response, suggesting that conventional dose therapy with micafungin would not be effective in treating infections due to such organisms [54]. However, yeast’s behavior with the most prominent FKS2 mutation Fks2p-S663F unlike FKS1 mutant, Fks1p-S629P, in C. glabrata has responded to

Y. Dubrovskaya et al.

elevated drug dosing [53]. Furthermore, C. glabrata strains harboring the mutation Fks2p-P667T and Fks2p-D666F also differentially responded in a dose-dependent fashion to the three echinocandin drugs [54]. Drug-response relationships for high MIC mutant Candida strains may provide an approach to stratify resistance and assess dosing solutions to overcome potential lack of clinical response to therapy without the need to change drug class [55].

Toxicities Systemic toxicity with AmB is well known. Nephrotoxicity is associated with dose-dependent reduction in glomerular filtration rate. Other effects on renal function include potassium, magnesium, and bicarbonate wasting and decreased erythropoietin production. Azotemia caused by AmB is often worse in patients taking other nephrotoxic drugs. Presence of hypotension, renal allograft transplantation, and preexisting chronic  kidney  disease increases the  probability for AmB  drug-induced azotemia. In infusion-related reactions such as fever, chills, rigors, tachypnea, and worsened hypoxemia in patients with preexisting cardiac or pulmonary disease. It is important to note that  infusion-related adverse events tend to improve in severity as treatment with AmB is  continued [3–5, 56]. The infusion toxicities are most prominent with AmB deoxycholate, whereas AmB lipid formulations are better tolerated [6, 7, 57]. Renal preservation was comparable for ABLC and L-AmB either given as prophylaxis or for treatment of invasive fungal disease [57]. Generally, azoles are well-tolerated  drugs.  Fluconazole has an excellent safety profile. Most adverse effects associated with fluconazole are minor and usually gastrointestinal in nature. Fluconazole carries modest risk of QTc (corrected QT interval)-interval prolongation rarely resulting in torsades de pointes. Elevation of hepatic transaminase levels is seldom seen even in patients treated with high-dose fluconazole given for an extended duration. These events typically occur in patients with a higher susceptibility for such events. Reversible alopecia is not uncommon with fluconazole [3, 4, 9, 58]. Posaconazole is associated with mild to moderate gastrointestinal symptoms including altered taste and reduced appetite; mild nausea is not uncommon in transplant  patients receiving posaconazole. Liver toxicity is however, a serious concern with this agent, especially in the transplant population, and often due to concurrent use of other agents with hepatotoxicity risk profile [3, 4, 11]. Two unique adverse events were noted with voriconazole use: (1) dose-related reversible disturbance of vision or photopsia that may present as photophobia, changes in color vision, increased or decreased visual acuity and light perception, or blurred vision and (2) cutaneous phototoxicity. Visual disturbances are usually mild and

52  Antifungal Consideration for Transplant Recipients

transient and abate as treatment is continued  beyond first week. Similarly, cutaneous  phototoxicity is reversible after discontinuation of therapy. An elevation in serum transaminases levels, skin rash reported in nearly 8% of patients, and visual hallucinations in up to 4% of patients receiving voriconazole therapy have been reported. The cyclodextrin vehicle in IV formulation of voriconazole can accumulate in patients with insufficient renal clearance [3, 4, 10]. Itraconazole carries less favorable toxicity profile among the azole-based drugs. A negative inotropic effect that may precipitate congestive heart failure is a unique cardiotoxicity associated with itraconazole.  The US federal registration and labeling guideline recommends avoidance of itraconazole in patients with heart failure. Oral itraconazole solution contains a cyclodextrin carrier which can cause gastrointestinal toxicity such as nausea, vomiting, diarrhea, and abdominal pain; these adverse events, if severe, may necessitate discontinuation of therapy. Like other azoles, itraconazole use may result in hepatic toxicity ranging from mild, transient elevations of hepatic enzymes to rare cases of life-threatening liver failure [3, 4, 8]. Close monitoring of  liver  function  is recommended with all members of the azole-based  drugs, especially in the at risk transplant population. Overall, the echinocandin class has the most  favorable safety profile. Echinocandin may infrequently lead to hepatic dysfunction, whereas,  acute  liver  failure  is an exceedingly rare complication. In clinical trials, all three currently licensed echinocandins show a comparable increase in liver enzymes, when compared with patients treated with polyene or triazole drugs. Monitoring liver enzymes is recommended during echinocandin therapy. A histamine-mediated, infusion-­related reaction was seen in some patients; slowing the rate of infusion and pre-infusion antihistamines are effective [3, 4, 12–14].

Clinical Efficacy  rimary Antifungal Prophylaxis in HSCT P Recipients Primary antifungal prophylaxis with fluconazole has become the standard for patients undergoing HSCT since the early 1990s. The studies compared fluconazole with placebo or oral nonabsorbable agents and demonstrated significant 8–14% reduction in the cases of proven IFIs among patients following transplantation [16, 59–64]. Furthermore, fewer IFI-related deaths in fluconazole prophylaxis arm was encouraging [16, 60–62, 64, 65]. A significant reduction in overall mortality and probability of death up to 3  months after stem cell transplantation was an important finding (31 vs. 52 deaths in fluconazole and placebo groups, respectively

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[p  =  0.004]) [16, 60]. The limitations for the prophylaxis studies are reflected in the variability among (a) the distribution of autologous vs. allogeneic HSCT recipients, (b) duration of antifungal prophylaxis after transplantation, and (c) dose of fluconazole used [16, 60–62, 64, 65]. In addition, breakthrough IFIs with C. glabrata, C. krusei, Aspergillus spp., and mucormycosis have occurred in patients given fluconazole prophylaxis [16, 60–62, 64]. Old age, concurrent use of antibacterial chemoprophylaxis, cytarabine plus anthracycline-based chemotherapy, and high Candida colonization index were identified as independent risk factors for fluconazole failure [64]. Routine use of recombinant myeloid growth factors, a decline in conventional myeloablative preparatory transplant conditioning regimens have favorably shortened the duration of pre-engraftment neutropenia. In addition, selective and less toxic conditioning regimens such as non-myeloablative stem cell transplantation and lower risk of orointestinal mucosal disruption have also favorably reduced invasive candidiasis risk during early transplant period. Despite these important improvements, risk for invasive mold infections continue to remain a serious concern for high-risk allogeneic HSCT recipients. The incidence of mold infection including IA in autologous stem cell transplant recipients is low, with a few following exceptions: (1) heavily pretreated patients with multiple myeloma and (2) those with fludarabine therapy for lymphoproliferative disorders [65]. The current National Comprehensive Cancer Network (NCCN) guidelines on prevention and treatment of cancer-­ related infections recommend fluconazole 400  mg daily among other antifungal agents for antifungal prophylaxis in autologous HSCT recipients until engraftment; for allogeneic HSCT recipients, it is recommended that prophylaxis should be continued for a minimum of 75 days after transplantation [66]. Lack of protection against infections caused by C. krusei and Aspergillus with fluconazole prophylaxis is important to note. Mold-active drug prophylaxis should be considered based on the assessment of patients’ risk  profile; furthermore taking into account the regional and local rates for such infections including seasonal variability for IFIs, where applicable [16]. Prophylaxis with a mold-active triazole drug like voriconazole or posaconazole is considered in select patients in whom treatment of acute or chronic GVHD requires accelerated immunosuppression. These drugs are also considered in patients undergoing high-risk transplant procedures with an anticipated delay in restitution of myeloid hematopoiesis. Anti-mold secondary prophylaxis is routinely introduced for patients with a history of successfully treated IFI prior to HSCT procedure. Voriconazole has extended spectrum of activity against medically important yeasts and filamentous fungi such as Aspergillus spp. and most black molds. In high-risk HSCT

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patients, voriconazole prophylaxis is an appealing alternative to fluconazole. A randomized, double-blind study compared voriconazole 200  mg twice daily with fluconazole 400  mg once daily given for first 100  days after transplantation. Patients underwent assessment of serum galactomannan twice weekly for 60 days, then weekly until day 100; empiric antifungal therapy was therefore given for individuals with probable breakthrough IFI. Patients with prior systemic candidiasis in 2 months and mold IFIs in 4 months prior were excluded from participation in this study. There was no significant difference in the incidence of IFIs or fungus-­free survival [67]. However, in patients with acute myeloid leukemia (AML) who underwent allogeneic HSCT, fewer IFIs (8.5 vs. 21%; p = 0.04) and improved fungus-free survival in voriconazole vs. fluconazole prophylaxis group  was encouraging (78% vs. 61%, respectively; p = 0.04). There was no difference in overall survival in any of the subgroups including patients with AML [67]. Based on this data, specific patients such as those with AML undergoing allogeneic HSCT, in whom the risk of IA and invasive candidiasis due to fluconazole nonsusceptible organisms is high, may be suitable candidates for prophylaxis with voriconazole. Micafungin is another agent recommended for prophylaxis in patients undergoing autologous or allogeneic HSCT.  The multi-institutional, randomized trial included 882 adult and pediatric autologous or allogeneic HSCT recipients who were given 50 mg of micafungin (n = 425) or 400 mg of fluconazole (n = 457) once daily and continued through stem cell engraftment. Successful prophylaxis was defined as the absence of suspected, proven, or probable IFIs through the end of therapy and no evidence of proven or probable IFIs 4 weeks after prophylaxis was completed. The overall efficacy of micafungin was 80% vs. 73.5% in fluconazole group (p = 0.03). In patients given micafungin prophylaxis, a trend toward lower rates of aspergillosis was also encouraging. There was no difference in mortality between the two groups. Breakthrough infections in this study included four cases of candidemia and one case of probable aspergillosis in the micafungin group, whereas two cases of candidemia and seven cases of aspergillosis (four proven, three probable) in  the  HSCT recipients given fluconazole prophylaxis. A major limitation of this study was the short duration of prophylaxis (until engraftment), which did not allow assessment of efficacy of micafungin prophylaxis in patients at continued risk for IFI during other at risk postengraftment period that coincide  with  acute GVHD  [16, 68– 70]. A small prospective, randomized, open-labeled trial included 104 HSCT recipients given antifungal prophylaxis with 150 mg daily micafungin compared with 400 mg a day of fluconazole. There were no differences in the rate of breakthrough IFI in this small study [68, 70]. The duration of prophylaxis in this study was 5  days after engraftment or 42  days after HSCT.  Currently, micafungin 50  mg daily is

Y. Dubrovskaya et al.

approved in the United States for prophylaxis in patients undergoing HSCT [13]. In stem cell transplant recipients with severe GVHD, an expanded antifungal coverage against mold infections is desirable. The role of posaconazole was assessed in a trial involving 600 patients, and the overall frequency of breakthrough IFIs within 16 weeks of randomization was 5.3% in posaconazole group given 600  mg in three divided doses vs. 9% in patients who were given 400 mg fluconazole daily (p = 0.07). Furthermore, frequency of proven or probable aspergillosis in posaconazole treatment cohort was 2.3% compared with 7% noted in patients, in whom fluconazole prophylaxis was given (p = 0.006). The rate of breakthrough invasive candidiasis was not significantly different between the two groups. The overall mortality in patients given posaconazole and fluconazole prophylaxis was 25% and 28%, respectively [16, 71]. The newer antifungal agents such as voriconazole, micafungin, posaconazole and isavuconazonium sulfate (presently only approved for the treatment of invasive aspergillosis and invasive mucormycosis)  have made prophylactic itraconazole use obsolete due to higher rates of adverse events and drug-drug interactions [65, 66, 72, 73]. Efficacy and safety of voriconazole and itraconazole was evaluated in 234 patients undergoing allogeneic HSCT. In this study, the primary composite endpoints were success of prophylaxis, ability to tolerate study drug for more than 100 days, and survival past 180  days after HSCT without proven or probable IFI.  Superiority of voriconazole in the composite primary endpoint was that patients given voriconazole prophylaxis were able to tolerate prophylaxis for 100 plus days with minimal treatment interruption [73]. Based on the toxicity profile of AmB deoxycholate, its use for antifungal prophylaxis in transplant patients is very limited. Selection of antifungal agent for primary prophylaxis in transplant population should include the following considerations: (a) identify the type of HSCT procedure that portends greater risk for IFI such as T cell-depleted grafts, cord blood stem cell grafts, and mismatched allografts; (b) identify patients for  high IFI  vulnerability like heavily treated individuals with  recurrent or treatment-refractory hematologic malignancy, high yeast colonization index, and evolving understating in disruptions in hosts’ microbiota and various  genetic polymorphisms in innate and adaptive immune pathways that may eccentuate post-transplant proclivity for fungal infections; the last two parameters are not routinely monitored. In addition, drug-related factors such as (1) oral bioavailability, (2) spectrum of antifungal activity, (3) voids in the antifungal coverage such as voriconazole’s lack of efficacy against agents of human mucormycosis, (4) safety and tolerability, and (5) importantly, potential for drug-drug interaction. The optimum duration of antifungal prophylaxis in HSCT recipients is not certain; most experts surmise  that antifungal prophylaxis  be continued beyond

52  Antifungal Consideration for Transplant Recipients

pre-engraftment neutropenic period [66]. A gathering consensus is  for  prophylaxis to be continued through the period(s) of moderate to severe GVHD. Since death in HSCT recipients in most cases, is cumulation of a number of factors, both infectious (i.e.,  CMV, IFIs, bacterial sepsis)  and noninfections (i.e.,  GVHD, cancer recurrence, graft failure) complications, it is, therefore, perhaps unwise to assess efficacy of IFI prophylaxis on the impact on overall mortality in this highly vulnerable complex population.

 rimary Antifungal Prophylaxis in SOT P Recipients Among SOT population, recipients of orthotopic liver transplantation (OLT) are at an increase  risk for locally invasive or systemic yeasts infections, whereas those undergoing lung and heart-lung transplantation have higher susceptibility for invasive mold disease [74–77]. Risk factors for invasive candidiasis in OLT recipients include (1) retransplantation, (2) serum creatinine >2.0  mg/dL, (3) ­choledochojejunostomy, (4) intraoperative use of >40 units of blood products, (5) prolonged intraoperative time > 1 h, and (6) demonstration of fungal colonization 2 days prior and 3 days following transplant surgery [77, 78]. In a randomized, placebo-­ controlled trial, fluconazole 400  mg given daily for 70 days after transplant surgery was associated with fungal infection rate of 6% compared with 23% in no prophylaxis group (p 24 h [21]. This probably accounts for the slower resumption of CMV growth after removal of ganciclovir from culture media, in comparison with some other CMV antivirals [22]. Oral ganciclovir has poor bioavailability [23] and is no longer marketed despite FDA approval for prevention of CMV disease in transplantation and AIDS.  Valganciclovir has better oral bioavailability of about 60% and is the preferred oral formulation. Ganciclovir and valganciclovir toxicity manifests primarily as bone marrow suppression, which can become dose limiting [24, 25]. Granulocyte colony-stimulating factors may help with marrow recovery. Clinical Indications The introduction of ganciclovir did little to alter the fatal outcome of advanced CMV pneumonia [26]. Thus, the prevention of serious CMV disease became the main antiviral goal in transplant recipients. Two approaches to prevention were formulated: early identification of CMV viremia prior to end-organ disease by regular monitoring, followed by prompt “preemptive” treatment; or antiviral prophylaxis for planned durations after transplantation. Clinical trials showed that either approach using IV or oral ganciclovir was effective, more so than acyclovir-based regimens [12, 27]. Randomized clinical trials resulted in the current FDA-­ approved indications for valganciclovir in transplantation (Table  54.1). A trial of 100  days of valganciclovir vs. oral ganciclovir in high-risk solid organ recipients (mainly liver and kidney) showed comparable efficacy at preventing CMV disease when assessed at 6 and 12  months post-transplant [28]. FDA approval of valganciclovir was withheld for liver transplant recipients because of a higher incidence of invasive CMV disease, but valganciclovir therapy for this recipient subset is widely used and recommended [29]. Another

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trial concluded that valganciclovir prophylaxis for 200 days was superior to 100  days in preventing CMV disease at 12  months in high-risk kidney recipients [30], resulting in FDA approval for extended prophylaxis in this patient subset. For treatment of overt CMV disease, ranging from an undifferentiated febrile syndrome to invasive disease such as colitis or pneumonia, IV ganciclovir remains a standard option. A controlled trial showed noninferiority of oral valganciclovir when compared to IV ganciclovir for the treatment of nonthreatening CMV disease in solid organ recipients [31], but this use of valganciclovir is not FDA-­ approved. Duration of therapy is dependent on clinical response but is typically several weeks followed by oral maintenance therapy until viremia is cleared.

 rug Resistance Mechanisms D Over 90% of ganciclovir-resistant clinical isolates contain a mutation in the UL97 kinase gene [32]. The most relevant mutations reduce the phosphorylation of ganciclovir while preserving biologically important UL97 kinase activity and near-normal viral growth. One of seven UL97 amino acid substitutions (Table 54.1) is found in about 80% of ganciclovir-­resistant clinical isolates [32]. These substitutions generally confer five- to tenfold increases in ganciclovir EC50, except for C592G which confers only a threefold increase. In the UL97 codon range 590–607, less common sequence variants include point mutations and in-frame codon deletions, which confer degrees of ganciclovir resistance ranging from none to 15-fold [33]. Many CMV DNA polymerase (UL54 pol) mutations found in clinical specimens have been analyzed for their drug resistance phenotype [32, 34]. Such mutations may confer resistance to one or more of the currently approved CMV drugs ganciclovir, foscarnet and cidofovir, and in the case of ganciclovir may combine with a preexisting UL97 mutation to increase the overall level of drug resistance several fold. Rarely, ganciclovir may select for a pol resistance mutation before a UL97 mutation is detected. In general, ganciclovir and cidofovir dual resistance without foscarnet cross-resistance results from mutation in the exonuclease domains or codon 987 in the thumb domain.

Foscarnet Foscarnet is trisodium phosphonoformate, a pyrophosphate analog, which inhibits the viral DNA polymerase by interfering with the release of pyrophosphate from the incoming nucleotide during DNA replication. The antiviral spectrum of foscarnet in  vitro includes all herpesviruses, HIV, and hepatitis B virus [35], but it is FDA-approved only for treatment of HSV and CMV.

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Pharmacology Foscarnet is available as a solution containing 24 mg/mL for IV use [35]. To reduce toxicity, saline prehydration of up to a liter is recommended. Foscarnet is not further metabolized but is renally excreted by glomerular filtration and secretion, and is significantly deposited in bone. Variable uptake in bone may explain the great variation in plasma pharmacokinetics of foscarnet, with peak concentrations expected around 500 μM and a plasma elimination half-life of about 4.5 h. There is a prolonged phase of slow clearance of accumulated drug from bone. Foscarnet therapy is frequently limited by nephrotoxicity and metabolic disturbances, such as hypocalcemia, hypophosphatemia, hypomagnesemia, and hypokalemia, all of which can become symptomatic (including tetany, seizures, and arrhythmias) and always require close monitoring and electrolyte repletion as needed. The infusion rate must be controlled to avoid acute impact on electrolyte concentrations. The need for prolonged IV infusions and access devices complicates treatment planning. The fluid and salt load of the saline prehydration may be poorly tolerated. Concentration of foscarnet in the urine may cause uroepithelial cytotoxicity and genital ulceration.

S. Chou and N. S. Lurain

ganciclovir and/or cidofovir cross-resistance. A few specific mutations such as A834P or deletion of codons 981–982 confer moderate triple drug resistance. The level of ganciclovir or foscarnet resistance conferred by CMV pol mutations is usually in the two- to fivefold range [32].

Cidofovir Cidofovir is an acyclic nucleoside phosphonate nucleotide analog. It does not require initial phosphorylation by a viral kinase. Instead, cellular enzymes convert cidofovir to its active diphosphate form, which is a nonobligate DNA chain terminator. Cidofovir was FDA-approved in 1996 for treatment of CMV retinitis in AIDS. This narrow approved usage is in contrast with its wide in vitro antiviral spectrum which includes herpesviruses, adenoviruses, poxviruses, and even papovaviruses that do not encode their own DNA polymerase [39]. Cidofovir has good in vitro potency against HSV, VZV, and CMV.

Pharmacology The specified cidofovir dosing protocol (see Table  54.1) includes extensive pre- and post-hydration and three doses of Clinical Indications probenecid in an attempt to reduce nephrotoxicity. Cidofovir For treatment of overt CMV disease, FDA approval of fos- is renally cleared and renal function must be closely monicarnet remains limited to retinitis, because there have been tored both to guide dosing and to discontinue use for deteriono controlled treatment trials for other tissue-invasive dis- rated renal function or proteinuria. The medication is given ease. There are, however, case series on the use of foscarnet at long intervals, in part to avoid the rapid development of especially in stem cell transplant recipients to avoid the dose-­ nephrotoxicity, and because the cidofovir diphosphate has a limiting hematologic toxicity of ganciclovir [36], and for long intracellular half-life. In clinical trials, about a quarter treatment of ganciclovir-resistant infection [37]. Overall data of subjects developed nephrotoxicity, a similar fraction as suggest similar virologic efficacy as ganciclovir, but with a foscarnet therapy despite the use of hydration and probenedifferent set of major toxicities as outlined above. Comparison cid [40]. Ophthalmologists using cidofovir as systemic or of 14 days of preemptive therapy with IV ganciclovir or fos- intravitreal therapy have reported uveitis and intraocular carnet after allogeneic stem cell transplantation [38] showed hypotony as distinctive complications [41]. Intolerance of similar efficacy in preventing CMV disease, with the cidofovir therapy may also result from adverse reactions to expected toxicities for each drug. the significant saline hydration and probenecid that accomFoscarnet is FDA-approved for treatment of acyclovir-­ panies each dose. resistant mucocutaneous HSV infection in immunocompromised hosts [13]. Although unapproved, this indication is in Clinical Indications practice extended to the treatment of acyclovir-resistant her- No controlled trials have established the efficacy of cidofovir for treating any tissue-invasive CMV disease in the transpes zoster. plant setting, whether as initial therapy or for salvage. In the Drug Resistance Mechanisms stem cell transplant population, a retrospective series was Foscarnet resistance mutations in HSV, VZV, and CMV are collected of cidofovir use as salvage or preemptive therapy clustered in the palm and finger structure domains of their for CMV disease [40]. Such uncontrolled studies carry a risk corresponding DNA polymerases [13, 18, 32]. However, of reporting bias. As salvage therapy, there was apparent some mutations map to locations well outside these domains. benefit in 9 of 16 cases of CMV pneumonia, and the efficacy Acyclovir and foscarnet cross-resistance of HSV and VZV of cidofovir as preemptive therapy was estimated at about may result from mutations that cluster in the same poly- 65%. Nephrotoxicity was noted in 26% and was persistent in merase domains for both drugs [13]. CMV foscarnet resis- more than half of the cases where it occurred. Cidofovir is tance mutations may show variable low-grade or borderline generally regarded as a third line treatment for resistant or

54  Antiviral Consideration for Transplantation Including Drug Resistance

refractory CMV disease in transplant populations. Efficacy is poorly documented, with both optimistic reports and those indicating only a transient virologic benefit followed by emergence of cidofovir resistance. An orally bioavailable lipid conjugate of cidofovir, hexadecyloxypropyl-­cidofovir or brincidofovir (CMX001), has undergone clinical trial. Nephrotoxicity is reduced with this formulation because cidofovir is not concentrated in renal tubular cells [42]. The in vitro antiviral potency of brincidofovir is orders of magnitude greater than the parent compound, but this did not allow a corresponding decrease in the prophylactic dose in a Phase II dose ranging trial in stem cell recipients [43]. At the selected dose, severe diarrhea and associated increased mortality caused the failure of a Phase III CMV prophylaxis trial in stem cell recipients (clinicaltrials.gov NCT01769170). Use of brincidofovir may possibly be revisited if an improved risk-benefit profile is established by use of new formulations or careful selection of treatment candidates. There is interest in the antiviral activity of cidofovir against adenoviruses and polyomaviruses (BK, JC), which are significant pathogens in transplant recipients [39]. Use of cidofovir has been suggested for adenovirus infections in allogeneic stem cell transplantation [44]. More recently, 9 of 13 subjects with adenovirus disease appeared to have a virologic response to brincidofovir [45]. An expanded access protocol (clinicaltrials.gov NCT02596997) was registered in late 2015 to provide brincidofovir for treatment of serious adenovirus infection or disease.

 rug Resistance Mechanisms D Mutations conferring drug resistance to cidofovir in the CMV DNA polymerase gene are clustered in the exonuclease and thumb domains [32], and cross-resistance with ganciclovir is expected. In some cases, a relatively large increase in cidofovir EC50 (10–20-fold) is conferred by these mutations. There is little information on resistance mutations of HSV and VZV that develop after cidofovir treatment.

I ncidence and Clinical Diagnosis of Herpesvirus Drug Resistance The risk of drug resistance increases with the duration and intensity of active viral replication while under treatment. Contributory host factors include severe immunosuppression and lack of preexisting immunity. Resistance usually emerges after weeks to months of drug exposure, and is suspected when there is active viral replication or progressive disease despite adequate antiviral drug delivery. The prevalence of acyclovir- and penciclovir-resistant HSV isolates among immunocompetent populations is generally