Severe Asthma in Children and Adolescents: Mechanisms and Management [1st ed. 2020] 978-3-030-27430-6, 978-3-030-27431-3

Table of contents :
Front Matter ....Pages i-xii
Front Matter ....Pages 1-1
The Epidemiology of Severe Childhood Asthma (Adnan Custovic, Fernando D. Martinez)....Pages 3-18
Special Considerations in Preschool Age (Maura Kere, Erik Melén)....Pages 19-46
Front Matter ....Pages 47-47
Confirming the Diagnosis of Severe Asthma in Children (Andrew Bush, Samatha Sonnappa)....Pages 49-71
Asthma Plus: Comorbidities in Severe Childhood Asthma (Marina Martinez-Garri, Jonathan M. Gaffin)....Pages 73-93
Front Matter ....Pages 95-95
A Structured Multidisciplinary Approach to Managing Difficult-to-Treat Asthma in Children (Dara B. O’Donoghue, Michael D. Shields)....Pages 97-112
Stepwise Pharmacological Approach to Severe Childhood Asthma (Ina St. Onge, Karen M. McDowell, Theresa W. Guilbert)....Pages 113-131
Immunotherapy and Immunomodulators (Nicole Akar-Ghibril, Ahmad Salaheddine Naja, Wanda Phipatanakul)....Pages 133-155
Special Considerations for the Management of Severe Preschool Wheeze (Katherine Rivera-Spoljaric, Leonard B. Bacharier)....Pages 157-181
Management of Medication Side Effects and Complications (Louise Selby, Louise J. Fleming)....Pages 183-211
Management of Acute, Severe, and Life-Threatening Exacerbations (Angela Marko, Elizabeth Pace, Kristie R. Ross)....Pages 213-235
Severe Asthma During Adolescence and the Transition to Adulthood (Erick Forno, Sejal Saglani)....Pages 237-247
Front Matter ....Pages 249-249
Basic Mechanisms Underpinning Severe Childhood Asthma (Sejal Saglani)....Pages 251-269
Severe Asthma: Clinical Studies and Clinical Trials in Children (Ngoc P. Ly)....Pages 271-285
Potential Therapeutic Options for Severe Asthma in Children: Lessons from Adult Trials (Elissa M. Abrams, Heather E. Hoch, Allan B. Becker, Stanley J. Szefler)....Pages 287-312
Genomics and Pharmacogenomics of Severe Childhood Asthma (Klaus Bønnelykke, Gerard H. Koppelman, Elise M. A. Slob, Susanne J. H. Vijverberg, Anke H. Maitland-van der Zee)....Pages 313-341
Future Directions in Severe Childhood Asthma (Erick Forno, Juan C. Celedón)....Pages 343-355
Back Matter ....Pages 357-365

Citation preview

Severe Asthma in Children and Adolescents Mechanisms and Management Erick Forno Sejal Saglani  Editors

123

Severe Asthma in Children and Adolescents

Erick Forno  •  Sejal Saglani Editors

Severe Asthma in Children and Adolescents Mechanisms and Management

Editors Erick Forno Children’s Hospital of Pittsburgh University of Pittsburgh Pittsburgh, PA USA

Sejal Saglani Imperial College London National Heart & Lung Institute London UK

ISBN 978-3-030-27433-7    ISBN 978-3-030-27431-3 (eBook) https://doi.org/10.1007/978-3-030-27431-3 © Springer Nature Switzerland AG 2020 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, expressed 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 Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

The word “asthma” is derived from the Greek άσθμα. It appears in the Iliad when the giant Ajax throws a boulder and strikes Hector in the chest and in other passages describing extreme breathlessness and panting during battle [1]. Hippocrates referred to “asthmas” in the plural, without a clear definition; and later in the Hippocratic Corpus, the word was used as a symptom of rapid, difficult breathing [2]. Aretaeus of Cappadocia was probably the first to describe asthma as a clinical entity, although likely in a much broader sense than we do today. He also discussed different possible etiologies, as well as an asthma attack [3]. Galen described asthma in a broad sense as a kind of dyspnea produced from exercises or other strong efforts, but that “might also appear without exercise when there is lack of room in the cavities of the lungs.” In his works, he went on to describe what might be severe asthma, in which “asthmatic patients prefer to sleep in an upright position, for they are afraid of dying while asleep” [3]. Clinical communications reported in 1918 in the Boston Medical and Surgical Journal (which went on to become The New England Journal of Medicine) referred to “asthma” in the plural, describing different types, including “inspired asthma,” “hay asthma,” and “bacterial asthma” (Fritz B. Talbot, MD, Boston, Massachusetts Medical Society meeting, June 18, 1918). The Royal Society of Medicine held a lecture in 1920 titled “Toxic idiopathies: The relationship between hay and other pollen fevers, animal asthmas, food idiosyncrasies, bronchial and spasmodic asthmas, etc.” (J Freeman, MD, March 15, 1920), which again described several different classes of asthma. Much progress has been made in medicine and science in the last 100 years (and certainly since Homer and Galen), but we have not yet fully understood asthma (or “the asthmas”). It affects hundreds of millions of people around the world, yet there are no “gold standard” predictive or diagnostic tests—neither a way to prevent it nor a cure. Mortality from asthma is relatively rare, but still some 1,000 people die from the disease every day around the globe. Total yearly asthma costs exceed $81 billion [4] in the USA and ~72€ billion in Europe [5, 6]. Furthermore, over the next 20 years, US adolescents and adults may lose over 18 million quality-adjusted life years due to uncontrolled asthma [7]. v

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Roughly one in every 200–300 children and adolescents worldwide may suffer from severe asthma. As editors of this book, we wanted to draw attention to the importance of the problem and to compile a resource for researchers, clinicians, and providers who take care of children with severe asthma. We review the epidemiology of severe asthma in children, the most recent advances in its management, and the current state of basic, clinical, and translational research on the disease and its underlying causes. Moreover, we discuss lessons learned along the way, knowledge gaps that remain, and future directions that will help us to better understand severe asthma. Finally, we make the case for a collaborative approach, both for the study of the disease and for the management of our patients. Pittsburgh, PA, USA London, UK

Erick Forno, MD, MPH, ATSF Sejal Saglani, BSc, MBChB, MRCPCH, MD

References 1. Netuveli G, Hurwitz B, Sheikh A. Lineages of language and the diagnosis of asthma. J R Soc Med. 2007;100(1):19–24. 2. Saunders KB. Origin of the word “asthma”. Thorax. 1993;48(6):647. 3. Marketos SG, Ballas CN.  Bronchial asthma in the medical literature of Greek antiquity. J Asthma. 1982;19(4):263–9. 4. Nurmagambetov T, Kuwahara R, Garbe P.  The economic burden of asthma in the United States, 2008-2013. Ann Am Thorac Soc. 2018;15(3):348–56. 5. Gibson GJ, Loddenkemper R, Sibille Y, Lundbäck B, editors. The economic burden of lung disease. In: The European lung white book: respiratory health and disease in Europe. Sheffield: European Respiratory Society; 2013. p. 16–27. 6. Gibson GJ, Loddenkemper R, Lundback B, Sibille Y, Lundbäck B.  Respiratory health and disease in Europe: the new European Lung White Book. Eur Respir J. 2013;42(3):559–63. 7. Yaghoubi M, Adibi A, Safari A, FitzGerald JM, Sadatsafavi M. Canadian Respiratory Research Network. The projected economic and health burden of uncontrolled asthma in the united states. Am J Respir Crit Care Med. 2019. https://doi.org/10.1164/rccm.201901-0016OC. [Epub ahead of print]

Contents

Part I General Overview 1 The Epidemiology of Severe Childhood Asthma����������������������������������    3 Adnan Custovic and Fernando D. Martinez 2 Special Considerations in Preschool Age ����������������������������������������������   19 Maura Kere and Erik Melén Part II Diagnosis of Severe Asthma 3 Confirming the Diagnosis of Severe Asthma in Children��������������������   49 Andrew Bush and Samatha Sonnappa 4 Asthma Plus: Comorbidities in Severe Childhood Asthma ����������������   73 Marina Martinez-Garri and Jonathan M. Gaffin Part III Management of Severe Asthma 5 A Structured Multidisciplinary Approach to Managing Difficult-to-Treat Asthma in Children���������������������������������������������������   97 Dara B. O’Donoghue and Michael D. Shields 6 Stepwise Pharmacological Approach to Severe Childhood Asthma������������������������������������������������������������������������������������������������������  113 Ina St. Onge, Karen M. McDowell, and Theresa W. Guilbert 7 Immunotherapy and Immunomodulators��������������������������������������������  133 Nicole Akar-Ghibril, Ahmad Salaheddine Naja, and Wanda Phipatanakul 8 Special Considerations for the Management of Severe Preschool Wheeze������������������������������������������������������������������������������������  157 Katherine Rivera-Spoljaric and Leonard B. Bacharier

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9 Management of Medication Side Effects and Complications��������������  183 Louise Selby and Louise J. Fleming 10 Management of Acute, Severe, and Life-­Threatening Exacerbations ������������������������������������������������������������������������������������������  213 Angela Marko, Elizabeth Pace, and Kristie R. Ross 11 Severe Asthma During Adolescence and the Transition to Adulthood ��������������������������������������������������������������������������������������������  237 Erick Forno and Sejal Saglani Part IV Current and Future Research 12 Basic Mechanisms Underpinning Severe Childhood Asthma��������������  251 Sejal Saglani 13 Severe Asthma: Clinical Studies and Clinical Trials in Children������������������������������������������������������������������������������������������������  271 Ngoc P. Ly 14 Potential Therapeutic Options for Severe Asthma in Children: Lessons from Adult Trials�������������������������������������������������  287 Elissa M. Abrams, Heather E. Hoch, Allan B. Becker, and Stanley J. Szefler 15 Genomics and Pharmacogenomics of Severe Childhood Asthma������������������������������������������������������������������������������������������������������  313 Klaus Bønnelykke, Gerard H. Koppelman, Elise M. A. Slob, Susanne J. H. Vijverberg, and Anke H. Maitland-van der Zee 16 Future Directions in Severe Childhood Asthma������������������������������������  343 Erick Forno and Juan C. Celedón Index������������������������������������������������������������������������������������������������������������������  357

Editors and Contributors

Editors Erick Forno, MD, MPH  Division of Pediatric Pulmonary Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Sejal Saglani, BSc, MBChB, MRCPCH, MD  Paediatric Respiratory Medicine, National Heart & Lung Institute, Imperial College London, London, UK Department of Respiratory Paediatrics, Royal Brompton Hospital, London, UK

Contributors Elissa M. Abrams, MD, FRCPC  Section of Allergy and Clinical Immunology, Department of Pediatrics, University of Manitoba, Winnipeg, MB, Canada Nicole Akar-Ghibril, MD  Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Leonard  B.  Bacharier, MD  Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, USA Allan B. Becker, MD  Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada Klaus  Bønnelykke, MD, PhD  Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Northern Sealand, Denmark ix

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Andrew Bush, MD, FRCP, FRCPCH  Paediatric Respiratory Medicine, Imperial College, London, UK Royal Brompton and Harefield NHS Foundation Trust, London, UK Juan  C.  Celedón, MD, DrPH  Division of Pediatric Pulmonary Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Departments of Epidemiology and Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA Adnan Custovic, MD, PhD  Department of Paediatrics, Imperial College London, St Mary’s Campus Medical School, London, UK Elizabeth Pace, MD  Division of Pediatric Critical Care, UH Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, OH, USA Louise J. Fleming, MBChB, MD  Department of Paediatric Respiratory Medicine, National Heart and Lung Institute, imperial College, London, UK Royal Brompton and Harefield NHS Foundation Trust, London, UK Jonathan  M.  Gaffin, MD, MMSc  Division of Pulmonary Medicine, Boston Children’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Theresa W. Guilbert, MD, MS  Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Heather E. Hoch, MD MSCS  The Breathing Institute, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA Maura Kere, Med. Kand.  Sachs’s Children’s Hospital, South General Hospital, Stockholm, Sweden Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden Gerard  H.  Koppelman, MD, PhD  Department of Pediatric Pulmonology and Allergology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands GRIAC Research Institute, Groningen, The Netherlands Ngoc P. Ly, MD, MPH  Division of Pulmonary Medicine, Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA Karen M. McDowell, MS, MD  Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Editors and Contributors

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Anke  H.  Maitland-van  der  Zee, PharmD, PhD  Department of Respiratory Medicine, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands Department of Paediatric Pulmonology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands Angela Marko, DO  Division of Pediatric Pulmonology, Allergy/Immunology, and Sleep Medicine, Department of Pediatrics, UH Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, OH, USA Fernando  D.  Martinez, MD  Asthma & Airway Disease Research Center, University of Arizona, Tucson, AZ, USA Marina Martinez-Garri, MD  Division of Pulmonary Medicine, Boston Children’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Erik  Melén, MD, PhD  Sachs’s Children’s Hospital, South General Hospital, Stockholm, Sweden Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden Ahmad Salaheddine Naja, MD  Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon Dara  B.  O’Donoghue, MB ChB, MD  Department of Respiratory Paediatrics, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland Wanda  Phipatanakul, MD, MS  Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Katherine Rivera-Spoljaric, MD, MSCI  Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, USA Kristie R. Ross, MD, MS  Division of Pediatric Pulmonology, Allergy/Immunology, and Sleep Medicine, Department of Pediatrics, UH Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, OH, USA Louise  Selby, BSc, MBBS, MRCPCH  Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK Michael D. Shields, MB ChB, MD  Department of Respiratory Paediatrics, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland Elise M. A. Slob, MSc, PharmD  Department of Respiratory Medicine, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands Department of Paediatric Pulmonology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

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Editors and Contributors

Samatha  Sonnappa, MD, FRCPCH, PhD  Paediatric Respiratory Medicine, Imperial College, London, UK Royal Brompton and Harefield NHS Foundation Trust, London, UK Ina  St.  Onge, DO  Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Stanley  J.  Szefler, MD  Pediatric Asthma Research Program, The Breathing Institute, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA Susanne  J.  H.  Vijverberg, MSc, PhD  Department of Respiratory Medicine, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands Department of Paediatric Pulmonology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

Part I

General Overview

Chapter 1

The Epidemiology of Severe Childhood Asthma Adnan Custovic and Fernando D. Martinez

Introduction Epidemiology is a scientific discipline that studies the distribution of diseases in populations and addresses the issues related to the definition of the outcome (disease) of interest, the overall morbidity and mortality in a given community, factors that may cause or predispose to the development of disease(s), and the effects of interventions on those outcomes. A large number of epidemiological cross-sectional studies have been carried out in children and adults to determine the prevalence of asthma and explore the risk factors associated with this condition, including large multinational studies such as the International Study of Asthma and Allergies in Childhood (ISAAC; http://isaac.auckland.ac.nz/) [1–3] and the European Community Respiratory Health Survey (ECRHS; http://www.ecrhs.org/) [4]. Results of these studies have confirmed that asthma is one of the most common chronic diseases globally (it is estimated that ~300 million people worldwide have asthma, and it is likely that by 2025 a further 100 million will be affected) that affects individuals throughout the world and across the life span and that it can be severe and sometimes fatal. Deaths from asthma are relatively rare and correlate poorly with prevalence; annual worldwide mortality has been estimated at ~250,000. Rates of mortality and hospital admissions with acute asthma attacks over time steadily increased in all age groups between 1960 and 1985, with the highest increase seen among young children under the age of 4 years [5]. Following this increase, a steady fall occurred during the 1990s and early 2000s (possibly due to

A. Custovic (*) Department of Paediatrics, Imperial College London, St Mary’s Campus Medical School, London, UK e-mail: [email protected] F. D. Martinez Asthma & Airway Disease Research Center, University of Arizona, Tucson, AZ, USA © Springer Nature Switzerland AG 2020 E. Forno, S. Saglani (eds.), Severe Asthma in Children and Adolescents, https://doi.org/10.1007/978-3-030-27431-3_1

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the better provision of medical care), but disappointingly, there has been no further improvement in the past decade [6], despite novel treatments and improved devices for inhaled drugs entering market. Rather than offering a complete overview of the epidemiology of severe asthma, this chapter will focus on examining the definitions of this key clinical outcome of interest and will include a discussion of the various estimates of the prevalence of “severe asthma” in different contexts; how it may differ in children from adults, as well as the natural history from birth into adolescence and adult life; and the impact of childhood disease on adult lung function and chronic obstructive pulmonary disease (COPD).

Definitions and Prevalence Estimates One of the challenges to understanding the epidemiology, pathophysiology, and etiology of severe asthma is the lack of consensus in defining what is “severe asthma.” To date, no single definition or validated diagnostic standard has gained universal acceptance [7]. A further level of complexity and ambiguity is introduced through the heterogeneity of asthma itself. Despite numerous attempts to reach a consensus definition for epidemiological studies and clinical practice, one review of the topic has shown that as many as 60 different definitions of “childhood asthma” were used in 122 publications investigating its risk factors [8]. Although there are only subtle differences between many of these definitions, and some of them may appear similar or almost identical, the overall impact of the heterogeneity in the way the primary outcome is defined on the reported prevalence and associated risk factors may be considerable. For example, when the four definitions commonly used in different studies were applied to children at high risk, the overall agreement between these definitions was relatively low (61%), suggesting that well over a third of the study participants could move from being considered as having asthma to being assigned as controls depending on a definition used [8]. In a recognition of the heterogeneity in both clinical presentation and mechanisms leading to symptoms, the approach to asthma has recently been changed, with a gradual emergence of a consensus that purports that asthma is not a single disease but an umbrella term for a collection of several diseases with similar symptoms and clinical manifestations that are underpinned by different underlying pathophysiological mechanisms [9]. A subtype of asthma that is characterized by a defined distinctive mechanism (including unique genetic and environmental risk factors) is often referred to in the literature as “asthma endotype” [10, 11]. Within this framework, asthma-related symptoms such as wheeze, and objective measures including but not limited to blood, sputum, and breath biomarkers and different measures of lung function (and/ or combinations thereof), should be considered as observable traits or phenotypes [12, 13]. Of note, similar or same observable traits can be caused by different pathophysiological mechanisms [14]. However, at the time of writing of this chapter, the framework of asthma endotypes remains primarily a hypothetical construct, and not

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a single “asthma endotype” has been identified with absolute certainty [12]; currently, occupational asthma caused by high-molecular-weight substances may be the closest to the definition of a true endotype. This concept, however, has value in helping us to better understand the frequency of asthma-related diseases within the population, their risk factors, and underlying pathophysiological mechanisms [12]. In the context of asthma endotyping and heterogeneity, it is important to note that it is highly unlikely that “severe asthma” represents a unique asthma endotype but that the condition we refer to as severe asthma is the extreme end of the spectrum of several different asthma endotypes [15–17]. There have been calls to abolish the term “asthma”, as this ambiguous label – and its numerous and different definitions – likely reflects a set of similar symptoms and clinical manifestations of several distinct diseases [18], and useful comparisons have been made with the way we view fever, which was considered to be a disease until the nineteenth century [19]. However, before we abolish the term, which provides a useful framework for clinicians to treat patients and for researchers to search for mechanisms to facilitate target discovery for mechanism-based treatments and enable stratified medicine, we first need to fully understand asthma heterogeneity and propose a more useful terminology (Table 1.1). A key clinical characteristic of severe asthma in children is the presence of continued symptoms despite maximum treatment, usually high doses of inhaled corticosteroids (ICS) or oral corticosteroids, often in combination with add-on therapy with long-acting β-2 agonists (LABA) and/or leukotriene receptor antagonists (LTRA) [20–22]. The European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force defines severe asthma as “asthma which requires treatment with high dose ICS plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’, or which remains ‘uncontrolled’ despite this therapy” [23]. However, there are potentially numerous different reasons for poor symptom control among patients on “maximum treatment,” ranging from the wrong diagnosis [24] to nonadherence with prescribed treatments [25] and ­genuinely therapy-resistant disease (see Chap. 3 for details). In recognition of this heterogeneity, in the context of pediatric severe asthma, Bush et al. have proposed that the term Table 1.1 Terminology Term Definition As we have mentioned, there is still ongoing debate and no consensus on the terminology used to designate different possibilities for “severe asthma.” Unless otherwise noted, throughout this book we will use the terms below: Severe asthma Asthma that is truly severe, synonym with the truly severe, treatment-resistant asthma (STRA) described in this chapter Difficult-to-treat asthma Asthma that is not severe per se but rather difficult to treat for other (usually extrinsic) reasons Asthma plus Asthma that is worsened by coexisting morbidities Problematic asthma Umbrella term for asthma that is not responding to management but is still is being evaluated and thus cannot yet be categorized into one of the above

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“problematic severe asthma” (PSA) should be used for all children who require referral to a specialist service due to the perceived lack of response to high doses of asthma medications [22]. Once other causes of symptoms are excluded (such as vascular rings or laryngeal webs, dysfunctional breathing syndrome, cystic fibrosis, etc.), patients with PSA may have either difficult asthma (DA, also called difficultto-treat asthma), “asthma plus,” or genuinely “severe therapy-resistant asthma” (STRA) [22]. In children with DA, the main reasons leading to troublesome symptoms include factors that are potentially modifiable, such as poor adherence with prescribed treatments [26], ongoing adverse environmental exposure (from tobacco smoke exposure [27] to ongoing allergen exposure [28, 29]), and adverse psychosocial factors [30]. If these modifiable factors are appropriately addressed and/or treated, this should lead to an improvement in outcomes, including better symptom control and/or reduction in exacerbations [31, 32]. The term “asthma plus” (see Chap. 4) has been suggested for children with comorbidities (e.g., allergic rhinitis [33], obesity [34], and food allergy), but it could be argued that if such comorbidities are treatable, these patients could fall under a broad category of DA. Some of the children in these categories may not improve despite interventions (e.g., due to the ongoing adverse environmental exposures and/or poor adherence with prescribed treatment), in which case they may be designated as refractory DA [24, 35]. In contrast, children with genuine STRA do not respond to standard therapies, such as systemic corticosteroids administered either as intramuscular injections [36] or oral direct observed therapy [35], and need different therapeutic approaches, including biologics such as omalizumab [37] (see Chap. 7). At least conceptually, of these three groups, only STRA is due to an intrinsic severity in the pathobiology of asthma, whereas DA and asthma plus obey to factors that are extrinsic to the pathophysiology of asthma. By definition, PSA is an umbrella term encompassing, among others, children with a wrong diagnosis. Consequently, it has been suggested “asthma-treatment-­ resistant symptoms” may be a more accurate term than PSA [24]. However, if we accept that we currently diagnose “asthma” as a set of symptoms and that asthma treatment is diagnosis-based (i.e., symptom-based) rather than mechanism-based, these subtle differences in terminology (see Table  1.1) remain largely academic, particularly as DA, asthma plus, and STRA are not mutually exclusive, and many patients may have features consistent with more than one category [24]. Therefore, while we accept that there is a considerable within-group heterogeneity in each of these categories, and that strict differentiations between the categories may be challenging, this framework, which broadly distinguishes PSA, DA, and STRA, is useful in both research and clinical context [38] and can be translated into the context of adult severe asthma [39]. The heterogeneity of severe asthma may result in difficulties in the interpretation of the findings across different populations and in considerable discrepancies between different studies investigating the epidemiology of severe asthma. It is therefore not surprising that prevalence estimates of severe asthma vary widely (e.g., in adults with asthma, from 4.2% among patients from primary care centers in Sweden [40] and 8% in Denmark [41] up to 20% or even more than 30% in some

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surveys [42, 43]). In childhood, the proportions of patients with severe asthma appear smaller than in adult asthma [44]. For example, in the Swedish BAMSE (Swedish acronym for children, allergy, milieu, Stockholm, epidemiology) birth cohort, among 329 children with asthma at age 12  years, only 7 met the World Health Organization (WHO) definition of severe asthma [45], with the estimated prevalence of 0.23% in the general population and 2.1% among children with the diagnosis of asthma [46]. Among 616 children in a Norwegian birth cohort (the Environment and Childhood Asthma Study), 67 had asthma at age 10  years, of whom only 3 had severe asthma, rendering the point prevalence of severe asthma of 0.5% in a population and 4.5% among current asthmatics [47]. However, due to the small numbers, the confidence intervals in both these studies were large, and the data need to be interpreted with caution. The proportion of children with troublesome symptoms within the population has also been estimated using data-driven techniques, rendering somewhat different results. In the Manchester birth cohort, a data-driven methodology (longitudinal latent class modelling) was applied to data from two different sources collected from infancy to mid-school age: questionnaire-based parental reports ascertained the presence of wheeze, and consultations with primary care physicians with confirmed wheeze transcribed from medical records were used as a proxy of severity [48]. The analysis identified a class of children with persistent troublesome wheezing, characterized by high number of severe exacerbations, hospitalizations, and unscheduled visits to healthcare professional for wheezing (Fig.  1.1) [48]. Furthermore, lung function tests have shown that these children had obstructed and hyperreactive airways, with a significant loss of lung function between 3 and 8 years of age [49]. All these characteristics are features of severe asthma, and the prevalence of this class in the general population was 3.2%, with ~10% of children with doctor-diagnosed asthma belonging to this class of troublesome wheezers [48]. However, when “severe asthma” was defined using ERS/ATS [23] or WHO [45] criteria (as in the abovementioned Swedish and Norwegian cohorts [46, 47]), only a handful of children were classified as severe asthmatics (personal communication), suggesting that we may need to rethink how we define the clinical concept of severity, particularly in pediatrics. Most current definitions of severe asthma include the requirement for a patient to be on maximum treatment, either with continued symptoms despite treatment or to prevent the loss of control [23, 45]. However, the “treatment requirements” and “asthma control” features do not adequately capture the burden of asthma on individual patients or on the society. As an example, the UK National Review of Asthma Deaths (NRAD, https://www.rcplondon.ac.uk/projects/outputs/why-asthma-stillkills) has reported that many patients who died from asthma would have been classified as having a mild-or-moderate disease based upon their treatment requirements [50]. This is a clear contradiction in terms, which demonstrates that reliance on the type and the dose of asthma medication prescribed, coupled with symptom control at any point in time, does not adequately capture patients who are at risk in a condition that is highly variable [24, 51]. One of the risk factors for asthma death identified by the NRAD was a recent severe acute asthma attack – approximately 10% of

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Fig. 1.1  Latent class analysis of persistent wheezing in the Manchester birth cohort. Characteristics of five wheeze classes derived using data-driven methodology (longitudinal latent class modelling) applied to information on wheezing from two different sources collected from infancy to mid-­ school age (questionnaire-based parental reports of current wheeze and confirmed wheeze transcribed from medical records): (Left panel) Percentage of participants with reported wheezing; and for each class, trajectories of (middle panel, top to bottom) asthma treatment, inhaled corticosteroid (ICSs) prescription, and specific airway resistance (sRaw); and (right panel, top to bottom) severe asthma exacerbations, hospital admissions with acute asthma attacks, and unscheduled visits to healthcare professionals due to asthma. (From Belgrave et al. [48], with permission)

patients who died had a hospitalization with severe exacerbation within a month prior to death, and 20% had emergency department attendance in the 12-month period before death [51]. Furthermore, the overuse of reliever medication (more than one inhaler per month), rather than just the high dose of ICS, was a possible indicator of poor control. A recent Lancet commission has suggested that the way forward is to be much clearer about the meaning of the labels we use and to recognize the uncertainties and assumptions associated with different labels [9], and this clearly applies to the domain of severe asthma.

Risk Factors for Severe Asthma A number of studies have attempted to describe risk factors associated with severe asthma. Relatively consistent associations have been reported for the age of onset of symptoms, with children with severe asthma generally starting to experience symptoms earlier compared to those with mild/moderate disease (and in most cases within the first 3 years of life) [52, 53]. Not surprisingly, severe childhood asthma is associated with airway hyperresponsiveness, diminished lung function, obstructed

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airways, air trapping, and high FeNO [48, 49, 52, 54–57], and low lung function in infancy may predict subsequent severe symptoms and diminished lung function in early adulthood [58, 59]. Troublesome asthma may also be associated with a loss of lung function during childhood [48, 60]. Genetics may also play an important role in severe asthma. A recent genome-­ wide association study (GWAS) in adults reported a substantial overlap between mild and moderate-to-severe asthma but also identified several genetic polymorphisms associated only with the moderate-to-severe disease, including variants in MUC5AC, GATA3, and KIAA1109, of which the signal in MUC5AC lost significance when analyses included patients with mild asthma [61]. In childhood asthma, a GWAS that used early-onset asthma with recurrent, severe exacerbations and hospital admissions as an outcome identified cadherin-related family member 3 (CDHR3) as a strong and highly significant associate of this phenotype of severe asthma [62]. In silico and mechanistic studies have suggested that CDHR3 may be a receptor for rhinovirus C (RV-C) and have demonstrated a tenfold higher RV-C binding and replication in cells transfected with the CDHR3 risk variant [63]. These data, and more recent findings that CDHR3 risk allele is associated with RV-C illnesses [64], suggest that CDHR3 may be a potential therapeutic target for reducing RV-C infections and RV-C-induced asthma exacerbations [64, 65]. Ethnicity has also been associated with severe asthma, and ethnic variations in response to intramuscular triamcinolone in children with STRA have been reported [66], which may be related to genetic susceptibility. The host innate immune responses to viruses may be important determinants of asthma severity and exacerbations [67, 68]. Impaired interferon induction to rhinovirus has been reported in children with STRA, with low interferon-β and interferon-λ induction in bronchial epithelial cells cultured ex vivo [69]. A recent study has identified markedly different patterns of multiple cytokine responses by peripheral blood mononuclear cells 24 hours after stimulation with rhinovirus-16 between children with early-onset troublesome asthma with multiple exacerbations and hospital admissions and those with later-onset milder allergic asthma [70]. Children with early-onset severe asthma and early-life allergic sensitization were more likely to have the lowest interferon induction and high pro-inflammatory cytokines, while those with robust interferon responses but the highest production of TH2 cytokines following stimulation with phytohemagglutinin (PHA) tended to have late-onset mild allergic asthma [70]. As outlined before, severe asthma is often associated with comorbid conditions [71], most common of which in childhood include allergic rhinitis [33], obesity [34], food allergy [72], and vocal cord dysfunction [73]. Comorbid conditions may contribute to poorer asthma control [71]; however, although it seems intuitive that appropriate management of comorbidities should improve severe asthma, there is a paucity of evidence from well-designed, randomized intervention trials [71]. A strong association between severe asthma and allergic sensitization has been observed in school-age children and adolescents [17, 52, 74–77]. The co-occurrence of sensitization and viral infection increases the risk of hospital admissions with asthma attacks, both in children [28] and in adults [78], and sensitization is associ-

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ated with a differential response to ICS [79]. Furthermore, a study of children with severe asthma reported no difference in the proportion of sensitized children between STRA and DA (with almost all children showing evidence of allergic sensitization) but has shown that children with STRA had significantly greater size of skin test responses to inhalant and food allergens compared to those with DA [80]. This suggests that there may be distinct types of sensitization that differ in their association with asthma severity [81], some being more pathologic than others [75]. A machine learning analysis (that took into account the type of sensitizing allergen and the timing of onset, progression, and remission of skin tests and specific IgE responses collected longitudinally from infancy to school age) suggested existence of four distinct classes of sensitization and uncovered one of these classes as a strong associate of severe asthma [82]. Children with “multiple early” sensitization had lower lung function and were at high risk of severe asthma exacerbations compared to all other sensitization classes [82, 83]. More recently, studies using component-­resolved diagnostics instead of standard tests to whole allergen extracts have identified cross-sectional [84] and longitudinal [85, 86] patterns of allergen component-specific IgE responses associated with different risks of asthma persistence and severity and have shown that the important associate of childhood asthma is an interaction pattern between component-specific IgEs [87]. However, if these findings are to be translated into useful diagnostic tests for asthma, technological advances in component-resolved allergen microarray chip techniques will have to be coupled with the development of interpretation software that will provide real value for clinicians and patients.

Severe Asthma and Obesity As explained earlier, obesity and asthma are common and strongly associated with each other, but the direction of the association is unclear. Many longitudinal studies have shown that obesity may precede the development of asthma [88–90] but also that children with asthma are more likely to become overweight or obese [91, 92]. Children with severe allergic asthma are more likely to be obese than those with mild asthma [93], and persistence of asthma from childhood into adolescence is more likely to occur in obese children [94]. Among minority children in the United States, a complex relation between sex, obesity, and asthma severity has been described [95]. Whereas in males higher BMI was consistently associated with worse asthma control, in females, asthma control was better in obese African Americans and worse in obese Mexican Americans. These results suggest that the mechanism connecting obesity with severe asthma may not solely be the increase in the amount of adipose tissue. Obesity is associated with “airway dysanapsis,” i.e., an inharmonious growth of the airways and the lung, which results in larger lung volumes, lower flows, and evidence indicators of ventilation inhomogeneity [96]. Obese children with asthma were more likely to have severe exacerbations and to need systemic corticosteroid if they also had evidence of “dysanapsis.” Interestingly,

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the association between obesity and “dysanapsis” was more evident in boys than in girls, and this could explain why increased asthma severity is more consistently observed in obese boys than in obese girls [95]. If asthma symptoms in some obese children could be attributable to abnormal lung growth and not to airway inflammation per se, this could explain why obese children appear to be less responsive to inhaled corticosteroids than their nonobese peers [97]. Given that both asthma and obesity are multifactorial disorders, it is unsurprising that their interaction would also be complex and that not all children with “obese asthma” would belong to the same endotype. An additional factor that seems to be strongly associated with asthma severity is metabolic syndrome, which is often but not always present in obese children. In overweight/obese adolescents, metabolic syndrome is associated with diminished FEV1/FVC ratio, and this effect is particularly strong among children with asthma [98]. It has also been reported that, after exposure to specific and non-specific stimuli, peripheral blood T-cells from obese adolescents with asthma show an increased Th1/Th2 ratio when compared with normal-weight subjects with asthma; this ratio showed a positive correlation with indices of insulin resistance [99]. However, no differences in immune responses were identified between obese subjects with or without asthma. These studies support the contention that the increased severity of asthma associated with metabolic syndrome may not be mediated by an enhanced Th2-type response but by alterations in airway/lung structure and responsiveness.

Exacerbation-Prone Asthma An important determinant of severe asthma, especially in children, is a predisposition to the development of severe exacerbations. Longitudinal studies have shown that children with a history of frequent exacerbations are more likely to have exacerbations during follow-up [100]. What remains unclear is whether exacerbations are simply one more manifestation of asthma severity or if there is a separate phenotype of children in whom the severity of the disease is enhanced by specific factors that render them exacerbation-prone (i.e., children who may not always have severe chronic symptoms but whose significant morbidity stems from frequent or serious exacerbations). In strong support of the existence of an exacerbation-prone phenotype is the previously described polymorphism in CDHR3 that specifically increases the risk for exacerbations [62]. It is important to stress that this polymorphism did not reach genome-wide statistical significance and showed heterogeneity between populations in a very large GWAS including over 20,000 asthma cases, suggesting that it could be specific to certain subphenotypes of asthma differentially present in the samples included in the study. Several studies have also described potential interactions between environmental exposures and genetic variants as determinants of increased risk for asthma exacerbations [101–103]. A recent, comprehensive assessment of data from the Severe Asthma Research Program in the United States described risk factors for exacerbation-prone asthma in children and

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adults with severe disease [104]. A history of sinusitis and of gastroesophageal reflux was shown to be associated with proneness for exacerbations. Of interest, sinusitis has also been associated with polymorphisms in CDHR3 [105], suggesting that susceptibility to viral infection may be a potential biological basis for the high concordance between sinusitis and asthma exacerbations. Other factors such as blood eosinophilia and increased exhaled nitric oxide (FeNO) seemed not to be specific for children prone to exacerbations, but since most were treated with corticosteroids, the interpretation of these results is less clear. Taken together, these results suggest that a specific exacerbation-prone phenotype may exist within the framework of severe childhood asthma, but it is still unclear how important it may be from a clinical point of view and if targeted therapies may be required to prevent exacerbations in this subgroup.

 ersistence of Severe Childhood Asthma, Lung Function P Deficits, and Chronic Obstructive Pulmonary Disease (COPD) Deficits in spirometric markers of airway function are characteristic of severe asthma and often made part of its definition. As discussed earlier, these deficits may be already present shortly after birth, but there is also evidence that children with severe asthma show impaired growth of airway function, especially during the preschool years [106]. Children with severe asthma contribute significantly to a group consistently identified by latent class analysis within large populations as having persistently low lung function trajectories [107, 108]. Children with asthma who reach adult life with a deficit in airway function growth are at increased risk of having persistent asthma into adult life [109]. Moreover, only 15% of children with severe asthma and marked lung function deficits had the disease remitted by the age of 50 years, and 70% of them had had active symptoms during the previous 3 months when they were questioned at age 50 [110]. Particularly important from a public health point of view is the finding that, among children with severe asthma, 44% fit the criteria for a diagnosis of COPD at the age of 50 years and that smoking had no effect on the likelihood of having COPD by that age [111]. These results strongly suggest that severe childhood asthma is a major determinant of early-onset COPD [112]. Since COPD is the third cause of death in developed countries, prevention of severe childhood asthma ought to be a major component of the efforts to decrease early mortality due to COPD.

Conclusions Severe asthma is a heterogeneous condition, with diverse disease mechanisms and evolution that affect 10–20% of all children diagnosed with the disease. Generally, patients in whom symptoms begin in early life have a more severe course, as do those with early development of atopy and a T2-like diathesis. Social and personal

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circumstances often determine that patients do not adhere to treatment with inhaled corticosteroids with or without other add-on controllers, and this presents to caregivers with uncontrolled asthma. Added morbidities such as obesity, metabolic syndrome, and gastroesophageal reflux contribute to disease severity. There may be a specific subgroup of severe asthmatics that are genetically at risk to develop recurrent asthma exacerbations, and a common genetic predisposition to abnormal responses to viruses may explain the strong association between chronic sinusitis and severe asthma. Severe childhood asthma almost invariably persists as a severe condition into adult life and is strongly associated with the early development of COPD.  A holistic approach, which goes beyond simple definitions and aims to understand epidemiology and reduce the burden of severe asthma, is urgently needed. Our focus should be firmly on lung health, with the aim of improving not only short-term symptoms but also the long-term respiratory and other health outcomes [113].

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34. Wang R, Custovic A, Simpson A, Belgrave DC, Lowe LA, Murray CS.  Differing associations of BMI and body fat with asthma and lung function in children. Pediatr Pulmonol. 2014;49(11):1049–57. 35. Bush A, Fleming L, Saglani S. Severe asthma in children. Respirology. 2017;22(5):886–97. 36. Bossley CJ, Fleming L, Ullmann N, Gupta A, Adams A, Nagakumar P, et al. Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach. J Allergy Clin Immunol. 2016;138(2):413–20.e6. 37. Fleming L, Koo M, Bossley CJ, Nagakumar P, Bush A, Saglani S. The utility of a multidomain assessment of steroid response for predicting clinical response to omalizumab. J Allergy Clin Immunol. 2016;138(1):292–4. 38. Pike KC, Levy ML, Moreiras J, Fleming L. Managing problematic severe asthma: beyond the guidelines. Arch Dis Child. 2018;103(4):392–7. 39. von Bulow A, Backer V, Bodtger U, Soes-Petersen NU, Vest S, Steffensen I, et al. Differentiation of adult severe asthma from difficult-to-treat asthma – outcomes of a systematic assessment protocol. Respir Med. 2018;145:41–7. 40. Larsson K, Stallberg B, Lisspers K, Telg G, Johansson G, Thuresson M, et  al. Prevalence and management of severe asthma in primary care: an observational cohort study in Sweden (PACEHR). Respir Res. 2018;19(1):12. 41. von Bulow A, Kriegbaum M, Backer V, Porsbjerg C. The prevalence of severe asthma and low asthma control among Danish adults. J Allergy Clin Immunol Pract. 2014;2(6):759–67. 42. Bleecker ER. An update on severe asthma. The epidemiology of severe asthma: The TENOR Study and SARP (NIH).World Allergy Organization. XXVII EAACI COngress 9 Jun 2008, Barcelona. https://www.worldallergy.org/educational_programs/world_allergy_forum/ barcelona2008/bleecker.php. Accessed 5 May 2019. 43. Mincheva R, Ekerljung L, Bossios A, Lundback B, Lotvall J. High prevalence of severe asthma in a large random population study. J Allergy Clin Immunol. 2018;141(6):2256–64. e2 44. Rusconi F, Fernandes RM, MWH P, Grigg J, SPACE Clinical Research Collaboration; European Lung Foundation severe asthma patient advisory group. The Severe Paediatric Asthma Collaborative in Europe (SPACE) ERS Clinical Research Collaboration: enhancing participation of children with asthma in therapeutic trials of new biologics and receptor blockers. Eur Respir J. 2018;52(4):1801665. 45. Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126(5):926–38. 46. Nordlund B, Melen E, Schultz ES, Gronlund H, Hedlin G, Kull I. Prevalence of severe childhood asthma according to the WHO. Respir Med. 2014;108(8):1234–7. 47. Lang A, Carlsen KH, Haaland G, Devulapalli CS, Munthe-Kaas M, Mowinckel P, et  al. Severe asthma in childhood: assessed in 10 year olds in a birth cohort study. Allergy. 2008;63(8):1054–60. 48. Belgrave DCM, Simpson A, Semic-Jusufagic A, Murray CS, Buchan I, Pickles A, et al. Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing. J Allergy Clin Immunol. 2013;132(3):575–83.e12. 49. Belgrave DC, Buchan I, Bishop C, Lowe L, Simpson A, Custovic A. Trajectories of lung function during childhood. Am J Respir Crit Care Med. 2014;189(9):1101–9. 50. Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report. London: Royal College of Physicians; 2014. 51. Levy ML, Winter R. Asthma deaths: what now? Thorax. 2015;70(3):209–10. 52. Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG, National Institutes of Health/National Heart L, Blood Institute Severe Asthma Research P. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide. J Allergy Clin Immunol. 2006;118(6):1218–25.

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53. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyperresponsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008;372(9643):1058–64. 54. Bossley CJ, Saglani S, Kavanagh C, Payne DN, Wilson N, Tsartsali L, et al. Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma. Eur Respir J. 2009;34(5):1052–9. 55. Chipps BE, Szefler SJ, Simons FE, Haselkorn T, Mink DR, Deniz Y, et al. Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2007;119(5):1156–63. 56. Lowe LA, Simpson A, Woodcock A, Morris J, Murray CS, Custovic A, et al. Wheeze phenotypes and lung function in preschool children. Am J Respir Crit Care Med. 2005;171(3):231–7. 57. Payne DN, Wilson NM, James A, Hablas H, Agrafioti C, Bush A. Evidence for different subgroups of difficult asthma in children. Thorax. 2001;56(5):345–50. 58. Haland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC, Pettersen M, et  al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med. 2006;355(16):1682–9. 59. Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD.  Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet. 2007;370(9589):758–64. 60. Childhood Asthma Management Program Research G, Szefler S, Weiss S, Tonascia J, Adkinson NF, Bender B, et al. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343(15):1054–63. 61. Shrine N, Portelli MA, John C, Soler Artigas M, Bennett N, Hall R, et al. Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study. Lancet Respir Med. 2018;7(1):20–34. 62. Bonnelykke K, Sleiman P, Nielsen K, Kreiner-Moller E, Mercader JM, Belgrave D, et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet. 2014;46(1):51–5. 63. Bochkov YA, Watters K, Ashraf S, Griggs TF, Devries MK, Jackson DJ, et al. Cadherin-­related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc Natl Acad Sci U S A. 2015;112(17):5485–90. 64. Bonnelykke K, Coleman AT, Evans MD, Thorsen J, Waage J, Vissing NH, et  al. Cadherin-­ related family member 3 genetics and rhinovirus C respiratory illnesses. Am J Respir Crit Care Med. 2018;197(5):589–94. 65. Bonnelykke K, Ober C. Leveraging gene-environment interactions and endotypes for asthma gene discovery. J Allergy Clin Immunol. 2016;137(3):667–79. 66. Koo S, Gupta A, Fainardi V, Bossley C, Bush A, Saglani S, et al. Ethnic variation in response to IM triamcinolone in children with severe therapy-resistant asthma. Chest. 2016;149(1):98–105. 67. Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol. 2010;125(6):1178–87; quiz 88–9 68. Kim CK, Callaway Z, Gern JE. Viral infections and associated factors that promote acute exacerbations of asthma. Allergy Asthma Immunol Res. 2018;10(1):12–7. 69. Edwards MR, Regamey N, Vareille M, Kieninger E, Gupta A, Shoemark A, et  al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol. 2013;6(4):797–806. 70. Custovic A, Belgrave D, Lin L, Bakhsoliani E, Telcian AG, Solari R, et al. Cytokine responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood. Am J Respir Crit Care Med. 2018;197(10):1265–74. 71. Porsbjerg C, Menzies-Gow A. Co-morbidities in severe asthma: clinical impact and management. Respirology. 2017;22(4):651–61. 72. Del Giacco SR, Bakirtas A, Bel E, Custovic A, Diamant Z, Hamelmann E, et al. Allergy in severe asthma. Allergy. 2017;72(2):207–20. 73. Ullmann N, Mirra V, Di Marco A, Pavone M, Porcaro F, Negro V, et al. Asthma: differential diagnosis and comorbidities. Front Pediatr. 2018;6:276.

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74. Frith J, Fleming L, Bossley C, Ullmann N, Bush A.  The complexities of defining atopy in severe childhood asthma. Clin Exp Allergy. 2011;41(7):948–53. 75. Holt PG, Strickland D, Bosco A, Belgrave D, Hales B, Simpson A, et al. Distinguishing benign from pathologic TH2 immunity in atopic children. J Allergy Clin Immunol. 2016;137(2):379–87. 76. Konradsen JR, Nordlund B, Onell A, Borres MP, Gronlund H, Hedlin G.  Severe childhood asthma and allergy to furry animals: refined assessment using molecular-based allergy diagnostics. Pediatr Allergy Immunol. 2014;25(2):187–92. 77. Sylvestre L, Jegu J, Metz-Favre C, Barnig C, Qi S, de Blay F.  Component-based allergen-­ microarray: Der p 2 and Der f 2 dust mite sensitization is more common in patients with severe asthma. J Investig Allergol Clin Immunol. 2016;26(2):141–3. 78. Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ. 2002;324(7340):763. 79. Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016;138(6):1608–18. e12 80. Sharples J, Gupta A, Fleming L, Bossley CJ, Bracken-King M, Hall P, et  al. Long-term effectiveness of a staged assessment for paediatric problematic severe asthma. Eur Respir J. 2012;40(1):264–7. 81. Oksel C, Custovic A.  Development of allergic sensitization and its relevance to paediatric asthma. Curr Opin Allergy Clin Immunol. 2018;18(2):109–16. 82. Simpson A, Tan VY, Winn J, Svensen M, Bishop CM, Heckerman DE, et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am J Respir Crit Care Med. 2010;181(11):1200–6. 83. Lazic N, Roberts G, Custovic A, Belgrave D, Bishop CM, Winn J, et al. Multiple atopy phenotypes and their associations with asthma: similar findings from two birth cohorts. Allergy. 2013;68(6):764–70. 84. Simpson A, Lazic N, Belgrave DCM, Johnson P, Bishop C, Mills C, et  al. Patterns of IgE responses to multiple allergen components and clinical symptoms at age 11 years. J Allergy Clin Immunol. 2015;136(5):1224–31. 85. Custovic A, Sonntag H-J, Buchan IE, Belgrave D, Simpson A, Prosperi MCF.  Evolution pathways of IgE responses to grass and mite allergens throughout childhood. J Allergy Clin Immunol. 2015;136(6):1645–52.e8. 86. Howard R, Belgrave D, Papastamoulis P, Simpson A, Rattray M, Custovic A. Evolution of IgE responses to multiple allergen components throughout childhood. J Allergy Clin Immunol. 2018;142(4):1322–30. 87. Fontanella S, Frainay C, Murray CS, Simpson A, Custovic A. Machine learning to identify pairwise interactions between specific IgE antibodies and their association with asthma: a crosssectional analysis within a population-based birth cohort. PLoS Med. 2018;15(11):e1002691. 88. Castro-Rodríguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med. 2001;163(6):1344–9. 89. Papoutsakis C, Priftis KN, Drakouli M, Prifti S, Konstantaki E, Chondronikola M, et  al. Childhood overweight/obesity and asthma: is there a link? A systematic review of recent epidemiologic evidence. J Acad Nutr Diet. 2013;113(1):77–105. 90. Lang JE, Bunnell HT, Hossain MJ, Wysocki T, Lima JJ, Finkel TH, et al. Being overweight or obese and the development of asthma. Pediatrics. 2018;142(6):e20182119. 91. Chen Z, Salam MT, Alderete TL, Habre R, Bastain TM, Berhane K, et al. Effects of childhood asthma on the development of obesity among school-aged children. Am J Respir Crit Care Med. 2017;195(9):1181–8. 92. Contreras ZA, Chen Z, Roumeliotaki T, Annesi-Maesano I, Baiz N, von Berg A, et al. Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts. Eur Respir J. 2018;52(3):1800504. 93. Ross MK, Romero T, Sim MS, Szilagyi PG. Obese- and allergic-related asthma phenotypes among children across the United States. J Asthma. 2019;56(5):512–21.

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94. Guerra S, Wright AL, Morgan WJ, Sherrill DL, Holberg CJ, Martinez FD.  Persistence of asthma symptoms during adolescence: role of obesity and age at the onset of puberty. Am J Respir Crit Care Med. 2004;170(1):78–85. 95. Borrell LN, Nguyen EA, Roth LA, Oh SS, Tcheurekdjian H, Sen S, et al. Childhood obesity and asthma control in the GALA II and SAGE II studies. Am J Respir Crit Care Med. 2013;187(7):697–702. 96. Forno E, Weiner DJ, Mullen J, Sawicki G, Kurland G, Han YY, et al. Obesity and airway dysanapsis in children with and without asthma. Am J Respir Crit Care Med. 2017;195(3):314–23. 97. Forno E, Lescher R, Strunk R, Weiss S, Fuhlbrigge A, Celedon JC, et al. Decreased response to inhaled steroids in overweight and obese asthmatic children. J Allergy Clin Immunol. 2011;127(3):741–9. 98. Forno E, Han YY, Muzumdar RH, Celedon JC.  Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. J Allergy Clin Immunol. 2015;136(2):304–11.e8. 99. Rastogi D, Fraser S, Oh J, Huber AM, Schulman Y, Bhagtani RH, et al. Inflammation, metabolic dysregulation, and pulmonary function among obese urban adolescents with asthma. Am J Respir Crit Care Med. 2015;191(2):149–60. 100. Covar RA, Szefler SJ, Zeiger RS, Sorkness CA, Moss M, Mauger DT, et al. Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children. J Allergy Clin Immunol. 2008;122(4):741–7.e4. 101. Kljaic-Bukvic B, Blekic M, Aberle N, Curtin JA, Hankinson J, Semic-Jusufagic A, et  al. Genetic variants in endotoxin signalling pathway, domestic endotoxin exposure and asthma exacerbations. Pediatr Allergy Immunol. 2014;25(6):552–7. 102. Sharma S, Raby BA, Hunninghake GM, Soto-Quiros M, Avila L, Murphy AJ, et al. Variants in TGFB1, dust mite exposure, and disease severity in children with asthma. Am J Respir Crit Care Med. 2009;179(5):356–62. 103. Bukvic BK, Blekic M, Simpson A, Marinho S, Curtin JA, Hankinson J, et al. Asthma severity, polymorphisms in 20p13 and their interaction with tobacco smoke exposure. Pediatr Allergy Immunol. 2013;24(1):10–8. 104. Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, et al. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med. 2017;195(3):302–13. 105. Chang EH, Willis AL, McCrary HC, Noutsios GT, Le CH, Chiu AG, et  al. Association between the CDHR3 rs6967330 risk allele and chronic rhinosinusitis. J Allergy Clin Immunol. 2017;139(6):1990–2.e2. 106. Martinez FD, Vercelli D. Asthma Lancet. 2013;382(9901):1360–72. 107. Berry CE, Billheimer D, Jenkins IC, Lu ZJ, Stern DA, Gerald LB, et al. A distinct low lung function trajectory from childhood to the fourth decade of life. Am J Respir Crit Care Med. 2016;194(5):607–12. 108. Belgrave DCM, Granell R, Turner SW, Curtin JA, Buchan IE, Le Souef PN, et  al. Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies. Lancet Respir Med. 2018;6(7):526–34. 109. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349(15):1414–22. 110. Tai A, Tran H, Roberts M, Clarke N, Gibson AM, Vidmar S, et al. Outcomes of childhood asthma to the age of 50 years. J Allergy Clin Immunol. 2014;133(6):1572–8.e3. 111. Tai A, Tran H, Roberts M, Clarke N, Wilson J, Robertson CF. The association between childhood asthma and adult chronic obstructive pulmonary disease. Thorax. 2014;69(9):805–10. 112. Martinez FD.  Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 2016;375(9):871–8. 113. Szefler SJ. Asthma across the lifespan: Time for a paradigm shift. J Allergy Clin Immunol. 2018;142(3):773–80.

Chapter 2

Special Considerations in Preschool Age Maura Kere and Erik Melén

 revalence of Severe Asthma and Wheezing Disorders P in Preschool Children Prevalence of Asthma There has been a significant increase of global preschool asthma prevalence since the early twentieth century, paralleled with reported increases in the prevalence of allergies. This increase may have leveled off in some areas, while in others the rise seems to continue [1]. Specifically, the prevalence of asthma seems to have reached a plateau in high-income countries, whereas in low- and middle-income countries, the prevalence is ever increasing. Factors affecting this increase in prevalence in preschool children have been actively studied but are yet to be fully understood, as both genetics and environmental exposures affect several aspects of disease risk and severity. There is a male predominance in prevalence of asthma and wheezing disorders before puberty and a “sex-shift” toward females after puberty [2]. Relating to environmental exposures, it has been hypothesized that the transition to a more urban environment may have driven the development of asthma in general and wheezing disorders in preschool children [3, 4]. Whether the prevalence of severe asthma in preschool children has changed in the last decades is largely unknown.

M. Kere · E. Melén (*) Sachs’ Children’s Hospital, South General Hospital, Stockholm, Sweden Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden e-mail: [email protected] © Springer Nature Switzerland AG 2020 E. Forno, S. Saglani (eds.), Severe Asthma in Children and Adolescents, https://doi.org/10.1007/978-3-030-27431-3_2

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Prevalence of Wheezing Disorders Population studies from the USA and Europe report that half of all children at age 6 have experienced wheezing during their lifetimes [5] and that one in three children has at least one episode of wheezing before their third birthday [6]. Approximately 40% of preschoolers who wheeze show respiratory symptoms later in their childhood, although there is variation from 22% to 55% [7–9]. Despite the high incidence and prevalence, there are knowledge gaps regarding the mechanisms of disease pathogenesis and the optimal treatment of wheezing disorders in preschool children. There is substantial heterogeneity in the spectrum of symptom development, duration, frequency, severity, and response to treatment, as well as the pathophysiology and risk factors behind preschool wheezing [10]. This hinders general preventive efforts and may also result in inadequate treatment. A special consideration with preschool wheezing compared to that of later age-groups is that wheezing is predominantly triggered by viral infections, whereas later in childhood reasons such as allergens or exercise dominate. Approximately one half of all preschoolers wheeze at some point in time, and one third of this group will have asthma later in their life [11]. Fortunately, most infants with wheezing disorders have a good prognosis and remain free from subsequent wheezing episodes later in life.

Definition Wheezing is defined as a high-pitched whistling sound produced in the chest during expiration, as a result of obstruction or narrowing of the air passages. Asthma and severe wheezing are common conditions in emergency departments at children’s hospitals. In addition to wheezing, children typically present with symptoms such as tachycardia, tachypnea, dyspnea, cough, and reduced blood saturation of oxygen. Older children may use their accessory muscles to aid their breathing, whereas in younger children chest wall recession (severe retractions) is observed. Older children with an acute asthma attack often have a history with asthma causing their symptoms; however, children in preschool age do not necessarily have known asthma or bronchospasm as the cardinal reasons behind their wheezing. In addition, lower respiratory tract infections or foreign body aspiration may manifest with similar symptoms. Details of the differential diagnoses of wheezing disorders are discussed in other chapters. In epidemiology studies, the prevalence of wheezing is often derived from questionnaires answered by parents using questions like “Has your child had wheezing or whistling in the chest in the last 12 months?” [12]. Asthma is challenging to diagnose in preschool children due to a wide spectrum of disease symptoms, lack of objective markers, and the fact that several asthma-­ related phenotypes may give rise to the same symptom (e.g., wheezing). In general, asthma is diagnosed based on presence of, or history of, symptoms like wheezing,

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coughing, chest tightness, and trouble breathing. In addition, information on symptom triggers, effect of asthma medications, family history, and atopic status may be used as basis for the diagnosis. It is important to keep in mind that many large epidemiological studies use questionnaire-based parental report of asthma symptoms or outcomes in order to define disease status and severity. Parental report may be subject to over- or underreporting, and even validated questionnaires are not fully free of the risk of bias. In older children objective tools such as spirometry, bronchodilator response, and methacholine challenges may be helpful; however, in the preschool years, such tools are difficult to administer.

Characterization of Wheezing Disorders Preschool wheezing may be divided into two groups based on temporal patterns and causal factors: episodic (or viral wheezing) and multiple-trigger wheezing [13]. The clinical phenotype and temporal patterns depend on characteristics such as prematurity or age of onset as well as congenital or previously acquired factors such as abnormal airway function, atopy, and tobacco smoke exposure. Although the two definitions can be clinically useful to differentiate between, it should be noted that the phenotypes also share similarities and pathophysiology and some children may present with a “mixed” wheezing phenotype and that phenotypes may switch within the same patient over time. Episodic wheezing is the most common type of wheezing in preschool children, characterized by acute attacks and symptoms, with periods of being completely well in between, a seasonal variation and usually precipitated by an underlying respiratory tract infection, which triggers the inflammation that leads to airway narrowing and wheezing. The most common causative viral pathogens include human rhinovirus (HRV), respiratory syncytial virus (RSV), coronavirus, and human metapneumovirus [13]. In addition, bacterial infections are shown to be associated independently of possible concurrent viral infections with wheezing episodes. Preschool children with or without wheezing have the same type of pathogens (bacteria or viruses), and hence the type of pathogen likely is not determinant for the wheezing but rather the presence of pathogens [14]. The long-term outcomes vary: wheezing may disappear, continue into school age, or develop into multiple-trigger wheezing and later manifest asthma. The prevalence of episodic wheezing decreases with age [15]. Multiple-trigger wheezing (also called persistent wheezing) is characterized by the presence of acute attacks but also symptoms of wheeze between episodes. Usually, the airways respond to several trigger factors such as allergen exposure, tobacco smoke, respiratory infections, crying, laughing, and exercising. The condition shows less seasonal variance compared to episodic wheezing mostly linked to viral infections, and its absolute prevalence throughout childhood remains rather constant, though its proportion compared to episodic wheezing increases with age. Children with multiple-trigger wheeze have a higher risk of later asthma compared to children with episodic wheeze [16]. Yet, although most wheezing in preschool

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children is associated with viral respiratory tract infections, there is insufficient evidence to show that the mechanisms driving preschool wheezing are the same as asthma [13]. Retrospectively, preschool wheezing can also be divided based on the duration of the symptoms into three groups as described in the hallmark paper from the Children’s Respiratory Study in Tucson, Arizona [17]. All three types can either be defined as episodic wheezing or multiple-trigger wheezing. Transient wheezing typically appears before the child is 3 years of age and disappears before their sixth birthday or around school age. Persistent wheezing continues beyond the child’s sixth birthday (or school age). Late-onset wheezing shows symptoms that begin after the age of 3. These definitions may be useful when discussing longitudinal studies. These studies and clinical phenotypes have been described in more detail in Chap 1.

Features of Severe Acute Wheezing in Young Children The spectrum of symptoms is broad and varied when it comes to preschool wheezing disorders. In acute, severe disease exacerbations (or attacks) oxygen saturation can be decreased, and the patient is tachycardic and tachypneic and has to exploit additional strategies to fill the lungs with air. This is perceived as a use of accessory breathing muscles in older children and chest wall recession in younger children as well as nasal flaring. The child may not be able to communicate effectively as completing a sentence with one breath may be difficult. Characteristics affiliated with severe or moderately acute clinical presentations of wheeze attacks are displayed in Table 2.1 [18]. Several definitions for non-acute severe asthma have been suggested. The suggested factors behind these definitions include dose of medication, ­symptomatology, exacerbation frequency, and severity as well as spirometry results. The ERS/ATS definition only starts at 6  years of age, and there is no established definition for patients younger than that. The definitions are presented in Table 2.2 [19, 20]. Table 2.1  Characteristics of severe and moderate acute asthma, divided by age [18] Age >5 years Severe acute 125 Respiratory >30 rate (bpm) Features Clear use of accessory muscles, nasal flaring Others Inability to complete sentence, feed

Moderate acute 92–95

Age 2–5 years Severe acute 140 >40

120–140 30–40

Some use of accessory muscles, nasal flaring Talking in short phrases

Clear chest wall recession, nasal flaring Inability to complete sentence, feed

Some chest wall recession, nasal flaring Talking in short phrases

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Table 2.2  Exact definitions of severe asthma by ERS/ATS and GINA European Respiratory Society (ERS)/American Thoracic Society (ATS) ERS/ATS definition of severe asthma for patients aged ≥6 years

Global Initiative on Asthma (GINA) GINA guideline definition assessed when the patient has been on regular controller treatment for several months. Criteria for severe asthma (all ages)

Definition, all quoted from [19] Asthma which requires treatment with guidelines suggested medications for GINA steps 4–5 (high-dose ICS and LABA or leukotriene modifier/theophylline) for the previous year or systemic CS for ≥50% of the previous year to prevent asthma from becoming “uncontrolled” or if asthma remains “uncontrolled” despite this therapy Uncontrolled asthma defined as at least one of the following:   1. P  oor symptom control: ACQ consistently ≥1.5, ACT 800mcg/d ICS, LAB2A and LTA Issues NOT or can’t be satisfactorially addressed: remains Difficult to Treat Asthma (DTA)

Severe Therapy Resistant Asthma (STRA)

Fig. 5.1  The Northern Ireland regional difficult-to-treat clinical outline algorithm. ICS inhaled corticosteroid, LAB2A long-acting beta-2 agonist, LTA leukotriene receptor antagonist

from time to time, may play a role, e.g. a radiologist if special imaging is needed to rule out a specific condition. In addition to the paediatric respiratory and/or allergy specialist, the core DTA clinic team members include the following asthma-trained specialists: • • • • • • • •

Asthma nurse or certified asthma educator. Respiratory physiologist or respiratory technician. Respiratory physiotherapist. Speech and language therapist. Child clinical psychologist. Pharmacist. Otorhinolaryngologist or ear nose throat (ENT) surgeon. Other centres may also have social workers and/or case coordinators.

We will use our DTA care pathway currently in operation at the Royal Belfast Hospital for Sick Children to illustrate this. This clinic was set up in 2010, and its underlying principle of operation was heavily influenced by a clinical trial addressing children with severe asthma. This trial had to be abandoned due to a failure to find children (on high-dose ICS/LABA) to randomise [12]. The interesting part of this study was that the run-in period was open-ended, and children had to prove that they were adherent to preventer/controller medication while being frequently monitored. The majority simply either improved during the run-in period or didn’t have adequate adherence. This trial illustrated that, if attention was paid to ensuring the basics of asthma care (adherence with good ICS inhaler technique) and frequent monitoring was in place, the majority of children with apparent difficult asthma can

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be shown not to have true STRA. The authors concluded: “These findings suggest that there are not as many children with moderate-to-severe persistent asthma as thought and that many children who appear to have moderate-to-severe asthma might not have underlying ‘severe’ disease, but rather might have poor adherence to prescribed medication.” [13].

Part A: Difficult-to-Treat Asthma Care Pathway At the Royal Belfast Hospital for Sick Children, when a child has been referred with apparent difficult or severe asthma, it is always worth starting the algorithm at the beginning and not presume that the referring paediatrician has correctly confirmed the diagnosis of asthma, has treated concomitant conditions, has properly trained the child in the correct inhaler technique and has trained the family in the correct use of and adherence to treatments as per their written asthma management plan.

Entry Point: New Referral from a Paediatrician Referral criteria: Difficult-to-control day-to-day symptoms, frequent severe asthma attacks in children aged 4–16 years old – each despite maximal therapy (step 4/5 Global Initiative for Asthma [GINA] or British Thoracic Society [BTS] guidelines or steps 4–6 in the US Expert Panel Report 3 [EPR3] guidelines) [3, 4, 14]. These criteria likely represent the usual “problematic asthma” defined in Chaps. 1 and 3.

Step 1 Previsit 1 For the previous 6–12 months, the specialist asthma nurse extracts and records the following information and makes it available for the first MDT clinic visit: • A record of all repeat refills of asthma medication (both reliever and preventer) from the general practitioner or primary care provider (GP/PCP) calculates the average adherence to the main preventers and details regarding patterns of reliever usage and requirement for oral corticosteroids. • The number of attendances to the GP/PCP, out of hours or urgent care clinics, emergency department visits and admissions for asthma are obtained from the N. Ireland Electronic Health Care Record.

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Multidisciplinary Team Clinic Visit 1 This is led by one of two respiratory and allergy paediatricians with an interest in DTA. • Spirometry, bronchodilator responsiveness (BDR) testing, and fractional exhaled nitric oxide (FeNO) are performed (respiratory physiologist) • While awaiting the clinic consultation, the child and parent fill in the Childhood Asthma Control Test (cACT; 6 years) –– Montelukast

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Step 3 Observed Optimised Therapy We then organise a period of monitoring to ensure that the optimised therapy is adequately delivered (respiratory and allergy paediatrician and specialist asthma nurse). In the past we have tried to ensure that treatment has been delivered by either using intramuscular triamcinolone or subcutaneous terbutaline infusions, although more recently it has been found that the use of remote directly observed therapy (R-DOT) has given good results [17]. We are aware that other DTA clinics may use DOT with a nurse observing the child either at home or at school [18]. Increasingly, inhalers with electronic monitors are being used to record adherence, and more recently they have been used to check the inhaler technique [19, 20]. Blood samples are taken including total IgE, specific IgE to common aeroallergens including moulds), full blood count and differential white blood cell count, immune function tests and vitamin D levels. These samples are taken to help later decide whether a child with true STRA would be suitable for anti-IgE or anti-IL-5 therapy.  DT Clinic Visit 3 (Respiratory and Allergy Paediatrician and Specialist M Asthma Nurse) The aim of this clinic attendance is to review the care pathway course and decide future action: • For those children who have improved, we consider strategies aimed at maintaining the improvement. • For those children continuing to have symptoms and poor asthma control despite good adherence to preventer therapy and who meet the definition of true STRA, we offer either anti-IgE therapy, anti-IL-5 therapy, or other biologicals as available (see Chap. 7). • For some children with ongoing asthma symptoms despite good adherence to preventer therapy, we are still not able to determine whether they truly have STRA. Often such children have ongoing home exposures that we have not been able to adequately address despite trying our best, e.g. home pets or major psychological stresses that are still ongoing despite clinical psychology team input. For these children we have still considered the option of using biologics based on the perceived risk/benefits. • We do not call children who fail to master their inhaler or regularly take their inhaler correctly as having STRA – we simply don’t know whether they would or would not get better if these matters were addressed. Although a case can be put for treating non-adherent children with more expensive biological therapies, it is our approach that this is not a correct use of scarce resources, and, as a last

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resort, addressing the issues with social services (child protection) may be needed. It is typically at this stage in the DTA care pathway that the team may recognise that an older child has dysfunctional breathing (e.g. hyperventilation, vocal cord dysfunction, EILO), and further assessment is required by the respiratory physiotherapist working with the speech and language therapist (SLP). If a major psychosocial stressor or issue is identified, then referral to psychology and social services is required (psychologist, social services).

Step 4 Biological Therapy for Severe Therapy-Resistant Asthma Once the MDT has agreed that a child would benefit from a biological therapy, an individual funding application is submitted to the Department of Health, and, once agreed, the specialist asthma nurse arranges for this to be administered on a regular basis. This requires administration skills to ensure medication is delivered from the pharmacy to coincide with patient appointments (specialist asthma nurse). Further details on biological therapies are provided in Chap. 7.

Part B: Roles of the Individuals in the MDT Specialist Asthma Nurse or Certified Asthma Educator The specialist asthma nurse is the core professional in the multidisciplinary team. An experienced asthma nurse will likely have the skills to manage the flow of the child through the DTA pathway and perform many of the tasks and skills of other team members. We believe all children/parents referred to a regional DTA clinic should have a significant amount of time set aside with the asthma nurse – in order to confirm that the asthma basics of care are in place including: 1. Once a PAAP has been formulated, it is then important that the child/parent is trained in its use. It is inadequate to simply have written out a PAAP and handed this to the child/parent. They need to know what medications to take when very well (and why), what to do at the onset of increased symptoms, what to do when an asthma attack occurs and when to seek help. The child/parents should be able to teach back to the nurse what they would do in each of these scenarios. It is always wrong to assume that this has been completed at the referring hospital. 2. The asthma nurse must understand how to use each of the many available inhalers with or without spacers. More importantly, the specialist asthma nurse must be able to teach children of all ages how to use the inhalers and to ensure that the child can demonstrate back to the nurse that they have mastered the inhaler tech-

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nique. This is important, as many children are simply shown how to use an inhaler often by a healthcare professional who doesn’t fully understand how to use it themselves [21]. In addition, simply demonstrating the use of an inhaler is only successful 30–40% of the time, and this rises to 90% if the teach-to-goal or teach-back technique is used [22]. We now routinely use this approach. 3. The asthma nurse must be able to educate the child/parents of the importance of taking their preventer/controller medication(s) regularly. Poor adherence and poor inhaler technique are most often the cause of DTA. In order to confirm that optimised therapy has/is being delivered, the asthma nurse may need to do DOT either at home, in school or remotely using remote or video DOT. Whichever way DOT is used, an attempt is made to ensure that (1) inhalers have been used and (2) they have been used correctly. DOT is an effective strategy either to improve asthma control or to determine which children have true STRA and who are in need of more expensive therapies. 4. It is important to know what allergens that a child with DTA is sensitised to. The asthma nurse can perform SPTs and/or arrange for blood total IgE and specific IgE to common aeroallergens to be taken. Our asthma nurses are skilled at this, and it is performed at their assessment clinics with specific trigger avoidance advice being given when the results are known (steps 1 and 2 of DTA care pathway). 5. Home (and/or school) visits (step 2). This is an important part of the DTA pathway. This aims to determine triggers of asthma that may need extra attention including the accessibility of inhalers in the school environment, presence of furry animals at home to which the child may be sensitised, presence of damp and mould and exposure to indoor aero-pollution from fires, tobacco smoke or other pollutants [23]. Information about potential adherence problems are facilitated by the nurse, recording the home medication readiness index [16]. Finally, during a home visit, if the nurse develops a rapport with the family, she/he may get an insight into family tensions and stressors that could be exacerbating the asthma. 6. Setting up services for the regular hospital administration of biologics for those with STRA.

Respiratory Physiologist or Respiratory Technician (RT) To help confirm a diagnosis of asthma in a child, they have the ability to: • Perform spirometry with bronchodilator responsiveness (BDR). • Measure FeNO and help to organise a FeNO suppression test. • Co-ordinate exercise-induced asthma (EIA) and exercise-induced laryngeal obstruction (EILO) challenge testing. • Perform bronchial hyperreactivity (BHR) testing.

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Diagnosis of Asthma The physiologists or RTs should be aware of the current use of medication and how this may affect the interpretation of test results. A high FeNO and BDR in a steroid-­ naïve child is supportive of an asthma diagnosis [23]. Within 5–7 days of starting an ICS, there is a rapid reduction in the FeNO towards normal in the majority of patients. Given that children on the DTA care pathway should be on high-dose ICS already, the finding of an elevated FeNO would suggest either ICS adherence has been suboptimal or the allergic asthma with high FeNO is not responding well to the ICS. A positive FeNO suppression test is suggestive of prior poor adherence or poor inhaler technique [15]. The use of methods for detecting airway obstruction and BDR in wheezing children is important and a developing area. This includes the use of impulse airway oscillometry (IOS). Several recent papers suggest that IOS is a reliable and repeatable method of confirming BDR in young children with wheeze [24, 25]. Monitoring Asthma Regular monitoring of FeNO, spirometry and BDR at each clinic visit. Identifying Concomitant Conditions Sleep-disordered breathing and obstructive sleep apnoea have been associated with more severe asthma symptoms, and, in addition, night-time snoring can be confused with night-time asthma symptoms. The respiratory physiologist has the expertise to perform overnight oximetry. In addition, parents could be asked to record a short mobile phone-based audio-video clip of the noisy breathing while asleep. If required, limited or full polysomnography may be required. In coordination with the specialist and an ENT surgeon, the physiologist may set up challenge testing for the diagnosis of VCD or EILO. This involves setting up a standard exercise test on a treadmill or cycle, monitoring heart rate and oxygen saturation while the ENT surgeon observes the vocal cord motion from an in situ laryngeal camera.

Respiratory Physiotherapist The respiratory physiotherapist has several roles to play in children with difficult-­ to-­treat asthma, including: • Helping to confirm the diagnosis of asthma especially where the predominant symptom is cough but also if induced mainly by exercise. An induced sputum sample can be very helpful in a child with a chronic cough as the sample can be

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submitted for both microbiological culture and cytology. Finding bacteria (e.g. H.  Influenzae, pneumococcus and/or Moraxella catarrhalis) in sputum along with a high neutrophil count suggests that persistent bacterial bronchitis will need to be treated and investigated. Finding elevated eosinophils would be suggestive of asthma. In the USA and other countries, this test may be performed by the respiratory technician (RT). • Dysfunctional breathing, including VCD and EILO, may complicate milder asthma (making asthma seem worse), worsen severe asthma and even masquerade as asthma (i.e. not asthma at all). Children and young people with dysfunctional breathing can have similar symptoms that are easily mistaken as asthma. They may then present as apparent asthma that is not responding to conventional asthma therapy. In the USA and other countries, the language therapists may take the lead in the management of dysfunctional breathing. Physiotherapy techniques include: • Education – explaining to the child or young person what is happening with their breathing • Breathing pattern retraining • Postural correction • Relaxation and activity tasks

Speech and Language Therapist The speech and language therapist does not attend the clinic routinely but provides specialist expertise when required for individual patients. The main role of the therapist also concerns the assessment and management of dysfunctional breathing. In the UK, their role can overlap with that of the respiratory physiotherapist. Inducible laryngeal obstruction is an inappropriate, transient, paroxysmal obstruction of the larynx in response to a number of triggers [26]. An early case series of five patients with “uncontrolled asthma” identified the entity of dyspnoea and wheeze arising from laryngeal obstruction and unresponsive to conventional asthma treatment. Laryngoscopy confirmed that wheezing was due to adduction of the true and false vocal cords when symptomatic, but when asymptomatic laryngoscopic examination was normal [27]. It can mimic and co-exist with asthma, making it challenging to treat. Similarly, a further case series presented three patients with “factitious asthma” who characteristically had wheezing heard loudest over the larynx, and one of them had the vocal cords intermittently adducted in fibre-optic bronchoscopy [28]. Following these early reports, a number of studies presented information regarding the presentation, investigation and management of ILO, and an international task force was established in 2010 by the European Respiratory Society and the European Laryngological Society to agree nomenclature for the spectrum of conditions and establish future research priorities. Speech and language therapists play an important role in treating functional laryngeal obstruction. VCD and EILO

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are two forms of this. EILO is a differential diagnosis of exercise-induced bronchoconstriction or exercise-induced asthma (EIA). Making a diagnosis is important as the conditions will typically not respond to asthma therapy. Diagnosis is based on direct visualisation of laryngeal narrowing by laryngoscopy. An interdisciplinary approach is essential; respiratory technicians and speech and language therapists work closely with the ENT surgeons in confirming the diagnosis and starting management. Establishing the diagnosis through direct-recorded visualisation can be reassuring to the patient and carers, and effective interventions can be instituted quickly [29]. These interventions involve distracting attention away from the larynx and include nasal breathing, panting and diaphragmatic breathing. Biofeedback techniques have been proposed as well as inspiratory muscle training [30, 31]. However, there have been concerns expressed about the placebo effect in studies using open-label designs and speech therapy or psychotherapy. No randomised controlled studies have yet been done [32].

Otorhinolaryngologist or ENT Surgeon ENT surgeons do not routinely attend the asthma clinic; however patients may present to them with conditions that co-exist with asthma such as allergic rhinitis (AR) or chronic rhinosinusitis (CRS) or conditions that may mimic asthma such as VCD or EILO.  Comorbidities such as AR or CRS can impact on asthma control [33]. Treating AR and CRS can improve asthma symptoms suggesting that the inflammatory process in the upper and lower airways may be related as suggested by the one airway hypothesis [34]. The ENT surgeon may be consulted before the respiratory physician in a child with asthma, and it is imperative that the treatment of AR and CRS is optimised. Following otorhinological examination, the ENT surgeon may request SPT or specific IgE testing to common aeroallergens or refer to the allergy team. Some children are referred with noisy breathing and dyspnoea in whom asthma is felt to be the diagnosis. However, the noise is predominantly inspiratory, and they are unresponsive to usual asthma medication. It is felt that the noise is originating in the upper airways. Spirometry may show a plateau in the inspiratory curve [35]. A differential diagnosis of vocal cord dysfunction is suggested. These children are referred to the ENT service and have flexible laryngoscopy that may show adduction of the anterior two thirds of the vocal cords in response to a number of triggers [27]. When this occurs during exercise and peaks during maximal activity, the differential diagnoses are exercise-induced asthma or exercise-induced laryngeal obstruction. Children will often complain of a tightness in their throat rather than the usual chest tightness of exercise-induced asthma. In this case the ENT surgeon may perform laryngoscopy at the same time as the child exercises to induce the obstruction. Therefore, continuous laryngoscopy during exercise is the gold standard test. This is performed in conjunction with a physiologist who organises an exercise test. Ideally, this should be performed when the child is doing the activity

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that precipitates the symptoms. This is most frequently done on an exercise bike but may be performed with the child on a bicycle ergometer or swimming. During exercise the larynx normally opens fully. The most common finding is the adduction of the vocal cords at the point of maximal activity. Confirmation of the diagnosis leads to referral to the speech and language therapy and/or respiratory physiotherapists for further management. Referral to clinical psychology may also be considered.

Clinical Psychology The clinical psychologist should attend the clinic as their assessment and intervention is often needed, especially in problematic severe asthma. Psychological risk factors are common in young people who subsequently die from asthma [36, 37]. Similarly, in life-threatening asthma episodes, children display denial, psychosocial difficulties and delay in seeking help [38]. There is evidence linking stress and worsening paediatric asthma [39], but this can be counterbalanced by experiencing more positive life events [40]. Asthma management behaviours, such as poor adherence to treatment secondary to psychosocial difficulties, can affect asthma control. It is also proposed that stress may impact on asthma control through neuroimmunological mechanisms and that this can result in steroid resistance [41, 42]. A Cochrane review of psychological interventions in children with asthma identified 12 randomised controlled trials of psychological intervention for children and adolescents under the age of 18 years [43]. Four broad psychological approaches were employed: relaxation, cognitive behavioural therapy, biofeedback assisted relaxation and behavioural therapy. The therapies were often combined to suit an individual’s needs. The outcomes measured were diverse including health service utilisation, lung function, asthma symptoms, medication use, school absenteeism and quality of life. As a result of this, a meta-analysis was only able to include two studies that demonstrated a positive effect of relaxation therapy on lung function (peak expiratory flow rate). The Cochrane review reported that it was not possible to draw firm conclusions as to the benefit of psychological intervention for children and adolescents with asthma.

Pharmacist The traditional role of hospital- and community-based pharmacists in asthma management has been to check and dispense prescriptions, but community pharmacists are transforming their role in chronic disease management including asthma. They are uniquely positioned within the primary care team to care for patients with asthma. Patients requiring chronic medications may visit pharmacies monthly for refills. Consultations with a community pharmacist occur at this interface without an appointment. Consequently, patients or parents of children with asthma may see

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their pharmacist more often than their nurse or doctor. They have access to important data such as frequency of pick-ups of repeat prescriptions, and this provides the opportunity to detect common medication-related problems such as poor inhaler technique and overuse of short-acting bronchodilators. Pharmacists use this information to do Medicines Under Review (MUR) consultations with the aim of improving patients’ adherence and experience of using their medication(s), maximise the benefits and reduce waste due to unused medicines. Asthma is one of four broad chronic disease areas targeted by the UK government for MURs [44]. Pharmacy-based intervention programmes can significantly improve patient outcomes in studies of adult asthma [45, 46]. Community pharmacists are increasingly running structured asthma review clinics following national guidelines. We believe that their expertise will allow them to take on many of the roles of other healthcare professionals in supporting hospital-based difficult asthma clinics, and this will be a developing area in the coming years.

Summary We have described how a structured multidisciplinary approach to children with problematic asthma can help to determine and address the reasons for ongoing symptoms and help to identify which children have STRA and may benefit from biological therapies. The multidisciplinary team plays a central role in minimising asthma morbidity, including chronic symptoms and severe acute exacerbations, which in turn leads to improved quality of life and to reduced healthcare utilisation.

References 1. Fleming L, Wilson N, Bush A. Difficult to control asthma in children. Curr Opin Allergy Clin Immunol. 2007;7(2):19–25. 2. Szefler SJ, Zeiger RS, Haselkorn T, Mink DR, Kamath TV, Fish JE, Chipps BE. Economic Burden of impairment in children with severe of difficult to treat asthma. Ann Allergy Asthma Immunol. 2011;107(2):110–9. 3. British Thoracic Society; Scottish Intercollegiate Guideline Network. British guideline on the management of asthma: a national clinical guideline. Revised 2019. https://www.sign.ac.uk/ assets/sign158.pdf. Accessed October 2019. 4. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2018. www.ginasthma.org. Accessed 25 Feb 2019. 5. FitzGerald JM, Lemiere C, Lougheed MD, Ducharme FM, Dell SD, Ramsey C, et  al. Recognition and management of severe asthma: a Canadian Thoracic Society position statement. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2017;1(4):199–221. 6. Clark VL, Gibson PG, Genn G, Hiles SA, Pavord ID, McDonald VM.  Multidimensional assessment of severe asthma: a systematic review and meta-analysis. Respirology. 2017;22(7):1262–75.

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7. Burke H, Davis J, Evans S, Flower L, Tan A, Kurukulaaratchy RJ. A multi-disciplinary case team management approach reduces the burden of frequent asthma admission. ERJ Open Res. 2016;2(3):00039. 8. Athanazio R, Carvalho-Pinto R, Fernandes FL, Rached S, Rabe K, Cukier A, Stelmach R. Can severe asthmatic patients achieve asthma control? A systematic approach in patients with difficult to control asthma followed in a specialized clinic. BMC Pulm Med. 2016;16(1):153. 9. Heaney LG, Conway E, Kelly C, Johnston BT, English C, Stevenson M, Gamble J. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax. 2003;58(7):561–6. 10. Cook J, Beresford F, Fainardi V, Hall P, Housley G, Jamalzadeh A, et  al. Managing the paediatric patient with refractory asthma: a multi-disciplinary approach. J Asthma Allergy. 2017;10:123–30. 11. Verkleij M, Beelen A, van Ewijk BE, Geenen R. Multidisciplinary treatment in children with problematic severe asthma: a prospective evaluation. Pediatr Pulmonol. 2017;52(5):588–97. 12. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et  al. International ERS/ ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–373. https://erj.ersjournals.com/content/43/2/343. Last accessed 25 May 2019. 13. Strunk RC. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-­to severe childhood asthma. J Allergy Clin Immunol. 2008;122(6):1138–44. 14. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: guidelines for the diagnosis and management of asthma. Full report 2007. NIH Publication No. 07–4051. Jul 1997; revised Jun 2002; Aug 2007. https:// www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed 14 May 2019. 15. Heaney LG, Busby J, Bradding P, Chaudhuri R, Mansur AH, Niven R, et al. Remotely monitored therapy and nitric oxide suppression identifies nonadherence in severe asthma. Am J Respir Crit Care Med. 2019;199(4):454–64. 16. Callaghan-Koru JA, Riekert KA, Ruvalcaba E, Rand CS, Eakin MN. Home medication readiness for preschool children with asthma. Pediatrics. 2018;142(3):e20180829. 17. Shields MD, ALQahtani F, Rivey MP, McElnay JC.  Mobile direct observation of therapy (MDOT)  – a rapid systematic review and pilot study in children with asthma. PLoS One. 2018;13(2):e0190031. 18. Salazar G, Tarwala G, Reznik M.  School-based supervised therapy programs to improve asthma outcomes: current perspectives. J Asthma Allergy. 2018;11:205–15. 19. Taylor TE, Zigel Y, De Looze C, Sulaiman I, Costello RW, Reilly RB. Advances in audio-based systems to monitor patient adherence and inhaler drug delivery. Chest. 2018;153(3):710–22. 20. Bonini M, Usmani OS. Novel methods for device and adherence monitoring in asthma. Curr Opin Pulm Med. 2018;24(1):63–9. 21. Plaza V, Giner J, Rodrigo GJ, Dolovich MB, Sanchis J. Errors in the use of inhalers by health care professionals: a systematic review. J Allergy Clin Immunol Pract. 2018;6(3):987–95. 22. Wu M, Woodrick NM, Arora VM, Farnan JM, Press VG. Developing a virtual Teach-To-Goal™ inhaler technique learning module: a mixed methods approach. J Allergy Clin Immunol Pract. 2017;5(6):1728–36. 23. Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, et al. The importance of nurse-led home visits in the assessment of children with problematic asthma. Arch Dis Child. 2009;94(10):780–4. 24. Galant SP, Komarow HD, Shin H-W, Siddiqui S, Lipworth BJ. The case for impulse oscillometry in the management of asthma in children and adults. Ann Allergy Asthma Immunol. 2017;8(6):664–71. 25. Knihtilä H, Kotaniemi-Syrjänen A, Pelkonen AS, Kalliola S, Mäkelä MJ, Malmberg LP. Sensitivity of newly defined oscillometry indices in pre-school wheeze. Pediatr Pulmonol. 2017;52(5):598–605.

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26. Halvorsen T, Walsted ES, Bucca C, Bush A, Cantarella G, Friedrich G, et al. Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. Eur Respir J. 2017;50(3):1602221. 27. Christopher KL, Wood RP 2nd, Eckert RC, Blager FB, Raney RA, Souhrada JF. Vocal-cord dysfunction presenting as asthma. N Engl J Med 1983;308(26):1566–1570. 28. Downing ET, Braman SS, Fox MJ, Corrao WM. Factitious asthma. Physiological approach to diagnosis. JAMA. 1982;248(21):2878–81. 29. Rameau A, Foltz RS, Wagner K, Zur KB. Multidisciplinary approach to vocal cord dysfunction diagnosis and treatment in one session: a single institutional outcome study. Int J Pediatr Otorhinolaryngol. 2012;76(1):31–5. 30. Earles J, Kerr B, Kellar M.  Psychophysiologic treatment of vocal cord dysfunction. Ann Allergy Asthma Immunol. 2003;90(6):669–71. 31. Mathers-Schmidt BA, Brilla LR. Inspiratory muscle training in exercise-induced paradoxical vocal fold motion. J Voice. 2005;19(4):635–44. 32. Røksund OD, Heimdal JH, Clemm H, Vollsæter M, Halvorsen T. Exercise inducible laryngeal obstruction: diagnostics and management. Paediatr Respir Rev. 2017;21:86–94. 33. Tay TR, Hew M. Comorbid “treatable traits” in difficult asthma: current evidence and clinical evaluation. Allergy. 2018;73(7):1369–82. 34. Grossman J. One airway, one disease. Chest. 1997;111(2 Suppl):11S–6S. Review 35. Miller RD, Hyatt RE.  Evaluation of obstructing lesions of the trachea and larynx by flow-­ volume loops. Am Rev Respir Dis. 1973;108(3):475–81. 36. Strunk RC, Mrazek DA, Fuhrmann GS, LaBrecque JF. Physiologic and psychological characteristics associated with deaths due to asthma in childhood. A case-controlled study. JAMA. 1985;254(9):1193–8. 37. Bergström SE, Boman G, Eriksson L, Formgren H, Foucard T, Hörte LG, et al. Asthma mortality among Swedish children and young adults, a 10-year study. Respir Med. 2008;102(9):1335–41. 38. Martin AJ, Campbell DA, Gluyas PA, Coates JR, Ruffin RE, Roder DM, et al. Characteristics of near fatal asthma in childhood. Pediatr Pulmonol. 1995;20(1):1–8. 39. Sandberg S, Paton JY, Ahola S, McCann DC, McGuinness D, Hillary CR, Oja H. The role of acute and chronic stress in asthma attacks in children. Lancet. 2000;356(8234):982–7. 40. Sandberg S, McCann DC, Ahola S, Oja H, Paton JY, McGuinness D. Positive experiences and the relationship between stress and asthma in children. Acta Paediatr. 2002;91(2):152–8. 41. Wright RJ. Further evidence that the wealthier are healthier: negative life events and asthma-­ specific quality of life. Thorax. 2007;62(2):106–8. 42. Miller GE, Chen E. Life stress and diminished expression of genes encoding glucocorticoid receptor and b2-adrenergic receptor in children with asthma. Proc Natl Acad Sci U S A. 2006;103(14):5496–501. 43. Yorke J, Fleming S, Shuldham C.  Psychological interventions for children with asthma. Cochrane Database Syst Rev. 2005;4:CD003272. 44. NHS Employers. Medicines use reviews MURS. htps://www.nhsemployers.org/pay pensions-and-reward/primary-care-contacts/community-pharmacy/medicines-use-reviewsmurs. Accessed 29 May 2019. 45. Mehuys E, Van Bortel L, De Bolle L, Van Tongelen I, Annemans L, Remon JP, Brusselle G.  Effectiveness of pharmacist intervention for asthma control improvement. Eur Respir J. 2008;31(4):790–9. 46. García-Cárdenas V, Sabater-Hernández D. Effect of a pharmacist intervention on asthma control. A cluster randomised trial. Respir Med. 2013;107(9):1346–55.

Chapter 6

Stepwise Pharmacological Approach to Severe Childhood Asthma Ina St. Onge, Karen M. McDowell, and Theresa W. Guilbert

General Principles The stepwise pharmacologic approach to management of severe asthma in children and adolescents is based on the principles of achieving good control of symptoms and minimizing the risk of future exacerbations and side effects [1]. The American Thoracic Society (ATS) and the European Respiratory Society (ERS) define severe asthma as that which requires treatment with high-dose inhaled corticosteroids (ICS) plus a second controller throughout the previous year, and/or systemic corticosteroids for 50% of the previous year to control the disease, or asthma that remains uncontrolled despite this therapy [2]. Asthma control encompasses multiple domains in addition to symptoms, including frequency and severity of exacerbations and baseline lung function. This is evident in the ATS/ERS definition of “uncontrolled” which is any of the following: frequent symptoms, ≥ 2 exacerbations requiring oral steroids in the previous year, hospitalization for asthma in the previous year, or airflow limitation. Management of asthma includes recognition of the risks of severe or poorly controlled asthma, as these risks are magnified for those with severe asthma. The risks of inadequate asthma control are incorporated into the World Health Organization (WHO) definition of severe asthma as a “disease which, when uncontrolled, can result in frequent or severe exacerbations (including death), adverse reactions to medications and/or chronic morbidity such as abnormal lung function, or in children, decreased lung growth [3].” This chapter will outline a stepwise approach to the pharmacologic treatment of severe asthma based on current evidence. Few efficacy studies have been performed in children with severe asthma, and most of the available evidence comes from clinical trials of children with mild-to-moderate asthma. The following recommendations are based on the I. St. Onge · K. M. McDowell · T. W. Guilbert (*) Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 E. Forno, S. Saglani (eds.), Severe Asthma in Children and Adolescents, https://doi.org/10.1007/978-3-030-27431-3_6

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assumptions that the correct diagnosis has already been made (please refer to Chap. 3), that adherence to prior therapy has been maximized, that delivery device technique has been fully addressed, and that management of comorbidities has been optimized (further discussed in Chap. 4). Once asthma treatment has been started, ongoing decisions about medication adjustment are based on a cycle of individualized assessment, modification, and monitoring of the response. Medications are adjusted up or down in a stepwise fashion based on assessment of control and medication side effects [1]. Response to changes in therapy should then be observed over a period of 2–3 months, with a goal to step-down therapy if possible. Treatment options should be tailored based on patient age and response to therapy. In most of the available national and international asthma guidelines, steps 1, 2, and 3 of treatment are applicable to intermittent, mild persistent, and moderate persistent asthma. Once therapy has been stepped up to include two or more controller medications including high-dose inhaled corticosteroids, the patient is considered to have severe asthma [2]. At present, the classes of pharmacologic therapy available for long-term asthma management include inhaled and systemic corticosteroids, long-acting β [beta]-agonists (LABAs), leukotriene receptor antagonists (LTRAs), long-acting muscarinic antagonists (LAMA), macrolide antibiotics, methylxanthines, and biologic therapies. In regard to specific asthma phenotypes and differential responses, there is some pediatric data to guide therapy. Children with a predominantly allergic eosinophilic phenotype are thought to respond better to corticosteroids [4, 5]. The airway inflammation in this group is thought to be mediated by cytokines produced by type 2 T cells, as well as eosinophils, elevated immunoglobulin E (IgE), and potentially elevated exhaled nitric oxide [6]. Children with a neutrophilic inflammatory phenotype, on the other hand, are thought to respond poorly to corticosteroids and have lower lung function [5, 7–9].

School-Age Children and Adolescents Inhaled Corticosteroids (ICS) Inhaled corticosteroids remain the mainstay of long-term or controller asthma therapy for all age groups. For severe asthma in school-age children and adolescents, two or more controllers are currently recommended, and one of those should be an ICS. The preferred controller at the Step 4 level is a combination of either medium-/ high-dose ICS plus LABA, LTRA, theophylline, biologic therapies, and/or prolonged use of oral corticosteroids [1] (Fig. 6.1). It should be noted that an increase in ICS dose above the high dose usually provides little added benefit when already combined with LABA.  High-dose ICS is recommended on a trial basis for 3–6 months only when good asthma control cannot be achieved on medium-dose

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From GINA with permission

Exacerbations Side-effects Patient satisfaction Lung function

REVIE W

Symptoms

SE ON SP

Inhaler technique & adherence Patient preference

SS SE AS

RE

Diagnosis Symptom control & risk factors (including lung function)

Asthma medications Non-pharmacological strategies Treat modifiable risk factors

AD

JU

ST TR E AT M

EN

T

STEP 5 STEP 4 STEP 2

STEP 1

STEP 3 Med/high ICS/LABA

Low dose ICS

Consider low dose ICS

Leukotriene receptor antagonist (LTRA) Low dose theophylline*

As-needed short-acting beta2-agonist (SABA)

Low dose ICS/LABA**

Med/high dose ICS Low dose ICS +LTRA (or + theoph*)

Add iotropium*† Med/high dose ICS + LTRA (or + theoph*)

Refer for add-on treatment

e.g.

tiotropium,*† anti-lgE, anti-lL5* Add low dose OCS

As-needed SABA or low dose ICS/formoteroI#

ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; med: medium dose; OCS: oral corticosteroids * Not for children 600–1200 Flunisolide (HFA)a 320 >320–640 Ciclesonide (HFA)b 200–400 >400–800 Fluticasone furoate (DPI)b 100 NA Fluticasone propionate (DPI) 100–300 >300–500 Fluticasone propionate (HFA) 88–264 >264–440 Mometasone furoate 200 400 Triamcinolone acetonide 300–750 >750–1500 School-age children 6–11 years (for children 5 years and younger, see Table 6.4) Beclomethasone dipropionate (HFA) 80–160 >160–320 Budesonide (DPI) 180–400 >400–800 Budesonide (nebules) 500 1000 Flunisolide (HFA)a 160 320 Ciclesonide (HFA)b 80 >80–160 Fluticasone furoate (DPI)b NA NA Fluticasone propionate (DPI) 100–200 >200–400 Fluticasone propionate (HFA) 88–176 >176–352 Mometasone furoateb 110 ≥220–600–900

High >480 >1200 >640 >800 200 >500 >440 >400 >1500 >320 >800 2000 ≥640 >160 NA >400 >352 ≥440 >900

Doses are adapted from NHLBI/NAEPP 2007 [14] unless otherwise noted DPI dry powder inhaler, HFA hydrofluoroalkane propellant, NA not applicable a Some delivery devices may not be available in the USA, and potency may vary depending on delivery device b Adapted from Global Initiative for Asthma (GINA) 2018 [1] Table 6.1 is not a table of equivalence but of estimated clinical comparability [1]

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Oral Corticosteroids (OCS) OCS help suppress and control airway inflammation [14]. A short course (20 μg/ mL regardless of patient age or weight [38, 39].

Macrolides The current guidelines either recommend against the routine use of macrolides like azithromycin for severe asthma in children or do not mention macrolides as an alternative or adjunctive option for therapy [1, 2, 14]. This recommendation is supported by a study of 55 children ages 6–17 years with moderate-to-severe asthma that were randomized to receive either nightly azithromycin, montelukast, or placebo, plus their established daily ICS and twice daily scheduled SABA [40]. The results indicated that there was no significant difference in time to loss of asthma control between the treatment groups compared to placebo. However, this trial was terminated early due to inadequate adherence to study medications. Two large systematic reviews concluded that for children with severe asthma, macrolides have not been shown to have a favorable effect on symptoms or rates of exacerbations, although there was some evidence for improvements in FEV1 and reduction in oral corticosteroid use [41, 42]. However, it is important to note that there have been very few and small trials of long-term macrolide use specifically involving children, and none have focused on severe or non-atopic asthma [41, 42].

School-Age and Adolescent Summary The stepwise approach to pharmacological therapy for severe asthma in older children and adolescents is largely based on national and international guidelines as described above, and there have been many recent advances in the understanding of this management. The mainstay of therapy for this population remains high-dose inhaled corticosteroids with the addition of another controller medication. The preferred additional controller medication in the majority of children is LABA administered as a combination device with ICS. Alternatives include an LTRA, theophylline if levels can be monitored and drug-drug interactions minimized, or the addition of tiotropium [1] (see Fig. 6.1). If exacerbations are the primary concern and source of symptoms, adding intermittent ICS can be helpful during those acute episodes. The next step-up includes biologic therapies, which are discussed in Chap. 7. For

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children that remain poorly controlled with these regimens, OCS as a controller therapy can be considered for as brief a period of time as possible, and once symptoms are controlled, every effort should be made to step-down therapy. More comparison studies are needed to identify the most efficacious treatment regimens by clinical phenotype in children with severe asthma.

Preschool-Age Children Inhaled Corticosteroids Inhaled corticosteroids are the mainstay of maintenance treatment for severe asthma in children under age 5 as well. The Individualized Therapy for Asthma in Toddlers (INFANT) study, using a crossover design, enrolled children aged 12–59 months of age with mild persistent asthma (Table 6.3) [13, 19–23, 32–35, 40, 43–46]. All subjects were treated with 16 weeks of the following therapy in a randomized order: daily ICS, intermittent ICS whenever a short-acting beta-agonist was used, and daily leukotriene receptor antagonist (LTRA). Asthma control was best during the daily ICS treatment periods, and this was further increased for the patients with aeroallergen sensitization or blood eosinophil counts of at least 300/μL [43]. If daily low-dose ICS does not adequately control symptom burden or exacerbations, the National Heart, Lung, and Blood Institute (NHLBI) recommends stepping up to either medium-dose ICS or medium dose in combination with LABA or LTRA (Step 3). High-dose ICS in combination with either a LABA or montelukast is then the next step [14]. The GINA guidelines differ slightly in their recommendations for severe asthma in preschool children: Step 3 recommends doubling the dose of ICS as the preferred controller and then adding an LTRA [1] (Fig. 6.2). Step 4 (the highest GINA step for preschool children) then recommends either increasing the frequency of ICS, increasing the dose of ICS, or adding intermittent ICS to daily ICS if exacerbations are the primary issue, adding LTRA, theophylline, or low-dose OCS for a few weeks while monitoring symptoms [1]. There are currently no trials of children in this age group with moderate-to-severe asthma that directly compare the efficacy of these treatment options. Low, medium, and high ICS dosing is summarized in Table 6.4.

Long-Acting Beta-Agonists (LABAs) In preschool children who remain uncontrolled on low-dose ICS, combination therapy with ICS and LABA can improve asthma outcomes, compared to either higher-­ dose ICS or addition of a leukotriene receptor antagonist (LTRA) [20]. As previously discussed, the VESTRI [21] trial demonstrated LABA safety in children ages 4–11 years with mild persistent asthma when added to ICS as combination step-up

Mild-to-­ moderate

Stempel [21] VESTRI

O’Byrne [22] Persistent symptoms on ICS

182 children ages 6–17 years

Mild-to-­ moderate

Lemanske [20] BADGER

6208 children ages 4–11 years 2760 patients ages 4–80 years

158 children ages 6–16 years

Mild-to-­ Vaessen-­ Verberne [19] moderate COMBO

Subjects

254 children ages 5–11 years

Severity

Mild-to-­ moderate

Jackson [13]

First author [ref] Study name Quintupling ICS dose for 7 days at early signs of loss of control vs continuing low-dose daily ICS

R, db, p

Quintupling ICS dose for exacerbations did not reduce the rate of exacerbations, symptom scores, or albuterol use and may be associated with decreased linear growth No differences between the treatment groups for any outcome measure

Exacerbations Symptom scores Albuterol use ICS exposure Linear growth

R, db, p

Salmeterol/fluticasone 50/100 μg BID vs 200 μg fluticasone, for children still symptomatic on 100 μg daily fluticasone

Best response occurred more frequently in the LABA step-up group, followed by the LTRA step-up group, followed by the ICS step-up group The risk of serious asthma-related adverse events was similar in both groups Budesonide/formoterol for both maintenance and relief reduced the risk and rate of severe exacerbations, the need for systemic steroids, and improved asthma symptoms and lung function compared with traditional fixed dosing regimens

Summary results

Outcomes

Symptom-free days Exacerbations Lung function (FEV1, FVC, PEF, MEF) Statural growth Adverse events 250 μg fluticasone BID vs fluticasone/ Differential responses R, db, requiring either OCS for three- period salmeterol 100/50 μg BID vs acute exacerbation, 100 μg fluticasone BID and 5 or crossover number of asthma control 10 mg montelukast days, and FEV1 R, db, active Fluticasone/salmeterol vs fluticasone Time to the first serious comparator alone asthma-related adverse event R, db, p Budesonide/formoterol 80/4.5 μg BID Time to first exacerbation, symptoms, lung function + PRN vs budesonide/formoterol (PEF, FEV1), adverse 80/4.5 μg BID + terbutaline 0.4 mg events, linear growth PRN vs budesonide 320 μg BID + (ages 4–11y) terbutaline 0.4 mg PRN Children received half the daily dose

Treatment

Design

Table 6.3  Significant randomized controlled trials

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Moderate to severe

Moderate

Severe

Vogelberg [33]

Hamelmann [34]

Szefler [35]

401 children ages 6–11 years

398 children ages 12–17 years

301 children ages 6–11 years

R, db, 300 children crossover ages 12–59 months

Mild

Fitzpatrick [43] INFANT

R, db, pc, p

R, db, pc, p

R, db, pc, incomplete crossover

R, db, crossover

279 children ages 6–14 years

Moderate

Simons [32]

R, db, p

341 children ages 4–11 years

Bisgaard [23] Persistent SMART symptoms on ICS

5 mg montelukast daily added to daily budesonide improved asthma control, FEV1, and decreased exacerbation days

Percent change in FEV1 from baseline, exacerbation rates, SABA use, global assessments, QOL measures, blood eosinophil counts Fluticasone 88 μg BID vs montelukast Differential response based on a composite 4 mg qHS vs fluticasone 88 μg PRN measure of asthma co-administered with SABA control, predictors of differential response Peak FEV1 5 μg daily tiotropium vs ACQ-7 2.5 μg daily tiotropium vs 1.25 μg PAQLQ[S] daily tiotropium vs placebo, each added to medium-dose ICS (200– 400 μg budesonide) with or without a leukotriene modifier Change from baseline in 5 μg daily tiotropium vs peak FEV1 at week 24 2.5 μg daily tiotropium vs placebo, each added to ICS therapy (200– 800 μg budesonide), with or without a leukotriene modifier FEV1 absolute change 5 μg daily tiotropium vs from baseline; FEV1% 2.5 μg daily tiotropium vs placebo, predicted change from each added to ICS and at least one baseline other controller medication

(continued)

Tiotropium, added onto existing asthma controller medications improved FEV1, with comparable safety and tolerability to placebo

Tiotropium add-on (in all doses) to ICS with or without a leukotriene modifier improved lung function, with good safety and tolerability

Children with aeroallergen sensitization and elevated blood eosinophils respond best to daily ICS as opposed to LTRA or PRN ICS + SABA Tiotropium add-on (in all doses) to medium-dose ICS with or without a leukotriene modifier improved lung function, with good safety and tolerability

Budesonide/formoterol for both maintenance and relief reduced the exacerbation rate compared to the other two treatment groups

Time to exacerbation, symptoms, lung function (FEV1)

Budesonide/formoterol 80/4.5 μg qd + PRN vs budesonide/formoterol 80/4.5 μg qd + terbutaline 0.4 mg PRN vs budesonide 320 μg qd + terbutaline 0.4 mg PRN 5 mg oral montelukast nightly vs placebo, each added to 200 μg budesonide BID

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Severity

Recurrent severe LRTIs and minimal daily impairment Recurrent asthma-like symptoms

Bacharier [45]

Design

Azithromycin (10 mg/kg/d for 3 days) Duration of the or placebo, after 3 days of asthma-like respiratory episode after treatment, adverse events symptoms

72 children R, db, pc ages 1–3 years

Once nightly azithromycin, montelukast, or matching placebos added to ICS + LABA (minimum 400 μg budesonide) BID

Asthma symptom score compared to baseline, adverse drug events

Summary results

Azithromycin significantly shortened respiratory episodes by 63%. If started before day 6 of illness, azithromycin shortened respiratory episodes by 83%. No differences in adverse events

Tiotropium was well tolerated as an add-on controller to ICS with or without additional maintenance therapy. No difference in symptom scores between tiotropium and placebo Neither azithromycin nor Time to inadequate asthma control following montelukast is likely to be an effective ICS-sparing alternative in sequential ICS dose reduction, electronic PEF, children with moderate-to-­severe asthma symptom scores, persistent asthma albuterol use The use of azithromycin early Number of RTIs not during an apparent RTI compared progressing to severe with placebo reduced the likelihood LRTI, presence of of severe LRTI. No difference in azithromycin-resistant azithromycin-­resistant organisms organisms

Outcomes

Azithromycin (12 mg/kg/d for 5 days) or placebo started early during each predefined RTI

R, db, p

5 μg daily tiotropium vs 2.5 μg daily tiotropium vs placebo, each added to ICS and other preexisting asthma controller medications

Treatment

R, db, pc, p 607 children ages 12–71 months

55 children ages 6–17 years

101 children R, db, pc, p ages 1–5 years

Subjects

R randomized, db double-blind, p parallel, pc placebo controlled, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, PEF peak expiratory flow, MEF maximum expiratory flow, OCS oral corticosteroid, BID twice daily, qd once daily, ICS inhaled corticosteroids, SABA short-acting beta-agonist, LTRA leukotriene receptor antagonist, QOL quality of life, ACQ-7 7-question asthma control questionnaire, PAQLQ[S] standardized pediatric asthma quality of life questionnaire, LRTI lower respiratory tract infection, RTI respiratory tract infection, mg milligrams, kg kilograms, d day

Stokholm [46]

Moderate to severe

Strunk [40] MARS

Vrijlandt [44] Mild to moderate

First author [ref] Study name

Table 6.3 (continued)

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SE ON SP

AS

REVIE W

SS SE

Asthma medications Non-pharmacological strategies Treat modifiable risk factors EN

T

Symptoms Exacerbations Side-effects Parent satisfaction

RE

Diagnosis Symptom control & risk factors Inhaler technique & adherence Patient preference

AD

JUST T R E A

TM

STEP 4

PREFERRED CONTROLLER CHOICE

STEP 1

STEP 2

Daily low dose ICS

Other controller options

Leukotriene receptor antagonist (LTRA) Intermittent ICS

KEY ISSUES

Continue controller & refer for specialist assessment

Double ‘low dose’ ICS Low dose ICS + LTRA

Add LTRA Inc. ICS frequency Add intermitt ICS

As-needed short-acting beta2-agonist (all children)

RELIEVER

CONSIDER THIS STEP FOR CHILDREN WITH:

STEP 3

Infrequent viral wheezing and no or few interval symptoms (Box 6-2)

Symptom pattern consistent with asthma (Box 6-2) and asthma symptoms not well-controlled (Box 6-4), or >3 exacerbations per year Symptom pattern not consistent with asthma (Box 6-2) but wheezing episodes occur frequently, e.g. every 6–8 weeks. Give diagnostic trial for 3 months.

Asthma diagnosis, and not well-controlled on low dose ICS

Not wellcontrolled on double ICS

First check diagnosis, inhaler skills, adherence, exposures

ALL CHILDREN • Assess symptom control, future risk (Box 6-4), comorbidities • Self-management: education, inhaler skills, written asthma action plan, adherence • Regular review: assess response, adverse events, establish minimal effective treatment • (Where relevant): environmental control for smoke, allergens, indoor/outdoor air pollution

Fig. 6.2  A stepwise summary for controlling asthma symptoms and minimizing future risk in children ages 0–5 years. (From Global Initiative for Asthma [1], with permission)

therapy. Indeed, only one combination product with fluticasone propionate and salmeterol is approved for children down to age 4 [28]. Combination devices are not approved for use in children under 4 years of age. As previously detailed, older children with mild-to-moderate asthma have, on average, the best response to addition of LABA to ICS when compared to adding either an LTRA or increasing the ICS dose [20]. This data was then extrapolated for the preschool age group recommendations.

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Table 6.4  Low, medium, and high daily doses (μg) of inhaled corticosteroids for preschool children Preschool children ages 0–5 years Drug Beclomethasone dipropionate (HFA)a Budesonide (DPI) Budesonide (nebules) Flunisolide (HFA)b Ciclesonide (HFA) Fluticasone propionate (HFA) Mometasone furoatea Triamcinolone acetonide

Low 100 (age ≥5) NA 250–500 NA NA 176 110 (age ≥4) NA

Medium NA NA >500–1000 NA NA >176–352 NA NA

High NA NA >1000 NA NA >352 NA NA

Doses are adapted from National Asthma Education and Prevention Program 2007 [14] unless otherwise noted DPI dry powder inhaler, HFA hydrofluoroalkane propellant, NA not applicable a Adapted from Global Initiative for Asthma (GINA) 2018 [1] b Some delivery devices may not be available in the USA, and potency may vary depending on delivery device Table 6.4 is not a table of equivalence but of estimated clinical comparability. A low daily dose is defined as the lowest approved dose for which safety and effectiveness have been adequately studied in this age group [1]

Leukotriene Receptor Antagonists (LTRAs) Just as in older children, when treating severe persistent asthma in the preschool age group, LTRAs should be used only in combination with ICS [1]. In children with mild persistent disease, LTRA monotherapy was found to be equally beneficial as daily ICS or intermittent ICS dosing in those children without eosinophilia [43]; however, there are no studies of comparative efficacy in the preschool severe asthma population.

Long-Acting Muscarinic Antagonists (LAMA) There are few studies in preschool children regarding anticholinergic bronchodilators such as tiotropium. One exploratory study included 102 children ages 1–5  years that had mild-moderate persistent asthma symptoms in the prior 6  months and need for inhaled corticosteroids. Children either received 2.5ug daily of tiotropium, 5ug daily of tiotropium, or placebo, in addition to their controller medication. The primary outcome of the study was safety, and the tolerability was similar in all groups. Fewer children in the tiotropium groups had asthma exacerbations compared to the placebo group, but this difference was not specifically analyzed for significance [44].

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Oral Corticosteroids (OCS) The highest step-up in management includes the addition of chronic oral corticosteroids (OCS) at the lowest efficacious dose to minimize side effects [14]. Long-term use of higher-dose systemic corticosteroids increases the risk of adverse effects including adrenal suppression, growth retardation, and altered bone metabolism [5] (please refer to Chap. 9). When control is achieved, persistent and frequent attempts to decrease OCS dose are strongly encouraged [14]. It is very rare to have young preschool children on maintenance OCS. If a preschool child requires OCS, it is essential that they are followed by a severe asthma specialist and that alternative diagnoses are fully investigated.

Macrolides The current guidelines either recommend against the routine use of macrolides for severe asthma in preschool children or do not mention macrolides as an alternative or adjunctive option for therapy. There are two recent studies that examined short courses of azithromycin for preschool children with intermittent asthma-like symptoms, but children with severe persistent asthma were not included in the study populations. One study randomized 607 children 12–71 months of age with a history of recurrent severe lower respiratory tract infections (LRTIs) not requiring daily controller therapy [45]. None of the patients had moderate or severe disease. Patients were treated with either a 5-day course of azithromycin or placebo at the earliest signs of a respiratory tract illness (RTI). Each patient was followed for 12–18  months. Azithromycin treatment was associated with a 36% reduced risk of progression to a severe episode and decreased albuterol rescue use during severe episodes. The Copenhagen Prospective Studies on Asthma in Childhood cohort (COPSAC) compared the use of a 3-day course of azithromycin vs placebo after at least 3 days of asthma-like episodes in 72 patients in a randomized controlled trial [46]. Patients had a history of recurrent asthma-like symptoms. The azithromycin group was found to have shorter symptom duration of 3.4 days, compared with 7.7 days in the placebo group. A more dramatic effect was seen if therapy was started earlier, with an 83% reduction in duration when initiated prior to day 6 of illness vs a 36% reduction if started after day 6. Importantly, this strategy has not been studied in severe asthma in preschool children, and it is unclear if it would be efficacious in this age group. Another concern about the use of macrolides is the risk of development of antibiotic resistance from inappropriate or excessive use. In the above study by Bacharier et al., numerically higher rates of azithromycin-resistant organisms were seen in a subset of the treatment group, yet there was evidence of similar acquisition in a subset of the placebo group [45].

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Methylxanthines Sustained-release theophylline previously has not been recommended as an alternative treatment in children less than 5 years of age due to variable metabolism during viral infections and febrile illnesses that are common in preschool-aged children [14]; however, in the most recent GINA guidelines, it is noted as a possible add-on therapy [1]. If used, serum drug levels need to be closely monitored [14], and there is potential for many drug-drug interactions [37]. As with older children, if using once-daily oral dosing with the extended release formulation, levels should be checked after 3  days of therapy and every 6–12  months thereafter, when clinically indicated or when medication is added that may affect theophylline concentrations [37–39]. Therapeutic concentrations are generally considered to be 5–15 mcg/mL with toxic concentrations being >20 mcg/mL regardless of patient age or weight [38, 39].

Preschool-Age Summary Treating severe asthma in the preschool population presents unique challenges. There is a paucity of data on the mechanisms driving disease, the nature of airway inflammation and its relationship to clinical phenotypes, and efficacy of the therapies available for this patient population, and further studies are needed. The stepwise approach to management ensures that the correct diagnosis has been made, that comorbidities are addressed, and that adherence has been maximized. If the patient remains uncontrolled on daily low-dose ICS therapy, the preferred step-up is to double the ICS dose and assess response after 3 months. Alternatively, an LTRA may be added to lowdose daily ICS, but this is based on data from older children. Atopy and blood eosinophils can predict greater short-term response to moderate-­dose ICS than to LTRA [43]. If this still fails to achieve good asthma control, the next step-up includes adding LTRA to the moderate-dose ICS, adding intermittent ICS with SABA use, or increasing ICS frequency [1] (see Fig. 6.2). While there is increasing evidence for the safety of LABA in combination with ICS, this strategy is currently not included in international guidelines due to insufficient data. If adding theophylline or a low-dose OCS, every effort should be made to step-down therapy once asthma control improves. Future studies are needed to define the best combination therapies to use in preschool-aged children with asthma which is not well controlled on ICS monotherapy.

Clinical Pearls • The mainstay of therapy for children and adolescents with severe asthma is higher-dose inhaled corticosteroids, in combination with other therapies. • The preferred additional controller medication in school-age children and adolescents is a long-acting beta-agonist delivered in combination with inhaled corticosteroids.

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• If needed, additional therapies include leukotriene receptor antagonists, theophylline, or tiotropium. • In preschool-aged children, the preferred step-up therapy is to double the inhaled corticosteroid dose or to add a leukotriene receptor antagonist to the low-dose inhaled corticosteroid. • Children with a predominantly allergic eosinophilic phenotype are thought to respond better to corticosteroids than children with a neutrophilic inflammatory phenotype.

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16. Wark PA, McDonald VM, Gibson PG. Adjusting prednisone using blood eosinophils reduces exacerbations and improves asthma control in difficult patients with asthma. Respirology. 2015;20(8):1282–4. 17. Hanratty CE, Matthews JG, Arron JR, Choy DF, Pavord ID, Bradding P, et al. A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial. Trials. 2018;19(1):5. 18. Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev. 2014;(1):Cd003137. 19. Vaessen-Verberne AA, van den Berg NJ, van Nierop JC, Brackel HJ, Gerrits GP, Hop WC, et al. COMBO study group. Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma. Am J Respir Crit Care Med. 2010;182(10):1221–7. 20. Lemanske RF Jr, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD, et  al. Childhood asthma research and education (CARE) network of the National Heart, Lung, and Blood Institute. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362(11):975–85. 21. Stempel DA, Szefler SJ, Pedersen S, Zeiger RS, Yeakey AM, Lee LA, et al. VESTRI investigators. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016;375(9):840–9. 22. O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. Budesonide/ formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005;171(2):129–36. 23. Bisgaard H, Le Roux P, Bjamer D, Dymek A, Vermeulen JH, Hultquist C.  Budesonide/ formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006;130(6):1733–43. 24. Jorup C, Lythgoe D, Bisgaard H. Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma. Eur Respir J. 2018;51(1):1701688. 25. AstraZeneca. Symbicort FDA prescribing information. 2017. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2017/021929s013lbl.pdf. Accessed 27 May 2019. 26. GlaxoSmithKline. Advair HFA FDA prescribing information. 2017. https://www.accessdata. fda.gov/drugsatfda_docs/label/2017/021929s013lbl.pdf. Accessed 27 May 2019. 27. GlaxoSmithKline. Advair Diskus prescribing information. 2017. https://www.accessdata.fda. gov/drugsatfda_docs/label/2017/021929s013lbl.pdf. Accessed 27 May 2019. 28. Merck & Co, Inc. Dulera prescribing information. 2015. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2017/021929s013lbl.pdf. Accessed 27 May 2019. 29. Teva Respiratory. AirDuo prescribing information. 2017. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2017/021929s013lbl.pdf. Accessed 27 May 2019. 30. GlaxoSmithKline. Breo Ellipta prescribing information. 2019. https://www.accessdata.fda. gov/drugsatfda_docs/label/2017/021929s013lbl.pdf. Accessed 27 May 2019. 31. Cazzola M, Calzetta L. Matera MG. β(2)-adrenoreceptor agonists: current and future directions. Br J Pharmacol. 2011 May;163(1):4–17. 32. Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, et al. Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study. J Pediatr. 2001;138(5):694–8. 33. Vogelberg C, Moroni-Zentgraf P, Leonaviciute-Klimantaviciene M, Sigmund R, Hamelmann E, Engel M, et al. A randomised dose-ranging study of tiotropium Respimat(R) in children with symptomatic asthma despite inhaled corticosteroids. Respir Res. 2015;16:20. 34. Hamelmann E, Bateman ED, Vogelberg C, Szefler SJ, Vandewalker M, Moroni-Zentgraf P, et al. Tiotropium add-on therapy in adolescents with moderate asthma: a 1-year randomized controlled trial. J Allergy Clin Immunol. 2016;138(2):441–50.e8. 35. Szefler SJ, Murphy K, Harper T 3rd, Boner A, Laki I, Engel M, et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J Allergy Clin Immunol. 2017;140(5):1277–87.

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36. Suessmuth S, Freihorst J, Gappa M. Low-dose theophylline in childhood asthma: a placebo-­ controlled, double-blind study. Pediatr Allergy Immunol. 2003;14(5):394–400. 37. Upton RA. Pharmacokinetic interactions between theophylline and other medication (part I). Clin Pharmacokinet. 1991;20(1):66–80. 38. Theophylline: Pediatric drug information [internet]. Wolters Kluwer. 2018 [cited 29 Nov 2018]. 39. Hendeles L, Jenkins J, Temple R. Revised FDA labeling guideline for theophylline oral dosage forms. Pharmacotherapy. 1995;15(4):409–27. 40. Strunk RC, Bacharier LB, Phillips BR, Szefler SJ, Zeiger RS, Chinchilli VM, et al. CARE Network. Azithromycin or montelukast as inhaled corticosteroid–sparing agents in moderate-­ to-­severe childhood asthma study. J Allergy Clinical Immunol. 2008;122(6):1138–44.e4. 41. Mikailov A, Kane I, Aronoff SC, Luck R, Delvecchio MT.  Utility of adjunctive macrolide therapy in treatment of children with asthma: a systematic review and meta-analysis. J Asthma Allergy. 2013;6:23–9. 42. Kew KM, Undela K, Kotortsi I, Ferrara G. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015;(9):Cd002997. 43. Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, et al. NIH/NHLBI AsthmaNet. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016;138(6):1608–18.e12. 44. Vrijlandt E, El Azzi G, Vandewalker M, Rupp N, Harper T, Graham L, et al. Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2018;6(2):127–37. 45. Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, et  al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034–44. 46. Stokholm J, Chawes BL, Vissing NH, Bjarnadottir E, Pedersen TM, Vinding RK, et  al. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(1):19–26.

Chapter 7

Immunotherapy and Immunomodulators Nicole Akar-Ghibril, Ahmad Salaheddine Naja, and Wanda Phipatanakul

Allergen Immunotherapy Mechanism of Action Allergen immunotherapy (AIT) has been used since the early 1900s [1]. In allergic disease, allergen-specific CD4+ T helper type 2 (TH2) cells differentiate and clonally expand in response to an allergen (Fig. 7.1) [2]. TH2 cells produce cytokines including interleukin (IL)-4 and IL-13, which are needed for B cells to undergo class switching, leading to the production of allergen-specific IgE antibodies. Allergenspecific IgE then binds to high-affinity IgE receptors (FcεRI) on basophils and mast cells, leading to sensitization. When this allergen is encountered again, cross linking of IgE-FcεRI complexes on sensitized mast cells and basophils leads to degranulation of mast cells and basophils and release of mediators of anaphylaxis [3]. AIT involves the administration of small and gradually increasing doses of allergen extracts in order to induce persistent immunologic and clinical tolerance [4]. In response to consistent AIT, there is an early decrease in mast cell and basophil degranulation [3]. Dendritic cells, which can stimulate allergic inflammation or immune tolerance, shift to foster immune tolerance through the production of IL-12, IL-27, and IL-10 [2]. This induces a switch from a TH2 to a regulatory T cell response [5]. Regulatory T cells produce IL-10 and transforming growth factor beta, which

N. Akar-Ghibril ∙ W. Phipatanakul (*) Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] A. S. Naja Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon © Springer Nature Switzerland AG 2020 E. Forno, S. Saglani (eds.), Severe Asthma in Children and Adolescents, https://doi.org/10.1007/978-3-030-27431-3_7

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Innate

IL-10

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TGF-β Plasma cell IgG/IgG4

IgG/lgG and 4 IgA1/lgA competes 2 with lgE for allergen binding

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Fig. 7.1  Mechanism of allergen immunotherapy. During sensitization, exposure to allergen activates epithelial cells leading to dendritic cell (DC) activation. Antigens are presented to naïve T cells by DCs, triggering a TH2 response. In AIT, high-dose allergen exposure induces DCs to promote immune tolerance, leading to induction of a regulatory T and B cell response. (EC Epithelial cells, TLR Toll-like receptor. From Shamji and Durham [2], with permission)

temper allergen-driven T cell proliferative responses and TH2 cytokine release [2]. Regulatory B cells also produce IL-10 and play a role in restraining T and dendritic cell-mediated inflammatory responses [2, 5]. AIT also regulates type 2 innate lymphoid cells (ILC2s), which secrete IL-5 and IL-13 [5]. This leads to an increase in allergen-specific IgG4 and a decrease in allergen-specific IgE [5]. IgG4 competes with IgE for allergen binding and blocks the formation of the allergen-IgE complex, inhibiting histamine release [2]. IgG also prevents binding of IgE to low-affinity receptors on B cells, thereby inhibiting IgE facilitated antigen presentation to T cells and allergen-specific TH2 responses [2]. In summary, AIT leads to downregulation of the TH2 response, induction of regulatory T and B cells, decrease in IgE antibodies, and production of IgG4 antibodies, ultimately leading to allergen tolerance.

 linical Indications for Allergen Immunotherapy in Severe C Asthma Clinical indications for AIT include moderate to severe intermittent or persistent symptoms of allergic rhinitis and/or asthma with evidence of allergen sensitization [1]. Guidelines from the National Asthma Education and Prevention Program (NAEPP), the Global Initiative for Asthma (GINA), and the Allergic Rhinitis and its Impact on Asthma (ARIA) recommend consideration of AIT for patients with allergic asthma [6–8]. Allergen sensitivity and exposure have been implicated in severe asthma in children [9]. However, it is important to note that severe asthma is a risk factor for AIT, so AIT is not routinely used in patients with severe asthma. AIT

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should only be considered in severe asthma if asthma is well controlled with pharmacotherapy. AIT is contraindicated in patients with uncontrolled asthma and during asthma exacerbations due to increased risk of a fatal systemic allergic reaction [1]. The use of AIT in children with allergic asthma is supported by studies that have demonstrated significant improvement in asthma symptom control following AIT [10]. Furthermore, AIT has the potential to decrease the risk of progression from allergic rhinitis to asthma and prevent new allergen sensitizations [11]. Unfortunately, most AIT studies have been conducted in patients with mild asthma, and patients with severe asthma have largely been excluded from these studies. AIT can be administered through the subcutaneous or sublingual route [1]. The use of allergen extracts for subcutaneous immunotherapy (SCIT) is approved to treat allergic asthma [12]; however, the use of sublingual immunotherapy (SLIT) for treatment of asthma is currently off-label [13]. Allergens are selected based on patient history and skin prick or in vitro tests [1]. SCIT is initially given weekly, with small amounts of allergen extract, increasing each week until a maintenance dose is reached. The maintenance dose is then administered every 4  weeks. Treatment is usually continued for 3–5 years [1]. Patients can receive SCIT with a single-allergen or an allergen mix. SLIT is administered daily under the tongue as a tablet. There is often no up-dosing schedule, and the regimen is typically administered prior to the start of allergen season.

Efficacy of Subcutaneous Immunotherapy SCIT can to reduce asthma symptoms, airway hyperresponsiveness, and medication requirements [4], but its effect on lung function is unclear [11]. This has been supported by a meta-analysis of 88 randomized controlled trials (RCTs) that demonstrated that SCIT reduced asthma symptoms, medication requirements, and allergen-specific bronchial hyperresponsiveness [14] as well as a systematic review of 54 RCTs that supported the efficacy of SCIT in reducing medication requirements [15]. One study reviewed only trials including children, four of which were included in the above mentioned studies. This systematic review found moderate-­strength evidence that singleallergen SCIT improves asthma symptoms; however, there was low-grade evidence that multiple-allergen SCIT may improve asthma symptoms in subjects with moderate to severe asthma. There was also some evidence that SCIT may improve medication use for asthma or combined symptom and medication scores [16]. In a study by Adkinson et al., 121 children, aged 5–12 years, with history of moderate to severe perennial asthma and allergen polysensitization were r­andomized to receive multi-allergen SCIT or placebo. Median daily medication scores and symptom scores declined significantly from randomization to the final follow-up in both treatment and placebo groups; however, there were no significant between-­group differences [17]. The study concluded that if patients were receiving appropriate medical treatment, SCIT was not clearly beneficial in the treatment of patients with allergic asthma [17]. At the same time, several double-blind RCTs have demonstrated significant improvement in asthma symptom scores as well as daily medication scores with use of SCIT in children with moderate to severe allergic asthma [18, 19].

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On the other hand, trials evaluating treatment with SCIT have not demonstrated significant improvements in lung function [20]. Pifferi et al. conducted an RCT comparing 3 years of house dust mite (HDM) SCIT to placebo in 29 children with asthma and monosensitization to HDM.  There was improvement in lung function data in patients receiving immunotherapy, although not significant compared to control [20]. In summary, in patients with allergic asthma, SCIT can improve asthma symptoms and reduce medication use, although improvements in lung function have not been shown to be significant.

Safety of Subcutaneous Immunotherapy Reactions to SCIT can be local or systemic. Local reactions include erythema, pruritus, and/or swelling at the injection site [1]. Individual local reactions are not predictive of subsequent systemic reactions [10]. Systemic reactions can be mild or severe. The incidence of severe systemic reactions is one in one million. Risk factors for systemic reactions include poorly controlled asthma and previous systemic reactions related to SCIT. Other contributing factors include build-up schedule, premedication regimen, and degree of sensitization [1]. Due to the risk of systemic reactions, SCIT must be administered in a medical setting with clinicians capable of managing anaphylaxis [11]. An asthma assessment should be done prior to each SCIT administration. Data on systemic reactions in children is limited and is often extrapolated from adult studies [21]. In one prospective European survey of 1563 pediatric patients initiating AIT, 29 systemic reactions were recorded. SCIT caused 79.3% of systemic reactions. Urticaria was the most frequently reported symptom. Three systemic reactions were classified as anaphylaxis [21].

Sublingual Immunotherapy Asthma guidelines recommend SLIT as add-on therapy for asthma in adults and adolescents with sensitizations to HDM, allergic rhinitis, and asthma exacerbations despite ICS with FEV1≥70% predicted [11]. Clinical trial data in adults have demonstrated that the addition of HDM SLIT to asthma maintenance therapies reduces ICS use or time to first exacerbation upon ICS reduction [11]. There are four SLIT products approved by the US Food and Drug Administration (FDA) for allergic rhinitis that are often used clinically for asthma (Table 7.1) [22–25].

Efficacy of Sublingual Immunotherapy Both a systematic review and a meta-analysis concluded that SLIT decreased asthma symptoms and medication use [15, 26]. Another systematic review that focused only

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Table 7.1  FDA-approved sublingual immunotherapy products Brand name Ragwitek® [22] (Merck, Kenilworth NJ)

Allergen extracts Short ragweed pollen allergen extract

Odactra® [23] (Merck, Kenilworth NJ)

Dermatophagoides farinae and Dermatophagoides pteronyssinus Allergen Extract Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract

Oralair® [24] (Stallergenes Greer, Boston MA)

Grastek® [25] Timothy Grass Pollen Allergen Extract (Merck, Kenilworth NJ)

Clinical indications Short ragweed pollen-­ induced allergic rhinitis

Ages Doses 18– One 65 years sublingual tablet daily

HDM-­ induced allergic rhinitis

18– One 65 years sublingual tablet daily

Grass pollen-­ induced allergic rhinitis

10– One 65 years sublingual tablet daily. There is a 3-day up-dosing period.

Grass pollen-­ induced allergic rhinitis

≥ 5 years

One sublingual tablet daily

Regimen Initiate treatment ≥12 weeks before onset of ragweed pollen season, continue throughout season Daily

Initiate treatment 4 months prior to onset of grass pollen season; continue throughout season Initiate treatment ≥12 weeks before onset of grass pollen season; continue throughout season

on studies that included children found high-strength evidence that SLIT improves asthma symptoms compared to placebo. However, there was low-strength evidence that SLIT decreases the combination of symptoms and medication use for asthma and rhinitis [16]. Most of the RCTs conducted to investigate the efficacy of SLIT included only patients with mild to moderate asthma.

Safety of Sublingual Immunotherapy SLIT can be administered at home; however, the first dose must be administered under the supervision of a physician. Local reactions to SLIT include throat irritation, oral and tongue pruritus, oral paresthesia, and lip swelling [27]. Eosinophilic esophagitis has been reported as an adverse event [23]. Several RCTs conducted in

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pediatric patients determined that SLIT was well tolerated [27–29]. Cases of anaphylaxis related to SLIT have been reported; however, there are no confirmed reports of deaths [1].

 ubcutaneous Immunotherapy (SCIT) vs Sublingual S Immunotherapy (SLIT) The systematic review by Kim compared SCIT with SLIT and found that there was low-strength evidence to support a greater decrease in asthma symptoms or medication use with SCIT compared to SLIT, while SLIT may be safer than SCIT. Among studies evaluating AIT in children, there is considerable variation in the study of allergens, dosages, dose units, duration of treatment, and reporting and scoring of outcomes and safety data [16]. One study evaluated 9 systematic reviews (3 SCIT reviews, 4 SLIT reviews, and 2 SCIT/SLIT reviews) and concluded that AIT via SCIT or SLIT can improve medication and symptom scores and measures of bronchial hyperreactivity, although the impact on lung function or asthma control is less clear. SLIT had a more favorable safety profile compared to SCIT [30]. See Table 7.2 for a summary of systematic reviews and Table 7.3 for a summarized comparison of SCIT vs. SLIT.

Allergen Immunotherapy and Asthma Prevention AIT may play a role in the prevention of asthma. A systematic review and meta-­ analysis evaluated 32 studies to determine if AIT reduced the risk of developing a first allergic disease. The analysis concluded there was a reduction in the short-term risk of developing asthma among subjects with allergic rhinitis, but there was inconclusive evidence that this benefit was maintained long term [33]. In the Preventive Allergy Treatment (PAT) study, among 151 school-aged children with allergic rhinoconjunctivitis sensitized to grass and/or birch pollen but without asthma, there was a 2.5-fold greater odds of preventing new-onset asthma after 3 years of SCIT versus no therapy [34], and the benefit persisted after 10 years [35]. However, the study was open label and not placebo controlled, limiting the rigor of this evidence. The Grazax Asthma Prevention (GAP) trial was a double-blind RCT that included 812 children, aged 5–12 years, with a history of grass pollen allergic rhinoconjunctivitis and no history of asthma. Treatment with grass SLIT significantly reduced the risk of asthma symptoms or using asthma medications at the end of the trial and during the 2  years posttreatment, but there was no effect on the time to onset of asthma [36]. A study by Marogna et al. investigated the preventive effects of SLIT in childhood in an open-label trial. Two hundred and sixteen children with allergic rhinitis with or without intermittent asthma were randomized to receive medications alone or medications with SLIT for 3 years. Mild persistent asthma occurred less frequently, and there was a significant decrease in asthma scores in the SLIT group compared to controls [37].

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Table 7.2  Overview of systematic reviews on immunotherapy Review SCIT and/ or SLIT No. of RCTs included Symptom scores

Abramson [14] SCIT

Normansell [31] SLIT

88

52

SMD: −0.59 (95% CI −0.83 to −0.35)

Unable to use SMD. 5 studies showed no significant differences, 9 studies showed significant reductions with SLIT compared to placebo

Kim [16] SCIT, SLIT, SCIT vs. SLIT 34

Moderate SOE that single-allergen SCIT improves asthma symptoms relative to placebo or PT. High SOE that SLIT improves asthma symptoms more than comparators. Low SOE favoring SCIT over SLIT Low SOE that SCIT Medication SMD: −0.53 7 studies showed improves medication no significant scores (95% CI scores more than difference, 4 −0.80 to comparators. studies showed −0.27) Moderate SOE that significant difference between SLIT improves medication use more SLIT and than comparators. comparators Low SOE favoring SCIT over SLIT Adverse events OR SLIT may be safer Safety Adverse events RR 1.4 1.70 (95% CI 1.21 than SCIT (0.97 to 2.02). to 2.38) Systemic reaction RR 2.45 (1.91 to 3.13)

Lin [32] SCIT, SLIT, SCIT vs. SLIT 54 on efficacy, 80 on safety Insufficient evidence regarding SCIT effect on asthma symptoms. High SOE that SLIT improves asthma symptoms. Insufficient evidence to compare SCIT to SLIT

Moderate SOE that SCIT reduces use of controller medications. Moderate SOE that SLIT decreases use of controller medications

Local and systemic reactions frequent

SCIT subcutaneous immunotherapy, SLIT sublingual immunotherapy, RCT randomized controlled trial, BHR  bronchial hyperresponsiveness, SMD standardized mean difference, CI confidence interval, RR pooled relative risk, OR odds ratio, PT pharmacotherapy, SOE strength of evidence

Contraindications to Allergen Immunotherapy There are several contraindications to the use of AIT. Uncontrolled asthma is the major risk factor for severe AIT-related adverse events [38], and thus AIT should not be initiated in patients with poorly controlled asthma. There is no consensus regarding the lower age limit for AIT [11]. According to the European Academy of Allergy and Clinical Immunology, age