Middleton’s Allergy Essentials FIRST EDITION Middleton’s Allergy Essentials Robyn E. O’Hehir, BSc, MBBS(Hons), FRACP, PhD, FRCP, FRCPath, FAHMS, FThorSoc Professor and Director, Department of Allergy, Immunology, and Respiratory Medicine, Alfred Hospital and Monash University Deputy Head, Central Clinical School, Monash University Deputy Director Research, Alfred Health, Melbourne, Vic, Australia Stephen T. Holgate, CBE, BSc, MBBS, MD, DSc, FRCP, FRCPath, FAAAAI, FERS, FMedSci, MEA MRC Clinical Professor of Immunopharmacology and Honorary Consultant Physician, Clinical and Experimental Sciences Faculty of Medicine Southampton University and Hospital Trust, Southampton, United Kingdom Aziz Sheikh, OBE, BSc, MBBS, MD, MSc, FRCGP, FRCP, FRCPE, FRSE, FFPH, FMedSci, FACMI Professor of Primary Care Research & Development Director, Asthma UK Centre for Applied Research Co-Director, Centre of Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, United Kingdom Honorary Consultant in Paediatric Allergy, NHS, Lothian, Scotland, United Kingdom For additional online content visit http://expertconsult.com Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto © 2017, Elsevier Inc. All rights reserved. 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Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-37579-5 E-ISBN: 978-0-323-39273-0 Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 Content Strategist: Belinda Kuhn Content Development Specialists: Joanne Scott, Devika Ponnambalam Project Manager: Anne Collett Design: Miles Hitchen Illustration Manager: Emily Costantino Illustrators: Oxford Illustrators, Chartwell; Dartmouth Publishing, Inc., Graphic World Inc. Marketing Manager(s) (UK/USA): Kristin Koehler FOREWORD I am honored to provide this foreword to the Elsevier text Middleton’s Allergy Essen- tials, edited by Professors O’Hehir, Holgate, and Sheikh. Not because I am an allergist or immunologist—I am a clinical informatician and academic general internist—nor because it will pad my curriculum vitae with another piece of writing. Rather, it gives me an opportunity to honor my father, Elliott Middleton Jr., M.D., and to share with readers of this text a glimpse into the man who inspired me and many others to pursue a career in medicine, and for his many fellows and trainees, a career in allergy and immunology. My dad had a passion both for life and for his work in clinical medicine, including research and teaching as well as a humility based upon a desire to help patients—those with asthma especially—and the myriad problems that may be associ- ated with allergic disorders and the diseases of clinical immunology. As I was growing up, my father always worked hard but always seemed to be having fun. There were frequent rounds in hospital early and late in the day, and extra time often spent in the lab Saturday mornings to ‘catch up’ after a busy week. Most nights were spent with the family for dinner, and then afterwards several hours on the living room couch editing one manuscript or chapter, or sorting slides on one of those now old-fashioned slide view-boxes, preparing for a lecture. For many years, it was a chapter for the text now known as Middleton’s Allergy: Principles and Practice. He absolutely loved putting this text together: crafting the outline of chapters, meeting with the co- editors, and reviewing chapters and occasionally cajoling authors to get things done. It may be his proudest accomplishment. On a couple of occasions we met at one of his national meetings, and I saw him in his element: gregarious, well known, interested in others, and respected. The passion my dad had about his work was infectious: he would always take the time to explain in simple terms what was going on with his laboratory and clinical investigations, whether it was the early work on mast cell functions and histamine release, leukotrienes, or bioflanonoids (we all came to recognize the terms quercetin, rutin, and others) and their impact on inflammation; the reverse transcriptase; or free radicals. Equally impor- tant, we came to know the good dietary sources for these compounds. He instilled in me a sense of wonder, not only about the incredible processes of chemistry and biology that impact the human system and may manifest when aberrant as disease states or worse, but also about the human interaction with the natural world that seemed filled with potential allergens—pollen, grasses, sage, cat dander, and more (his fellows have told me his ‘weed walks’ were fun and informative). He viewed his research—whether it was basic laboratory investigation or clinical trials—from the patient’s perspective and honored the patient as the center of his clinical attention. One cannot really know the perception people have of one’s parents as we as children are always too close, too intertwined with them, or even as adults as we try to both distance ourselves from them and take from them all that they have to offer that is good, as we come to define ourselves. In my training, I have been surprised to see people’s faces light up and smile if the occasion ever arose for me to acknowledge that Elliott Middleton Jr. was my dad. It is a delight—he left an indelible mark on the world that I aspire to leave as well. Blackford Middleton, MD, MPH, MSc vi  vii PREFACE In 1978, the late Elliott Middleton Jr., along with founding editors Elliot Ellis and Charles Reed, published a landmark comprehensive book, Middleton’s Allergy: Prin- ciples and Practice. This 2-volume set has been the definitive text on allergy practice and disease mechanisms worldwide, and, as a result, is now in its 8th edition. Over the last decade, the understanding of allergic diseases and their diagnosis, prevention, and management has advanced considerably. In addition, the prevalence, spectrum, and severity of allergy have increased so that allergic disorders have become a public health problem affecting a high proportion of the global population. There is, in some quarters, a perception that allergy has little impact on the lives of sufferers, but nothing could be further from the truth. Diseases such as asthma, food allergy, drug allergy, and insect allergy can be life-threatening if not diagnosed and treated properly. Allergy often affects multiple organs in the same individual, magnifying the overall health burden that patients experience. Of note, allergy manifests in all age groups, being influenced by strong genetic, environmental, and epigenetic drivers. Recognizing that most allergic disease is managed by busy clinicians in primary and secondary care settings, we have identified a need for a book that is both easily accessible and authoritative for the practitioner. The result is Middleton’s Allergy Essentials. In this first edition, we have extracted what we considered to be most useful to the healthcare practitioner in his or her daily practice, with a strong emphasis on disease diagnosis and management. Because the field is evolving so rapidly, we have also included some sections on mechanisms, but only when this adds value to each disease covered. In creating this text, the authors were asked to identify relevant sections in Middleton’s Allergy: Principles and Practice, 8th edition, update these, and present the revised, abridged chapters with a generalist audience in mind. Naturally, such a text has to be selective, but we hope that the topics covered address the needs of both trainee and established practitioners across the healthcare sector, to enable them to access novel information to beneficially inform their practice. The text portion of each section is relatively brief and easy to review, with illustra- tions and tables aimed at providing additional and more detailed information when considered informative. We have attempted to adopt a similar format for each chapter. Throughout, there is emphasis on a practical approach to evaluation, differential diag- nosis, and treatment of allergic disorders, to maximize its use. To achieve this, we have called upon the same internationally outstanding authors of the original Middleton’s Allergy: Principles and Practice, 8th edition, chapters. The editors wish to express their sincere thanks to all of our authors for the very considerable amount of work they have undertaken to produce this easily accessible book. None of this would have been possible without Joanne Scott, Belinda Kuhn, and Devika Ponnambalam, who were the brainchildren and instigators of the project, and their team at Elsevier who have worked seamlessly with us throughout the commission- ing and editorial process. As editors of this ‘offspring’ of Middleton’s Allergy: Principles and Practice, 8th edition, we express our very sincere thanks to all the editors and authors of the parent publication but especially to its three founders, who had the vision to produce such a consistent beacon of success in the field of allergy. We are also indebted to Professor Blackford Middleton—son of Elliott Middleton, Jr.—for writing the Fore- word to Middleton’s Allergy Essentials. The best testament to Elliott and his coauthors would be its widespread use and impact across the way allergy treatment is delivered to our patients worldwide; after all, it is they who continue to motivate us to want to deliver ever better care. Robyn E. O’Hehir Stephen T. Holgate Aziz Sheikh vii CONTRIBUTORS Cezmi A. Akdis, MD Pascal Demoly, MD, PhD Professor and Director, Swiss Institute of Professor of Respiratory Medicine, Allergy and Asthma Research Department of Respiratory Medicine University of Zürich; Director, and Addictology, Arnaud de Christine Kühne Center for Allergy Villeneuve Hospital, University Research and Education; President, Hospital of Montpellier, Montpellier, European Academy of Allergy and France Clinical Immunology, Zürich, Switzerland Anthony J. Frew, MD, FRCP Professor of Allergy and Respiratory Mark Boguniewicz, MD Medicine, Department of Respiratory Professor, Division of Allergy– Medicine, Royal Sussex County Immunology, Department of Hospital, Brighton, United Kingdom Pediatrics, National Jewish Health University of Colorado School of David B. K. Golden, MD Medicine, Denver, CO, USA Associate Professor of Medicine, Division of Allergy and Clinical Jean Bousquet, MD Immunology, Department of Medicine, Professor of Pulmonary Medicine, Johns Hopkins University School of CHRU Arnaud de Villeneuve, Medicine, Baltimore, MD, USA Montpellier, France Clive E. H. Grattan, MD Simon G. A. Brown, MBBS, PhD, FACEM Consultant Dermatologist, Dermatology Professor of Emergency Medicine. Centre, Norfolk and Norwich University of Western Australia, Royal University Hospital, Norfolk, UK Perth Hospital, Perth, WA, Australia Oliver Hausmann, MD A. Wesley Burks, MD Specialist Consultant for Allergology and Professor and Chair, Pediatrics; Immunology, Department of Physician-in-Chief, North Carolina Rheumatology, Immunology and Children’s Hospital, University of Allergology, Inselspital, University North Carolina at Chapel Hill, Chapel Hospital, Bern, Switzerland; Private Hill, NC, USA Practice, Loewenpraxis, Lucerne, Switzerland Anca Mirela Chiriac, MD Allergologist, Department of Respiratory Stephen T. Holgate, CBE, BSc, MB BS, MD, Medicine and Addictology, Arnaud de DSc, FRCP, FRCPath, FAAAAI, FERS, Villeneuve Hospital, University FMedSci, MEA MRC Hospital of Montpellier, Montpellier, Clinical Professor of France Immunopharmacology and Honorary Consultant Physician Clinical and Jonathan Corren, MD Experimental Sciences Faculty of Associate Clinical Professor of Medicine, Medicine, Southampton University David Geffen School of Medicine, and Hospital Trust, Southampton, University of California, Los Angeles, United Kingdom Los Angeles, CA, USA Adnan Custovic, MD, PhD Professor of Allergy, Imperial College, London, United Kingdom viii CONTRIBUTORS ix John W. Holloway, PhD Sarbjit S. Saini, MD Professor of Allergy and Respiratory Associate Professor of Medicine, Genetics, Faculty of Medicine, Division of Allergy and Clinical University of Southampton, Immunology, Johns Hopkins Southampton, United Kingdom University School of Medicine, Baltimore, MD, USA Terufumi Kubo, MD, PhD Research Fellow, Swiss Institute of Hugh A. Sampson, MD Allergy and Asthma Research (SIAF), Professor, Department of Pediatrics; Davos, Switzerland Dean for Translational Biomedical Sciences, Icahn School of Medicine at Catherine Lemière, MD, MSc Mount Sinai, New York, NY, USA Professor, Department of Medicine, University of Montréal, Montréal, Helen E. Smith, DM QC, Canada; Department of Chest Chair of Primary Care, Division of Medicine, Hôpital du Sacré-Coeur de Primary Care and Public Health, Montréal Brighton and Sussex Medical School, University of Sussex, Brighton, UK Donald Y. M. Leung, MD, PhD Edelstein Family Chair of Pediatric Geoffrey A. Stewart, BSC, PhD Allergy and Immunology, National Professor, School of Pathology and Jewish Health; Professor, Department Laboratory Medicine, The University of Pediatrics, University of Colorado of Western Australia, Perth, WA, School of Medicine, Denver, CO, USA Australia Hideaki Morita, MD, PhD Kazunari Sugita, MD, PhD Research Fellow, Swiss Institute of Research Fellow, Swiss Institute of Allergy and Asthma Research (SIAF), Allergy and Asthma Research (SIAF), Davos, Switzerland Davos, Switzerland Anna Nowak-We˛grzyn, MD Mike Thomas, MBBS, FRCP, PhD Associate Professor, Department of Professor of Primary Care Research, Pediatrics, Jaffe Food Allergy Institute, Primary Care and Population Sciences, Icahn School of Medicine at Mount Faculty of Medicine, University of Sinai, New York, NY, USA Southampton, UK Susan L. Prescott, MD, PhD Paul J. Turner, BMBCh, PhD, FRACP Winthrop Professor, School of MRC Clinician Scientist in Paediatric Paediatrics and Child Health, Allergy and Immunology, Imperial University of Western Australia; College London, United Kingdom; Paediatric Allergist and Immunologist, Associate Clinical Professor in Princess Margaret Hospital, Perth, Paediatrics, University of Sydney, WA, Australia Sydney, NSW. Australia Clive Robinson, PhD, FHEA, FSB Olivier Vandenplas, MD, PhD Professor of Respiratory Cell Science, Professor of Medicine, Department of Division of Biomedical Sciences, Chest Medicine, Centre Hospitalier St. George’s University of London, Universitaire de Mont-Godinne, London, United Kingdom Université Catholique de Louvain, Yvoir, Belgium Robyn E. O’Hehir This book is dedicated by Professor Robyn O’Hehir to two of the founders of the discipline of allergy, Professors Dan Czarny and Barry Kay, from whom so many learned so much. Stephen T. Holgate I dedicate this book to my Mentor and good friend, Dr. K. Frank Austen, who set me on a career in allergy and asthma that has been so enriching. Aziz Sheikh In loving memory of Tanveer Sheikh. 1 C H A P T E R Introduction to Mechanisms of Allergic Diseases Terufumi Kubo, Hideaki Morita, Kazunari Sugita, and Cezmi A. Akdis CHAPTER OUTLINE INTRODUCTION CYTOKINES AND CHEMOKINES IN ALLERGIC INNATE IMMUNITY INFLAMMATION Microbial Pattern Recognition by the Innate Cytokines in Allergic Inflammation Immune System Interleukin-4 (IL-4) Pattern Recognition Receptors Interleukin-5 (IL-5) Cellular Responses of Innate Immunity Interleukin-9 (IL-9) Innate Instruction of Adaptive Immune Responses Interleukin-13 (IL-13) Innate Immunity and Allergy Interleukin-25 (IL-25) ADAPTIVE IMMUNITY Interleukin-33 (IL-33) Adaptive Immune Response in Allergic Disease Thymic Stromal Lymphopoietin (TSLP) Main Components of the Adaptive Immune Chemokines in Allergic Diseases System Asthma Features of the Adaptive Immune Response Atopic Dermatitis Mechanisms of Diseases Involving Adaptive BIOLOGY OF IMMUNE CELLS Immunity T Lymphocytes IMMUNOGLOBULIN STRUCTURE AND FUNCTION B Lymphocytes B Lymphocytes and the Humoral Immune Type 2 Innate Lymphoid Cells Response Antigen-Presenting Dendritic Cells Immunoglobulin Structure and Gene Mast Cells Rearrangement Basophils Immunoglobulin Function Eosinophils IMMUNOGLOBULINS AND HUMAN DISEASE CONTRIBUTION OF STRUCTURAL CELLS TO IMMUNE TOLERANCE ALLERGIC INFLAMMATIONS Introduction Introduction Central and Peripheral Tolerance Mechanisms Airway Epithelial Cells Central Tolerance Airway Smooth Muscle Cells Peripheral Tolerance Neuronal Control of Airway Function Immune Effector Cells and Molecules CYTOKINE NETWORKS IN ALLERGIC Regulatory T Cells INFLAMMATION Transforming Growth Factor-β (TGF-β) RESOLUTION OF ALLERGIC INFLAMMATION AND Interleukin-10 (IL-10) MAJOR PATHWAYS SUMMARY OF IMPORTANT CONCEPTS • Allergic inflammation is a result of a complex interplay amongst structural tissue cells and inflammatory cells, including mast cells, basophils, lymphocytes, dendritic cells, eosinophils, and sometimes, neutrophils. • Cytokines are families of secreted proteins that mediate immune and inflammatory reactions at local or distant sites. • The innate immune system first responds to early infectious and inflammatory signals, activates and instructs the adaptive immune system for antigen-specific T and B lymphocyte responses and the development of immunologic memory. 1 2 1 InTroDuCTIon To MeChAnIsMs of AllergIC DIseAses • Allergen recognition and uptake, allergic sensitization, inflammation, and disease originate in the innate immune system. • Adaptive immune responses depend on activation of naive CD4+ T cells and differentiation into effector cells. CD4+ Th2 cells are critical mediators of allergic inflammation. • Production of Ige antibody is regulated mainly by Th2 cells. Activated Th2 cells trigger Ige production in B cells through a combination of signals, including secreted cytokine (Il-4 or Il-13) and cell surface (CD40l). • Better understanding of the pathophysiology of allergic inflammation will enable us to identify novel therapeutic targets in the treatment of chronic allergic inflammation. INTRODUCTION The inflammatory process has several common characteristics shared by various differ- ent allergic diseases, including asthma, allergic rhinitis or rhinosinusitis, and atopic dermatitis (eczema). Allergic inflammation is characterized by Ige-dependent activation of mucosal mast cells and an infiltration of eosinophils that is orchestrated by increased numbers of activated CD4+ T helper type 2 (Th2) lymphocytes. In addition to these cells, various types of inflammatory cells produce multiple inflammatory mediators, including lipids, purines, cytokines, chemokines, and reactive oxygen species. Both innate and adaptive immune mechanisms and involvement of multiple cytokines and chemokines play roles. INNATE IMMUNITY Microbial Pattern Recognition by the Innate Immune System Microbial recognition by the innate immune system is mediated by germline-encoded receptors with genetically predetermined specificities for microbial constituents. natural selection has formed and refined the repertoire of innate immune receptors to recognize highly conserved molecular structures that distinguish large groups of microorganisms from the host. These microbe-specific structures are called pathogen-associated molecu- lar patterns (PAMPs), and the pattern recognition receptors (Prrs) of the innate immune system recognize these structures (Table 1-1). Pattern Recognition Receptors Prrs of the innate immune system can be divided into two groups: secreted receptors and transmembrane signal-transducing receptors (Table 1-1). Secreted PRRs typically have multiple effects in innate immunity and host defense, including direct microbial killing, serving as helper proteins for transmembrane receptors, opsonization for phago- cytosis, and chemoattraction of innate and adaptive immune effector cells. Antimicrobial peptides (AMPs) are secreted Prrs that are microbicidal and rapidly acting. When secreted onto skin and mucous membranes, they create a microbicidal shield against microbial attachment and invasion. Transmembrane PRRs are expressed on many innate immune cell types, including macrophages, dendritic cells (DCs), monocytes, and B lymphocytes (fig. 1-1). These Prrs are exemplified by the Toll-like receptors and their associated recognition, enhancing, and signal transduction proteins (fig. 1-1). Innate immune response at the epithelial cell- and DC-related processes are controlled by the activation of the epithelial Prr by pathogen-associated molecular patterns (PAMPs) found in the microorganisms as well as the host-derived damage-associated molecular patterns (DAMPs). Airway epithelial cells and dendritic cells express a wide range of Toll-like receptors (Tlrs); noD-like receptors (nlrs); rIg-I-like receptors (rlrs); AIM2-like receptors (Alrs); C-type lectin receptors (Clrs); protease-activated recep- tors (PAr); and others.1