Middleton's Allergy Essentials, 1e

409 Pages·2017·31.94 MB·English

by  Robyn E O'Hehir FRACP PhD FRCPath

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
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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