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2015v1.0
Middleton’s
Allergy Essentials
This page intentionally left blank
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.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic
or mechanical, including photocopying, recording, or any information storage and retrieval system,
without permission in writing from the publisher. Details on how to seek permission, further
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This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein. In
using such information or methods they should be mindful of their own safety and the safety of
others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the
most current information provided (i) on procedures featured or (ii) by the manufacturer of each
product to be administered, to verify the recommended dose or formula, the method and duration
of administration, and contraindications. It is the responsibility of practitioners, relying on their
own experience and knowledge of their patients, to make diagnoses, to determine dosages and the
best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.
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
CONTENTS
Foreword.........................................................................................................vi
Preface............................................................................................................vii
Contributors..................................................................................................viii
Dedication.........................................................................................................x
1. Introduction.to.Mechanisms.of.Allergic.Diseases.....................................1
Terufumi Kubo, Hideaki Morita, Kazunari Sugita, and Cezmi A. Akdis
2. The.Origins.of.Allergic.Disease..............................................................29
John W. Holloway and Susan L. Prescott
3. Epidemiology.of.Allergic.Diseases..........................................................51
Adnan Custovic
4. Indoor.and.Outdoor.Allergens.and.Pollutants........................................73
Geoffrey A. Stewart and Clive Robinson
5. Principles.of.Allergy.Diagnosis.............................................................117
Anca Mirela Chiriac, Jean Bousquet, and Pascal Demoly
6. Allergen-specific.Immunotherapy..........................................................133
Anthony J. Frew and Helen E. Smith
7. Asthma..................................................................................................151
Stephen T. Holgate and Mike Thomas
8. Allergic.Rhinitis.and.Conjunctivitis......................................................205
Jonathan Corren
9. Drug.Allergy.........................................................................................225
Oliver Hausmann
10. Urticaria.and.Angioedema.without.Wheals..........................................249
Clive E. H. Grattan and Sarbjit S. Saini
11. Atopic.Dermatitis.and.Allergic.Contact.Dermatitis..............................265
Donald Y. M. Leung and Mark Boguniewicz
12. Food.Allergy.and.Gastrointestinal.Syndromes......................................301
Anna Nowak-We˛grzyn, A. Wesley Burks, and Hugh A. Sampson
13. Anaphylaxis..........................................................................................345
Simon G. A. Brown and Paul J. Turner
14. Occupational.Allergy............................................................................361
Catherine Lemière and Olivier Vandenplas
15. Insect.Allergy........................................................................................377
David B. K. Golden
APPENDIX.A:.Internet.Resources................................................................395
Index.............................................................................................................397
v
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
