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Preface
Over thirty years ago, Elliott Middleton, Jr., Charles E. Reed, andElliot story’ in a comprehensive, integrated and understandable manner. We
F. Ellis conceived of the idea for a new comprehensive textbook of asthma are grateful for the care, dedication and knowledge of the 174 authors
and allergic disorders, and they set about to publish the first edition of and co-authors who contributed to the 97 chapters of this 7th edition.
Allergy: Principles and Practice. The seventh edition of the now classic Of these authors 90 are new to the 7th edition and reflect the editors’
Middleton’s Allergy: Principles and Practice is an ongoing tribute to the commitment to find the best contributors within an increasingly global
original editors’ foresight in bringing their innovative vision to fruition, scientific and medical community. Another aspect of this commitment
subsequent wide acceptance, and preeminence. As stated in their original to the inclusion of new and fresh perspectives is our longstanding policy
preface, which is traditionally reprinted in each edition, ‘it is our opinion of turning over the authorship of even the most excellent chapters every
that some chapters in this book represent the most comprehensive sum- second or third edition.
maries of the subject material found in print. Thus, Allergy: Principles and The growth of knowledge in biomedical science during the past dec-
Practice serves as not only a textbook, but as a reference book.’ Moreover, ade has been nothing short of stupendous, and allergy and clinical im-
it was their goal that ‘the final product … turns out to be a book we munology have been no exceptions to this. To recognize these advances,
hope will be useful to all students of allergy, practitioners, clinical inves- 14 new chapters have been added to Middleton’s seventh edition. These
tigators, other researchers, allergy trainees, and medical students.’ Each include the new scientific arenas of innate immunity, stem cells, and
subsequent edition has also achieved this goal. It is the design and hope dendritic cell biology. A new chapter reviews the factors associated with
of the current editors that our efforts have produced a worthy sequel that the increasing prevalence of allergic disorders and asthma. New clinical
provides updated and new authoritative information on every important chapters detail current knowledge of eosinophilic gastroenteropathies,
aspect of allergic inflammation, and associated allergic disorders. immunologic non-asthmatic lung diseases, oral challenge testing, ap-
To accomplish this, we have adhered to the successful strategy devel- proach to the patient with chronic cough, and approach to the patient
oped by our original forebears to provide information on the basic sci- requiring emergency treatment for acute asthma. Other new chapters on
ence underpinnings of allergy (principles) and integrate this information therapeutics in the seventh edition include the important topics of envi-
into clinical applications (practice). Our approach follows current efforts ronmental controls for allergic diseases, adherence to medical regimens,
in ‘translational’ research to follow findings or knowledge in basic science and pharmacogenomics, as well as the evolving role of anti-IgE therapy.
discoveries through to their applications in clinical medicine. Funda- Noteworthy is chapter 27, ‘Protease-activated Pathways of Inflamma-
mental ‘principles’ of allergic inflammation and its origins is addressed in tion,’ contributed by founding editor Charles Reed along with Hirohito
Volume 1 with sections for immunology (including the cellular biology Kita and Catherine Weiler. Although the final application of this new
of immunology, as it relates to allergic processes), aerobiology and aller- field to allergic diseases and asthma has yet to be fully defined, Charles
gens; and then physiology, which reflects the functional interactions of Reed’s vision of new horizons of importance to allergy has always been
the sensitized host with its environment. Volume 2 presents the ‘practice’ keen, and we are delighted to include his ‘cutting edge’ viewpoint.
implications of these basic sciences as they are translated to clinical sci- We think it will not go unnoticed that this edition of Middleton’s
ences, the diagnostic approach to the patient, and finally therapeutics. Allergy: Principles and Practice is for the first time printed in full-color
Within this structure, we have attempted to infuse the clinical sciences format. The design includes color coding and accenting to further en-
with evidence-based medicine for best practices in the specialty of al- hance organizational structure. And there are more than 400 new illus-
lergy and clinical immunology. trations (700 in all) to bring home the message graphically on virtually
The achievement of these ambitious goals was a collaborative venture every page. Appendix A has been thoroughly updated and now covers
undertaken with our knowledgeable and dedicated authors of the various all 334 CD surface markers and their cellular expression patterns. This
chapters. As in the past, authors were chosen not only because they are seventh edition has also expanded its appendix of Internet Resources
experts in their subject matter, but also because they are able to ‘tell the useful in the science and practice of allergology. We have also provided
xiii
Preface
in Appendix C summary tables from the new Expert Panel 3 Report Lastly, the editors are very grateful for all of the goodwill and patient
outlining US Guidelines for the Diagnosis and Management of Asthma, cooperation that made this collaborative venture possible. In addition to
and the corresponding GINA (Global Initiative for Asthma) guidelines our stalwart authors, there are a few other people without whose skills
that we hope will be of use and benefit to our readership. We have also and persistence this seventh edition would never have been completed.
added a new feature at the beginning of each chapter: a bulleted list We acknowledge with gratitude the excellent editorial planning and
of the salient scientific or clinical principles highlighted in the chapter. oversight from our three acquisitions editors at Elsevier, Thu Nguyen,
These principles should make the text more useful for a wide range of Karen Bowler and Claire Bonnett. And we are especially thankful for
readers seeking information at differing levels of detail. Overall these the indispensable editorial assistance from our Elsevier team who saw
innovations are intended to make this seventh edition the best yet. us through to completion: Joanne Scott, Kirsten Lowson, John Leonard
John Yunginger stepped down as an editor with the completion of and Alan Nicholson.
the sixth edition and his immense contributions have been missed.
Dr. Yunginger was a seasoned and savvy member of the editorial team to N Franklin Adkinson, Jr
which he brought understanding and knowledge in insect hypersensitiv- Managing Editor
ity, latex allergy, and allergen structure, as well as an important pediatric Bruce S Bochner
perspective. Equally important were his uncanny ability to encapsulate William W Busse
key points, and his dogged insistence on clarity and brevity. We thank Stephen T Holgate
him for his years of service and leadership. Robert F. Lemanske, Jr., is our Robert F Lemanske, Jr
new pediatric editor who brings valuable special interests and expertise F Estelle R Simons
to this enterprise, particular in the arenas of pediatric asthma and the
origins of asthma and allergic diseases. May, 2008
xiv
Preface to the
first edition
Allergy, once a confusing subject for clinician and researcher alike, has It is our opinion that some chapters in this book represent the most
emerged as a medical science in which immunology, physiology, and comprehensive summaries of the subject matter to be found in print.
pharmacology interface uniquely. Our present state of knowledge is the Thus Allergy: Principles and Practice serves not only as a textbook but
culmination of the efforts of many workers over many decades of re- as a reference book. Indeed, this was our intent, but original estimates
search in the clinic and laboratory. We want to acknowledge our incal- for the length of the book were necessarily revised upward as it became
culable debt to these investigators, both basic scientists and clinicians, clear that much excellent material could not properly be left out. The
who taught us not only fact but more importantly concepts and scientific final product then turns out to be a book we hope will be useful to all
method. students of allergy: practitioners, clinical investigators, other researchers,
Several textbooks on allergy are already in existence. Why another one? allergy trainees, and medical students.
We pondered this question for some time before embarking on what The generous and unstinting help of many people in addition to the
turned out to be, expectedly, a rather formidable task. It was our opinion contributors made this book possible. Without the competent and de-
that a truly comprehensive book about allergy should focus strongly not voted secretarial assistance of Marci Dame, Evelyn Beimers, Bonnie
only on the exciting developments of the past decade or two in immunol- Barcy, Carol Speery, and Candace Anderson, the task could not have
ogy but also provide in-depth coverage of equally pertinent new informa- been accomplished. We thank our wives and families for their forbear-
tion on physiology and pharmacology, two areas of critical importance to ance, while we were sequestered away from home for day and night
the student of allergy. We have made no attempt to cover all of the subject weekend sessions during the planning and editing phases. From the be-
matter considered to fall under the general rubric of clinical immunology ginning their support has been essential to the successful completion of
and so do not include sections dealing with rheumatology, other con- our job. A number of colleagues, too numerous to name, provided help
nective tissue disorders, immunohematology, or tumor immunology, for in critical reading of manuscripts. To these and others who were helpful
example, since these subjects are well covered elsewhere. in a variety of ways, we offer thanks.
The chapters dealing with immunology, pharmacology, and physiol- We are saddened that two contributors died during the preparation of
ogy appear at the beginning in the basic science section of the book the book. Jane Harnett is the senior author of the chapter dealing with
to provide the necessary conceptual framework for the clinical science aspirin idiosyncrasy. Dr. Harnett compiled much of the information for
section, which deals with the variety of clinical states that fall within the the chapter and worked on the manuscript under extremely difficult cir-
purview of allergy and the allergist. The value of the clinical descriptions cumstances up to within only a few days of her untimely death. She is re-
is vastly enhanced by a careful reading of the earlier chapters. membered fondly and with respect by all those with whom she worked.
We were most fortunate in securing a truly outstanding “star-studded” Robert P. Orange, one of the most brilliant and creative investigators of
cast of contributors who managed to find time in their already over- his generation, died suddenly during the preparation of the book. No
crowded schedules to help us write the book. We thank them all for their one can guess what additional important discoveries Dr. Orange would
efforts and are grateful for the patient indulgence of a few who put up have made had he not died so prematurely.
with some predictable editorial fussing meant to achieve proper balance We would like to record here our personal sorrow at the loss of these
and avoid excessive overlap. fine physicians. We hope that their representation in this textbook will
Most of the chapters can be read as free-standing articles or mono- help keep memories of them alive.
graphs on that particular subject. This has led to a certain irreducible
amount of duplication. By and large, there is consistency among chapters
in which comparable material has been presented by different authors, Elliott Middleton, Jr
but the reader will find occasional areas of controversy, a natural state of Charles E Reed
affairs in a rapidly growing field. Elliot F Ellis
xv
Contributors
DARRyL J ADAMKO MD FRCpC ANDREA J AptER MD MA MSC
Associate Professor, Pulmonary Research Group Professor of Medicine
Department of Pediatrics Division of Pulmonary, Allergy and Critical Care Medicine
Heritage Medical Research Centre Department of Medicine
University of Alberta School of Medicine
Edmonton AB University of Pennsylvania
Canada Philadelphia PA
USA
N FRANKLIN ADKINSON JR MD
ERIKA AVILA-tANg MHS pHD
Professor of Medicine
and Training Program Director Research Associate
Division of Allergy and Clinical Immunology Department of Epidemiology
Johns Hopkins University School of Medicine Johns Hopkins Bloomberg School of Public Health
Johns Hopkins Asthma and Allergy Center Baltimore MD
Baltimore MD USA
USA
CLAUS BACHERt MD pHD
CEzMI A AKDIS MD
Professor of Medicine, Chief of Clinics
Professor of Immunology Head, Upper Airway Research Laboratory
Director ENT Department
Swiss Institute of Allergy and Asthma Research University Hospital Ghent
Davos Ghent
Switzerland Belgium
yASSINE AMRANI pHD KAtHERINE J BAINES BBIOMEDSCI (HONS) pHD
Reader in Respiratory Immunology Post�Doctoral Fellow
Department of Infection, Immunity and Inflammation Department of Respiratory Medicine
University of Leicester School of Medicine Center for Asthma and Respiratory Diseases
Leicester University of Newcastle
UK Newcastle NSW
Australia
xvii
Contributors
MARK BALLOW MD EUgENE R BLEECKER MD
Professor of Pediatrics Professor of Medicine
University of Buffalo School of Medicine and Biomedical Sciences Co�Director, Center for Human Genomics
Division of Allergy and Immunology Wake Forest University
Women and Children�s Hospital of Buffalo Winston�Salem NC
Buffalo NY USA
USA
BRUCE S BOCHNER MD
JENNIFER L BANKERS-FULBRIgHt pHD
Professor of Medicine
Assistant Professor of Medicine Director, Division of Allergy and Clinical Immunology
Division of Allergy Johns Hopkins University School of Medicine
Mayo Clinic Johns Hopkins Asthma and Allergy Center
Rochester MN Baltimore MD
USA USA
pEtER J BARNES DM DSC FMEDSCI FRS MARK BOgUNIEWICz MD
Head of Respiratory Medicine Professor of Pediatrics
National Heart and Lung Institute Division of Allergy�Immunology
Imperial College London National Jewish Medical and Research Center
London and University of Colorado School of Medicine
UK Denver CO
USA
NEAL p BARNEy MD
LARRy BORISH MD
Associate Professor of Ophthalmology
Department of Ophthalmology and Visual Sciences Professor of Medicine
University of Wisconsin School of Medicine Asthma and Allergic Disease Center
Madison WI University of Virginia Health System
USA Charlottesville VA
USA
LEAH BELLEHSEN pHD
LOUIS-pHILIppE BOULEt MD FRCpC FCCp
Visiting Professor
Department of Pharmacology and Experimental Therapeutics Lung Specialist
School of Pharmacy, Faculty of Medicine Institute of Cardiology and Pulmonology of Laval University
The Hebrew University of Jerusalem Laval Hospital
Jerusalem Quebec QC
Israel Canada
BRUCE g BENDER pHD JEAN BOUSqUEt MD
Professor of Psychiatry Professor of Pulmonology
Head, Division of Pediatric Behavioral Health Department of Allergology
National Jewish Medical and Research Center Arnaud de Villeneuve Hospital
Denver CO University Hospital of Montpellier
USA Montpellier
France
pAUL J BERtICS pHD
JOSHUA A BOyCE MD
Kellett Professor of Biomolecular Chemistry
School of Medicine and Public Health Co�Director, Inflammation and Allergic Diseases Research Section
Department of Biomolecular Chemistry Associate Professor of Medicine
University of Wisconsin Harvard Medical School
Madison WI Division of Rheumatology, Immunology and Allergy
USA Brigham and Women�s Hospital
Boston MA
USA
xviii
Contributors
DAVID H BROIDE MBCHB CARLOS A CAMARgO JR MD DRpH
Professor of Medicine Associate Professor of Medicine
Division of Allergy and Immunology Department of Emergency Medicine
University of California, San Diego Massachusetts General Hospital
La Jolla CA Harvard Medical School
USA Boston MA
USA
REBECCA H BUCKLEy MD
BRENDAN J CANNINg pHD
J Buren Sidbury Professor of Pediatrics
Professor of Immunology Associate Professor of Medicine
Departments of Pediatrics and Immunology Johns Hopkins University School of Medicine
Duke University Medical Center Johns Hopkins Asthma and Allergy Center
Durham NC Baltimore MD
USA USA
A WESLEy BURKS MD tHOMAS B CASALE MD
Professor of Pediatrics Professor of Medicine
Pediatric Allergy and Immunology Chief, Division of Allergy/Immunology
Duke University Medical Center Division of Allergy/Immunology
Durham NC Creighton University School of Medicine
USA Omaha NE
USA
ROBERt K BUSH MD
güLFEM ELIF ÇELIK MD
Professor of Medicine
Department of Medicine Professor of Chest Disease and Allergy
University of Wisconsin School of Medicine and Public Health Department of Allergy
Madison WI Ankara University School of Medicine
USA Cebeci Hospital
Ankara
pAULA J BUSSE MD Turkey
Assistant Professor of Medicine
CHRIStINA D CHAMBERS pHD MpH
Department of Internal Medicine
Mount Sinai School of Medicine Associate Professor
New York NY Department of Pediatrics and Family and Preventative Medicine
USA University of California San Diego School of Medicine
UCSD Medical Center
WILLIAM W BUSSE MD San Diego CA
Professor of Medicine USA
Department of Medicine
MOIRA CHAN-yEUNg MB FRCpC FRCp
University of Wisconsin School of Medicine and Public Health
Madison WI Professor of Medicine
USA Respiratory Division
Department of Medicine
WILLIAM J CALHOUN MD University of British Columbia
Sealy and Smith Distinguished Professor Vancouver BC
Vice Chair for Research Canada
Department of Internal Medicine
University of Texas Medical Branch
Galveston TX
USA
xix
Contributors
JAVIER CHINEN MD pHD tIMOtHy DECApItE MD
Assistant Professor Dermatology Resident
Department of Pediatrics Department of Dermatology
Allergy and Immunology Section University of Maryland
Baylor College of Medicine Baltimore MD
Houston TX USA
USA
pASCAL DEMOLy MD pHD
DONALD W COCKCROFt MD FRCpC
Professor of Pulmonology
Professor of Respiratory Medicine Department of Allergology
Division of Pulmonary Medicine INSERM
University of Saskatchewan Arnaud de Villeneuve Hospital
Royal University Hospital Montpellier
Saskatoon SK France
Canada
ANNE E DIxON MA BM BCH
LAUREN COHN MD
Assistant Professor of Medicine
Associate Professor, Pulmonary and Critical Care Vermont Lung Center
Department of Internal Medicine University of Vermont
Yale University School of Medicine Burlington VT
New Haven CT USA
USA
MyRNA B DOLOVICH p.ENg
ELLEN B COOK pHD
Associate Clinical Professor Medicine
Associate Scientist Faculty of Health Sciences
Department of Medicine Head, Firestone Research Aerosol Laboratory
University of Wisconsin Medical School Center for Molecular Imaging of the Lung
Madison WI St Joseph�s Healthcare
USA Hamilton ON
Canada
JONAtHAN CORREN MD
StEpHEN R DURHAM MA MD FRCp
Associate Clinical Professor of Medicine
David Geffen School of Medicine Professor of Allergy and Respiratory Medicine
University of California National Heart and Lung Institute
Los Angeles CA Imperial College School of Medicine
USA London
UK
RONINA COVAR MD
RONALD ECCLES DSC
Staff Physician
Department of Pediatrics Professor
National Jewish Medical and Research Center Common Cold Centre
Denver CO Cardiff School of Biosciences
USA Cardiff
UK
ADNAN CUStOVIC MD pHD
ALAN M EDWARDS MBBCHIR
Professor of Allergy
North West Lung Centre Clinical Assistant (Allergy)
University of Manchester The David Hide Asthma and Allergy Research Centre
Wythenshawe Hospital St. Mary�s Hospital
Manchester Newport
UK Isle of Wight
UK
xx
Contributors
ROBERt E ESCH pHD ANtHONy A gASpARI MD
Vice President Professor of Dermatology
Research and Development Department of Dermatology
Greer Laboratories, Inc. University of Maryland
Lenoir NC Baltimore MD
USA USA
JOHN V FAHy MD pHILIppE gEVAERt MD pHD
Professor of Medicine Scientific Staff
Division of Pulmonary and Critical Care Medicine Department of Otorhinolaryngology
University of California, San Francisco Faculty of Medicine and Health Sciences
San Francisco CA University of Ghent
USA Ghent
Belgium
REUBEN FALKOFF MD pHD
pEtER g gIBSON MBBS FRACp
Clinical Physician
Department of Allergy Clinical Professor of Medicine
Kaiser Permanente Medical Center Department of Respiratory Medicine
San Diego CA Hunter Medical Research Institute
USA John Hunter Hospital
New Lambton NSW
tHOMAS A FLEISHER MD Australia
Chief, Department of Laboratory Medicine
MICHAEL D gOBER MD pHD
NIH Clinical Center
National Institutes of Health Resident Physician
Bethesda MD Department of Dermatology
USA University of Pennsylvania
Philadelphia PA
SUSAN C FOLEy MD USA
Postdoctoral Fellow
DAVID B K gOLDEN MD
Meakins�Christie Laboratories
Department of Medicine Associate Professor of Medicine
McGill University White Marsh Professional Center
Montreal QC Johns Hopkins University School of Medicine
Canada Baltimore MD
USA
MICHAEL M FRANK MD
FRANK M gRAzIANO MD pHD
Samuel L Katz Professor of Pediatrics, Medicine and Immunology
Department of Pediatrics Professor of Medicine
Duke University Medical Center Department of Medicine
Durham NC University of Wisconsin School of Medicine and Public Health
USA Madison WI
USA
ALLISON D FRyER pHD
tHERESA gUILBERt MD
Professor of Physiology and Pharmacology
Professor of Pulmonary and Critical Care Medicine Assistant Professor of Pediatrics
Department of Physiology and Pharmacology Department of Pediatrics
Oregon Health Sciences University University of Wisconsin
Portland OR Madison WI
USA USA
xxi
Contributors
SUDHIR gUptA MD pHD MMAACCpp FFRRCCppCC FLORENCE IDA HSU MD
Professor of Medicine, Pathology, and Laboratory Medicine Instructor in Medicine, Harvard Medical School
and Microbiology and Molecular Genetics Division of Rheumatology, Immunology and Allergy
Chief, Basic and Clinical Immunology Brigham and Women�s Hospital
University of California, Irvine Chestnut Hill MA
Irvine CA USA
USA
CHARLES g IRVIN pHD
qUtAyBA HAMID MD pHD
Professor, Department of Medicine
James McGill Professor of Medicine Director, Vermont Lung Center
and Associate Director Department of Medicine
Meakins�Christie Laboratories University of Vermont
Department of Medicine Burlington VT
McGill University USA
Montréal QC
Canada ELLIOt ISRAEL MD
Director, Pulmonary Clinical Research
ROBERt g HAMILtON pHD D.ABMLI
Associate Professor of Medicine
Professor of Medicine and Pathology Harvard Medical School
Division of Allergy and Clinical Immunology Brigham and Women�s Hospital
Johns Hopkins University School of Medicine Boston MA
Johns Hopkins Asthma and Allergy Center USA
Baltimore MD
USA DAVID B JACOBy MD
Professor of Physiology and Pharmacology
HAMIDA HAMMAD pHD
Professor of Pulmonary and Critical Care Medicine
Assistant Professor of Medicine Department of Physiology and Pharmacology
Division of Internal Medicine Oregon Health and Science University
Laboratory of Immunoregulation and Mucosal Immunology Portland OR
University Hospital Ghent USA
Ghent
Belgium pEtER K JEFFERy FRCpAtH DSC (MED) pHD MSC BSC
Emeritus Professor of Lung Pathology
C gARREN HEStER MD
Senior Research Investigator
Laboratory Research Analyst Honorary Consultant Pathologist
Department of Pediatrics Lung Pathology Unit
Duke University Medical Center Royal Brompton Hospital
Durham NC Imperial College London
USA London
UK
StEpHEN t HOLgAtE BSC MD DSC FRCp FRCpAtH FIBIOL
FMEDSCI CHRIStINE COLE JOHNSON pHD MpH
MRC Clinical Professor of Immunopharmacology Senior Scientist and Director
School of Medicine Department for Biostatistics and Research Epidemiology
Infection, Inflammation and Repair Henry Ford Hospital Center for Allergy, Asthma and Immunology
Southampton University and Hospitals Trust Research
Southampton Detroit MI
UK USA
xxii
