Molecular Allergy Diagnostics: Innovation for a Better Patient Management

537 Pages·2017·13.25 MB·English

by  Jörg Kleine-Tebbe, Thilo Jakob (eds.)

Jörg Kleine-Tebbe
Thilo Jakob Editors
Molecular Allergy
Diagnostics
Innovation for a Better
Patient Management
Forewords by
Robert G. Hamilton
and Stefan Vieths
123
Molecular Allergy Diagnostics
Jörg Kleine-Tebbe • Thilo Jakob
Editors
Molecular Allergy
Diagnostics
Innovation for a Better Patient Management
Foreword 1 by Robert G. Hamilton
Foreword 2 by Stefan Vieths
Editors
Jörg Kleine-Tebbe, MD Thilo Jakob, MD
Professor of Dermatology and Allergology Professor of Dermatology and Allergology
Allergy and Asthma Center Westend Chairman of the Department of
Outpatient Clinic Hanf Dermatology and Allergology
Ackermann and Kleine-Tebbe University Medical Center Gießen and
Berlin Marburg, Campus Gießen
Germany Justus Liebig University Gießen
Gießen
Germany
ISBN 978-3-319-42498-9 ISBN 978-3-319-42499-6 (eBook)
DOI 10.1007/978-3-319-42499-6
Library of Congress Control Number: 2016963214
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Based partially on the German language edition: Molekulare Allergiediagnostik by Jörg Kleine-Tebbe,
Thilo Jakob.
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Foreword 1
Since 1967, when immunoglobulin E (IgE) was identified as the reagin in the blood that
could transfer allergic sensitization, allergists have been striving to achieve increasingly
“allergen-s pecific” diagnoses to help their patients with more targeted management
strategies. In the USA in particular, complex allergen extracts have been almost exclu-
sively used in both, in vivo (skin test and provocation testing) and in vitro (serological
IgE antibody) assays. Of the 1269 extracts used in vivo for diagnosis in the USA, only
19 have limited “standardization.” Thus, the remaining 1250 extracts have no defined
potency, no known composition, and no documented stability. Importantly, 45 % of
extracts used in skin testing have no peer-reviewed literature documenting their efficacy
and may be deleted from use in the USA. Moreover, extracts cannot readily differentiate
between primary sensitization and immunological cross-r eactivity, and they cannot pre-
dict risk or identify a prognostically significant sensitization. Despite these serious limi-
tations, these crude extracts are being exclusively used in allergy diagnosis throughout
North America because they are grandfathered by regulatory agencies, relatively easy to
prepare, and are thought to contain the most comprehensive profile of allergens of clini-
cal relevance achievable for that specificity.
The increasing availability of clinically relevant allergenic molecules has begun
to change the manner in which allergy diagnosis is performed. The age of “molecu-
lar allergology” has brought with it the promise of enhanced specificity and
increased predictability for serious allergic reactions. Much of the innovative sci-
ence related to allergenic molecules has emerged from basic and clinical studies
performed in Europe. Thus, it is fitting that this excellent, comprehensive, practical
text entitled Molecular Allergy Diagnostics has been edited by our German col-
leagues Drs. Kleine-Tebbe and Jakob. They have succeeded in obtaining authorita-
tive and well-referenced reviews from the most experienced and knowledgeable
authors from all over the world on topics relating to the allergenic plant and animal
protein families and cross-reactive allergens due to their structure similarity. Despite
the expanding repertoire of allergenic molecules available for serological dissection
of the patient’s IgE antibody sensitization profile, the North American allergist has
been slow to adopt most of the available molecular allergen-specific IgE analyses
into their routine diagnostic algorithm. The exceptions are peanut (Ara h 1, 2, 3, 8,
and 9) and hazelnut (Cor a 1, 8, 9, and 14) where distinction can be made between
cross-reactive and primary sensitization and in some cases relative risk for serious
allergic reactions.
v
vi Foreword 1
Drs. Kleine-Tebbe and Jakob and the contributing authors of Molecular Allergy
Diagnostics are to be commended for their hard work and insightful preparation of
this practical guide. This text serves as a unique, comprehensive, and simplified
guidance with practical applications of the clinically important molecular allergen
families as they are increasingly applied to the mainstream diagnostic algorithm for
human allergic disease. For North American allergists who will probably not see
recombinant molecular allergens used in skin testing or therapy, this textbook serves
as a well-written primer on the topic of molecular allergen families available in IgE
antibody serology and how they can enhance the accuracy (analytical and subse-
quently diagnostic sensitivity and specificity) of allergic diagnosis. This textbook
also serves as a comprehensive compendium of the current science related to the
application of allergen molecules in the diagnosis of the allergic patient. It is a must
read for clinicians, clinical and research laboratory personnel, and governmental
regulators who are involved in the use, interpretation, or regulation of allergen
reagents and IgE antibody measurement used in allergy diagnosis. Finally, the lay
public who suffer from allergic disease will enjoy reading this well-organized text
while also gaining a clearer understanding of how diagnostic molecular allergens
can simplify the complexity of their disease.
Robert G. Hamilton, Ph.D., D.ABMLI
Professor of Medicine and Pathology
Johns Hopkins University School of Medicine, and
Director of the Johns Hopkins Dermatology, Allergy and
Clinical Immunology Reference Laboratory,
Baltimore, MD, USA
Foreword 2
The term “molecular allergology” refers to the use of allergen molecules or particu-
lar fragments, such as peptides or carbohydrate chains for the diagnosis and allergen-
specific immunotherapy of allergic diseases. The focus of this book is a clear and
practice-oriented introduction to this complex topic.
The first allergens, from house dust mite and birch pollen, were cloned in the late
1980s, becoming available as highly purified recombinant proteins for molecular
allergy research. The enormous potential for basic and clinical research was quickly
recognized. Since then, more than 1000 allergen sequences have been identified.
The availability of molecular allergens has caused a quantum leap in the field of
allergy and offers great potential for the diagnosis and treatment of allergic diseases.
The following areas of application are particularly worthy of note:
• Molecular-level studies on the mechanisms of type-I allergies (IgE-mediated
immediate-type hypersensitivity reactions)
• Analysis of the B- and T-cell epitopes of allergens, with the goal of optimizing
allergen-specific immunotherapy (AIT)
• Study on the mode of action of AIT
• Differentiation between clinically important and less relevant allergens from an
allergen source or from comparable allergen families of different allergen sources
• Development of innovative immunotherapeutics of precisely defined composi-
tion and dosage
• Potential for the development of personalized mixtures of recombinant allergens
for immunotherapy
Molecular diagnostics using single allergens is without doubt the area of applica-
tion that has seen the greatest development and has already found its way into many
areas of clinical routine. For allergists not primarily involved in research or molecu-
lar diagnostics, the multitude of publications on the topic can be confusing: What
are the clinical consequences, e.g., of IgE binding to strongly cross-reactive minor
allergens vs. species-specific major allergens from pollen? Which treatment recom-
mendations for AIT can be derived from this? Should IgE responses to cross-r eactive
carbohydrate epitopes be classified as clinically irrelevant? Are all patients with IgE
to the major allergen Ara h 2 from peanut at significant risk of anaphylaxis? Are
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viii Foreword 2
these patients at high risk of reacting to trace quantities of peanut? Is the evidence
solid enough to form the basis for recommendations for routine clinical practice?
This work addresses these questions by elaborating the background of molecular
allergology in an easily comprehensible manner, hopefully without succumbing to
the temptation to over-interpret the often exciting science uncovered in this still-
evolving field. The authors, many of them well-known allergy researchers in
German-speaking countries, have attempted to impart the interdisciplinary funda-
mentals in a clear and concise manner.
The boundaries of serological IgE diagnostics using single allergens are also
clearly defined: Each IgE test represents a detection of sensitization, equivalent to
an increased predisposition to allergies, not an actual allergy test. The use of aller-
gen components changes nothing in this regard; the guidelines and basic principles
of allergy diagnostics continue to remain valid.
With this book, the editors have succeeded in making the field of molecular
allergy diagnostics accessible to a wide readership, thereby smoothing the way to an
increased application in clinical practice.
Stefan Vieths, PhD
Vice President of the Paul-Ehrlich-Institut, and
Deputy Research Manager of the Allergology Unit,
Federal Institute for Vaccines and Biomedicines,
Langen, Germany
Preface
Molecular Allergology: From Research Topic to Innovative
Allergy Diagnosis
Allergology—the recognition and treatment of allergic diseases—is regarded as an
interdisciplinary field. Indeed, physicians with various organ specialties (i.e., der-
matology, ENT, pediatrics, pulmonology) take care of allergic patients in Germany.
In other countries, physicians practice as full specialists of allergy and clinical
immunology. Immediate-type allergic reactions can affect multiple organs and all
age groups. A multidisciplinary conceptual and detailed approach is key to under-
standing patterns of allergic responses and sequelae. The “scientific method,” medi-
cal detective work, and clinical experience go hand in hand here. Successfully
practiced allergology always considers the whole person, seeks individual solu-
tions, and requires narrative-based medicine.
Rapid advances in modern allergy research have set this medically diverse spe-
cialty on a new course. With purified and synthetically produced (recombinant)
allergens, basic and clinical research have gained important reagents with which
new areas of allergology can be explored and old problems surprisingly easily
solved.
ix
x Preface
This work on molecular allergology summarizes the most important develop-
ments of recent years. The first section presents examples of various allergic plant
protein families and structurally related allergens, such as the Bet v 1 homologs/
PR-10-like proteins, profilins, polcalcins, lipid transfer proteins, and storage pro-
teins. This is followed by an introduction to animal allergens from the lipocalin,
albumin, and Ca++-binding protein families. Thus, the biological definition of
important allergen sources (e.g., pollen, mites, mammals, molds, and foods) is
expanded to a molecular dimension. It is, in fact, the actual allergic constituents that
really matter!
The second section deals with methods of immunoglobulin E (IgE) determina-
tion to identify specific allergenic triggers: single determinations using singleplex
or allergen screening using multiplex assays. Which type of diagnostician are you?
Hunter or gatherer? Single allergens primarily improve the accuracy of IgE determi-
nations, the test variants of which will be discussed in detail. The basic diagnostic
rules remain unchanged: Positive IgE tests are only relevant in the case of corre-
sponding symptoms. Thus, the individual patient history, quantifiable challenge
tests, and astute interpretation retain their central importance in allergy diagnostics.
Ultimately, it is the physician who determines the clinical relevance of allergy find-
ings, not the test. The third section is devoted to molecular allergy diagnostics in
routine clinical practice. How does one interpret symptoms conclusively and iden-
tify reaction patterns correctly? How can one effectively enhance the accuracy of
allergy diagnostics? Molecular allergology opens up new avenues—it begins when
one “thinks molecular” and makes use of the testing options which have recently
become available. The benefits and boundaries of molecular allergy diagnostics are
discussed using the gamut of common allergen sources as a basis. The final section
looks ahead to future applications of molecular allergology, such as the develop-
ment of recombinant allergy vaccines and hypoallergenic foods.
Molecular allergology is an exciting and rapidly developing field that has evolved
from fragmented foci of research to an essential body of knowledge—particularly
in relation to diagnostic questions in clinical allergology. It is our hope that, with
this book, the authors will succeed in stimulating the reader’s enthusiasm for this
still-evolving discipline and provide possibilities for its implementation in clinical
routine. Well-targeted, specific allergy diagnostics will, hopefully, augment the
counseling and treatment of allergic patients in the future.
Berlin/Gießen, Germany Jörg Kleine-Tebbe
January 2017 Thilo Jakob