Allergy Frontiers, Volume 5: Therapy and Prevention

Allergy Frontiers: Therapy and Prevention Volume 5

Ruby Pawankar • Stephen T. Holgate Lanny J. Rosenwasser Editors

Allergy Frontiers: Therapy and Prevention Volume 5

Editors Ruby Pawankar, M.D., Ph.D. Nippon Medical School 1-1-5 Sendagi, Bunkyo-ku Tokyo Japan

Lanny J. Rosenwasser, M.D. Children’s Mercy Hospitals and Clinics UMKC School of Medicine 2401 Gillham Road Kansas City, MO 64108 USA

Stephen T. Holgate, M.D., Ph.D. University of Southampton Southampton General Hospital Tremona Road Southampton UK

ISBN: 978-4-431-99361-2 e-ISBN: 978-4-431-99362-9 DOI 10.1007/978-4-431-99362-9 Springer Tokyo Berlin Heidelberg New York Library of Congress Control Number: 2009934782 © Springer 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Foreword

When I entered the field of allergy in the early 1970s, the standard textbook was a few hundred pages, and the specialty was so compact that texts were often authored entirely by a single individual and were never larger than one volume. Compare this with Allergy Frontiers: Epigenetics, Allergens, and Risk Factors, the present sixvolume text with well over 150 contributors from throughout the world. This book captures the explosive growth of our specialty since the single-author textbooks referred to above. The unprecedented format of this work lies in its meticulous attention to detail yet comprehensive scope. For example, great detail is seen in manuscripts dealing with topics such as “Exosomes, naturally occurring minimal antigen presenting units” and “Neuropeptide S receptor 1 (NPSR1), an asthma susceptibility gene.” The scope is exemplified by the unique approach to disease entities normally dealt with in a single chapter in most texts. For example, anaphylaxis, a topic usually confined to one chapter in most textbooks, is given five chapters in Allergy Frontiers. This approach allows the text to employ multiple contributors for a single topic, giving the reader the advantage of being introduced to more than one viewpoint regarding a single disease. This broad scope is further illustrated in the way this text deals with the more frequently encountered disorder, asthma. There are no fewer than 26 chapters dealing with various aspects of this disease. Previously, to obtain such a comprehensive approach to a single condition, one would have had to purchase a text devoted solely to that disease state. In addition, the volume includes titles which to my knowledge have never been presented in an allergy text before. These include topics such as “NKT ligand conjugated immunotherapy,” “Hypersensitivity reactions to nano medicines: causative factors and optimization,” and “An environmental systems biology approach to the study of asthma.” It is not hard to see that this textbook is unique, offering the reader a means of obtaining a detailed review of a single highly focused subject, such as the neuropeptide S receptor, while also providing the ability to access a panoramic and remarkably in-depth view of a broader subject, such as asthma. Clearly it is intended primarily for the serious student of allergy and immunology, but can also serve as a resource text for those with an interest in medicine in general. v

vi

Foreword

I find it most reassuring that even though we have surpassed the stage of the one-volume, single-author texts, because of the wonderful complexity of our specialty and its broadening scope that has evolved over the years, the reader can still obtain an all-inclusive and comprehensive review of allergy in a single source. It should become part of the canon of our specialty. Phillip Lieberman, M.D.

Foreword

When I started immunology under Professor Kimishige Ishizaka in the early 1950s, allergy was a mere group of odd syndromes of almost unknown etiology. An immunological origin was only suspected but not proven. The term “atopy,” originally from the Greek word à-topòs, represents the oddness of allergic diseases. I would call this era “stage 1,” or the primitive era of allergology. Even in the 1950s, there was some doubt as to whether the antibody that causes an allergic reaction was really an antibody, and was thus called a “reagin,” and allergens were known as peculiar substances that caused allergy, differentiating them from other known antigens. It was only in 1965 that reagin was proven to be an antibody having a light chain and a unique heavy chain, which was designated as IgE in 1967 with international consensus. The discovery of IgE opened up an entirely new era in the field of allergology, and the mechanisms of the immediate type of allergic reaction was soon evaluated and described. At that point in time we believed that the nature of allergic diseases was a mere IgE-mediated inflammation, and that these could soon be cured by studying the IgE and the various mediators that induced the inflammation. This era I would like to call “stage 2,” or the classic era. The classic belief that allergic diseases would be explained by a mere allergenIgE antibody reaction did not last long. People were dismayed by the complexity and diversity of allergic diseases that could not be explained by mere IgE-mediated inflammation. Scientists soon realized that the mechanisms involved in allergic diseases were far more complex and that they extended beyond the conventional idea of a pure IgE-mediated inflammation. A variety of cells and their products (cytokines/chemokines and other inflammatory molecules) have been found to interact in a more complex manner; they create a network of reactions via their receptors to produce various forms of inflammatory changes that could never be categorized as a single entity of inflammation. This opened a new era, which I would like to call the modern age of allergology or “stage 3.” The modern era stage 3 coincided with the discovery that similar kinds of cytokines and cells are involved in the regulation of IgE production. When immunologists investigated the cell types and cytokines that regulate IgE production, they found that two types of helper T cells, distinguishable by the profile of cytokines they produce, play important regulatory roles in not only IgE production vii

viii

Foreword

but also in regulating allergic inflammation. The advancement of modern molecular technologies has enabled detailed analyses of molecules and genes involved in this extremely complex regulatory mechanism. Hence, there are a number of important discoveries in this area, which are still of major interest to allergologists, as can be seen in the six volumes of this book. We realize that allergology has rapidly progressed during the last century, but mechanisms of allergic diseases are far more complex than we had expected. New discoveries have created new questions, and new facts have reminded us of old concepts. For example, the genetic disposition of allergic diseases was suspected even in the earlier, primitive era but is still only partially proven on a molecular basis. Even the molecular mechanisms of allergic inflammation continue to be a matter of debate and there is no single answer to explain the phenomenon. There is little doubt that the etiology of allergic diseases is far more varied and complex than we had expected. An immunological origin is not the only mechanism, and there are more unknown origins of similar reactions. Although therapeutic means have also progressed, we remain far from our goal to cure and prevent allergic diseases. We have to admit that while we have more knowledge of the many intricate mechanisms that are involved in the various forms of allergic disease, we are still at the primitive stage of allergology in this respect. We are undoubtedly proceeding into a new stage, stage 4, that may be called the postmodern age of allergology and hope this era will bring us closer to finding a true solution for the enigma of allergy and allergic diseases. We are happy that at this turning point the editors, Ruby Pawankar, Stephen Holgate, and Lanny Rosenwasser, are able to bring out such a comprehensive book which summarizes the most current knowledge on allergic diseases, from epidemiology to mechanisms, the impact of environmental and genetic factors on allergy and asthma, clinical aspects, recent therapeutic and preventive strategies, as well as future perspectives. This comprehensive knowledge is a valuable resource and will give young investigators and clinicians new insights into modern allergology which is an ever-growing field. Tomio Tada, M.D., Ph.D., D.Med.Sci.

Foreword

Allergic diseases represent one of the major health problems in most modern societies. The increase in prevalence over the last decades is dramatic. The reasons for this increase are only partly known. While in former times allergy was regarded as a disease of the rich industrialized countries only, it has become clear that all over the world, even in marginal societies and in all geographic areas—north and south of the equator—allergy is a major global health problem. The complexity and the interdisciplinary character of allergology, being the science of allergic diseases, needs a concert of clinical disciplines (internal medicine, dermatology, pediatrics, pulmonology, otolaryngology, occupational medicine, etc.), basic sciences (immunology, molecular biology, botany, zoology, ecology), epidemiology, economics and social sciences, and psychology and psychosomatics, just to name a few. It is obvious that an undertaking like this book series must involve a multitude of authors; indeed, the wide spectrum of disciplines relevant to allergy is reflected by the excellent group of experts serving as authors who come from all over the world and from various fields of medicine and other sciences in a pooling of geographic, scientific, theoretical, and practical clinical diversity. The first volume concentrates on the basics of etiology, namely, the causes of the many allergic diseases with epigenetics, allergens and risk factors. Here, the reader will find up-to-date information on the nature, distribution, and chemical structure of allergenic molecules, the genetic and epigenetic phenomena underlying the susceptibility of certain individuals to develop allergic diseases, and the manifold risk factors from the environment playing the role of modulators, both in enhancing and preventing the development of allergic reactions. In times when economics plays an increasing role in medicine, it is important to reflect on this aspect and gather the available data which—as I modestly assume— may be yet rather scarce. The big effort needed to undertake well-controlled studies to establish the socio-economic burden of the various allergic diseases is still mainly ahead of us. The Global Allergy and Asthma European Network (GA2LEN), a group of centers of excellence in the European Union, will start an initiative regarding this topic this year. In volume 2, the pathomechanisms of various allergic diseases and their classification are given, including such important special aspects as allergy and the bone marrow, allergy and the nervous system, and allergy and mucosal immunology. ix

x

Foreword

Volume 3 deals with manifold clinical manifestations, from allergic rhinitis to drug allergy and allergic bronchopulmonary aspergillosis, as well as including other allergic reactions such as lactose and fructose intolerances. Volume 4 deals with the practical aspects of diagnosis and differential diagnosis of allergic diseases and also reflects educational programs on asthma. Volume 5 deals with therapy and prevention of allergies, including pharmacotherapy, as well as allergen-specific immunotherapy with novel aspects and special considerations for different groups such as children, the elderly, and pregnant women. Volume 6 concludes the series with future perspectives, presenting a whole spectrum of exciting new approaches in allergy research possibly leading to new strategies in diagnosis, therapy, and prevention of allergic diseases. The editors have accomplished an enormous task to first select and then motivate the many prominent authors. They and the authors have to be congratulated. The editors are masters in the field and come from different disciplines. Ruby Pawankar, from Asia, is one of the leaders in allergy who has contributed to the understanding of the cellular and immune mechanisms of allergic airway disease, in particular upper airway disease. Stephen Holgate, from the United Kingdom, has contributed enormously to the understanding of the pathophysiology of allergic airway reactions beyond the mere immune deviation, and focuses on the function of the epithelial barrier. He and Lanny Rosenwasser, who is from the United States, have contributed immensely to the elucidation of genetic factors in the susceptibility to allergy. All three editors are members of the Collegium Internationale Allergologicum (CIA) and serve on the Board of Directors of the World Allergy Organization (WAO). I have had the pleasure of knowing them for many years and have cooperated with them at various levels in the endeavor to promote and advance clinical care, research, and education in allergy. Together with Lanny Rosenwasser as co-editor-in-chief, we have just started the new WAO Journal (electronic only), where the global representation in allergy research and education will be reflected on a continuous basis. Finally, Springer, the publisher, has to be congratulated on their courage and enthusiasm with which they have launched this endeavor. Springer has a lot of experience in allergy—I think back to the series New Trends in Allergy, started in 1985, as well as to my own book Allergy in Practice, to the Handbook of Atopic Eczema and many other excellent publications. I wish this book and the whole series of Allergy Frontiers complete success! It should be on the shelves of every physician or researcher who is interested in allergy, clinical immunology, or related fields. Johannes Ring, M.D., Ph.D.

Preface

Allergic diseases are increasing in prevalence worldwide, in industrialized as well as industrializing countries, affecting from 10%–50% of the global population with a marked impact on the quality of life of patients and with substantial costs. Thus, allergy can be rightfully considered an epidemic of the twenty-first century, a global public health problem, and a socioeconomic burden. With the projected increase in the world’s population, especially in the rapidly growing economies, it is predicted to worsen as this century moves forward. Allergies are also becoming more complex. Patients frequently have multiple allergic disorders that involve multiple allergens and a combination of organs through which allergic diseases manifest. Thus exposure to aeroallergens or ingested allergens frequently gives rise to a combination of upper and lower airways disease, whereas direct contact or ingestion leads to atopic dermatitis with or without food allergy. Food allergy, allergic drug responses and anaphylaxis are often severe and can be life-threatening. However, even the less severe allergic diseases can have a major adverse effect on the health of hundreds of millions of patients and diminish quality of life and work productivity. The need of the hour to combat these issues is to promote a better understanding of the science of allergy and clinical immunology through research, training and dissemination of information and evidence-based better practice parameters. Allergy Frontiers is a comprehensive series comprising six volumes, with each volume dedicated to a specific aspect of allergic disease to reflect the multidisciplinary character of the field and to capture the explosive growth of this specialty. The series summarizes the latest information about allergic diseases, ranging from epidemiology to the mechanisms and environmental and genetic factors that influence the development of allergy; clinical aspects of allergic diseases; recent therapeutic and preventive strategies; and future perspectives. The chapters of individual volumes in the series highlight the roles of eosinophils, mast cells, lymphocytes, dendritic cells, epithelial cells, neutrophils and T cells, adhesion molecules, and cytokines/chemokines in the pathomechanisms of allergic diseases. Some specific new features are the impact of infection and innate immunity on allergy, and mucosal immunology of the various target organs and allergies, and the impact of the nervous system on allergies. The most recent, emerging therapeutic strategies are discussed, including allergen-specific immunotherapy and anti-IgE treatment, xi

xii

Preface

while also covering future perspectives from immunostimulatory DNA-based therapies to probiotics and nanomedicine. A unique feature of the series is that a single topic is addressed by multiple contributors from various fields and regions of the world, giving the reader the advantage of being introduced to more than one point of view and being provided with comprehensive knowledge about a single disease. The reader thus obtains a detailed review of a single, highly focused topic and at the same time has access to a panoramic, in-depth view of a broader subject such as asthma. The chapters attest to the multidisciplinary character of component parts of the series: environmental, genetics, molecular, and cellular biology; allergy; otolaryngology; pulmonology; dermatology; and others. Representing a collection of stateof-the-art reviews by world-renowned scientists from the United Kingdom and other parts of Europe, North America, South America, Australia, Japan, and South Africa, the volumes in this comprehensive, up-to-date series contain more than 150 chapters covering virtually all aspects of basic and clinical allergy. The publication of this extensive collection of reviews is being brought out within a span of two years and with the greatest precision to keep it as updated as possible. This sixvolume series will be followed up by yearly updates on the cutting-edge advances in any specific aspect of allergy. The editors would like to sincerely thank all the authors for having agreed to contribute and who, despite their busy schedules, contributed to this monumental work. We also thank the editorial staff of Springer Japan for their assistance in the preparation of this series. We hope that the series will serve as a valuable information tool for scientists and as a practical guide for clinicians and residents working and/or interested in the field of allergy, asthma, and immunology. Ruby Pawankar, Stephen T. Holgate, and Lanny J. Rosenwasser

Contents

Part I Therapy and Prevention of Allergies Allergen Avoidance and Prevention of Allergy............................................ Syed Hasan Arshad

3

Pharmacotherapy of Allergic Rhinitis ......................................................... Jeffrey M. Lehman and Michael S. Blaiss

19

Antihistamines in Rhinitis and Asthma ....................................................... Todor A. Popov

37

Antiallergic and Vasoactive Drugs for Allergic Rhinitis............................. Friedrich Horak

51

Antileukotrienes in Asthma and Rhinitis..................................................... Anthony Peter Sampson

63

Mechanisms of Action of b2 Adrenoceptor Agonists ................................... Ian P. Hall and Ian Sayers

91

Alkylxanthines and Phosphodiesterase 4 Inhibitors for Allergic Diseases ....................................................................................... Mark A. Giembycz

105

Glucocorticoid Insensitive Asthma ............................................................... Sally E. Wenzel

133

Recalcitrant Asthma ...................................................................................... Sharmilee M. Nyenhuis and William W. Busse

145

Mechanisms and Management of Exercise-Induced Bronchoconstriction ....................................................................................... John D. Brannan and Paul M. O’Byrne

171

xiii

xiv

Contents

Use of Theophylline and Sodium Cromoglycate in Adult Asthma ............ Hironori Sagara, Kenya Kouyama, Takeshi Fukuda, and Sohei Makino New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma .................................................................................. Giovanni Passalacqua and Giorgio Walter Canonica Sublingual Immunotherapy in Allergic Rhinitis and Asthma ................... Paul Potter Anti-IgE in Allergic Airway Diseases: Indications and Applications ............................................................................................. Jennifer Preston DeMore and William W. Busse

187

195

217

227

Drug Delivery Devices and Propellants ....................................................... Bruce K. Rubin and James B. Fink

245

Update on the Management of Atopic Dermatitis/Eczema ........................ Sherrif F. Ibrahim, Anna De Benedetto, and Lisa A. Beck

259

Immunosuppressants as Treatment for Atopic Dermatitis ........................ Bartlomiej Kwiek and Natalija Novak

291

Management of Anaphylaxis......................................................................... Phillip Lieberman

311

Anaphylaxis: Are Regulatory T Cells the Target of Venom Immunotherapy? .......................................................................... Marek Jutel, Mübeccel Akdis, Kurt Blaser, and Cezmi A. Akdis

325

Food Allergy: Opportunities and Challenges in the Clinical Practice of Allergy and Immunology............................................................ Julie Wang and Hugh A. Sampson

335

Early Immunological Influences on Asthma Development: Opportunities for Early Intervention........................................................... Patrick G. Holt

347

Asthma and Allergy in Childhood: Prediction and Early Diagnosis ....................................................................................... Karin C. Lødrup Carlsen and Göran Wennergren

365

Early Interventions in Allergic Diseases ...................................................... L. Karla Arruda, Dirceu Solé, and Charles K. Naspitz

379

Contents

xv

Birth Cohort Studies for the Prevention of Allergy: New Perspectives—Where Do We Go from Now? ...................................... Mascha Rochat and Erika von Mutius

397

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma ..................................................................................... Susan L. Prescott

417

Recombinant Allergens for Therapy and Prevention: Molecular Design and Delivery of Allergy Vaccines ................................... Shyam S. Mohapatra and Shawna A. Shirley

433

Prevention of Allergic Diseases ..................................................................... Leena von Hertzen and Tari Haahtela Emerging Nonsteroidal Anti-Inflammatory Therapies Targeting Specific Mechanisms in Asthma and Allergy ............................................... Leif Bjermer and Zuzana Diamant Part II

447

465

Special Considerations in Children, Elderly and Pregnancy

Asthma and Rhinitis in Pregnancy ............................................................... Vanessa E. Murphy and Peter G. Gibson

485

Asthma in the Elderly .................................................................................... Charles E. Reed

499

The Natural History of Childhood Asthma ................................................. Miles Weinberger and Dirceu Solé

511

The Wheezing Infant and Young Child........................................................ Peter J. Helms

531

Acute Severe Asthma in Children................................................................. Barbara P. Yawn

543

Best Estimates of Asthma Control in Children ........................................... Megan E. Partridge and William K. Dolen

565

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids....... Hugo P. Van Bever, Lynette P. Shek, and Daniel Y.T. Goh

577

Risk-Benefit of Asthma Therapy in Children: Nonsteroidal Anti-Inflammatory Drugs ............................................................................. James P. Kemp

593

xvi

Contents

The Role of Influenza Vaccination in Asthmatic Children ......................... Herman J. Bueving and Johannes C. van der Wouden

611

Treatment of Infants with Atopic Dermatitis .............................................. Ulrich Wahn

621

Diagnosing Food Allergy in Children ........................................................... Dan Atkins

635

Diagnosis and Treatment of Latex Allergy .................................................. Kevin J. Kelly and Brian T. Kelly

653

New Aspects of Peanut and Tree Nut Allergy .............................................. Corinne A. Keet and Robert A. Wood

675

Allergic Fungal Sinusitis: Controversy and Evolution of Understanding with Therapeutic Implications ....................................... Berrylin J. Ferguson and Arpita Mehta

695

Immunomodulatory Role of Bacillus Calmette-Guérin in the Prevention and Therapy of Allergy and Asthma .............................. Toluwalope O. Makinde, Againdra K. Bewtra, and Devendra K. Agrawal

713

Use of Theophylline and Sodium Cromoglycate in Pediatric Asthma........................................................................................ Akihiro Morikawa

727

Antibody Deficiency Syndromes (Including Diagnosis and Treatment) ........................................................... Kenneth Paris, Lily Leiva, and Ricardo U. Sorensen

737

Index ................................................................................................................

755

Contributors

Devendra K. Agrawal Departments of Biomedical Sciences, Internal Medicine, and Medical Microbiology and Immunology, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178, USA Cezmi A. Akdis Swiss Institute of Allergy and Asthma Research (SIAF), Obere str. 22, CH-7270 Davos, Switzerland Mübeccel Akdis Swiss Institute of Allergy and Asthma Research (SIAF), Obere str. 22, CH-7270 Davos, Switzerland Syed Hasan Arshad Infection, Inflammation and Immunity Research Division, School of Medicine, University of Southampton, Mailpoint 810, Level F, South Block, Southampton General Hospital, Southampton SO16 6YD, UK L. Karla Arruda Division of Clinical Immunology, Department of Medicine, School of Medicine of Riberão Preto, University of São Paulo, Brazil Dan Atkins Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO80206, USA Lisa A. Beck Departments of Dermatology and Medicine, University of Rochester, 601 Elmwood Ave, Box 697, Rochester, NY 14642, USA Anna De Benedetto Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA Againdra K. Bewtra Department of Internal Medicine, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE, USA xvii

xviii

Contributors

Leif Bjermer Department of Respiratory Medicine and Allergology, Heart and Lund Division, University Hospital of Lund, 221 85 Sweden Michael S. Blaiss Department of Medicine and Pediatrics, Division of Clinical Allergy and Immunology, University of Tennessee Health Science Center, 7205 Wolf River Blvd. Suite 200, Germantown, TN 38138, USA Kurt Blaser Swiss Institute of Allergy and Asthma Research (SIAF), Obere str. 22, CH-7270 Davos, Switzerland John D. Brannan Firestone Institute for Respiratory Health and the Department of Medicine, Michael G DeGroot School of Medicine, McMaster University, 50 Charlton Ave, East, Room T3213, Hamilton, ON, Canada L8N 4A6 Herman J. Bueving Department of General Practice, Erasmus MC, University Medical Center Rotterdam, Burg. S’Jacobsplein 51, 3015 CA Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands William W. Busse Division of Allergy and Immunology, Department of Medicine, University of Wisconsin; University of Wisconsin School of Medicine and Public Health, J5/219 CSC-2454, 600 Highland Avenue, Madison, WI 53792, USA Giorgio Walter Canonica Allergy and Respiratory Diseases, Department of Internal Medicine, Padiglione Maragliano, L.go R. Benzi 10, 16132 Genoa, Italy Karin C. Lødrup Carlsen Department of Paediatrics, Division of Woman and Child, Oslo University Hospital, Ullevål University Hospital, NO-0407, Oslo, Norway; The Faculty of Medicine, University of Oslo, Oslo, Norway Jennifer Preston DeMore University of Wisconsin School of Medicine and Public Health, J5/219 CSC-2454, 600 Highland Avenue, Madison, WI 53792, USA Zuzana Diamant Departments of Allergology and Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands William K. Dolen Allergy-Immunology Section, Departments of Pediatrics and Medicine, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA

Contributors

xix

Berrylin J. Ferguson Division of Sino-Nasal Disorders and Allergy, Department of Otolaryngology, University of Pittsburgh School of Medicine, The Eye and Ear Institute Building, 200 Lothrop Street, Suite 500, Pittsburgh, PA 15213, USA James B. Fink Independent Consultant, San Mateo, CF, USA Takeshi Fukuda Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Japan Peter G. Gibson Hunter Medical Research Institute, Level 3, John Hunter Hospital, Locked Bag #1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia Mark A. Giembycz Department of Pharmacology and Therapeutics, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, Calgary, AB, Canada Daniel Y.T. Goh Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; University Children’s Medical Institute, National University Hospital, Singapore Tari Haahtela Skin and Allergy Hospital, Helsinki University Central Hospital, P.O. Box 160, 00029 HUS, Finland Ian P. Hall Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK Peter J. Helms Department of Child Health, University of Aberdeen; Royal Aberdeen Children’s Hospital, Westburn Road, Aberdeen, Scotland AB25 2ZG, UK Patrick G. Holt Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia Friedrich Horak Ear Nose and Throat Department, Allergy Centre Vienna West, Medical University Vienna, Huetteldorferstrasse 46, A-1150 Vienna, Austria Sherrif F. Ibrahim Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

xx

Contributors

Marek Jutel Swiss Institute of Allergy and Asthma Research (SIAF), Obere Street 22, CH-7270, Davos, Switzerland; Department of Clinical Immunology, Wroclaw Medical University, Traugutta 57, PL- 50-417 Wroclaw, Poland Corinne A. Keet Department of Pediatrics, Division of Pediatric Allergy and Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Brian T. Kelly Medical College of Wisconsin, 8700 W. Wisconsin Avenue Milwaukee, WI 53226, USA Kevin J. Kelly Department of Pediatrics, University of Missouri Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA James P. Kemp Department of Pediatrics, University of California School of Medicine, San Diego; Allergy and Asthma Medical Group and Research Center, 9610 Granite Ridge Drive, Suite B, San Diego, CA 92123, USA Kenya Kouyama Department of Respiratory Medicine, Dokkyo Medical University Koshigaya Hospital, Japan Bartlomiej Kwiek Department of Dermatology, Medical University of Warsaw, Warsaw, Poland Jeffrey M. Lehman Department of Medicine and Pediatrics, Division of Allergy and Immunology, University of Tennessee Health Science Center, 50 N. Dunlap, WPT Rm 401, Memphis, TN 38103, USA Lily Leiva Department of Pediatrics, Research Institute for Children 4th Floor, Louisiana State University Health Sciences Center; Jeffrey Modell Diagnostic Center, Children’s Hospital, 200 Henry Clay Avenue, New Orleans, LA 70118, USA Phillip Lieberman Division of Allergy and Immunology, Department of Medicine and Pediatrics, University of Tennessee, Memphis, 7205 Wolf River Boulevard, Suite 200, Germantown, TN 38138, USA Toluwalope O. Makinde Department of Biomedical Sciences, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178, USA Sohei Makino Jobu Hospital for Respiratory Diseases, Japan

Contributors

xxi

Arpita Mehta Division of Sino-Nasal Disorders and Allergy, Department of Otolaryngology, University of Pittsburgh School of Medicine, The Eye and Ear Institute Building, 200 Lothrop Street, Suite 500, Pittsburgh, PA 15213, USA Shyam S. Mohapatra Division of Allergy and Immunology, Joy Airway Disease and Nanomedicine Research Center, Department of Internal Medicine, Department of Molecular Medicine, University of South Florida, College of Medicine and James A. Haley Veteran’s Hospital, Tampa, FL, USA Akihiro Morikawa Kitakanto Allergy Institute, Kibounoie Hospital, 22-4 Ohmama, Ohmama-machi, Midori, Gunma 376-0101, Japan Vanessa E. Murphy Hunter Medical Research Institute, Level 3, John Hunter Hospital, Locked Bag #1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia Erika von Mutius University Children’s Hospital, Lindwurmstr. 4, 80337, Munich, Germany Charles K. Naspitz Division of Allergy, Clinical Immunology and Rheumatology, Federal University of São Paulo, São Paulo, Brazil Natalija Novak Department of Dermatology and Allergy, University of Bonn, Sigmund-FreudStrasse 25, 53105 Bonn, Germany Sharmilee M. Nyenhuis Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, CSC 2454/J5-219, 600 Highland Avenue, Madison, WI 53792, USA Paul M. O’Byrne Firestone Institute for Respiratory Health and the Department of Medicine, Michael G DeGroot School of Medicine, McMaster University, 50 Charlton Ave, East, Room T3213, Hamilton, ON, Canada L8N 4A6 Kenneth Paris Department of Pediatrics, Research Institute for Children 4th Floor, Louisiana State University Health Sciences Center; Jeffrey Modell Diagnostic Center, Children’s Hospital, 200 Henry Clay Avenue, New Orleans, LA 70118, USA Megan E. Partridge Allergy-Immunology Section, Departments of Pediatrics and Medicine, Medical College of Georgia, 1120 15th Street, Augusta, GA, USA Giovanni Passalacqua Allergy and Respiratory Diseases, DIMI, University of Genoa, Italy

xxii

Contributors

Todor A. Popov Clinic of Allergy and Asthma, Alexander’s University Hospital, 1, Sv. Georgi Sofiyski St., 1431 Sofia, Bulgaria Paul Potter Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, George Street, Mowbray, Cape Town 7700, South Africa Susan L. Prescott School Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia; Princess Margaret Hospital, P.O. Box D184, Perth, WA 6001, Australia Charles E. Reed Mayo Medical School, Rochester, MN, USA Mascha Rochat University Children’s Hospital, Lindwurmstr. 4, 80337, Munich, Germany Bruce K. Rubin Jessie Ball duPont Professor and Chairman of the Department of Pediatrics, Professor of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23219, USA Hironori Sagara Department of Respiratory Medicine, Dokkyo Medical University Koshigaya Hospital, Japan Hugh A. Sampson Division of Allergy and Immunology, Department of Pediatrics, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, NY, USA Anthony P. Sampson Division of Infection, Inflammation & Immunity (III), University of Southampton School of Medicine, The Sir Henry Wellcome Building (MP825), Southampton General Hospital, Tremona Road, Southampton, S016 6YD, UK Ian Sayers Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK Lynette P. Shek Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Shawna A. Shirley Department of Molecular Medicine, University of South Florida, College of Medicine and James A. Haley Veteran’s Hospital, Tampa, FL, USA Dirceu Solé Division of Allergy, Clinical Immunology and Rheumatology, Federal University of São Paulo, São Paulo, Brazil

Contributors

xxiii

Ricardo U. Sorensen Department of Pediatrics, Research Institute for Children 4th Floor, Louisiana State University Health Sciences Center; Jeffrey Modell Diagnostic Center, Children’s Hospital, 200 Henry Clay Avenue, New Orleans, LA 70118, USA Hugo P. Van Bever Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; Department of Paediatrics, National University Hospital, 5 Lower Kent Ridge Road, 119074 Singapore Johannes C. van der Wouden Department of General Practice, Erasmus MC, University Medical Center Rotterdam, Burg.s’ Jacobsplein 51, 3015 CA Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Leena von Hertzen Skin and Allergy Hospital/ HUCH, P.O. Box 160, 00029 HUS, Finland Ulrich Wahn Department for Pediatric Pneumology and Immunology, Charité Berlin, Germany Julie Wang Division of Allergy and Immunology, Department of Pediatrics, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, NY, USA Miles Weinberger Pediatric Department, University of Iowa Hospital, 200 Hawkins Drive, Iowa City, IA 52242, USA Göran Wennergren Department of Paediatrics, Göteborg University, Queen Silvia Children’s Hospital, SE-416 85 Göteborg, Sweden Sally E. Wenzel University of Pittsburgh, NW 628 Montefiore, 3459 Fifth Ave., Pittsburgh, PA 15213, USA Robert A. Wood Department of Pediatrics, Division of Allergy and Immunology, Johns Hopkins University School of Medicine; Johns Hopkins Hospital, CMSC 1102, 600 North Wolfe Street, Baltimore, MD 21287, USA Barbara P. Yawn University of Minnesota; Olmsted Medical Center, MN, USA

Part I Therapy and Prevention of Allergies

Allergen Avoidance and Prevention of Allergy Syed Hasan Arshad

Introduction Definitions Atopy is the inherited tendency to produce Immunoglobulin E (IgE) antibodies in response to exposure to allergens. This can be identified clinically by measurement of specific IgE to allergens in the serum or by skin prick test, where IgE bound to skin mast cells is detected. The atopic predisposition leads to a higher risk of development of allergic diseases such as allergic asthma and rhinitis, atopic dermatitis and some allergic food and drug reactions, specifically those that are IgE mediated. Epidemiological studies have shown that nearly 40% of the population in Western, developed countries are atopic [1]. However, not all subjects with atopy develop clinical manifestations. Some remain asymptomatic, while others develop various symptoms related to allergic diseases. The disease may also go into remission. Indeed, it is not uncommon for atopic children to grow out of one set of allergic diseases, usually food allergy and atopic dermatitis, only to be replaced by allergic asthma and rhinitis in later childhood. This is commonly known as atopic march. In this chapter, atopy will be considered as meaning both allergic sensitization and atopic/allergic disease. Primary prevention aims at reducing the development of disease in previously healthy subjects while secondary preventive measures seek to reduce morbidity in individuals with disease.

S.H. Arshad () Infection, Inflammation and Immunity Research Division, School of Medicine, University of Southampton, Mailpoint 810, Level F, South Block, Southampton General Hospital, Southampton, SO16 6YD, UK e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_1, © Springer 2010

3

4

S.H. Arshad

Risk Factors The development of asthma and other allergic diseases is determined by gene– environment interactions. Those with the right combination of genes and appropriate environmental stimuli may develop the disease. Exposure to allergen is, of course, essential in the development of allergic sensitization and symptomatic diseases in atopic individuals. Other environmental factors may predispose to the phenotypic expression in genetically susceptible individuals and may include exposure to pollutants, dietary factors and infections.

At Risk Population The high prevalence of allergic diseases, in the community, has become a major public health problem. There is an urgent need to devise effective methods to prevent the development of these disorders. Individuals who develop atopy are both genetically susceptible and have been exposed to appropriate allergens. Despite advances in identification of asthma and atopy genes, genetic manipulation to reduce the development of atopy may not be possible in the near future. Therefore, the focus has been on allergen avoidance as a means of preventing atopy. One of the difficulties in preventing atopy is that of identifying susceptible individuals, who would be at high risk and stand to benefit most from an effective intervention. For high-risk children, more intensive and expensive measures may be justified, if their effectiveness can be proven. At present, these individuals are identified by positive responses on skin prick test or presence of specific IgE in their serum, both indicating sensitization. However, by the time sensitization has developed it may be too late to intervene. Moreover, the onset of allergic manifestations is often during early childhood. Rapid advances in human genetics will result in better identification of at-risk children at birth or even earlier. Until then, most studies have relied upon family history of atopy as a means of identifying children at high risk of atopy and thus suitable for preventive measures. This is not entirely satisfactory as a significant number of allergy problems develop in individuals with no history of atopy in the immediate family.

Early Critical Period Allergic diseases are common in early childhood and many children develop sensitization during the first 3 years of their life. This may be because pre-natal and immediate post-natal periods are critical in the development of the immune system. There is evidence to suggest that a maturational deficiency exists in the immune system during infancy in children who are at high risk due to family history of atopy [2].

Prevention of Allergy

5

It is likely that environmental exposures during this period will have a more profound influence on the developing immune system. It has also been argued that fetal exposure to allergens should be minimized in order to protect the developing immune system. A susceptible child will develop tolerance or sensitization depending on the type, amount and route of exposure of an allergen. Further exposure to the same allergens may lead to allergic reaction, which may be systemic or confined to one organ system. Thus, efforts at reducing allergens exposure to prevent atopy have primarily focussed on infancy and occasionally included the third trimester of pregnancy.

Allergen Exposure Certain allergens are ubiquitous and most – if not all – of us are exposed to these allergens in varying degrees. For example, food allergens such as cows’ milk and egg are foreign proteins that children are often exposed to, early in life. The “normal” response of the immune system is that of tolerance and production of IgG antibodies. However, some but not all, susceptible individuals may produce IgE antibodies instead, detectable on skin prick test or radioallergosorbent test (RAST), which may lead to cow’s milk or egg allergy and may contribute to the development of atopic eczema. Similarly, exposure to house dust mite and pollen allergens is almost universal in temperate, humid climates and yet not all atopic individuals are sensitized to these ubiquitous allergens.

Exposure and Disease Even among those with atopic heredity, it is not clear why exposure to some allergens induces tolerance, while others cause sensitization.This may depend on a number of factors like dose and route of exposure and these factors may act differently with different allergens. For example, for dust mite allergen there seems to be a dose response effect, where increasing level of exposure may increase the risk of sensitization [3]. However, there is some evidence that exposure to cat allergen may work differently where extremely low and high exposure may lead to tolerance while middle level exposure may increase sensitization [4]. Recent evidence also suggests that environmental exposure (through skin or airway) to some food allergens may cause sensitization, while oral route induces tolerance [5]. In this state of a relative lack of knowledge regarding critical issues, the evidence to support the hypothesis – if prevention of atopy is possible by allergen avoidance – would undoubtedly be patchy. Nonetheless, this idea remains attractive to the investigators across the world and several studies have been performed to test the effectiveness of allergen avoidance. There are several reasons for this. First, if exposure to allergen causes sensitization and subsequently clinical diseases, then it is logical to try to

6

S.H. Arshad

reduce exposure to allergen to prevent atopy. Secondly, there have been successes with this approach, albeit in slightly different circumstances. For example, with the increased use of latex gloves, latex allergy became a considerable problem in 1980s and 1990s. With reduction in exposure, primarily with the increased use of latex free gloves and instruments, the prevalence of latex allergy has been reduced.

Primary Prevention Food Allergen Avoidance Breast Feeding Cow’s milk is often introduced to the infant either as replacement or as supplement to breast feeding. Thus, cow’s milk allergy is relatively common in infancy with a prevalence of around 2–3% when strict criteria and/or challenge protocols were used for diagnosis [6]. Exclusive breast feeding, which avoids exposure to cows’ milk in early life, has been proposed as an atopy reducing measure for several decades. In 1930s, Grlulee and Sanford reported seven times higher incidence of eczema in children fed cow’s milk formula as opposed to those fed breast milk [7]. Since then, a large number of studies have produced conflicting results [8]. Most of these studies have been observational, as it is not considered ethical to randomize children into breast or formula fed groups. This and other methodological flaws (retrospective collection of information, short duration of follow-up, poor definition of outcomes) in studies may account for some of the controversial results. The weight of the evidence favors a protective effect of exclusive breast feeding for at least up to 3 months, on infantile wheeze and atopic eczema. There is no clear protective effect on asthma and rhinitis. The effect of exclusive breast feeding may be modified by atopic heredity. A recent study suggested that those with genetic predisposition had lower incidence of sensitization and allergic rhinitis with exclusive breast feeding, while children without such predisposition had an increased risk [9]. However, the effect of breast milk on immune system is more complex (e.g. protection against infection, nutritional factors such as omega-3 fatty acids) than simple avoidance of cow’s milk exposure. Breast feeding has numerous nutritional, immunological, and psychological advantages and should be recommended for all, irrespective of its effect on atopy prevention. In terms of allergen exposure, it is known for some time that breast fed infants are exposed to small amounts of food protein, ingested by the mother. These small quantities of food protein antigen carry a significant potential for sensitizing the infant at a very early age. Several randomized controlled trials (RCTs) have tested the hypothesis that maternal avoidance of highly allergenic food (such as dairy produce, egg, fish and nuts) during lactation may reduce susceptible infant’s

Prevention of Allergy

7

Table 1 Randomized controlled trials of maternal avoidance of highly allergenic foods during lactation (with or without restriction during pregnancy) Study (year reported)

Primary outcomes

Zeiger et al. (1989), Zeiger and Heller (1995)a

Atopy

Herrmann et al. (1996)a

ADb/food allergic sensitization AD

Sigurs et al. (1992), Hattevig et al. (1999)a a b

Duration of follow-up (years) 1 7 1 4 10

Benefit Cows’ milk allergy and AD reduced No effect No difference AD No difference

References: [10–14] AD atopic dermatitis

exposure to these allergenic foods through breast milk and thus prevent the development of atopy (Table 1). The results are variable with some studies showing a reduction in atopic diseases, especially in cow’s milk allergy and atopic eczema in early childhood, while others failed to show any protective effect [10–14]. Although maternal avoidance diet during lactation is difficult to adhere to, none of the studies restricting maternal diet during lactation only [13, 14], reported any adverse nutritional effects for mother or child. A Cochrane database review concluded that restricting maternal diet during lactation might be of some benefit in children at high risk of atopy [15].

During Pregnancy Fetus is also exposed to food ingested by the mother as cord blood mononuclear cells recognize and proliferate when stimulated by food (such as cows’ milk and egg) proteins. To prevent this sensitization, the protective effect of maternal avoidance of highly allergenic foods during late pregnancy was assessed in a prospective study [16, 17]. Restricting maternal diet (excluding cow’s milk and egg) during the third trimester of pregnancy seems to have little beneficial effect in genetically predisposed children. Indeed, there was some concern regarding the health of the mother and child, as the weight gain during pregnancy was lower than expected, and infants had slightly lower birth weight compared to the control group. Two RCTs combined the dietary restriction of highly allergenic foods (cow’s milk, egg, nuts, fish, and soy) during late pregnancy and lactation up to 6 months [10–12]. There was a reduction in food allergic manifestations and atopic dermatitis at the age of 2 years in one study, but no long-term benefit beyond early childhood was observed. Weight gain during the third trimester was again a concern in mothers who practiced avoidance diet.

8

S.H. Arshad

Late Introduction of Solid Foods Several observational studies have suggested that delaying the introduction of solid foods up to at least 6 months, thus avoiding infants’ exposure to potentially allergenic foods may reduce the occurrence of food allergy and atopic eczema in genetically predisposed children [18, 19]. On this basis, most atopy prevention guidelines recommend late (after 6 months) introduction of solid foods. Peanut is a specific example. Observational studies suggested that ingestion of peanut by the mother during pregnancy and early introduction of peanut in infants’ diet (e.g. peanut butter) might increase the risk of peanut allergy [20]. In the UK, mothers with a history of atopy in the immediate family were advised to avoid peanut during pregnancy and delay introduction in the child’s diet for up to 3 years. However, it is uncertain if peanut avoidance in early life has any effect on the prevalence of peanut allergy in children [21]. Importantly, no RCT has been done to address specifically the benefit of delayed introduction of solid foods. Most intervention studies have combined late introduction of solids with other intervention measures and thus it is difficult to know if this strategy alone has any protective effect. The evidence is weak to support a preventive effect of late introduction of solid foods, including peanut, as the sole intervention [21]. Indeed, a recent study suggests that oral ingestion of peanut may lead to tolerance rather than sensitization which is likely to occur through the environmental (skin, airway) route [5].

Hydrolyzed Milk Formulae In hydrolyzed milk formulae, protein is broken down into small peptides rendering it non-allergenic. The resulting small molecules loses epitops essential for IgE binding – a pre-requisite for IgE mediated allergic reaction. Extensive hydrolyzate contains only a tiny fraction of the remaining large size peptides, whereas partial hydrolyzate has significant amount of relatively large peptides with IgE binding capacity. These formulae are designed to be used as replacement therapy for children with allergy to cows’ milk. However, in children at high risk of atopy, who are not breast fed, hydrolyzed formulae can be used as a primary prevention strategy, avoiding early exposure to cows’ milk. A number of RCTs have been done to assess the preventive effect of replacing cows’ milk formula with a hydrolyzate from birth (Table 2). A reduction in cow’s milk allergy and atopic dermatitis in the first year has generally been documented but any longer term effect is uncertain [22–26]. There is some controversy regarding the extent of hydrolysis needed for primary prevention. Overall, extensive hydrolyzate is considered more effective [26]. There is also some uncertainty regarding the differential effect of the type of protein (casein vs. whey) used to produce hydrolyzate [26]. Most RCTs indicate a greater preventive effect of extensively hydrolyzed casein formula on allergic manifestations. Overall, protein hydrolyzate, as supplement or alternative to breast feeding, reduces allergic manifestations (cow’s milk allergy and atopic eczema) during the first 2–3 years of life in children at high risk of atopy. These hydrolyzates have

Prevention of Allergy

9

Table 2 Randomized controlled trials of the use of hydrolyzed milk formula for primary prevention of atopy Study (year reported)

Primary outcomes

Mallet and Henocq (1992)a Marini et al. (1996)a

Wheeze

Fukushima et al. (1997)a Chan et al. (2002)a GINIb Study (2003)a

ADc/recurrent wheeze AD/cows’ milk allergy AD AD/food allergy

Duration of follow-up (years) 1 2 1 2 3 1

Benefit No difference AD 3-fold reduction in allergic manifestations Significant reduction in both diseases AD but not wheeze AD reduced

a

References: [22–26] GINI German Infant Nutrition Intervention c AD atopic dermatitis b

shown to be nutritionally adequate for the need of the infant. However, these have not been shown to be superior to exclusive breast feeding. Most studies found that soy formula does not protect against allergy in high-risk infants [27]. In summary, avoidance of food allergens in early life, in children at high risk of atopy may reduce the development of cow’s milk allergy and atopic eczema in the first 2–3 years of life. Any additional protective long-term effect or reduction in asthma or allergic rhinitis remains uncertain.

Aeroallergens Common aeroallergens include dust mites, pollens, furry pets, molds, and cockroaches (Table 3). Exposure to these allergens is known to cause morbidity in those with allergic diseases such as asthma, allergic rhinitis, and atopic eczema. There is less agreement if exposure to these allergens causes the development of these diseases in previously healthy children but the bulk of evidence favours the hypothesis [28]. Thus, it is likely that allergen avoidance could prevent the development of atopy (primary prevention) and may also reduce symptoms in those with allergic disease (secondary prevention).

House Dust Mite Allergen Avoidance House dust mite is one of the most common indoor allergen. Dust mites reside in carpets, bedding, soft furnishings, and soft toys, and the allergen they produce in their faeces and body parts, enriches the dust collected in these items. With human activity, the dust – and with it, the mite allergen – gets airborne and inhaled.

10

S.H. Arshad Table 3 Common airborne (inhalant) allergens Group

Common allergens

Dust mites

Dermatophagoides pteronyssinus Dermatophagoides farinae Cladosporium Penicillium Aspergillus Alternaria Grass Weed Tree Flower Cat Dog Rabbit Horse Cockroach Cockatiel Budgerigar Mouse Rat Hamster Guinea pig Gerbil

Molds

Pollens

Domestic animals

Insects Birds Rodents

Exposure to dust mite allergen causes sensitization in genetically susceptible children in a dose dependent manner [3] and dust mite sensitization has been shown to increase the risk of future development of asthma and allergic rhinitis [29]. There is some evidence of a direct link between exposure to house dust mite and development of asthma [30]. Presuming that immediate post-natal period is a particularly critical time for allergen exposure to have it maximal effect on the developing immune system, most intervention studies have attempted to reduce infant’s exposure to dust mite allergen exposure from birth. Some of these studies have been carefully designed and executed, showing a reduction in the content of dust mite allergen in the collected dust in the intervention group [31–38]. However, in most studies, this reduction in exposure did not have the desired effect of reducing the development of atopy (Table 4). Thus, recent evidence indicates that current avoidance measures, including mattress impermeable covers reduce dust mite allergen exposure, but this may not be sufficient to prevent clinical allergy. Longer term follow-up is required to make a firm conclusion, but it seems unlikely that current dust mite allergen avoidance measures are effective in achieving a significant reduction in the burden of atopy.

Prevention of Allergy

11

Table 4 Randomized controlled trials evaluating the effect of house dust mite allergen avoidance on primary prevention of atopy Age at recruitment

N

Birth

696

2–4 years

636

5–7 years

242

MAASa,b

Prenatal

620

PIAMAa,b

Prenatal

810

CAPSa,b

Prenatal

616

Study SPACE

a,b

Allergen avoidance measures

Outcome at (years)

Mattress covers provided and advice given to reduce exposure to dust mite and cigarette smoke

1 2 1 1

Mattresses covers, HEPAc filter, hard wood flooring and use of acarosan Mattress covers and general advice Mattress covers and general advice

1

2 1.5 3

Preventive effect on Allergic sensitization No effect Allergic sensitization Allergic sensitization Severe wheeze only

Nocturnal cough only No effect Dust mite sensitization

a

SPACE Study of Prevention of Allergy in Children of Europe, MAAS Manchester Asthma and Allergy Study, PIAMA Prevention and Incidence of Asthma and Mite Allergy Study, CAPS Childhood Asthma Prevention Study b References: [31–38] c HEPA: High Efficiency Particulate Arresting

Other Aeroallergens Although, dust mite is the most important allergen worldwide for asthma, other aeroallergens assume importance in various climates. For example, in the dry hot climate of Arizona, most subjects with asthma are sensitized to Alternaria Alternata, a common indoor mold. In Scandinavian countries, where dust mites do not thrive due to cold and dry environment, animals, particularly cat is a major allergen. Similarly, in inner cities of the US and other countries, cockroach allergen may cause most morbidity. No RCT has yet been carried out to assess the effect of reduction in mold, animal, or cockroach allergen in primary prevention of atopy. Another set of important aeroallergens are grass, tree and weed pollen, which causes seasonal allergic rhinitis and asthma. Observational studies provide evidence to support the view that early exposure to high levels of pollen may increase the risk of later development of seasonal allergic rhinitis [39]. However, an RCT to assess the effectiveness of primary prevention by reducing exposure to pollen would be extremely difficult to perform.

12

S.H. Arshad

Table 5 Randomized controlled trials assessing the effectiveness of combined food and environmental allergen avoidance on primary prevention of atopy Study

N

Isle of Wight Prevention Studya

120

Canadian Asthma Primary Prevention Studya

545

PREVASCa,b

443

a b

Allergen avoidance measures

Follow-up at (years)

Breast feeding with maternal dietary restriction, hydrolyzed formula, delayed introduction of solids, acaricide applications and mattress covers Breast feeding, delayed introduction of solids, reduction of dust-mite and pet allergen Breast feeding, delayed introduction of solids, hydrolyzed formula, reduction of dust-mite and pet allergen

1 2 4 8 1 2 7 2

Reduction in Asthma, eczema, allergic sensitization Allergic sensitization Allergic sensitization Asthma, allergic sensitization Asthma, allergic rhinitis Asthma Asthma (but not eczema or atopy) Asthma

References: [40–43] Prevention of Asthma in Childhood Study

Combined Approach Reduction in one set of allergens, either food or dust-mite, does not seem to be highly effective in preventing atopy. Perhaps a comprehensive approach in allergen reduction is required (Table 5). This hypothesis was tested originally in the Isle of Wight prevention study where strict avoidance of highly allergenic food was combined with dust-mite allergen reduction in high risk infants [40]. These children have also been followed-up for the longest period (birth to 8 years). Overall, there has been significant reduction in allergen sensitization as well as clinical manifestations of atopy such as asthma, atopic eczema, and allergic rhinitis [41]. A Canadian study, which combined dust-mite avoidance with breast feeding and general environmental measures also showed a reduction in asthma but not allergic sensitization [42]. A recent Dutch study further supports this concept where high-risk infants developed less atopy when breast fed and avoided dust-mite and smoke exposure [43]. A recent review concluded that multi-faceted approach to allergen avoidance addressing both food and dust-mite allergen reduction may afford better protection to infants at high risk [44].

Secondary Prevention Secondary prevention aims to achieve better control of disease and improve prognosis by avoidance of exacerbating factors such as allergens and pollutants. Environment control, including allergen avoidance should be an essential part of the management of allergic disease.

Prevention of Allergy

13

Occupational Allergens Occupational allergen exposure may cause asthma, rhinitis, and dermatitis, which may be atopic or non-atopic. Reduction in exposure to occupational allergens, by changes in industrial processes or use of protective gear, is essential to reduce morbidity due to occupational disease. Latex allergy is one such example where use of non-latex gloves and other appropriate precautions has resulted in significant reduction in morbidity and mortality.

Food Allergens Exposure to food allergens may cause relatively minor symptoms such as itching and numbness in the mouth, as occurs in oral allergy syndrome due to cross reactivity of certain fruits proteins with tree pollens. It may cause or exacerbate organ-specific disease such as atopic eczema. However, it may also result in severe and life threatening anaphylaxis. Prevention by avoidance of relevant food allergen remains the mainstay of treatment of food allergy. In children with cow’s milk allergy, extensive hydrolyzate is often tolerated and those with extreme sensitivity can be given amino-acid based formula. Once the diagnosis is made, detailed information regarding avoidance should be provided. Written information with a list of prepared or packaged food that may contain specific food allergens helps to reduce inadvertent exposure. The patient should be taught how to glean relevant information from the packaged food labels. The services of a dietician may be invaluable. Accidental exposure often occurs outside home. Therefore people should also be encouraged to ask, when unsure, the details of the constituents of the meal, for example in a restaurant or at a dinner party. Nuts are particularly difficult to avoid as traces occur in many foods. For fear of litigation, manufacturers often label a vast number of packaged foods as “may contain traces of nuts,” which limits the choice of food available to those with nut allergy. Accurate labelling is also difficult due to uncertainty regarding the “minimal safe dose” i.e. the amount of a food, such as peanut, that can be regarded as safe for highly food allergic patients.

Aeroallergens In subjects with allergic asthma and rhinitis, exposure to common allergens such as pollen, mold, and dust-mite is associated with increase in morbidity and risk of emergency care attendance. Most studies have focussed on avoidance of dust-mite allergen. In the 1980s, extreme measures such as removing children with asthma and dust-mite sensitivity to several thousand feet above sea level in Alps, where the environment was cold and dry (not suitable for dust-mite survival) resulted in significant improvement in asthma symptoms and bronchial hyper-reactivity [45].

14

S.H. Arshad

Several RCTs have shown that it is possible to achieve a reduction in mite allergen exposure with environmental measures including the use of dust-mite allergen impermeable covers [46]. Some, but not all, studies have shown reduction in symptoms and/or need for medication [46]. Recent studies however, indicate that simply handing out dust-mite allergen mattress covers alone is not adequate for a clinically relevant benefit in asthma or rhinitis [47,48]. What is needed is a comprehensive approach with identification and removal of allergens and pollutants in the patient’s environment, and specific advice and education on environmental control. In inner city homes, heavily infested with cockroaches, an intensive intervention and education program can achieve a significant and clinically relevant reduction in cockroach allergen levels [49]. Thus, allergen avoidance is feasible, and it is a desirable part of the allergy management program, in addition to pharmacotherapy and allergen specific immunotherapy.

Summary The worldwide increase in the prevalence of atopy continues to underline the importance of primary prevention. Food allergy and atopic eczema, which is often associated with food allergy, is common in early childhood. Attempted reductions in exposure to food allergens, by breast feeding with or without maternal dietary restriction, delayed introduction of solid foods and the use of hydrolyzed milk formulae have at best achieved partial success. There has been some reduction in cow’s milk allergy, atopic eczema, and wheeze in the first 2 years of life, but this benefit is not sustained in later childhood. Simple, inexpensive and safe methods, such as prolonged and exclusive breast feeding, may be recommended for the whole population. However, apart from breast feeding, which has a number of other advantages, none of the other methods can be recommended for implementation on a wider scale for prevention of atopy. In some children who are at significantly higher risk, maternal dietary avoidance of allergenic foods may be advised, if dietary supervision is available. In these children, if breast feeding is not feasible, current evidence favours extensively hydrolyzed casein formula as a supplement or alternative to breast milk. Further research is urgently needed, especially large RCTs, to develop recommendations based on good scientific evidence. A number of RCTs have evaluated the effect of dust mite allergen avoidance in primary prevention of asthma. Dust-mite allergen avoidance methods have been applied from birth, as well as later in childhood. It has been clearly shown that reduction in exposure to dust mite allergen is possible with extensive environmental measures. However, this reduction does not translate into reduction in atopy. Any reduction in allergen sensitization has been modest and the effect on clinical manifestations of atopy, such as asthma and rhinitis, is generally disappointing. It can be argued that while multiple allergen exposure leads to sensitization, it is unrealistic to expect that intervention with avoidance of single allergen, such as dust-mite or even one group of allergen such as food allergens will result in

Prevention of Allergy

15

significant reduction in atopy. Studies, which have applied multi-faceted allergen avoidance regime, have met with greater success. The Isle of Wight prevention study which assessed the effect of both food and dust mite allergen avoidance has shown that atopy can be significantly reduced and the benefit may continue into later childhood, years after active intervention is stopped. Other studies testing multiple allergen avoidance regimes have also shown significant benefit. Food allergen avoidance remains the only practical method to avoid morbidity in those with food allergic reactions. Patients should be told how to avoid food allergen in question, and provided with a list of alternative foods that can be safely consumed. Avoidance of aero-allergens may be even more difficult. Trials of dust mite avoidance measures, currently in practice, such as allergen impermeable mattress covers have not consistently shown to be of benefit. Those with animal allergy are often reluctant to give up their pets. Pollens, dust mites, molds, and cockroach allergens are ubiquitous in their appropriate environments. However, with rigorous environmental intervention, exposure can be reduced with significant improvement in symptoms and medication requirement for patients with asthma and allergic rhinitis.

References 1. Janson C, Anto J, Burney P, Chinn Sde, Marco R, Heinrich J, et al. European Community Respiratory Health Survey II The European Community Respiratory Health Survey: what are the main results so far? European Community Respiratory Health Survey II. Eur Respir J. 2001 Sep;18(3):598–611 2. Holt PG, Clough J, Holt BJ, Baron-Hay MJ, Rose AH, Robinson BW, et al. Genetic ‘risk’ for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy.1992;22(12):1093–9 3. Kuehr J, Frischer T, Meinert R, Barth R, Forster J, Schraub S, et al. Mite allergen exposure is a risk for the incidence of specific sensitization. J Allergy Clin Immunol 1994;94(1):44–52 4. Custovic A, Simpson BM, Simpson A, Hallam CL, Marolia H, Walsh D, et al. Current mite, cat, and dog allergen exposure, pet ownership, and sensitization to inhalant allergens in adults. J Allergy Clin Immunol. 2003;111(2):402–7 5. Lack G, Fox D, Northstone K, Golding J, Avon Longitudinal Study of Parents and Children Study Team. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348(11):977–85 6. Høst A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):33–7 7. Grulee CG, Sanford HN. The influence of breast and artificial feeding on infantile eczema. J Pediatr 1930;9:223–5 8. Friedman NJ, Zeiger RS. The role of breast-feeding in the development of allergies and asthma. J Allergy Clin Immunol. 2005;115(6):1238–48 9. Siltanen M, Kajosaari M, Poussa T, Saarinen KM, Savilahti E. A dual long-term effect of breastfeeding on atopy in relation to heredity in children at 4 years of age. Allergy 2003;58(6):524–30 10. Zeiger RS, Heller S, Mellon MH, Forsythe AB, O’Connor RD, Hamburger RN, et al. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol 1989;84(1):72–89

16

S.H. Arshad

11. Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol 1995;95(6):1179–90 12. Herrmann ME, Dannemann A, Gruters A, Radisch B, Dudenhausen JW, Bergmann R, et al. Prospective study of the atopy preventive effect of maternal avoidance of milk and eggs during pregnancy and lactation. Eur J Pediatr 1996;155(9):770–4 13. Sigurs N, Hattevig G, Kjellman B. Maternal avoidance of eggs, cow’s milk, and fish during lactation: effect on allergic manifestations, skin-prick tests, and specific IgE antibodies in children at age 4 years. Pediatrics 1992;89(4 Pt 2):735–9 14. Hattevig G, Sigurs N, Kjellman B. Effects of maternal dietary avoidance during lactation on allergy in children at 10 years of age. Acta Paediatr 1999;88(1):7–12 15. Kramer MS, Kakuma R. Maternal dietary antigen avoidance during pregnancy and/or lactation for preventing or treating atopic disease in the child. Cochrane Database Syst Rev 2003; 4:CD000133 16. Falth-Magnusson K, Kjellman NI. Development of atopic disease in babies whose mothers were receiving exclusion diet during pregnancy – a randomized study. J Allergy Clin Immunol 1987;80(6):868–75 17. Falth-Magnusson K, Kjellman NI. Allergy prevention by maternal elimination diet during late pregnancy – a 5-year follow-up of a randomized study. J Allergy Clin Immunol 1992;89(3):709–13 18. Fergusson DM, Horwood LJ. Early solid food diet and eczema in childhood: a 10-year longitudinal study. Pediatr Allergy Immunol 1994;5(6 Suppl):44–7 19. Zutavern A, von Mutius E, Harris J, Mills P, Moffatt S, White C, et al. The introduction of solids in relation to asthma and eczema. Arch Dis Child 2004;89(4):303–8 20. Hourihane JO, Dean TP, Warner JO. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 1996;313(7056):518–21 21. Hourihane JO, Aiken R, Briggs R, Gudgeon LA, Grimshaw KE, DunnGalvin A, et al. The impact of government advice to pregnant mothers regarding peanut avoidance on the prevalence of peanut allergy in United Kingdom children at school entry. J Allergy Clin Immunol 2007;119(5):1197–202 22. Mallet E, Henocq A. Long-term prevention of allergic diseases by using protein hydrolysate formula in at-risk infants. J Pediatr 1992;121(5 Pt 2):S95–100 23. Marini A, Agosti M, Motta G, Mosca F. Effects of a dietary and environmental prevention programme on the incidence of allergic symptoms in high atopic risk infants: three years’ follow-up. Acta Paediatr Suppl 1996;414:1–21 24. Fukushima Y, Iwamoto K, Takeuchi-Nakashima A, Akamatsu N, Fujino-Numata N, Yoshikoshi M, et al. Preventive effect of whey hydrolysate formulas for mothers and infants against allergy development in infants for the first 2 years. J Nutr Sci Vitaminol 1997;43(3):397–411 25. Chan YH, Shek LP, Aw M, Quak SH, Lee BW. Use of hypoallergenic formula in the prevention of atopic disease among Asian children. J Paediatr Child Health 2002;38(1):84–8 26. von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, et al. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol 2003;111(3):533–40 27. Osborn DA, Sinn J. Soy formula for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev 2004;3:CD003741 28. Arshad SH. Exposure to indoor allergens in the development of asthma and allergy (Review). Curr Allergy Asthma Rep 2003; 3(2):115–20 29. Arshad SH, Tariq SM, Matthews SM, Hakim EA. Sensitisation to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics 2001;108(2):e33

Prevention of Allergy

17

30. Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323(8):502–7 31. Halmerbauer G, Gartner C, Schier M, Arshad H, Dean T, Koller DY, et al. Study on the prevention of allergy in Children in Europe (SPACE): allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth. Pediatr Allergy Immunol 2002;13 (Suppl 15):47–54 32. Horak F Jr., Matthews S, Ihorst G, Arshad SH, Frischer T, Kuehr J, et al. Effect of miteimpermeable mattress encasings and an educational package on the development of allergies in a multinational randomized, controlled birth-cohort study – 24 months results of the Study of Prevention of Allergy in Children in Europe. Clin Exp Allergy 2004;34(8):1220–5 33. Tsitoura S, Nestoridou K, Botis P, Karmaus W, Botezan C, Bojarskas J, et al. Randomized trial to prevent sensitization to mite allergens in toddlers and preschoolers by allergen reduction and education: one-year results. Arch Pediatr Adolesc Med 2002;156(10):1021–7 34. Arshad SH, Bojarskas J, Tsitoura S, Matthews S, Mealy B, Dean T, et al. Prevention of sensitization to house dust mite by allergen avoidance in school age children: a randomized controlled study. Clin Exp Allergy 2002;32(6):843–9 35. Custovic A, Simpson BM, Simpson A, Kissen P, Woodcock A. Effect of environmental manipulation in pregnancy and early life on respiratory symptoms and atopy during first year of life: a randomised trial. Lancet 2001;358(9277):188–93 36. van Strien RT, Kerkhof M, Oldenwening M, de Jongste JC, Gerritsen J, Neijens HJ, et al., Prevention and Incidence of Asthma and Mite Allergy Study. Mattress encasings and mite allergen levels in the Prevention and Incidence of Asthma and Mite Allergy study. Clin Exp Allergy 2003;33(4):490–5 37. Mihrshahi S, Peat JK, Marks GB, Mellis CM, Tovey ER, Webb K, et al. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2003;111(1):162–8 38. Peat JK, Mihrshahi S, Kemp AS, Marks GB, Tovey ER, Webb K, et al. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. J Allergy Clin Immunol 2004;114(4):807–13 39. Saitoh Y, Dake Y, Shimazu S, Sakoda T, Sogo H, Fujiki Y, et al. Month of birth, atopic disease, and atopic sensitization. J Investig Allergol Clin Immunol 2001;11(3):183–7 40. Arshad SH, Matthews S, Gant C, Hide DW. Effect of allergen avoidance on development of allergic disorders in infancy. Lancet 1992;339(8808):1493–7 41. Arshad SH, Bateman B, Sadeghnejad A, Gant C, Matthews SM. Prevention of allergic disease during childhood by allergen avoidance- The Isle of Wight prevention study. J Allergy Clin Immunol 2007;119(2):307–13 42. Chan-Yeung M, Manfreda J, Dimich-Ward H, Ferguson A, Watson W, Becker A, et al. A randomized controlled study on the effectiveness of a multifaceted intervention program in the primary prevention of asthma in high-risk infants. Arch Pediatr Adolesc Med 2000;154(7):657–63 43. Schönberger HJAM, Dompeling E, Knottnerus JA, Maas T, Muris JWM, van Weel C, et al. The PREVASC study: the clinical effect of a multifaceted educational intervention to prevent childhood asthma. Eur Respir J 2005;25(4):660–70 44. van Schayck OCP, Maas T, Kaper J, Knottnerus AJA, Sheikh A. Is there any role for allergen avoidance in the primary prevention of childhood asthma? J Allergy Clin Immunol 2007;119(6):1323–8 45. Piacentini GL, Martinati L, Fornari A, Comis A, Carcereri L, Boccagni P, et al. Antigen avoidance in a mountain environment: influence on basophil releasability in children with allergic asthma. J Allergy Clin Immunol 1993;92(5):644–50 46. Eggleston PA. Improving indoor environments: reducing allergen exposures. J Allergy Clin Immunol 2005;116(1):122–6

18

S.H. Arshad

47. Woodcock A, Forster L, Matthews E, Martin J, Letley L, Vickers M, et al. Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N Engl J Med 2003;349(3):225–36 48. Terreehorst I, Hak E, Oosting AJ, Tempels-Pavlica Z, de Monchy JG, Bruijnzeel-Koomen CA, et al. Evaluation of impermeable covers for bedding in patients with allergic rhinitis. N Engl J Med 2003;349(3):237–46 49. Eggleston PA, Butz A, Rand C, Curtin-Brosnan J, Kanchanaraksa S, Swartz L, et al. Home environmental intervention in inner-city asthma: a randomized controlled clinical trial. Ann Allergy Asthma Immunol 2005;95(6):518–24

Pharmacotherapy of Allergic Rhinitis Jeffrey M. Lehman and Michael S. Blaiss

Introduction The primary goal of allergic rhinitis (AR) treatment is to alleviate symptoms, improve quality of life and prevent comorbidities. In addition to allergen avoidance there are several pharmacologic agents available: oral and topical H1-antihistamines, intranasal glucocorticosteroids, leukotriene receptor antagonists, mast cell stabilizers, anticholinergic agents and decongestants. Medications used for AR are typically administered orally or intranasally. The intranasal route allows for higher concentrations of the drug to be delivered thus minimizing the systemic side effects. However, many patients with AR have an aversion to using nasal spray, and oral medications are typically used in these patients.

Oral H1-Antihistamines Histamine is an important chemical mediator of allergic inflammation and is released in large quantities from tissue mast cells and basophils upon antigen binding to IgE on the cell surface and crosslinking FceRI (high affinity receptor for IgE) during the early allergic response [1, 2]. Histamine then acts in the nose to cause

J.M. Lehman Department of Medicine and Pediatrics, Division of Allergy and Immunology, University of Tennessee Health Science Center, 50 N. Dunlap, WPT Rm 401, Memphis, TN 38103, USA M.S. Blaiss () Department of Medicine and Pediatrics, Division of Clinical Allergy and Immunology, University of Tennessee Health Science Center, 7205 Wolf River Blvd. Suite 200, Germantown, TN 38138, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_2, © Springer 2010

19

20

J.M. Lehman and M.S. Blaiss

vasodilatation and increased vascular permeability, and stimulation of sensory nerves leading to the sensation of itching [1, 2]. This manifests clinically as sneezing, rhinorrhea, and pruritus [2]. There are at least four types of histamine receptors that have been identified. However, the majority of allergic responses are mediated via the H1 receptor [3]. H1-antihistamines are inverse agonists, rather than H1-antagonists, that combine with and stabilize the inactive form of the H1 receptor leading toward a shift in equilibrium to the inactive state [3]. In addition to the inverse agonist effect at the H1 receptor, the newer second-generation agents have both antiallergic and antiinflammatory properties. They have been shown to inhibit the release of mediators from mast cells and basophils through a direct inhibitory effect on calcium-ion channels [4]. Pretreatment with an H1 antihistamine has been shown to decrease the early response to an allergen challenge through decreasing the levels of proinflammatory cell adhesion molecules, cytokines, mediators such as histamine, leukotrienes, and prostaglandins [4–8].

First Generation H1-Antihistamines The first generation H1 antihistamines such as diphenhydramine, chlorpheniramine, brompheniramine and hydroxyzine are also referred to as the sedating antihistamines. These agents are effective in controlling the rhinorrhea, sneezing and pruritus associated with AR. Unfortunately these agents cross the blood-brain barrier producing undesirable side-effects such as central nervous system depression, sedation leading to impaired performance at home, work and school and cardiotoxicity [9–11]. There are no long-term safety studies on the first generation antihistamines. These agents have poor H1 receptor selectivity and act on muscarinic receptors causing anticholinergic effects such as dry mouth, urinary retention, constipation and tachycardia [9]. The high risk to benefit ratio makes the first generation H1 antihistamines a less attractive therapeutic option and are not recommended as first line therapy in AR.

Second Generation H1-Antihistamines The second generation antihistamines (Table 1), developed in the early 1980s, have improved H1 receptor selectivity, absent or decreased sedation, faster onset and longer duration of action and fewer adverse effects [11, 12]. To date, no clinically significant cardiotoxic effects have been reported for loratadine, desloratadine, fexofenadine, cetirizine and levocetirizine. In general, second generation antihistamines exhibit favorable pharmacokinetics. They have a relatively quick onset of action, near complete absorption, widespread tissue distribution with minimal CNS

Pharmacotherapy of Allergic Rhinitis

21

Table 1 Available second generation H1-antihistamines Usual pediatric daily dosage

Usual adult daily dosage

Sedation

2–5 yrs: 5 mg 6–11 mos: 1 mg 12 mos–5 yrs: 1.25 mg 6–11 yrs: 2.5 mg 6–11 mos: 2.5 mg 12 mos–5 yrs: 2.5–5 mg 6–11 yrs: 30 mg twice daily

10 mg 5 mg

Noa Noa

5–10 mg

Yes No

6–11 yrs: 2.5 mg

60 mg twice daily; 120 mg or 180 mg daily 5 mg

5–11 yrs: 1 spray twice daily >12 yrs: 2 sprays twice daily

2 sprays twice daily 2 sprays twice daily

Yes Yes

Oral Loratadine Desloratadine

Cetirizine Fexofenadine Levocetirizine Intranasal Azelastine Olopatadine

Yes

yrs years; mos months a Cause sedation at higher than recommended doses

penetration unlike first generation antihistamines, and relatively long half-life allowing for once daily dosing [13]. Several controlled trials of second generation H1 antihistamines have been published and have shown overall relief of symptoms including sneezing, pruritus, rhinorrhea, and conjunctival symptoms, and improved quality of life [2, 14, 15].

Cetirizine Cetirizine is rapidly absorbed and achieves peak plasma concentration in ~1 h [3]. In addition to H1 receptor antagonism, cetirizine was found to inhibit eosinophil chemotaxis during the allergic response and therefore blunted the late-phase reaction [16]. Cetirizine can cause an increased incidence of sedation at its recommended dose in patients aged 12 or older [17]. Cetirizine is classified as mildly-sedating and should not be prescribed to patients whose jobs require high psychomotor skills such as pilots. Cetirizine has been shown in numerous clinical trials to be more efficacious compared to placebo in the treatment of both seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) [18–23]. Cetirizine significantly improved QOL measures of general health, physical functioning, vitality, social functioning, and emotional and mental health within one week of treatment and continued up to 6 weeks [24].

22

J.M. Lehman and M.S. Blaiss

Levocetirizine Levocetirizine is the enantiomer of cetirizine. Levocetirizine, like cetirizine, has been shown to inhibit eotaxin-induced transendothelial migration of eosinophils in vitro, thus blunting the late phase response [16]. Levocetrizine shows lower sedating effects in clinical studies than cetirizine [25]. A randomized trial involving >400 patients with SAR found that levocetirizine significantly reduced symptom scores over an 8-week period [26]. A multinational placebo-controlled study found that levocetirizine significantly improved QOL over 6 months of treatment [11]. A large multicenter study in children with SAR and PAR found that 4–6 weeks of treatment with levocetirizine significantly improved symptoms and QOL [27].

Loratadine Loratadine has been found to blunt the early- and late-phase of allergic reactions [7]. Loratadine is a nonsedating antihistamine, and psychomotor tests confirm its safety at the recommended dosage (10 mg/day) [28]. However, performance studies with higher, off-label loratadine doses of 20 and 40 mg showed significant impairment and sedation in some objective performance tests compared with placebo [29]. Although the placebo controlled studies with loratadine are limited, two studies have shown that loratadine was superior to placebo in the treatment of AR [30, 31].

Desloratadine Desloratadine, an active metabolite of loratadine, has been shown to inhibit IgEmediated and non-IgE-mediated release of IL-4 and IL-13 from human basophils in vitro [32]. Like loratadine, desloratadine significantly reduces the symptoms of SAR. However, as in the case of loratadine, somnolence has been noted at higherthan-recommended doses [29]. Two multicenter, randomized, double-blind studies comparing the efficacy of desloratadine to placebo showed a statistically significant reduction in symptoms in patients with SAR over a 2-week study period [33, 34]. Desloratadine rapidly and safely reduced the symptoms of PAR, and its efficacy did not diminish during 4 weeks of treatment [35]. There have been no large clinical trials studying the effect of desloratadine on QOL.

Pharmacotherapy of Allergic Rhinitis

23

Fexofenadine Fexofenadine, the active metabolite of terfenadine, is a potent H1 receptor antagonist that does not display cardiotoxicity like its predecessor [36]. In addition to blocking H1 receptors, in vitro and in vivo studies have shown that fexofenadine reduces allergic inflammatory responses mediated by mast cells, basophils, epithelial cells, eosinophils and lymphocytes [37]. Fexofenadine has also been shown to demonstrate anti-inflammatory activity through inhibition of ICAM-1 expression on nasal epithelium in vitro [20]. Numerous clinical trials have shown fexofenadine to be more efficacious than placebo for the symptoms of SAR [38–44]. van Cauwenberge et al. [45] conducted a large multinational, double-blinded, placebo-controlled, 2 week trial of fexofenadine (120 mg once a day) versus loratadine (10 mg once a day) in patients with SAR. Individual symptoms were self-assessed and no difference in overall symptom scores was observed between fexofenadine and loratadine. However, fexofenadine significantly improved the individual symptoms of nasal congestion and itchy, watery, red eyes compared with loratadine. Fexofenadine has also been found to decrease work impairment and benefit emotions, sleep and practical problems [43]. Fexofenadine is a substrate for P-glycoprotein (P-gp), which is a membrane-bound transporter that inhibits absorption and promotes excretion [46]. Grapefruit juice has been found in vitro to inhibit P-gp activity and when consumed with grapefruit juice, the plasma concentration of fexofenadine can be decreased by up to 40% [47]. Conversely, when fexofenadine is taken in conjunction with ketoconazole and erythromycin, plasma levels may be increased, thus increasing the potential for adverse effects [48]. It is important to note that no serious adverse effects attributable to drug interactions with this second generation H1 antihistamine have been reported.

Intranasal H1-Antihistamines Topical second generation H1-antihistamines (Table 1) are considered to be similar in efficacy to oral H1-antihistamines and are also considered as first-line therapy for mild-moderate AR [9, 11].

Azelastine Dose-ranging trials have shown a therapeutic onset of action within 3 h after initial dosing and persistence of efficacy over a 12-h interval. The most common side effects seen with azelastine at the recommended dose of two sprays per nostril twice a day, are bitter taste (19.7% vs. 0.6% placebo) and sedation (11.5% vs. 5.4% placebo) [49,50]. Studies have shown that azelastine improved all symptoms in SAR and PAR including ocular symptoms, and can also reduce nasal congestion [9, 11, 51].

24

J.M. Lehman and M.S. Blaiss

Azelastine has demonstrated efficacy in SAR [52–54], and in recent studies azelastine appears to be slightly superior to cetirizine [55], desloratadine [56], and fexofenadine [49] in its ability to reduce total nasal symptoms scores, including nasal congestion. An older study, however, did not find that azelastine was superior to cetirizine in seasonal AR [57].

Olopatadine Olopatadine nasal spray provided reductions in total nasal symptom scores at 30 min compared to placebo and maintained an effect for at least 12 h after dosing [58]. A multicenter, randomized, double-blind SAR study comparing olopatadine to placebo nasal spray found that olopatadine was an effective antiallergy medication that significantly improved the QOL of patients suffering from SAR [59]. Olopatadine nasal spray (0.4% and 0.6%) provided statistically significant improvements in AR symptoms compared with placebo regarding TNSSs and in quality-of-life variables in patients with SAR [60]. Olopatadine nasal spray administered twice daily was safe and well tolerated in adolescents and adults. Olopatadine was also found to be superior to placebo spray and mometasone furoate in reducing allergy symptoms associated with SAR [61].

Intranasal Corticosteroids Intranasal corticosteroids (INS; Table 2) are recommended as first-line therapy for moderate-severe AR [62]. Corticosteroids target the inflammatory mechanism of the early and late phase allergic processes and are therefore effective in treating most symptoms of AR including: congestion; sneezing; rhinorrhea and nasal pruritus [9, 11, 62]. Table 2 Available intranasal corticosteroids Usual pediatric daily dosage Triamcinolone acetonide

Budesonide Fluticasone propionate Mometasone furoate Beclomethasone diproprionate Flunisolide Fluticasone furoate Ciclesonide

2–5 yrs: 1 spray/nostril daily 6–12 yrs: 1–2 sprays/nostril daily 6–11 yrs: 2 sprays/nostril daily 6–12 yrs: 1–2 sprays/nostril daily ³4 yrs: 1–2 sprays/nostril daily 2–12 yrs: 1 spray/nostril daily 6–12 yrs: 1–2 sprays/nostril twice daily 6–14 yrs: 2 sprays/nostril twice daily >2–11 yrs: 1–2 sprays/nostril daily ³12 yrs: 2 sprays/nostril daily

yrs years; mos months; HFA hydrofluoroalkane

Usual adult daily dosage 1–2 sprays/nostril daily 2–4 sprays/nostril daily 1–4 sprays/nostril daily 2 sprays/nostril daily 2 sprays/nostril daily 1–2 sprays/nostril twice daily 2 sprays/nostril twice-three times daily 2 sprays/nostril daily 2 sprays/nostril daily

Pharmacotherapy of Allergic Rhinitis

25

INS Compared with Placebo When INS are compared to placebo, this treatment group shows improvement in all parameters examined. A randomized, double blind, 3-week study of 429 patients, 12 years and older with AR who were treated with triamcinolone acetonide 220 µg/ day showed a significant decrease in nasal congestion, discharge and sneezing compared to placebo [63]. In placebo-controlled, double blind studies of fluticasone propionate (100 µg twice daily or 200 µg/day), fluticasone propionate was significantly more effective than placebo in improving nasal and ocular symptoms and increasing the number of symptom free days [64]. A double blind, placebo controlled, randomized study of patients with AR comparing mometasone furoate versus placebo showed a significant decrease with mometasone furoate in total symptom scores, total nasal scores and individual nasal symptoms [65]. Fluticasone furoate (110 µg/day), was recently found to significantly improve nasal congestion, itching, rhinorrhea, and sneezing over a 2-week period when compared to placebo in children and adults greater than 12 years [66]. Ciclesonide for intranasal use is formulated in a hypotonic suspension, which has been shown in preclinical in vivo models to provide enhanced tissue uptake when compared with a traditional isotonic formulation [67]. In addition, the intranasal formulation of ciclesonide is preserved with potassium sorbate rather than benzalkonium chloride, which is used in many INSs. Benzalkonium chloride is believed to interfere with mucociliary transport and can lead to the development of hypersensitivity, rhinitis medicamentosa, and neutrophil dysfunction, though there are no clinical studies showing significant adverse effects in humans [68, 69]. Ciclesonide is administered as an inactive parent compound that is metabolized by endogenous esterases in the upper and lower airways to the pharmacologically active metabolite desisobutyrylciclesonide. A recent clinical study evaluated the efficacy of 200 µg of ciclesonide nasal spray administered once daily compared with that of placebo on nasal symptoms and signs of AR in adults and adolescents with SAR over a 28-day period. Intranasal ciclesonide was found to be superior to placebo in relieving nasal congestion, rhinorrhea, sneezing and itching [70].

Comparison of Individual INS Several studies have compared individual INS and it appears that there is no clinically significant difference in the efficacy of various INS. Welsh et al. compared beclomethasone diproprionate, 168 µg twice daily, versus flunisolide propionate, 100 µg twice daily, in patients with SAR and found the two drugs to be equally effective [71]. Similarly, trials comparing beclomethasone, flunisolide, triamcinolone and budesonide in patient with AR found them to be equally effective [72]. Beclomethasone dipropionate and fluticasone propionate have been compared in multiple trials. A two week study in patients with SAR found beclomethasone dipropionate to be as effective as fluticasone propionate [73]. A 3-week study in

26

J.M. Lehman and M.S. Blaiss

patients with PAR found that beclomethasone and fluticasone propionate were equally effective [74]. Conversely, a 12-month study in patients with PAR found fluticasone propionate to be superior to beclomethasone diproprionate [75]. Onset of action of individual INS may differ. Recent studies suggest that fluticasone propionate, budesonide, mometasone and triamcinolone show clinical benefit within 1–2 days [71, 76–78], whereas fluticasone furoate showed benefit within 8 h of administration [66]. Jen et al. [76] demonstrated that fluticasone propionate nasal spray was more effective than placebo within 12 h of treatment, although peak efficacy took several days to obtain. Similarly, one dose of triamcinolone acetonide provided symptom relief in patients with AR within 12 h of administration [78]. Mometasone furoate was found to provide relief of AR symptoms within 12 h [77] and budesonide was demonstrated to act within 3 h of administration, although maximum efficacy occurred within days to weeks [78].

INS Compared with Oral H1 Antihistamines A meta-analysis of 16 studies involving 2267 subjects (ages 12–75 years) with AR showed that INS produced significantly greater improvement with total nasal symptoms compared to oral H1 antihistamines [79]. Significant findings from this meta-analysis include: INS produced significantly greater relief of nasal congestion, decreased nasal discharge, and decreased nasal pruritus than oral H1 antihistamines. Two studies from this meta-analysis demonstrated that INS showed a modest but significant decrease in post-nasal drip compared to oral H1 antihistamines. However, there was no difference in ocular symptoms.

Adverse Effects of INS The goal for an ideal AR therapy is an INS with a high therapeutic ratio (i.e., high efficacy, good tolerability, and low systemic bioavailability) [80, 81]. The systemic bioavailability of an INS is related to its deposition in the nasal cavity, followed by mucociliary clearance to the throat and, eventually, to the gastrointestinal tract; absorption from the mucosal surface can contribute up to 50% systemic bioavailability of the INS [80, 82]. The most common local side effects of INS, reported by 2–10% of patients, include burning, irritation, and drying. There have also been a few reported cases of nasal septal perforation [80, 83, 84]. Epistaxis, due to drying or thinning of the nasal mucosa, is another common local side effect associated with the use of INS and occurs in 17–23% of patients treated with INS and in 10–15% of patients treated with placebo in clinical trials [80, 85]. Interestingly, the incidences of epistaxis reported with placebo in clinical trials of INS are high as well; therefore, the physical trauma caused by the nasal spray application device, as well as the

Pharmacotherapy of Allergic Rhinitis

27

formulation additives, most likely also contribute to epistaxis [80,85]. To minimize epistaxis patients should be instructed on the proper technique for administration, which is to direct the spray away from the septum. Systemic exposure of INS occurs because of direct absorption of INS from the nasal mucosa as well as runoff down the throat to the gastrointestinal tract [80]. The major effect of corticosteroids on the hypothalamic-pituitary-adrenal (HPA) axis is the negative feedback effect caused by suppression of corticotrophin-releasing hormone and adrenocorticotropic hormone (ACTH) levels, leading to lower cortisol secretion and eventual atrophy of the adrenal cortex [80]. The majority of secondgeneration INS have little effect on HPA-axis function [80]. In pediatric patients with AR, treatment with fluticasone propionate 200 µg/day for 6 weeks did not suppress 12-h urine cortisol levels [86]. However, in another study of pediatric patients with PAR, intranasal fluticasone propionate 200 µg/day suppressed 12-h urine cortisol compared with placebo, whereas intranasal triamcinolone acetonide 110 µg/day did not [87]. Similarly, treatment with fluticasone propionate 200 µg/day for 4 days suppressed 12-h urinary-free cortisol secretion, whereas treatment with triamcinolone acetonide 220 µg/day or beclomethasone diproprionate 336 µg/day did not suppress cortisol levels [88]. In contrast, treatment with budesonide or mometasone furoate, each at a daily dose of 200 µg, or triamcinolone acetonide at a daily dose of 220 µg for 5 days did not have any suppressive effect on morning, 12-h, or 24-h plasma cortisol levels or on 12- and 24-h urinary free cortisol levels [89]. Finally, in children with PAR, treatment with intranasal budesonide 400 µg/day for 1 year and an aqueous suspension of budesonide 400 µg/day for an additional 6 months did not suppress morning plasma and 24-h urinary-free cortisol levels during the first and second year of treatment [90]. Effects of INS on the HPA axis are influenced by the frequency of drug administration. Once-daily administration of INS would have a negligible effect on the HPA axis [91]. A once-daily morning dosing regimen is very important in prepubertal children, in whom growth hormone secretion is pulsatile and nocturnal, with initiation of pulses corresponding to the normal late-evening low levels of plasma cortisol [80, 91]. Absorption of exogenous corticosteroid at this time from a twicedaily regimen could have a suppressive effect on growth hormone release [80]. Consistent with this observation, randomized, parallel-group, short-term studies of intranasal budesonide 200 µg given twice daily to 44 children with AR caused significant suppression of lower-leg growth [92], whereas in another double-blind, parallel-group study of 38 children, budesonide 200 µg or 400 µg given once daily in the morning did not suppress lower-leg growth [93]. Inhaled corticosteroids have been shown to have significant effects on eyes resulting in glaucoma and subcapsular cataracts and on bone [94]. However, enough data are not available on the effects of INS on eyes or bone to draw a definitive conclusion [80]. A retrospective chart review study of 12 patients showed that INS use resulted in an increase in intraocular pressure and a significant reduction in intraocular pressure was observed after discontinuation [95]. In another study, similar effects on intraocular pressure were observed with intranasal or inhaled beclomethasone diproprionate [96].

28

J.M. Lehman and M.S. Blaiss

In summary, currently available INS are effective and safe for the treatment of AR. However, the risk of side effects may be increased by high doses or prolonged exposure to more potent INS, especially in younger or older patients. Furthermore, there is a risk of an additive inhibitory effect on the HPA axis in patients receiving concomitant ICS and INS therapy [80].

Leukotriene Modifying Agents Leukotrienes appear to be important mediators of nasal allergic reactions, and their presence in the nose induces nasal obstruction [11]. Leukotrienes have significant proinflammatory effects as well as causing vasodilatation, increased vascular permeability, airway smooth muscle contraction, mucus secretion and chemoattraction towards eosinophils [62]. Therefore, they are involved in both the early and late phase allergic response. A meta-analysis demonstrated that montelukast, compared to placebo, demonstrated a moderate but significant reduction in relieving nasal symptoms in patients with AR, whereas INS induced a significant and substantial reduction in symptoms [97, 98]. A randomized, double-blind, placebo controlled trial comparing montelukast, loratadine and placebo in patients with SAR demonstrated that montelukast was more effective than placebo in improving scores for the primary endpoint of daytime nasal symptoms and the secondary endpoints of night-time, composite, and daytime eye symptoms, patient’s and physician’s global evaluations of AR, rhinoconjunctivitis and quality-of-life [99]. Loratadine also improved scores for the primary endpoint and the majority of the secondary endpoints. When analyzed by week, the treatment effect of montelukast was more persistent than loratadine over all 4 weeks of treatment. A combined analysis of three multicenter, randomized, double-blind, parallel-group studies was performed involving 1,862 patients with SAR, comparing montelukast to placebo over a two week treatment period. Montelukast significantly improved daytime nasal symptoms score and individual scores of congestion, rhinorrhea, itching, and sneezing compared with placebo [100]. A meta-analysis of seventeen randomized controlled trials involving 6,231 adults with SAR was performed to evaluate the effect of oral leukotriene receptor antagonists as monotherapy or combined with other drugs in the treatment of SAR [101]. Oral leukotriene antagonists significantly reduced daytime nasal symptoms, nighttime nasal symptoms, eye symptoms, and significantly improved quality of life compared with placebo. There were no significant differences between oral leukotriene antagonists and oral histamine H1 antagonists on nasal and eye symptoms, and quality-of-life. However, the authors found that leukotriene receptor antagonists were inferior to INS for decreasing daytime and nighttime nasal symptoms. The combination of leukotriene receptor antagonists plus histamine H1 antagonists produced greater relief of eye symptoms compared with histamine H1 antagonists alone. Finally, INS significantly reduced nasal congestion compared with leukotriene receptor antagonists plus histamine H1 antagonists. Therefore, the authors concluded

Pharmacotherapy of Allergic Rhinitis

29

that leukotriene receptor antagonists were better than placebo, equivalent to oral histamine H1 antagonists, and inferior to INS for treating SAR. Alternatively, leukotriene receptor antagonists plus histamine H1 antagonists were more effective than histamine H1 antagonists alone but inferior to INS. In a multicenter, double-blind, randomized, parallel-group, placebo-controlled 2-week trial, 460 men and women, aged 15–75 years, with SAR were randomly allocated to receive one of the following five treatments: montelukast 10 or 20 mg, loratadine 10 mg, montelukast, 10 mg with loratadine 10 mg, or placebo, once daily in the evening [102]. Concomitant montelukast with loratadine significantly improved daytime nasal symptoms score compared to placebo. Compared with placebo, montelukast with loratadine also significantly improved eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations, and quality of life.

Local Chromones Mast cell stabilizers inhibit mast cell degranulation and thus inhibit the release of histamine and other mediators of the early phase of allergic inflammation. Cromolyn sodium, which is available over-the-counter, is generally not as effective as antihistamines or INS but has been shown to be superior to placebo in reducing symptoms of the early phase [62]. Cromolyn is likely to be more effective when administered just prior to contact with an allergen [11]. Although the safety profile of cromolyn is very good, the dosing interval of four times a day make this a less attractive option.

Local Anticholinergics Double-blind, placebo-controlled studies have shown that ipratropium bromide is effective in controlling watery nasal discharge, but that it does not affect sneezing or nasal obstruction in perennial allergic and nonallergic (vasomotor) rhinitis [103, 104]. Anticholinergic side effects are uncommon and usually dosedependent [11].

Decongestants Decongestants reduce nasal congestion by activating a-adrenergic receptors on the nasal vasculature leading to vasoconstriction [62]. Decongestants do not improve nasal itching, sneezing or rhinorrhea associated with AR. Oral decongestants such as ephedrine, phenylephrine, phenylpropanolamine and pseudoephedrine are the

30

J.M. Lehman and M.S. Blaiss

most commonly used oral decongestants. Systemic side effects include irritability, dizziness, headache, tremor, insomnia as well as tachycardia and hypertension [11]. Patients with glaucoma or hyperthyroidism and elderly men with prostate enlargement are also at risk when using oral sympathomimetic decongestants. Pseudoephedrine was recently banned for Olympic athletes [105]. A recent study showed that the combination of pseudoephedrine and an antihistamine was significantly more effective in reducing total nasal symptoms than either agent alone [106]. There are very few randomized/controlled clinical studies on the effects of pseudoephedrine alone in AR. Topical decongestants, oxymetazoline and phenylephrine are also available over-the-counter. These medications can be effective with nasal congestion associated with AR. However, prolonged use (>10 days) of intranasal decongestants may lead to tachyphylaxis, a rebound swelling of the nasal mucosa and “drug-induced rhinitis” termed rhinitis medicamentosa [107].

Summary AR is a common chronic disorder that can significantly interfere with a patient’s QOL. The goals of treatment are to provide the patient with symptom relief and improvement in QOL with minimal number of side effects. Prescribing physicians must take into account patient preferences, symptoms and side effect profile. Lack of treatment or treatment with suboptimal therapy may result in reduced quality of life and compromise productivity at work or school. Many different classes of medications are now available, and they have been shown to be effective and safe in a large number of well-designed clinical trials. Table 3 provides a stepwise approach to the treatment of AR [11]. Table 3 Management of allergic rhinitis Intermittent symptoms a

Persistent symptoms

Mild

Moderate/severe

•

•

Oral or intranasal H1antihistamine and/or • Oral/intranasal decongestant or • LTRA

a

Oral or intranasal H1antihistamine and/or • Oral/intranasal decongestant or • INS or • LTRA or • Intranasal chromone

Milda

Moderate/severeb

•

•

Oral or intranasal H1 antihistamine and/or • Oral/intranasal decongestant or • INS or • LTRA or • Intranasal chromone

LTRA leukotriene receptor antagonist; ICS intranasal corticosteroid Not in preferred order b In preferred order a

INS and Oral or intranasal H1 antihistamine or LTRA • Add decongestant for blockage • Add intranasal anticholinergic for rhinorrhea

Pharmacotherapy of Allergic Rhinitis

31

References 1. Simons FER (2003) H1-antihistamines: more relevant than ever in the treatment of allergic disorders. J Allergy Clin Immunol 112:S42–52 2. Lehman JM, Blaiss MS (2006) Selecting the optimal oral H1 antihistamine for patients with allergic rhinitis. Drugs 66:2309–19 3. Simons FER (2004) Advances in H1-anthistamines. N Engl J Med 351:2203–17 4. Rimmer SJ, Church MK (1990) The pharmacology and mechanisms of action of histamine H1-antagonists. Clin Exp Allergy 20:3–17 5. Leurs R, Church MK, Taglialatela M (2002) H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 32:489–98 6. Naclerio RM (1993) The effect of antihistamines on the immediate allergic response: a comparative review. Otolaryngol Head Neck Surg 108:723–30 7. Ciprandi G, Passalacqua G, Canonica GW (1999) Effects of H1 antihistamines on adhesion molecules: a possible rationale for long-term treatment. Clin Exp Allergy 29:49–53 8. Schroeder JT, Schleimer RP, Lichtenstein LM, Kreutner W (2001) Inhibition of cytokine generation and mediator release by human basophils treated with desloratadine. Clin Exp Allergy 31:1369–77 9. Dykewicz MS, Fineman S, Skoner DP, Nicklas R, Lee R, Blessing-Moore J, Li JT, Bernstein IL, Berger W, Spector S, Schuller D (1998) Diagnosis and management of rhinitis: complete guidelines of the joint task force on practice parameters in allergy, asthma and immunology. Ann Allergy Asthma Immunol 81:478–518 10. Kay GG (2000) The effects of antihistamines on cognition and performance. J Allergy Clin Immunol 105:S622–27 11. Bousquet J, Van Cauwenberge P, Khaltaev N (2001) Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 108:147–334 12. Meltzer EO (2005) Evaluation of the optimal oral antihistamine for patients with allergic rhinitis. Mayo Clin Proc 80:1170–76 13. Simons FER, Simons KJ (1999) Clinical pharmacology of new histamine H1 receptor antagonists. Clin Pharmacokinet 36:329–52 14. Golightly LK, Greos LS (2005) Second-generation antihistamines. Actions and efficacy in the management of allergic disorders. Drugs 65:341–84 15. Slater JW, Zechnich AD, Haxby DG (1999) Second-generation antihistamines: a comparative review. Drugs 57:31–47 16. Thomson L, Blaylock MG, Sexton DW, Campbell A, Walsh GM (2002) Cetirizine and levocetirizine inhibit eotaxin-induced eosinophil transendothelial migration through human dermal or lung microvascular endothelial cells. Clin Exp Allergy 32:1187 17. Zyrtec® (cetirizine hydrochloride) tablets and syrup: package insert. 2002 Pfizer Inc., New York 18. Meltzer EO, Weiler JM, Widlitz MD (1996) Comparative outdoor study of the efficacy, onset and duration of action, and safety of cetirizine, loratadine, and placebo for seasonal allergic rhinitis. J Allergy Clin Immunol 97:617–6 19. Ciprandi G, Passalacqua G, Mincarini M, Ricca V, Canonica GW (1997) Continuous versus on demand treatment with cetirizine for allergic rhinitis. Ann Allergy Asthma Immunol 79:507–11 20. Ciprandi G, Tosca M, Ricca V, Passalacqua G, Riccio AM, Bagnasco M, Canonica GW (1997) Cetirizine treatment of rhinitis in children with pollen allergy: evidence of its antiallergic activity. Clin Exp Allergy 27:1160–6 21. Pearlman DS, Lumry WR, Winder JA, Noonan MJ (1997) Once-daily cetirizine effective in the treatment of seasonal allergic rhinitis in children aged 6 to 11 years: a randomized, doubleblind, placebo-controlled study. Clin Pediatr 36:209–15 22. Sabbah A, Daele J, Wade AG, Ben-Soussen P, Attali P (1999) Comparison of the efficacy, safety, and onset of action of mizolastine, cetirizine, and placebo in the management of seasonal allergic rhinoconjunctivitis. Ann Allergy Asthma Immunol 83:319–25

32

J.M. Lehman and M.S. Blaiss

23. Murray JJ, Nathan RA, Bronsky EA, Olufade AO, Chapman D, Kramer B (2002) Comprehensive evaluation of cetirizine in the management of seasonal allergic rhinitis: impact on symptoms, quality of life, productivity, and activity impairment. Allergy Asthma Proc 23:391–8 24. Burtin B, Duchateau J, Pignat JC, Donnelly F, Bousquet J (2000) Further improvement of quality of life by cetirizine in perennial allergic rhinitis as a function of treatment duration. Invest Allergol Clin Immunol 10:66–70 25. De Vos, Mitchev K, Pinnelli, et al. (2008) Non-interventional study comparing treatment satisfaction in patients treated with antihistamines. Clin Drug Invest 28 (4): 221–230 26. Mohler, SR, Nicholson A, Harvey RP, Miura Y, Meeves SG (2002) The use of antihistamines in safety-critical jobs: a meeting report. Curr Med Res Opin 18:332–7 27. de Blic J, Wahn U, Potter P (2004) Levocetirizine for SAR and PAR in children. Eur Respir J 24:s164 28. Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, Sukenik E, Harris AG (1997) Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 157:2350–6 29. Hindmarch I, Shamsi Z (1999) Antihistamines: models to assess sedative properties, assessment of sedation, safety and other side-effects. Clin Exp Allergy 29:133–142 30. Serra HA, Alves O, Rizzo LF, Devoto FM, Ascierto H (1998) Loratadine-pseudoephedrine in children with allergic rhinitis, a controlled double-blind trial. Br J Clin Pharmacol 45:147–50 31. Druce HM, Thoden WR, Mure P, Furey SA, Lockhart EA, Xie T, Galant S, Prenner BM, Weinstein S, Ziering R, Brandon ML (1998) Brompheniramine, loratadine, and placebo in allergic rhinitis: a placebo-controlled comparative trial. J Clin Pharmacol 38:382–9 32. Schroeder JT, Schleimer RP, Lichtenstein LM, Kreutner W (2001) Inhibition of cytokine generation and mediator release by human basophils treated with desloratadine. Clin Exp Allergy 31:1369–77 33. Meltzer EO, Prenner BM, Nayak A (2001) Efficacy and tolerability of once-daily 5 mg desloratadine, an H1-receptor antagonist, in patients with seasonal allergic rhinitis: assessment during the spring and fall allergy seasons. Clin Drug Invest 21:25–32 34. Berger WE, Schenkel EJ, Mansfield LE; Desloratadine Study Group (2002) Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Ann Allergy Asthma Immunol 89:485–91 35. Simons FER, Prenner BM, Finn A (2003) Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol 111:617–22 36. Bielory L, Lien KW, Bigelsen S (2005) Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis. Drugs 65:215–28 37. Paolieri F, Battifora M, Riccio A, Bertolini C, Cutolo M, Bloom M, Ciprandi G, Canonica GW, Bagnasco M (1998) Terfenadine and fexofenadine reduce in vitro ICAM-1 expression on human continuous cell lines. Ann Allergy Asthma Immunol 81:601–7 38. Day JH, Briscoe MP, Welsh A, Smith JN, Clark A, Ellis AK, Mason J (1997) Onset of action, efficacy, and safety of a single dose of fexofenadine hydrochloride for ragweed allergy using an environmental exposure unit. Ann Allergy Asthma Immunol 79:533–40 39. Wahn U, Meltzer EO, Finn AF, Kowalski ML, Decosta P, Hedlin G, Scheinmann P, Bachert C, Rosado Pinto JE, Baena-Cagnani C, Potter P, Simons FE, Ruuth E (2003) Fexofenadine is efficacious and safe in children (aged 6–11 years) with seasonal allergic rhinitis. J Allergy Clin Immunol 111:763–9 40. Sussman GL, Mason J, Compton D, Stewart J, Ricard N (1999) The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal allergic rhinitis. J Allergy Clin Immunol 104:100–6 41. Casale TB, Andrade C, Qu R (1999) Safety and efficacy of once-daily fexofenadine HCl in the treatment of autumn seasonal allergy rhinitis. Allergy Asthma Proc 20:193–8 42. Bronsky EA, Falliers CJ, Kaiser HB, Ahlbrandt R, Mason JM (1998) Effectiveness and safety of fexofenadine, a new nonsedating H1-receptor antagonist, in the treatment of fall allergies. Allergy Asthma Proc 19:135–41

Pharmacotherapy of Allergic Rhinitis

33

43. Meltzer EO, Casale TB, Nathan RA, Thompson AK (1999) Once-daily fexofenadine HCl improves quality of life and reduces work and activity impairment in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 83:311–7 44. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J (1997) Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 79:443–8 45. van Cauwenberge P, Juniper EF (2000) Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis. Clin Exp Allergy 30:891–9 46. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–98 47. Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, Kim RB (2002) Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 71:11–20 48. Milne RW, Larson LA, Jorgensen KL, Bastlund J, Stretch GR, Evans AM (2000) Hepatic disposition of fexofenadine: influence of the inhibitors erythromycin and dibromosulphothalein. Pharm Res 17:1511–5 49. LaForce CF, Corren J, Wheeler WJ, Berger WE (2004) Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine. Ann Allergy Asthma Immunol 93:154–9 50. Astelin® (Azelastine HCL) nasal spray: package insert. MedPointe Pharmaceuticals, Somerset, NJ. 2006 51. Lieberman PL, Settipane RA (2003) Azelastine nasal spray: a review of pharmacology and clinical efficacy in allergic and nonallergic rhinitis. Allergy Asthma Proc 24:95–105 52. Storms WW, Pearlman DS, Chervinsky P, Grossman J, Halverson PC, Freitag JJ, Widlitz MD (1994) Effectiveness of azelastine nasal solution in seasonal allergic rhinitis. Ear Nose Throat J 73(382–6):390–4 53. Ratner PH, Findlay SR, Hampel F Jr, van Bavel J, Widlitz MD, Freitag JJ (1994) A doubleblind, controlled trial to assess the safety and efficacy of azelastine nasal spray in seasonal allergic rhinitis. J Allergy Clin Immunol 94:818–25 54. Meltzer EO, Weiler JM, Dockhorn RJ, Widlitz MD, Freitag JJ (1994) Azelastine nasal spray in the management of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 72:354–9 55. Corren J, Storms W, Bernstein J, Berger W, Nayak A, Sacks H (2005) Effectiveness of azelastine nasal spray compared with oral cetirizine in patients with seasonal allergic rhinitis. Clin Ther 27:543–53 56. Horak F, Zieglmayer UP, Zieglmayer R, Kavina A, Marschall K, Munzel U, Petzold U (2006) Azelastine nasal spray and desloratadine tablets in pollen-induced seasonal allergic rhinitis: a pharmacodynamic study of onset of action and efficacy. Curr Med Res Opin 22:151–7 57. Charpin D, Godard P, Garay RP, Baehre M, Herman D, Michel FB (1995) A multicenter clinical study of the efficacy and tolerability of azelastine nasal spray in the treatment of seasonal allergic rhinitis: a comparison with oral cetirizine. Eur Arch Otorhinolaryngol 252:455–8 58. Patel P, Roland PS, Marple BF, Benninger PJ, Margalias H, Brubaker M, Beezley SF, Drake M, Potts SL, Wall GM (2007) An assessment of the onset and duration of action of olopatadine nasal spray. Otolaryngol Head Neck Surg 137:918–24 59. Hampel FC Jr, Ratner PH, Amar NJ, van Bavel JH, Mohar D, Fairchild CJ, Wall GM, Brubaker MJ, Drake M, Crenshaw KM (2006) Improved quality of life among seasonal allergic rhinitis patients treated with olopatadine HCl nasal spray 0.4% and olopatadine HCl nasal spray 0.6% compared with vehicle placebo. Allergy Asthma Proc 27:202–7 60. Meltzer EO, Hampel FC, Ratner PH, Bernstein DI, Larsen LV, Berger WE, Finn AF Jr, Marple BF, Roland PS, Wall GM, Brubaker MJ, Dimas C, Potts SL, Silver LH, Barnes JR (2005) Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 95:600–6

34

J.M. Lehman and M.S. Blaiss

61. Patel D, Garadi R, Brubaker M, Conroy JP, Kaji Y, Crenshaw K, Whitling A, Wall GM (2007) Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc 28:592–9 62. Gandhi RK, Blaiss MS (2005) Current concepts and therapeutic strategies for allergic rhinitis. Otorinolaringologia 55:187–201 63. Settipane G, Korenblat PE, Winder J, Lumry W, Murphree J, Alderfer VB, Simpson B, Smith JA (1995) Triamcinolone acetonide aqueous nasal spray in patients with seasonal ragweed allergic rhinitis: a placebo-controlled, double-blind study. Clin Ther 17:252–63 64. Wiseman LR, Benfield P (1997) Intranasal fluticasone propionate. A reappraisal of its pharmacology and clinical efficacy in the treatment of rhinitis. Drugs 53:885–907 65. Meltzer EO, Jalowayski AA, Orgel HA, Harris AG (1998) Subjective and objective assessments in patients with seasonal allergic rhinitis: effects of therapy with mometasone furoate nasal spray. J Allergy Clin Immunol 102:39–49 66. Kaiser HB, Naclerio RM, Given J, Toler TN, Ellsworth A, Philpot EE (2007) Fluticasone furoate nasal spray: A single treatment option for the symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 119:1430–7 67. Wingertzahn MA, Sato H, Nave R, Nonaka T, Mochizuki T, Takahama S,Kondo S (2005) Comparison of nasal tissue concentrations in rabbits following administration of hypotonic and isotonic ciclesonide suspensions. J Allergy Clin Immunol 115:S126 68. Graf P (1999) Adverse effects of benzalkonium chloride on the nasal mucosa: allergic rhinitis and rhinitis medicamentosa. Clin Ther 21:1749–55 69. Bernstein IL (2000) Is the use of benzalkonium chloride as a preservative for nasal formulations a safety concern? A cautionary note based on compromised mucociliary transport. J Allergy Clin Immunol 105:39–44 70. Ratner PH, Wingertzahn MA, van Bavel JH, Hampel F, Darken PF, Shah T (2006) Efficacy and safety of ciclesonide nasal spray for the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 118:1142–8 71. Welsh PW, Stricker WE, Chu CP, Naessens JM, Reese ME, Reed CE, Marcoux JP (1987) Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc 62:125–34 72. Corren J (1999) Intranasal corticosteroids for allergic rhinitis: how do different agents compare? J Allergy Clin Immunol 104:S144–9 73. Scadding GK, Lund VJ, Jacques LA, Richards DH (1995) A placebo-controlled study of fluticasone propionate aqueous nasal spray and beclomethasone dipropionate in perennial rhinitis: efficacy in allergic and non-allergic perennial rhinitis. Clin Exp Allergy 25:737–43 74. van As A, Bronsky EA, Dockhorn RJ, Grossman J, Lumry W, Meltzer EO, Seltzer JM, Rogenes PR (1993) Once daily fluticasone propionate is as effective for perennial allergic rhinitis as twice daily beclomethasone diproprionate. J Allergy Clin Immunol 91:1146–54 75. Haye R, Gomez EG (1993) A multicentre study to assess long-term use of fluticasone propionate aqueous nasal spray in comparison with beclomethasone dipropionate aqueous nasal spray in the treatment of perennial rhinitis. Rhinology 31:169–74 76. Jen A, Baroody F, de Tineo M, Haney L, Blair C, Naclerio R (2000) As-needed use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 105:732–8 77. Berkowitz RB, Nolop RB, Mesarina-Wicki BE, C93-184 Study Group (1997) Onset of action of mometasone furoate (Nasonex) nasal spray in seasonal allergic rhinitis. J Allergy Clin Immunol 99:S441 78. Nielsen LP, Dahl R (2003) Comparison of intranasal corticosteroids and antihistamines in allergic rhinitis: a review of randomized, controlled trials. Am J Respir Med 2:55–65 79. Weiner JM, Abramson MJ, Puy RM (1998) Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomized controlled trials. BMJ 317:1624–9 80. Blaiss MS (2007) Safety considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Allergy Asthma Proc 28:145–52

Pharmacotherapy of Allergic Rhinitis

35

81. Szefler SJ (2001) Pharmacokinetics of intranasal corticosteroids. J Allergy Clin Immunol 108:S26–31 82. Lipworth BJ, Seckl JR (1997) Measures for detecting systemic bioactivity with inhaled and intranasal corticosteroids. Thorax 52:476–82 83. Trangsrud AJ, Whitaker AL, Small RE (2002) Intranasal corticosteroids for allergic rhinitis. Pharmacotherapy 22:1458–67 84. Cervin A, Hansson C, Greiff L, Andersson M (2003) Nasal septal perforations during treatment with topical nasal glucocorticosteroids are generally not associated with contact allergy to steroids. ORL J Otorhinolaryngol Relat Spec 65:103–05 85. Waddell AN, Patel SK, Toma AG, Maw AR (2003) Intranasal steroid sprays in the treatment of rhinitis: is one better than another? J Laryngol Otol 117:843–45 86. Galant SP, Melamed IR, Nayak AS, Blake KV, Prillaman BA, Reed KD, Cook CK, Philpot EE, Rickard KA (2003) Lack of effect of fluticasone propionate aqueous nasal spray on the hypothalamic-pituitary-adrenal axis in 2- and 3-year-old patients. Pediatrics 112:96–100 87. Skoner D, Gentile D, Angelini B, Kane R, Birdsall D, Banerji D (2003) The effects of intranasal triamcinolone acetonide and intranasal fluticasone propionate on short-term bone growth and HPA axis in children with allergic rhinitis. Ann Allergy Asthma Immunol 90:56–62 88. Wilson AM, McFarlane LC, Lipworth BJ (1998) Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitaryadrenal-axis activity. J Allergy Clin Immunol 101:470–74 89. Wilson AM, Sims EJ, McFarlane LC, Lipworth BJ (1998) Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis. J Allergy Clin Immunol 102:598–604 90. Moller C, Ahlstrom H, Henricson KA, Malmqvist LA, Akerlund A, Hildebrand H (2003) Safety of nasal budesonide in the long-term treatment of children with perennial rhinitis. Clin Exp Allergy 33:816–22 91. Juniper EF, Stahl E, Doty RL, Simons FE, Allen DB, Howarth PH (2005) Clinical outcomes and adverse effect monitoring in allergic rhinitis. J Allergy Clin Immunol 115:S390–413 92. Wolthers OD, Pedersen S (1993) Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids. Acta Paediatr 82:635–40 93. Wolthers OD, Pedersen S (1994) Knemometric assessment of systemic activity of once daily intranasal dry-powder budesonide in children. Allergy 49:96–9 94. Bielory L, Blaiss M, Fineman SM, Ledford DK, Lieberman P, Simons FE, Skoner DP, Storms WW (2006) Concerns about intranasal corticosteroids for over-the-counter use: position statement of the Joint Task Force for the American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 96:514–25 95. Bui CM, Chen H, Shyr Y, Joos KM (2005) Discontinuing nasal steroids might lower intraocular pressure in glaucoma. J Allergy Clin Immunol 116:1042–47 96. Opatowsky I, Feldman RM, Gross R, Feldman ST (1995) Intraocular pressure elevation associated with inhalation and nasal corticosteroids. Ophthalmology 102:177–79 97. Plautt M, Valentine MD (2005) Allergic rhinitis. N Engl J Med 353:1934–44 98. Wilson AM, O’Byrne PM, Parameswaran K (2004) Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 116:338–44 99. van Adelsberg J, Philip G, Pedinoff AJ, Meltzer EO, Ratner PH, Menten J, Reiss TF; Montelukast Fall Rhinitis Study Group (2003) Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy 58:1268–76 100. Chervinsky P, Philip G, Malice MP, Bardelas J, Nayak A, Marchal JL, van Adelsberg J, Bousquet J, Tozzi CA, Reiss TF (2004) Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies. Ann Allergy Asthma Immunol 92:367–73 101. Rodrigo GJ, Yanez A (2006) The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials. Ann Allergy Asthma Immunol 96:779–86

36

J.M. Lehman and M.S. Blaiss

102. Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF, Wolfe JD, Reiss TF (2000) Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 105:917–22 103. Borum P, Mygind N, Schultz Larsen F (1979) Intranasal ipratropium: a new treatment for perennial rhinitis. Clin Otolaryngol 4:407–11 104. Wagenmann M, Naclerio RM (1992) Complications of sinusitis. J Allergy Clin Immunol 90:552–4 105. Bonini S, Bonini M, Bousquet J, Brusasco V, Canonica GW, Carlsen KH, Corbetta L, Cummiskey J, Delgado L, Del Giacco SR, Haahtela T, Jaeger S, Moretti C, Palange P, Passalacqua G, Passali D, Pedersen BK, Popov T, Rasi G, Ventura MT, Vignola AM (2006) Rhinitis and asthma in athletes: an ARIA document in collaboration with GA2LEN. Allergy 61:681–92 106. Pleskow W, Grubbe R, Weiss S, Lutsky B (2005) Efficacy and safety of an extended-release formulation of desloratadine and pseudoephedrine vs the individual components in the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 94:348–54 107. Lockey RF (2006) Rhinitis medicamentosa and the stuffy nose. J Allergy Clin Immunol 118:1017–8

Antihistamines in Rhinitis and Asthma Todor A. Popov

Histamine: Role in Health and Disease Just several years after the concept “allergy” was coined about a century ago [1], histamine was identified by Sir Henry Dale [2] and subsequently emerged as one of the most important allergy substrates. This marked the onset of a spiral of scientific achievements, which resulted in the development of multiple drug formulations used in the prevention and treatment of allergic disorders and in elucidation of the pleiotropic role histamine plays in health and disease. Histamine belongs to a group of locally produced tissue hormones (including serotonin and others) referred to as “autacoids.”1 It plays a vital role in the regulation of the many important functions related to circadian influences, adaptation to environment and stress. Conversely, histamine is intimately implicated in the pathogenesis of allergic diseases, which develop as defective systemic trait of genetically predisposed individuals and may have different organ expressions. Airway allergic morbidity in particular accounts for a lot of individual suffering and disability, and poses a substantial economic burden to society [3, 4]. Therefore, the correct prescription of existing antihistamine products and the development of new and more effective formulations devoid of unwanted effects are two important avenues in the global crusade to control these morbidities affecting millions of people. Endogenous histamine is produced in neurons as part of the histaminergic neuronal system originating in the tuberomamillary nucleus of the hypothalamus [5]. It is a low molecular weight amine, synthesized from l-histidine by the enzyme histidine decarboxylase. It plays a pivotal role in maintaining the state of wakefulness and alertness by modulating the firing potential of neurons in the cortex of the brain and by interfering with the neuronal excitation of other neurons using different transmitters: acetylcholine, serotonin, dopamine, g-aminobutyric acid (GABA), and T.A. Popov () Clinic of Allergy and Asthma, Alexander’s University Hospital, 1, Sv. Georgi Sofiyski Street, 1431 Sofia, Bulgaria e-mail: [email protected] 1

From Greek: autoV = own, proper and akoV = medicinal product.

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_3, © Springer 2010

37

38

T.A. Popov

noradrenaline. The cellular sources of histamine are mucosal and skin mast cells and basophils in the blood. These two cell types degranulate their histamine load as part of a classical IgE mediated reaction or under the influence of other non-IgE triggers, thus initiating local allergic or systemic anaphylactic reactions [6, 7]. Historically, a lot of effort has been invested in creating drugs countering the effects of histamine released from these cells. Many of these drugs, though, are lipophilic and penetrate the blood-brain barrier, antagonizing the effects of histamine in the central nervous system (CNS) with ensuing sedation and impairment of coordination [8, 9].

Histamine Receptors and Agonists: Diversity of Action Histamine exerts its multiple effects by coupling to receptors expressed on the membrane of cells in different tissues [10]. Four different receptors denoted sequentially as H1–H4 [11–14] have been identified and sequenced so far. Their structure, position in the genome and encoding differ substantially, which reflects the complexity of their biological role. Generally, these receptors are composed of seven transmembrane chains and when activated, they exert their cellular effects through the G-protein system, triggering in action second messengers specific for each receptor (Table 1). Interestingly, sometimes they display activity in the absence of agonists. This is important, as blocking this spontaneous activity may interfere with standard physiological functions. The H-receptors exhibit stereochemical differences, which can be recognized by different chemical compounds, referred to as specific receptor agonists. A big proportion of these invert the original effects of histamine by rendering the receptor – G-protein complex inactive, which categorizes them as “inverse” agonists [15]. However, as they abolish the effects of histamine, they are popularly known as histamine receptor antagonists. In 1937 Bovet and Staub described the first pharmaceutical formulation to counter the effects of histamine in guinea pig [16]. The compound was too toxic for subsequent clinical development, but still sparked a lot of enthusiasm for research. Five years later, the first product aiming to treat nasal and skin allergic symptoms appeared on the market. Some 40 drugs with similar pharmacological profile were introduced in clinical practice until 1980, which became subsequently known as first generation antihistamines. Based on their chemical structure, they were divided into ethylendiamines, ethanolamines, alkylamines, phenothiazines, piperazines and piperidines [17]. While this classification helped at a time when analogy was sought with the molecule of histamine, the introduction of bigger and more complex molecules of the second generation H1 inverse agonists – some of which defy labeling into the scheme – make it rather useless. The introduction of second generation of H1 inverse agonists (Table 2) in clinical practice brought about significant improvement in the quality of antihistamine treatment, as these drugs had improved pharmacokinetic and pharmacodynamic profiles. They hardly penetrate the blood-brain barrier, which make them relatively free of the most bothersome adverse effects of the first generation: drowsiness,

G-protein signaling pathway

Through phospholipase C/ phosphatidyl-inositol: opening up Ca2+ influx

Through adenylate cyclase: elevation in intracellular cAMP

Through adenylate cyclase: inhibition of the formation of cAMP: reduction of the influx of Ca2+

Through adenylate cyclase or phospholipase C activation: elevation in intracellular cAMP or Ca2+ influx

Receptor

H1

H2

H3

H4 Airways: dendritic cells, trachea

Ubiquitous, specifically in: Airways: smooth muscles, vascular endothelial cells Heart Central nervous system Gastric parietal cells (oxyntic cells) Airways: mucous glands, vascular smooth muscle, dendritic cells Heart Central nervous system Central nervous system peripheral nerves: Airways Heart Gastrointestinal tract Dendritic cells Endothelial cells Bone marrow and cells of the hemopoietic lineage

Location

Table 1 Distinctive features of the histamine (H) receptors [10,13–17]

Thioperamide

JNJ 7777120

Release of neutrophils from the bone marrow Function of mast cells and eosinohils Involvement in inflammation mechanisms

Cimetidine

Mepyramine

Specific inverse agonist

Histaminergic neurons (block of Ca2+ channels), regulating neurotransmitter release

Smooth muscle relaxation; positive chronotropic/ionotropic cardiac effects

Stimulation of gastric acid secretion

Smooth muscle contraction Increased vascular permeability Negative inotropic cardiac effect

Function

Antihistamines in Rhinitis and Asthma 39

40

T.A. Popov

Table 2 Generations of histamine type 1 (H1) receptor inverse agonists introduced in clinical practice over the years H1 receptor inverse agonists First generation

Second generation

Acrivastine Alimemazine Antazoline Betahistine Brompheniramine Carebastine Chlorpheniramine Cinnarizine Clemastine Cyclizine Cyproheptadine Dexchlorpheniramine Dexbrompheniramine Dimenhydrinate Dimetindene Diphenhydramine Diphenylpyraline

Doxylamine Emedastine Flunarizine Hydroxyzine Ketotifen Mebhydrolin Meclozine Mepyramine Mequitazine Methapyrilene Oxatomide Phenindamine Pheniramine Promethazine Thiazinamium Tripelennamine Triprolidine

Astemizolea Cetirizine Ebastine Epinastine Loratadine Mizolastine Rupatadine Terfenadinea

Locally applied Azelastinee

Ketotifen

Levocabastinee

“Modern” second generation Desloratadineb Fexofenadinec Levocetirizined

Olopatadinee,f

Epinastinee,f

a

Withdrawn in most countries due to increased risk of cardiotoxicity Metabolite of loratadine c Metabolite of terfenadine d Enantiomer of cetirizine e Developed only as topical preparation f Registered only as eye drops b

lassitude, dizziness, incoordination. They also have other important advantages: higher specificity for the H1 receptors, no affinity for muscarinic, serotoninergic, dopaminergic, adrenergic and other receptors with the ensuing untoward symptoms, and longer half-life allowing once daily dosing regimen [18]. A setback to the process of fast and wide introduction of second generation antihistamines in routine clinical practice were reports of life threatening arrhythmias and fatalities associated with the intake of the early representatives of this class of drugs: astemizole and terfenadine [19]. These triggered intensive research to identify the mechanisms of these cardiotoxic effects. It turned out that they relate to the binding affinity of a K channel – -iKr – a potassium inward rectifying current coded by the Human Ether go-go Related Gene (HERG), which has high homology to the H1 receptor [15]. All second generation preparations were scrutinized in this respect with particular focus on the ability of higher doses to prolong the QT interval of the electrocardiogram (ECG) tracings. As it turned out, other second generation drugs did not affect the electrical activity of the heart. Astemizone and terfenadine were withdrawn from the market in most countries.

Antihistamines in Rhinitis and Asthma

41

Meanwhile the quest for new drugs with improved pharmacokinetic and pharmacodynamic profiles continued and three novel H1 inverse agonists were added to the list: desloratadine, fexofenadine and levocetirizine. What they had in common was their origin from older second generation drugs – desloratadine and fexofenadine being active metabolites of terfenadine and loratadine respectively, and levocetirizine being the active enantiomer of cetirizine [20]. Suggestions were made to classify these new formulations as “third generation” antihistamines. However, as they do not present properties, which make them dramatically different from their predecessors and other members of this class, it is more reasonable to label them as “modern second generation H1 inverse agonists,” while waiting for real third generation molecules to be created with novel (not necessarily antiallergic) properties (Table 2). It is conceivable that with the new molecular techniques and with all different histamine receptors and their splicing variants sequenced and visualized in three dimensions, new formulations will be tailored to create the prefect drugs to treat selectively the unwanted effects of histamine in allergic reactions.

Classifications of Allergic Rhinitis and Implications for Treatment Allergic rhinitis is clinically defined as a symptomatic disorder of the nose, induced by an IgE-mediated inflammation after allergen exposure of the membranes lining the nose [5]. Its prominent features had been identified as early as 1929: “The three cardinal symptoms in nasal reactions occurring in allergy are sneezing, nasal obstruction, and mucous discharge” [21]. Nowadays nasal obstruction, rhinorrhea, nasal itching, and sneezing still form the basis of our clinical diagnosis, but these are supplemented by other subtler, simpler, and composite outcomes related to quality of life, impairment of social behavior, and the ability to cope with tasks in school and at the workplace. However, these are rather nonspecific signs and are shared with other forms of rhinitis related to different causes (infectious, occupational, medicinal, neurogenic, hormonal, etc.) or effectuated by various other non-IgE mediated mechanisms, shaping sophisticated classification tables with still more intricate algorithms for management of the respective conditions [5, 22]. The picture is rendered still more complex by considerations related to comorbidities like sinusitis, conjunctivitis, asthma, chronic cough, or to special conditions like pregnancy and lactation, specific aspects of childhood and advanced age. For many years allergic rhinitis has been subdivided to seasonal-associated to high pollen counts – and perennial – attributed mostly to indoor allergens. In 1999, a panel of experts suggested a more global perspective during a World Health Organization (WHO) supported workshop on Allergic Rhinitis and its Impact on Asthma (ARIA), accounting for places on Earth with perennial pollen allergens and others with seasonal indoor allergen fluctuations [5]. It was proposed that allergic rhinitis should rather be assessed based on continuity and severity of symptoms. Subjects with the “Intermittent” form would have symptoms for less than 4 days a

42

T.A. Popov

week for less than 4 consecutive weeks, whereas patients with the “Persistent” form would have symptoms more than 4 days a week for more than 4 consecutive weeks. If symptoms do not affect in any way the daily performance and the night rest of subjects with either form, severity would be defined as “Mild;” otherwise it would range between “Moderate” and “Severe,” depending largely on the individual perception of the symptoms. Subsequently the new ARIA classification was validated by an epidemiological study, which demonstrated that intermittent and persistent allergic rhinitis represent a new different stratum of the disease with consequences reflecting on its management [23]. Pharmacological treatment provides the fastest and most effective way of getting rid of the annoying symptoms of allergic rhinitis. There is no doubt whatsoever, that the most widely used drugs are the H1 antihistamines and the topical nasal corticosteroids. Usually judgements about treatment strategies are made based on the ranking of symptoms by the patients themselves, the severity of their condition, the knowledge of the strengths and weaknesses of the different drug classes and the separate compounds within them, the overall individual profiles of the subjects, not disregarding relevant financial considerations. A starting point may be to allocate the patient to one of the two groups of the simple clinical classification of rhinitis patients – “sneezers and runners” and “blockers” [24]. “Sneezers and runners” have itching, sneezing, and rhinorrhea as their leading symptoms. As these symptoms are readily reproduced by a histamine nasal challenge, it is logical to assume that drugs antagonizing the histamine effects would have a good chance to be effective in these subjects. “Blockers” are more likely to respond to the predominantly antiinflammatory action of corticosteroids. However, this conditional approach should not be regarded as a “rule of the thumb,” as individuals may respond differently to treatment options, and may have preference of one product over the other. The advent of pharmacogenetics may help identify subjects with a high likelihood to respond to different treatment modalities.

Antihistamines in the Treatment of Allergic Rhinitis: Beyond the Histamine Effects By definition, patients with allergic rhinitis are sensitized to outdoor and/or indoor allergens. When they are subjected to exposures above certain threshold levels, it would unleash an IgE mediated reaction with a cascade of cellular, humoral, and neurogenic events set in motion with inflammation of the nasal mucosa as a net result. Many of the developing symptoms may be attributed to the direct action of histamine, as it is released in high quantities during the degranulation of mast cells [6]. This explains the beneficial effect from the application of antihistamines in allergic rhinitis, which is backed up by decades-long experience with the multitude of members of the big family of H1 receptor inverse agonists. However, after an early phase in the IgE mediated reaction, where degranulation of mast cells, respectively histamine, plays a critical role, there follows a late phase

Antihistamines in Rhinitis and Asthma

43

reaction involving other cell types, with T cells and eosinophils taking the lead [25]. Once chronic inflammation sets in the airway mucosa, it is sustained even at times of relative remission, when house dust mite levels or pollen counts are at a minimum. This prepared the ground for introducion of the concept of “minimal persistent inflammation” [26, 27]. A beneficial effect of a second generation antihistamine on this kind of smoldering process without the dramatic involvement of histamine has been demonstrated [28]. Besides, evidence has emerged along the road that allergens, because of their enzymatic proteolytic activity, may directly activate epithelial cells to promote a Th2-immune response, inducing airway inflammation independent of IgE [29, 30]. Taken together, the discussed mechanisms shape nonspecific nasal hyperreactivity, which is an important feature of rhinitis and can be defined as an increased nasal response to a normal stimulus, resulting in sneezing, nasal congestion and secretion, either as single symptoms or in various combinations [31]. The good clinical effect of antihistamines in a condition, in which many factors in addition to histamine have a stake, has instigated research to establish possible mechanisms, by which they may influence inflammatory outcomes. It appears that at least some of these anti-inflammatory effects are also related to the H1 receptor, which exists in two forms – inactive and active – even in the absence of its natural agonist histamine [32]. The active form upregulates Nuclear Factor Kappa B (NFkB), which in turn migrates to the cell nucleus and affects transcription and subsequent production of many proinflammatory mediators and molecules such as Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), inducible Nitric Oxide Synthase (iNOS), Interleukin 6 (IL-6) or Granulocyte Monocyte Colony Stimulating Factor (GMCSF). H1 inverse agonists bring about stabilization of the inactive form of the receptor and thereby have a number of receptor dependent anti-inflammatory effects, which are characteristic of the whole class of drugs. There are also receptor independent effects, some of them achieved through competitive inhibition of the binding of calcium, which seem to be more compound specific (Table 3). As already indicated in Table 2, the family of H1 receptor inverse agonists is rather numerous and heterogeneous. They possess features common to all the members, but also others that differentiate between subgroups within them. All of them antagonize the effects of histamine by coupling to H1 receptors, but the second generation representatives display much higher H1 receptor affinity for them. Most products are prescribed for oral use, but there are also topical preparations for nasal/ ocular application. Attempts have been made to rank the separate compounds based on their ability to block the histamine-induced wheal and flare reactions in the skin of volunteers [33–35]. While a clear cut distinction between the separate formulations was established using this test system, clinical trials comparing effectiveness of antihistamines in subjects with allergic rhinitis could only pick marginal differences if any [36]. This discrepancy may be due to variable H1 blocking activity of different drugs, their additional antiallergic effects, and possibly, their differences in lipophilicity and tissue deposition. Moreover, it appears that not all H1 antihistamines have similar effects on patients and thus nonresponders with one drug may respond favorably to another [37].

44

T.A. Popov

Table 3 Properties of H1 inverse agonists beneficial for the treatment of allergic rhinitis [5,61,62] Properties related to Effect on H1-receptor

Direct effect on

Mechanism of action Antagonizing the effect of histamine at the level of nasal epithelium, glands, sensory nerves and vascular endothelium Rendering the H1 receptor inactive, thus precluding the activation of Nuclear Factor Kappa B (NFkB) to trigger the production of inflammatory mediators Suppression of mediator release from mast cells through competitive inhibition of the binding of calcium

Relevant to symptoms

Clinical significance

Rhinorrhea, nasal itching, sneezing

Very high

Nasal congestion, itching

Not clear. Demonstrated in few trials at doses higher than usual

Rhinorrhea, nasal itching, sneezing, nasal congestion

Difficult to distinguish from receptor mediated clinical effects

The second generation H1 receptor inverse agonists have undisputed advantages over the first generation formulations. Therefore, it has been recommended that they should be considered as a first-choice treatment for allergic rhinitis when they are available and affordable [5]. Surprisingly, it has been found that they are more cost-effective than the cheap first generation products because of the cost of the associated sedation [38]. The onset of action of the second generation antihistamines occurs between 20 and 120 min after oral intake and covers 24 h (with the exception of acrivastin). Some individual compounds have specific properties, which need to be taken into account if related to important clinical effects. Certain foods have been found to alter the absorption of some oral H1 receptor inverse agonists, depending on their proclivity to interact with a 170 kDa plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp) or an Organic Anion Transport Polypeptide (OATP) [39]. By this mechanism, grapefruit, orange, and apple juices may decrease the oral availability of fexofenadine [40]. Some of the second generation antihistamines (but not cetirizine, levocetirizine and fexofenadine) undergo hepatic metabolism via the Cytochrome P450 (CYP3A) system and are transformed into active metabolites. As CYP3A is also involved in the metabolism of many chemically diverse drugs administered to humans, this can lead to unwanted and unexpected drug–drug interactions [41]. Effectiveness of second generation H1 receptor inverse agonists in allergic rhinitis, particularly on rhinorrhea, nasal itching and sneezing, has been proven in many double blind placebo controlled clinical trials [5]. The “modern” second generation formulations (Table 2) nourished expectations that they may have an effect on nasal congestion [42–44]. However, such an effect tended to be rather modest in comparison with local corticosteroids.

Antihistamines in Rhinitis and Asthma

45

No significant tachyphylaxis has been reported with any of the second generation antihistamines so far. Oral H1-antihistamines have been shown to be safe and effective in children and have been approved for very young ones [45, 46]. Several H1 antihistamines have been engineered (some of them exclusively) for topical application (Table 2). This administration route offers several advantages, like fast onset of their effect and the possibility of delivering high concentrations directly into the nose, avoiding or minimizing systemic effects. This approach is most appropriate in patients with symptoms confined to the nose, as multiple organ manifestations would require additional medication.

Antihistamines in Asthma: Same Airway Disease, but Dramatically Different The links between nose and lung have been empirically recognized long ago, but only recently the ARIA report ascribed special importance to the similarities between the nasal and bronchial mucosa [47]. The concept of “one airway – one disease” was explored from different angles, emphasizing mostly the functional complementarity of upper and lower airways and the common immunological defect related to the systemic nature of allergic sensitization. It has been acknowledged that histamine may mimic all the important asthma symptoms and histamine challenges have been used for decades for the diagnosis of asthma. The role of histamine has been extensively studied, and its involvement in the development of bronchial airway inflammation well documented [48]. Histamine provokes bronchoconstriction by direct muscle stimulation, as well as indirect stimulation of airway parasympathetic afferent nerves. It increases vascular permeability through venular dilatation and extravasation of plasma proteins and leukocytes with resulting mucosal edema, produces cough by direct stimulation of H1 receptors on sensory nerves and mucus hypersecretion through H2 receptor stimulation on mucosal glands [49, 50]. It is also chemotactic for eosinophils and neutrophils and increases the reactivity of the bronchial epithelium. Despite all these compelling facts prompting the importance of histamine in asthma, treatment strategies relying on blocking of the histamine effect in the lower airways have been rather disappointing. No H1 receptor inverse agonist has gained peer review recognition of the Global Initiative for Asthma (GINA) experts, for inclusion as a treatment option of asthma in the international guidelines. Notwithstanding the lack of distinct therapeutic effect on asthma, studies have provided some modest pieces of evidence that antihistamines may not be so hopeless for asthma management after all. Most antihistamines produce some acute bronchodilation in subjects with reversible lower airway obstruction [51]. They also exert a positive effect on airway hyperresponsiveness [52]. While studies demonstrating anti-inflammatory effects of different antihistamine compounds may have questionable clinical relevance, some others on patients with both allergic

46

T.A. Popov

rhinitis and asthma report some benefits regarding the asthmatic condition [53,54]. Although for the present antihistamines are not recommended for the treatment of asthma, when used for rhinitis they may improve concomitant asthma. Apart from asthma and conjunctivitis, which go hand in hand with allergic rhinitis, other comorbidities like nasal polyps, adenoid hypertrophy, tubal dysfunction, otitis media with effusion, chronic cough, laryngitis, etc. are often present too. There is no solid evidence regarding a positive therapeutic effect of antihistamines in any of them.

Antihistamines in Children, Elderly and Pregnant Women with Rhinitis Allergic rhinitis is one of the most common chronic diseases in all ages and walks of life. Beyond the plateau of adulthood, its management has specific features for the pediatric and geriatric populations. Nasal symptoms of mothers-to-be also need to be handled with special consideration to their future offspring. Allergic rhinitis can have a serious negative impact on children. The H1 receptor inverse agonists present a viable option for its management, as they do not affect the growth and physical development. However, a critical aspect of their application in childhood may be related to their effects on the functions of the CNS at a time of vigorous learning, mental and emotional development. Allergic rhinitis may by itself affect learning ability and concentration [55]. Therefore choosing the most appropriate formulation, which should not additionally induce sedation and impairment, is a responsible task [56]. The second generation H1 receptor inverse agonists certainly offer a better chance to circumvent adverse effects, which involve a wide spectrum of symptoms from drowsiness and fatigue to paradoxical hyperactivity, insomnia, and irritability with the representatives of the first generation. While second generation drugs are considered effective and safe, there are few clinical trials (especially in infants) addressing all aspects of the application of the existing molecules in different age groups. Otherwise, pediatric treatment strategies do not differ substantially from the general principles discussed so far. Elderly patients with allergic rhinitis have typically multiple comorbidities, different metabolic rates, slowing further with the advance of age, and, subsequently higher risk to develop drug–drug interactions [57]. These circumstances should discourage prescription of first-generation antihistamines with their inherent anticholinergic and sedating effects on elderly subjects, particularly on those with impaired cognitive function. Second generation antihistamines should be the drugs of choice in advanced age too, with possible need for dosage adjustments in case of impaired hepatic metabolism and renal excretion. In women with perennial rhinitis, symptoms may improve or deteriorate during pregnancy [58]. A specific condition called “persistent hormonal rhinitis or rhinosinusitis” may develop in the last trimester of pregnancy in otherwise healthy women. Its severity parallels the blood estrogen level and symptoms disappear at delivery.

Antihistamines in Rhinitis and Asthma

47

Treatment relies on the same drugs as in the general population of rhinitic subjects. Caution must be exercised when administering any medication during pregnancy, as most medications cross the placenta and could potentially exert teratogenic effect on the fetus [59]. For most drugs, limited studies have been performed only on small groups without long-term analysis. The American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology have issued a joint position paper regarding the treatment of allergic rhinitis during pregnancy [60]. Based on safety data available before 2000, these organizations recommended chlorpheniramine, loratadine, and cetirizine as reasonable choices for allergic rhinitis management during pregnancy (ideally after the first trimester). However, the selection has to be further narrowed, based on the sedative and performance-impairing effects of first-generation agents, favoring the use of secondgeneration agents.

The Ideal Antihistamine: Basis for Comparison of all Existing Preparations With the long list of existing antihistamines, it is quite frustrating to make judgements about relative potencies, clinical merits, and foreseeable risks in prescribing one product or another to individual patients. Recently an attempt was made to come up with definitions of the properties of an “ideal” antihistamine preparation to set a standard for future drug development [32]. The list of optimal characteristics of this utopic molecule used as a bench mark will also help physicians to form an opinion about pharmaceutical products they are about to add to their armamentarium. The pharmacological properties should involve H1 receptor selectivity, high potency, additional antiallergic/anti-inflammatory properties, no interactions with intestinal/liver enzymes, infectious agents and other drugs, no toxicity. Their onset of action should be rapid, lasting long enough to allow one daily application. The clinical efficacy should be high in all forms and severity levels of allergic rhinitis, in coping with all symptoms including nasal congestion, and acting on eye and subjective and objective asthma symptoms, affecting positively the long term asthma outcomes. The ideal preparation should be devoid of side effects, including those commonly registered with existing preparations – no sedation, cognitive or psychomotor impairment, no effects related to other CNS receptors, no cardiac arrhythmias, and no metabolic disturbances including weight gain. The ideal molecule should be proven effective and safe in special population groups: children of different ages, elderly people, pregnant and lactating women. Antihistamines bear potential for further improvement, which can favorably affect the quality of life of millions with allergic rhinitis. In the meantime, it is the responsibility of the healthcare professional to disseminate knowledge about treatment modalities and to upgrade management guidelines based on sound evidence.

48

T.A. Popov

References 1. von Pirquet C (1906) Allergie. Munchen Med Wehnschr 53: 1457 2. Dale HH, Laidlaw PP (1910) The physiological actions of iminazolethylamine. J Physiol 41: 318–344 3. Passani MB, Giannoni P, Bucherelli C, Baldi E, Blandina P (2007) Histamine in the brain: beyond sleep and memory. Biochem Pharmacol 73: 1113–1122 4. Global initiative for asthma. Global strategy for asthma management and prevention. NHLBI/ WHO workshop report. Revision 2006. NIH publication no. 02-3659 5. Bousquet J, Van Cauwenberge P, Khaltaev N (2001) Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 108: S147–S334 6. Theoharides TC, Kalogeromitros D (2006) The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 1088: 78–99 7. Schwartz LB (2004) Effector cells of anaphylaxis: mast cells and basophils. Novartis Found Symp 257: 65–74 8. Walsh GM (2007) Antihistamines (H1 receptor antagonists). Side Effects Drugs Annu 29: 161–167 9. Jauregui I, Mullol J, Bartra J, del Cuvillo A, Davila I, Montoro J, Sastre J, Valero AL (2006) H1 antihistamines: psychomotor performance and driving. J Investig Allergol Clin Immunol 16: S37–S44 10. Parsons ME, CR Ganellin (2006) Histamine and its receptors. Brit J Pharmacol 147: S127–S135 11. Ash A, Schild H (1966) Receptors mediating some actions of histamine. Br J Pharmacol 27: 427–439 12. Black W, Dunian W, Durant C, Ganellin C, Parsons E (1972) Definition and antagonism of histamine H2 receptors. Nature 236: 385–390 13. Arrang J, Garbarg M, Lancelot J, Lecomte J, Schwartz J (1987) Highly potent and selective ligands for histamine H3 receptors. Nature 327: 117–123 14. Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O’Dowd BF (2001) Discovery of a novel member of the histamine receptor family. J Mol Pharmacol 59: 427–433 15. Leurs R, Church MK, Taglialatela M (2002) H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 32: 489–498. 16. Bovet D, Staub A-M (1937) Protective action of phenol ethers in the course of histamine intoxication. C R Soc Biol (Paris) 124: 547–549 (French) 17. Passalaqua G, Canonica GW, Bousquet J (2002) Structure and classification of H1-antihistamines and overview of their activities. In: Simons FER (ed) Histamine and H1-antihistamines in allergic disease. Marcel Dekker Inc, New York, pp 65–100 18. Hill SJ, Ganellin CR, Timmerman H, Schwartz J-C, Shankley NP, Young JM, Schunack W, Levi R, Haas HL (1997) International Union of Pharmacology. XIII Classification of histamine receptors. Pharmacol Rev 49: 253–278 19. Black JW, Duncan WAM, Durant GJ, Ganellin CR, Parsons ME (1972) Definition and antagonism of histamine H2-receptors. Nature 236: 385–390 20. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P (2004) The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol Sci 25: 618–625 21. Hansel F (1929) Clinical and histopathologic studies of the nose and sinuses in allergy. J Allergy 1: 43–70 22. Greiner AN, Meltzer EO (2006) Pharmacologic rationale for treating allergic and nonallergic rhinitis. J Allergy Clin Immunol 118: 985–996 23. Bauchau V, Durham SR (2005) Epidemiological characterization of the intermittent and persistent types of allergic rhinitis. Allergy 60(3):350–353. 24. International Rhinitis Management Working Group (1994) International consensus report on diagnosis and management of rhinitis. Allergy 49(19 Suppl): 1–34

Antihistamines in Rhinitis and Asthma

49

25. Kay AB (2001) Allergy and allergic diseases. Second of two parts. New Engl J Med 344: 109–113 26. Ciprandi G, Buscaglia S, Pesce G, Pronzato C, Ricca V, Parmiani S, Bagnasco M, Canonica GW (1995) Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy. J Allergy Clin Immunol 96: 971–979 27. Ricca V, Landi M, Ferrero P, Bairo A, Tazzer C, Canonica GW, Ciprandi G (2000) Minimal persistent inflammation is also present in patients with seasonal allergic rhinitis. J Allergy Clin Immunol 105: 54–57 28. Canonica GW, Ciprandi G (1999) Minimal persistent inflammation may be controlled by cetirizine. Ann Allergy Asthma Immunol 83: 445–448 29. Roche N, Chinet TC, Huchon GJ (1997) Allergic and nonallergic interactions between house dust mite allergens and airway mucosa. Eur Respir J 10: 719–726 30. Reed CE, Kita H (2004) The role of protease activation of inflammation in allergic respiratory diseases. J Allergy Clin Immunol 114: 997–1008 31. van Wijk RG, de Graaf-in ‘t Veld C, Garrelds IM (1999) Nasal hyperreactivity. Rhinology 37: 50–55 32. Bousquet J, Van Cauwenberge P, Bachert C, Canonica GW, Demoly P, Durham SR, Fokkens W, Lockey R, Meltzer EO, Mullol J, Naclerio RM, Price D, Simons FER, Vignola AM, Warner JO (2003) Requirements for medications commonly used in the treatment of allergic rhinitis. Allergy 58: 192–197 33. Simons FE, McMillan JL, Simons KJ (1990) A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares during 24 h in normal subjects. J Allergy Clin Immunol 86: 540–547. 34. Grant JA, Danielson L, Rihoux JP, DeVos C (1999) A double-blind, single-dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine induced wheal and flare response for 24 h in healthy male subjects. Allergy 54: 700–707 35. Popov TA, Dumitrascu D, Bachvarova A, Bocsan C, Dimitrov V, Church MK (2006) A comparison of levocetirizine and desloratadine in the histamine-induced wheal and flare response in human skin in vivo. Inflamm Res 55: 241–244 36. Bousquet J, Czarlewski W, Cougnard J, Danzig M, Michel FB (1998) Changes in skin-test reactivity do not correlate with clinical efficacy of H1-blockers in seasonal allergic rhinitis. Allergy 53: 579–585 37. Carlsen KH, Kramer J, Fagertun HE, Larsen S (1993) Loratadine and terfenadine in perennial allergic rhinitis. Treatment of nonresponders to the one drug with the other drug. Allergy 48: 431–436 38. Sullivan PW, Follin SL, Nichol MB (2004) Cost-benefit analysis of first-generation antihistamines in the treatment of allergic rhinitis. Pharmacoeconomics 22: 929–942 39. Doherty MM, Charman WN (2002) The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? Clin Pharmacokinet 4: 235–253 40. Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, Kim RB (2002) Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 71: 11–20 41. Renwick AG (1999) The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes. Clin Exp Allergy 3: 116–124 42. Nayak AS, Schenkel E (2001) Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy 56: 1077–1080 43. Ciprandi G, Cosentino C, Milanese M, Mondino C, Canonica GW (2001) Fexofenadine reduces nasal congestion in perennial allergic rhinitis. Allergy 56: 1068–1070 44. Klimek L (2005) Potential of levocetirizine in the relief of nasal congestion. Int J Clin Pract 59: 721–729 45. de Blic J, Wahn U, Billard E, Alt R, Pujazon MC (2005) Levocetirizine in children: evidenced efficacy and safety in a 6-week randomized seasonal allergic rhinitis trial. Pediatr Allergy Immunol 16: 267–275

50

T.A. Popov

46. Simons FE (2002) H1-antihistamines in children. Clin Allergy Immunol 17: 437–464 47. Cruz AA, Popov TA, Pawankar R, Annesi-Maesano I, Fokkens W, Kemp J, Ohta K, Price D, Bousquet J (2007) Common characteristics of upper and lower airways disease in rhinitis and asthma: ARIA update, in collaboration with GA2LEN. Allergy (in press) 48. Gelfand EW (2002) Role of histamine in the pathophysiology of asthma: immunomodulatory and antiinflammatory activities of H1-receptor antagonists. Am J Med 113: 2S–7S 49. Larsen JS (2001) Do antihistamines have a role in asthma therapy? Pharmacotherapy 21: 28S–33S 50. Borade PS, Ballary CC, Currie GP, Lee DKC (2006) Modern H1-antihistamines in asthma. Drug Discov Today: Ther Strateg 3: 253–259 51. Borade PS, Ballary CC, Currie GP, Lee DKC (2006) Modern H1-antihistamines in asthma. Drug Discov Today: Ther Strateg 3: 253–259 52. Aubier M, Neukirch C, Peiffer C, Melac M (2001) Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma. Allergy 56: 35–42 53. Berger WE, Schenkel EJ, Mansfield LE (2002) Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Ann Allergy Asthma Immunol 89: 485–491 54. Baena-Cagnani CE, Berger WE, DuBuske LM, Gurne SE, Stryszak P, Lorber R, Danzig M (2003) Comparative effects of desloratadine versus montelukast on asthma symptoms and use of beta 2-agonists in patients with seasonal allergic rhinitis and asthma. Int Arch Allergy Immunol 130: 307–313 55. Spaeth J, Klimek L, Mosges R (1996) Sedation in allergic rhinitis is caused by the condition and not by antihistamine treatment. Allergy 51: 893–906 56. Gelfand EW (2005) Pediatric allergic rhinitis: factors affecting treatment choice. Ear Nose Throat J 84(3): 163–168 57. McCue JD (1996) Safety of antihistamines in the treatment of allergic rhinitis in elderly patients. Arch Fam Med 5: 464–468 58. Schatz M (1998) Special considerations for the pregnant woman and senior citizen with airway disease. J Allergy Clin Immunol 101: S373–S378 59. Demoly P, Piette V, Daures JP (2003) Treatment of allergic rhinitis during pregnancy. Drugs 63: 1813–1820 60. Joint committee of the American College of Obstetricians and Gynecologoists (ACOG) and the American College of Allergy (ACAAI) (2000) The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 84: 475–480

Antiallergic and Vasoactive Drugs for Allergic Rhinitis Friedrich Horak

Introduction Rhinitis is defined as the inflammation of the lining of the nose with one or more symptoms. The symptom profile of allergic rhinitis (AR) includes sneezing, itching of the eyes, nose, and throat, nasal obstruction, and rhinorrhoea. However, other problems and symptoms are also commonly associated with AR. For example, patients with seasonal AR commonly have conjunctivitis and may also have bronchial asthma. In central Europe, the association with bronchial asthma is greater with birch pollen allergy than grass pollen allergy. Headache and fatigue are other symptoms commonly associated with AR [1]. The most bothering symptom of AR is blocked nose, but loss of taste and smell are also associated symptoms. AR is linked with asthma; more than 30% of patients with perennial AR have signs of asthma, and about 75% of patients with allergic asthma also have perennial AR [2]. The upper and lower airway tracts are very closely related. The combination of symptoms in AR causes impairment of day-to-day physical, emotional, occupational, and social functioning. In particular, patients with perennial AR have severely impaired quality of life and some sleep disturbances, and the disease has a significant impact in terms of lost productivity [3]. Thus, symptom relief is a priority in AR. A complex system within the nasal vascular system controls nasal patency. Fenestrations within the subepithelial capillaries allow the rapid flow of water into the lumen for evaporation and heat loss. These are unique to this part of the respiratory tract. Other vessels that play an important part in the blocked nose include the capacitance vessels, which regulate airflow in the nose and are involved in congestion and decongestion. Arteriovenous anastomoses are responsible for temperature control.

F. Horak () Ear, Nose, and Throat Department, Medical University Vienna, Head of Allergy Centre Vienna West, Huetteldorferstrasse, 46, A-1150 Vienna, Austria e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_4, © Springer 2010

51

52

F. Horak

The effects of histamine and other mediators are closely related to this vascular system. For example, histamine acts on the postcapillary venules, causing plasma extravasation during the immediate and late phase of the allergic reaction by opening gaps in the intercellular junctions between the endothelial cells. A potent histamine antagonist could help reduce this activity. However, mediators other than histamine, such as bradykinin, prostaglandin D2, leukotrienes, platelet activating factor, and others also cause plasma extravasation [4]. Thus, a drug that only possesses antihistamine activity would not completely inhibit this effect. During an allergic reaction, the diameter of capillaries increases dramatically within about 15 min. A similar effect occurs on vessels in the deeper layers of the mucous membrane. It is known that symptoms, particularly those of the long-acting late-phase reaction, lead to greater immunoglobulin (Ig)-G synthesis and increasing morbidity. Several mediators are responsible for the different parts of the late-phase reaction, including the 5-lipoxygenase enzyme, which is responsible for the synthesis of leukotrienes. The immediate-phase reaction is characterized by itching and sneezing, some discharge, and some congestion, whereas the late-phase reaction is characterized by nasal blockage, loss of smell, and nonspecific hyperreactivity. Antihistamines are active in reducing the immediate-phase reaction, particularly those symptoms induced mainly by histamine, such as itching, sneezing, and discharge. Some of the second-generation antihistamines are also active in the late phase, and may act by reducing 5-lipoxygenase activity, ICAM-1 expression, or IL-4 activity. Therefore, these modern antihistamines are not only H1-receptor antagonists but also antiallergic drugs that are active in parts of the late-phase reaction.

Guidelines for the Treatment of AR Prior treatment guidelines published by the International Rhinitis Management Working Group in 1994 recommended a stepwise approach to treating AR, starting with oral and/or topical antihistamines, particularly for mild and moderate disease [5]. More recently, the WHO ARIA (Allergic Rhinitis and its Impact on Asthma) workshop published a new classification of AR based on frequency, duration, severity, and influence on quality of life [6]. The pharmacologic treatment of AR proposed by ARIA is an evidence-based and stepwise approach. These recommendations have been subsequently modified and validated [7–9]. However, the stepwise approach to treating AR, starting with oral and/or topical antihistamines followed by topically used steroids, was the same as described already in the early 1990s [5].

Cornerstones of Rhinitis Treatment 1. Education of patients, parents, and their contacts

Antiallergic and Vasoactive Drugs for Allergic Rhinitis

53

2. Allergen avoidance according to a recent allergy diagnosis 3. Pharmacotherapy a. Oral H1-receptor antagonists b. Topical nasal H1-receptor antagonists c. Topical nasal corticosteroids d. Systemic corticosteroids e. Antileukotrienes f. Sodium cromoglicate g. Anti-IgE h. Intranasal decongestants i. Oral decongestants 4. Specific allergen vaccination (immunotherapy) The following sections will deal with “Pharmacotherapy of allergic rhinitis.”

Oral H1-Receptor Antagonists Because histamine release is a common feature of AR, antihistamines have been the treatment of choice. Since the early 1970s, the design and development of antihistamines have evolved, with the goal of improving specificity and reducing side effects. First-generation H1-antagonists (diphenhydramine, promethazine, hydroxyzine, chlorpheniramine, azatadine) represent a chemically heterogeneous group of agents that effectively reduced itch, nasal discharge, and sneezing, but not congestion, in patients with SAR. Because of their high lipophilicity and marked tendency to cross the blood–brain barrier, these agents were plagued with anticholinergic and CNSrelated antihistamine side effects of dry mouth, sedation, and daytime drowsiness, and a tendency to cause urinary retention in the elderly [10–12]. The use of these agents in treating allergic disease was further limited by their short plasma half-life [11]. First-generation H1-receptor antagonists are no longer used in AR. There is a number of second-generation H1-receptor antagonists in the market and some more under development: (1) acrivastine, (2) azelastine, (3) cetirizine, (4) bilastine, (5) desloratadine, (6) ebastine, (7) emedastine, (8) epinastine, (9) fexofenadine, (10) levocetirizine, (11) loratadine, (12) mizolastine, (13) norastemizole, (14) rupatadine (astemizole and terfenadine were widely withdrawn from the market). Compared to first-generation H1-receptor antagonists, second-generation H1antagonists exert their antiallergic effects through multiple mechanisms, including suppression of the inflammatory response. However, the clinical relevance of these additional activities is still questionable [11,13–17]. Although second-generation H1-antagonists effectively reduced nasal itch, discharge, and sneezing, they did not reduce congestion in patients with AR satisfactorily [18–20]. However, it is evident that few second-generation H1-antagonists have some effect on nasal obstruction [21–24].

54

F. Horak

Nevertheless, some of the second-generation antihistamines (e.g. azelastine, cetirizine, levocetirizine) are associated with sedation and psychomotor impairment, but not in the same amount as first-generation drugs [25–27]. Furthermore, drug– drug interactions raised major concerns with some of these agents, since coadministration of terfenadine or astemizole with cytochrome P enzyme inhibitors (e.g. ketoconazole and erythromycin) resulted in significant cardiotoxicity and cardiac arrhythmias [11, 25]. Overall, second-generation antihistamines are much safer than the first-generation ones and have unquestionable advantages over them. According to the ARIA guidelines, antihistamines are the first choice of pharmacotherapy in mild to severe AR. Since 1985, more than 50 studies have compared the effects of different secondgeneration antihistamines in controlling the nasal symptoms of patients with AR. There was no consistent pattern of one antihistamine showing superiority over other antihistamines [28, 29]. However, there is still a need for improved H1-receptor antagonists for more effective treatment of allergic disease. A symptom reduction of about 40% more than placebo is clinically relevant but does not meet the patients’ need completely. Ideally, such agents should have an additional low potential for drug interaction and undesirable CNS-related side effects, combined with proven anti-inflammatory and decongestant properties.

Topical Nasal H1-Receptor Antagonists Because of the fast onset of action [30–32], topical nasal H1-receptor antagonists like azelastine, epinastine, ketotifen, or levocabastin are very useful as rescue medication. Their therapeutic effect is similar to oral antihistamines for all rhinitis symptoms and there is even some effect on conjunctival symptoms [33–36]. Therefore, it also makes sense to use this topical treatment for mild AR as first line treatment, optionally combined with the topical treatment of allergic conjunctivitis. Furthermore, there is some information indicating the benefit of topical antihistamines for AR patients who do not respond to oral antihistamines [37, 38]. However, it is to be considered that topically used antihistamines do not improve symptoms due to histamine at other sites, such as lower airways or skin.

Topical Nasal Corticosteroids There are some opposing positions in terms of the place of topical corticosteroids in the management of AR: These compounds may be used in second line in addition to antihistamines in terms of moderate to severe AR or as first line therapy for moderate to severe AR and treatment failures with antihistamines alone. Whatever, it is evident that intranasal corticosteroids are, to some extent,

Antiallergic and Vasoactive Drugs for Allergic Rhinitis

55

superior to antihistamines [39]. However, although corticosteroids act by suppressing allergic inflammation at multiple points in the allergic cascade, their therapeutic potency is in the range of oral antihistamines, leading to a symptom reduction of about 50% only [40, 41]. In contrast to antihistamines, the onset of action is not before 6–12 h (topical antihistamines are active after 15–30 min, oral antihistamines are active after 30–90 min) and the maximal effect may not be apparent until after 2 weeks (5–7 days in terms of antihistamines) [42–44]. In recent years, new corticosteroids, which offer greater topical efficacy with lower systemic absorption (triamcinolone acetonide, budesonide, fluticasone proprionate, mometasone fuorate) [45, 46], have been developed for nasal use. A new approach to decrease systemic side effects of corticosteroids is the development of the so-called “soft steroids” like loteprednol etabonate (just not on the market) [47, 48].

Systemic Corticosteroids Systemic oral corticosteroids are rarely indicated in the management of AR. They may be an option used briefly and supporting the conventional pharmacotherapy for uncontrolled symptoms only. A circadian rhythm, taking the drug before 8:00 a.m. (preferably every second day), would reduce the potency of side effects. The treatment should not last longer than 5–10 days, with a limit of 0.5 mg per kg. Systemic intramuscular depot corticosteroids are not recommended for AR at all. The risk/benefit ration is more than poor compared to other treatment options [49].

Antileukotrienes Besides histamine, which is the most important mediator of the allergic cascade, leukotrienes play an important role in allergic inflammation [50–54]. Therefore, leukotriene receptor antagonists like montelukast or zafirlukast as well as leukotriene systesis inhibitors like zileuton can reduce the essential components of allergic inflammation in AR. These drugs are orally active, can be administered once daily, and provide a systemic approach to the management of patients with AR or bronchial asthma. The wide range of clinical effects favors the compound, especially when the AR is accompanied by allergic bronchial asthma. The majority of allergic asthmatics suffer from concomitant rhinitis. For this large group of patients, leukotriene receptor antagonists can be the suitable medication. Leukotriene receptor antagonists have confirmed efficacy in AR and have a level of therapeutic potency close to H1-receptor antagonists [55]. However, the response is less consistent than that observed for antihistamines. Moreover, synergistic benefits were documented with antihistamines in AR as

56

F. Horak

well as with corticosteroids and long acting beta-2 agonists in bronchial asthma [56–58]. As this synergistic effect is not clearly convincing in terms of the clinically relevant extent, this treatment option is still under discussion. Leukotriene receptor antagonists have their place in the therapy of AR if allergic bronchial asthma is co-morbid [59, 60].

Sodium Cromoglicate In recent times, the use of sodium cromoglicate or nedocromil is disputed. Although they have an excellent safety profile, their efficacy is limited and the need for frequent dosing is not compliant. Cromones are generally less effective than all other medications used for the treatment of AR [61, 62]. Children with mild symptoms of AR and only sporadic problems may take an advantage of the drug [63].

Anti-IgE A monoclonal antibody to IgE, omalizumab has been developed recently, only in the 1990s. It is a recombinant humanized form of a mouse antibody, and because it is humanized it does not generate immune responses in humans [64–67]. This antibody is directed at the part of the IgE molecule that is normally obscured, when IgE is attacked, to the high-affinity receptor on the mast cells, and omalizulab is able to bind to and neutralize circulating IgE without causing mast call degranulation. Casale et al. showed that omalizumab suppresses serum IgE in patients with SAR, which is encouraging as serum IgE levels were correlated with symptom scores in the same study [68]. The clinical efficacy of omalizumab has since been confirmed in patients with SAR, as well as in various studies in patients with asthma [69]. Anti-IgE therapy, therefore, promises to be a useful addition to the treatment options in patients with allergies. However, due to the bad cost/benefit ratio, it will be restricted to some cases of severe bronchial asthma only. Further use may include treatment with immunotherapy in high-risk patients.

Intranasal Decongestants The use of decongestants in AR may be beneficial in reducing the bothering symptom of blocked nose, but because of the potential risks of side effects and rhinitis medicamentosa they should be handled with utmost care. Currently available topical decongestants (ephedrine, xylometazoline, oxymetazoline) are limited by tachyphylaxis and they have the tendency to cause rebound congestion when discontinued [70–72].

Antiallergic and Vasoactive Drugs for Allergic Rhinitis

57

Several combined preparations of intranasal decongestants with antihistamines are on the market. They have shown a greater efficacy than the drugs given separately [70]. However, these combinations have the same limitations and side effects as decongestants alone. Therefore, the use of all intranasal decongestants and their combinations is to be restricted to a maximum of 10 days only.

Oral Decongestants Although oral decongestants do not suffer from a rebound effect, they are not free of problems. On the one hand, they are less effective than the topical medication and on the other, they are rich on side effects like insomnia, increase in blood pressure, and urinary retention. However, some slow-release preparations may have an efficacy up to 24 h [73, 74]. The safety and efficacy of pseudoephedrine is generally limited, with 240 mg per day. Antihistamine and decongestant combinations are on the market, with firstgeneration antihistamines and second-generation antihistamines like loratadine, desloratadine, cetirizine, and fexofenadine. They have shown a greater efficacy than the drugs given separately [75, 76]. Because of the side effects, oral decongestants and combined preparations are not generally recommended and should be used only in selected cases. In some states, there are restrictions on the availability of pseudoephedrine because it can be used to produce methamphetamine. Therefore, phenylephrine was suggested to substitute pseudoephedrine. Phenylephrine cannot be converted to methamphetamine and can be sold without restrictions. However, phenylephrine, at the FDA-approved dose of 10 mg for adults, is unlikely to provide relief from nasal congestion [77].

Conclusion Several effective medications for AR are on the market. They can be tailored for the individual patient in order to reduce the burden of allergy. The following guidelines may help. However, the efficacy of each preparation is limited and some patients still have residual symptoms. Therefore, there is still a need for more improvement and new molecules.

References 1. Temmel AFP, Schleinzer K, Marks B, et al (1998) Prospective epidemiological longitudinal study in allergic diseases. Otorhinolaryngol Nova 8:47 2. Corren J (1997) Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol 99(2):781–786

58

F. Horak

3. Juniper EF, Thompson AK, Ferrie PJ, et al (2000) Development and validation of the mini Rhinoconjunctivitis Quality of Life Questionaire. Clin Exp Allergy 30:132–140 4. Mygind N, Dahl R, Pedersen S, et al (1996) Pathogenesis of allergic rhinitis. In: Mygind N, Dahl R, Pedersen S, Thestrup-Pedersen K, eds. Essential allergy. Second edition. Berlin: Blackwell Science:201–206 5. International Rhinitis Management Working Group. International consensus report on the diagnosis and management of rhinitis (1994). Allergy 49 (suppl 19):1–34 6. Bousquet J, Van Cauwenberge P, Khaltaev N, Aria Workshop Group, World Health Organization (2001) Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 108 (suppl 5):S147–334 7. Bousquet J, Van Cauwenberge P, Aït Khaled N, et al (2006) Pharmacologic and anti-IgE treatment of allergic rhinitis ARIA update (in collaboration with GA2LEN). Allergy 61:1086–1096 8. Bachert C, Vignola AM, Gevaert P, et al (2004) Allergic rhinitis, rhinosinusitis and asthma: one airway disease. Immunol Allergy Clin North Am 24:19–43 9. Demoly P, Allaert FA, Lecasble M, et al (2003) Validation of the classification of ARIA. Allergy 58:672–675 10. Simons FER (1994) H1-receptor antagonists: comparative tolerability and safety. Drug Saf 10:350–380 11. Walsh GM, Annunziato L, Frossard N, et al (2001) New insights into the second-generation antihistamines. Drugs 61:207–236 12. Hadley JA (1999) Evaluation and management of allergic rhinitis. Med Clin North Am 83:13–25 13. Howarth PH, Salagean M, Dokic D (2000) Allergic rhinitis: not purely a histamine-related disease. Allergy 55:7–16 14. Taborda-Barata L, Jacobson M, Walker S, et al (1996) Effect of cetirizine and prednisolone on cellular infiltration and cytokine mRNA expression during allergen-induced late cutaneous responses. Clin Exp Allergy 26:68–78 15. Zweiman B, Atkins PC, Moskovitz A, et al (19997) Cellular inflammatory responses during immediate, developing, and established late-phase allergic cutaneous reactions: effects of cetirizine. J Allergy Clin Immunol 100:341–347 16. Atkins PC, Zweiman B, Moskovitz A, et al (1997) Cellular inflammatory responses and mediator release during early developing late-phase allergic cutaneous inflammatory responses: effects of cetirizine. J Allergy Clin Immunol 99:806–811 17. Horak F (2000) Clinical advantages of dual activity in allergic rhinitis. Allergy 55 (suppl 64):34–39 18. Corey JP, Houser SM (2000) Nasal congestion: a review of its etiology, evaluation and treatment. Ear Nose Throat J 79:690–702 19. Horak F (2002) Impact and modulation of nasal obstruction. Allergy 57 (suppl 75):25–28 20. Ciprandy G, Cirillo I, Vizzaccaro A, et al (2004) Nasal obstruction in patients with seasonal allergic rhinitis: Relationship between allergic inflammation and nasal airflow. Int Arch Allergy Immunol 134:34–40 21. Ciprandi G, Cirillo I, Vizzaccaro A, et al (2005) Levocetirizine improves nasal symptoms and airflow in patients with perennial allergic rhinitis: A pilot study. Eur Ann Allergy Clin Immunol 37:25–29 22. Horak F, Stübner P, Zieglmayer R, et al (2003) Comparison of the effect of desloratadine 5-mg daily and placebo on nasal airflow and seasonal allergic rhinitis symptoms induced by grass pollen exposure. Allergy 58:481–485 23. Horak F, Stübner UP (2002) Decongestant activity of desloratadine in controlled-allergenexposure trials. Clin Drug Invest 22 (suppl 2):13–20 24. Horak F, Stuebner UP, Zieglmayer R, et al (2002) Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen induced allergic rhinitis in an allergen exposure unit. J Allergy Clin Immunol 109:956–961 25. Horak F, Stuebner UP (1999) Comparative tolerability of second generation antihistamines. Drug Saf 20:385–401

Antiallergic and Vasoactive Drugs for Allergic Rhinitis

59

26. Mann RD, Pearce GL, Dunn N, et al (2000) Sedation with “non-sedating” antihistamines: four prescription-event monitoring studies in general practice. Br Med J 320:1184–1186 27. Gonzalez MA, Estes KS (1998) Pharmacokinetic overview of oral second-generation H1 antihistamines. Int J Clin Pharmacol Ther 36:292–300 28. Devillier P, Bousquet J (2007) Inhibition of the histamine-induced weal and flare response: a valid surrogate measure for antihistamine clinical efficacy? Clin Exp Allergy 37:400–414 29. Plaut M, Valentine MD (2005) Clinical practice. Allergic rhinitis. N Engl J Med 353:1934–1944 30. Horak F, Stübner P, Zieglmayer R, et al (2006) Azelastine nasal spray and desloratadine tablets in pollen-induced seasonal allergic rhinitis: A pharmacodynamic study of onset of action and efficacy. Curr Med Res Opin 22:151–157 31. Drouin MA, Yang WH, Horak F (1995) Faster onset of action with topical levocabastine than with oral cetirizine. Mediators Inflamm 44:5–10 32. Horak F, Jäger S, Toth J, et al (1994) Azelastine in pollen-induced allergic rhinitis. A pharmacodynamic study of action and efficacy. Drug Invest 7:34–40 33. Noble S, Mc Tavish D (1995) Levocabastine. An update of its pharmacology, clinical efficacy and tolerability in the topical treatment of allergic rhinitis and conjunctivitis. Drugs 50:1032–1049 34. Mc Neeley W, Wiseman LR (1998) Intranasal azelastine. A review of its efficacy in the management of allergic rhinitis. Drugs 56:91–114 35. Crampton HJ (2003) Comparison of ketotifen fumerate ophthalmic solution alone, desloratadine alone, and their combination for inhibition of the signs and symptoms of seasonal allergic rhinoconjunctivitis in the conjunctival allergen challenge model: A double-masked, placeboand active-controlled trial. Clin Ther 25:1975–1987 36. Corren J, Storms W, Azelastine Cetirizine Trial No. 1 (ACT 1) Study Group (2005) Effevtiveness of azelastine nasal spray compared with oral cetirizine in patients with seasonal allergic rhinitis. Clin Ther 27(5):543–553 37. Berger WE, White MV (2003) Efficacy of azelastine nasal spry in patients with an unsatisfactory response to loratadine. Ann Allergy Asthma Immunol 91:205–211 38. Laforce CF, Corren J, Wheeler WJ, et al (2004) Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients whose symptoms remain after treatment with fexofenadine. Ann Allergy Asthma Immunol 93:154–159 39. Yanez A, Rodrigo GJ (2002) Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: A systematic review with meta-analysis. Ann Allergy Asthma Immunol 89:479–484 40. Fokkkens WJ, Godthelp T, Holm AF, et al (1998) Local corticosteroid treatment: The effect on cells and cytokines in nasal allergic inflammation. Am J Rhinol 12:21–26 41. Weiner JM, Abramson MJ, puy RM (1998) Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: Systematic review of randomised controlled trials. BMJ 317:1624–1629 42. Jen A, Baroody F, De Tineo M, et al (2000) As-need use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 105:732–738 43. Graft D, Aaronson D, Chervinsky P, et al (1996) A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone fuorate aqueous nasal spray. J Allergy Clin Immunol 98:724–731 44. Fokkens WJ, Cserhati E, Dos Santos JM, et al (2002) Budesonide queousus nasal spray is an effective treatment in children with perennial allergic rhinitis, with an onset of action within 12 hours. Ann Allergy Asthma Immunol 89:279–284 45. Lumry WR (1999) A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis. J Allergy Clin Immunol 104:150–158 46. Trangsrud AJ, Whitaker AL, Small RE (2002) Intranasal corticosteroids for allergic rhinitis. Pharmacotherapy 22:1458–1467 47. Szelenyi I, Hochhaus G, Heer S, et al (2000) Loteprednol etabonate: A soft steroid for the treatment of allergic diseases of the airways. Drugs Today 36:313–320

60

F. Horak

48. Bodor N, Buchwald P (2000) Soft drug design: General principles and recent applications. Med Res Rev 20:58–101 49. Nasser SM, Ewan PW (2001) Lesson of the week: Ddepot corticosteroid treatment for hay fever causing avascular necrosis of both hips. BMJ 322:1589–1591 50. Busse W, Kraft M (2005) Cysteinyl leukotrienes in allergic inflammation. Strategic target for therapy. Chest 127:1312–1326 51. Haberal I, Corey JP (2003) The role of leukotrienes in nasal allergy. Otolaryngol Head Neck Surg 129:274–279 52. Shahab R, Phillips DE, Johnes AS (2004) Prostaglandins, leukotrienes and perennial rhinitis. J Laryngol Otol 118:500–507 53. Turner P, Dear J, Scadding G, et al (2001) Role of kinins in seasonal allergic rhinitis: Icatibant, a bradykinin B2 receptor antagonist, abolished the hyperresponsiveness and nasal eosinophilia induced by antigen. J Allergy Clin Immunol 107:105–113 54. Lipworth BJ (1999) Leukotriene-receptor antagonists. Lancet 353:57–62 55. Philip G, Malmstrom K, Hampel FC, et al (2002) Montelucast for treating seasonal allergic rhinitis: A randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy 32:1020–1028 56. Currie GP, Srivastava P, Dempsey OJ, et al (2005) Therapeutic modulation of allergic airways disease with leukotrien receptor antagonists. Q J Med 98:171–182 57. Nayak AS, Philip G, Lu S, et al (2002) Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: A multicenter, randomized, doubleblind, placebo controlled trial performed in fall. Ann Allergy Asthma Immunol 88:592–600 58. Meltzer EO, Malmstrom K, Lu S, et al (2000) Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: Aa randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 105:917–922 59. Keskin O, Alyamac E, Tuncer A, et al (2006) Do the leukotriene receptor antagonists work in children with grass pollen-induced allergic rhinitis? Pediatr Allergy Immunol 17:259–268 60. Pawankar R (2003) Exploring the role of leukotriene receptor antagonists in the management of allergic rhinitis and comorbid asthma. Clin Exp Allergy Rev 3:74–80 61. Bousquet J, Chanal I, Alquie MC, et al (1993) Prevention of pollen rhinitis symptoms: Comparison of fluticasone propionate aqueous nasal spray and disodium cromoglycate aqueous nasal spray. A multicenter, double-blind, double-dummy, parallel-group study. Allergy 48:327–333 62. Bousquet J, van Cauwenberge P, Khaltaev N (2004) ARIA in the pharmacy: Management of allergic rhinitis symptoms in the pharmacy. Allergy 59:373–387 63. Hadley JA (2003) Cost-effective pharmacotherapy for inhalant allergic rhinitis. Otolaryngol Clin North Am 36:825–836 64. Easthope S, Jarvis B (2001) Omalizumab. Drugs 61:253–260 65. Jardieu PM, Fick RB (1999) IgE inhibition as a therapy for allergic disease. Int Arch Allergy Immunol 118:112–115 66. Bez C, Schubert R, Kopp M, et al (2004) Effect of anti-immunoglobulinE on nasal inflammation in patients with seasonal allergic rhinoconjunctivitis. Clin Exp Allergy 34:1079–1085 67. Holgate ST, Corne J, Jardieu P, et al (1998) Treatment of allergic disease with anti-IgE. Allergy 53(suppl 45):83–88 68. Casale TB, Bernstein IL, Busse WW, et al (1997) Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 100:110–121 69. Adelroth E, Rak S, Haahtela T, et al (2000) Recombinant humanized mAb-E25, and anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 106:253–259 70. Van Cauwenberge P, Bachert C, Passalacqua G, et al (2000) Consensus statement on the treatment of allergic rhinitis. European Acad Allergol Clin Immunol Allergy 55:116–134 71. Storms WW (2004) Pharmacologic approaches to daytime and night time symptoms of allergic rhinitis. J Allergy Clin Immunol 114:146–153 72. Scadding GK (1995) Rhinitis medicamentosa. Clin Exp Allergy 25:391–394

Antiallergic and Vasoactive Drugs for Allergic Rhinitis

61

73. Beck RA, Mercado DL, Seguin SM, et al (1992) Cardiovascular effects of pseudoephedrine in medically controlled hypertensive patients. Arch Intern Med 152:1242–1245 74. Bradley JG (1991) Nonprescription drugs and hypertension. Which ones affect blood pressure? Postgrad Med 89:195–202 75. Zieglmayer UP, Horak F, Toth J, et al (2005) Efficacy and safety of an oral formulation of cetirizine and prolonged-release pseudoephedrine versus budesonide nasal spray in the management of nasal congestion in allergic rhinitis. Treat Respir Med 4:283–287 76. Horak F, Toth J, Marks B, et al (1998) Efficacy and safety relative to placebo of an oral formulation of cetirizine and sustained-release pseudoephedrine in the management of nasal congestion. Allergy 53:849–856 77. Hendeles L, Hatton RC (2006) Oral phenylephrine: an ineffective replacement for pseudoephedrine? J Allergy Clin Immunol 118:279–280

Antileukotrienes in Asthma and Rhinitis Anthony Peter Sampson

Introduction Leukotrienes are lipid mediators synthesized from arachidonic acid liberated from the membranes of activated inflammatory cells [1]. The subfamily of cysteinylleukotrienes (cys-LTs) represented by LTC4, LTD4 and LTE4 are the first inflammatory mediators to have a proven role in the pathophysiology of asthma [2] and which mimic many of the features of allergic rhinitis [3]. Antileukotriene drugs that block the synthesis of leukotrienes or antagonize cys-LT receptors have been licensed for asthma therapy in most countries in the last dozen years [4], with some of these drugs also being registered for use in allergic rhinitis [2]. This chapter will outline the sources and actions of cys-LTs in allergic airway inflammation and the clinical evidence underlying the use of antileukotriene drugs in asthma and allergic rhinitis.

The Leukotriene Biosynthetic Pathway Inflammatory processes in the allergic airway depend on a complex network of cellular interactions regulated by mediators of numerous chemical classes, including lipids. These include the leukotriene and prostanoid families of eicosanoids, which are derivatives of the 20-carbon polyunsaturated fatty acid – arachidonic acid. Arachidonate is usually found esterified in phospholipids in cellular membranes, particularly the nuclear envelope, and is metabolized to the potent neutrophil chemotaxin leukotriene (LT)B4 or to the bronchoconstrictor and proinflammatory cysteinyl-LTs (LTC4, LTD4 and LTE4) by the 5-lipoxygenase pathway (Fig. 1).

A.P. Sampson () Division of Infection, Inflammation & Immunity (III), University of Southampton School of Medicine, The Sir Henry Wellcome Building (MP825), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_5, © Springer 2010

63

Fig. 1 Stimuli that activate cells by increasing intracellular Ca2+ concentrations activate cytosolic phospholipase A2 (cPLA2) which liberates arachidonate from the nuclear envelope and transfers it to the 5-lipoxygenase activating protein (FLAP) located within the membrane. FLAP is thought to donate arachidonate to 5-lipoxygenase (5-LO), which translocates from the cytosol to convert arachidonate in two stages to leukotriene (LT)A4. Depending on cell-type, LTA4 is then converted to the potent neutrophil chemoattractant LTB4 by cells expressing LTA4 hydrolase and/or to the first of the cysteinyl-LTs, LTC4, by cells expressing microsomal glutathione-S-transferase type II or a specific LTC4 synthase. After cellular export by multidrug resistance-associated protein 1 (MRP1), extracellular cleavage of the peptide side-chain of LTC4 by gamma-glutamyl-transpeptidase (GGT) and dipeptidase forms LTD4 and LTE4 respectively, which together with LTC4 are termed sulphidopeptide-leukotrienes or cysteinyl-leukotrienes (cys-LTs). These act at specific CysLT1 or CysLT2 receptors on target cell membranes, while (non-cysteinyl) LTB4 acts at distinct BLT1 and BLT2 receptors and at nuclear peroxisome proliferator activated receptors (PPARa). X and Y show the respective sites of action of the 5-LO inhibitor zileuton and the lukast class of CysLT1 receptor antagonists. From [1] with permission

64 A.P. Sampson

Antileukotrienes in Asthma and Rhinitis

65

Cellular Sources of Leukotrienes The cells with the highest capacity to generate cys-LTs are subsets of myeloid leukocytes. In vitro, eosinophils preferentially or exclusively secrete LTC4 [5], while monocytes generate both LTB4 and smaller amounts of LTC4 [6]. Mature blood basophils and human lung mast cells have a high capacity to generate LTC4 [7]. In contrast to myeloid cells, the capacity of lymphocytes to generate LTs is contentious, but reports suggest that B-cells and T-cells can generate LTB4 de novo or by transcellular donation of LTA4 from myeloid cells, but cannot generate cys-LTs [8]. Within the airway, bronchial epithelial cells may also generate cys-LTs in relatively small amounts, either constitutively or following viral infection [9,10]. Other structural cells, such as fibroblasts, smooth muscle cells, and endothelial cells may also generate cys-LTs or LTB4, either de novo, or following transcellular donation by other cell-types of arachidonate, or of the intermediate LTA4 [11–13]. Although such cell-types have a limited capacity to generate LTs, their numerical predominance may make them significant contributors to cys-LT levels within the airway as a whole.

Cysteinyl-Leukotriene Receptors The actions of cys-LTs are mediated by specific CysLT receptors. Pharmacological studies in human bronchi originally identified a receptor at which both LTC4 and LTD4 were full constrictor agonists, with LTD4 being the most potent, and this receptor was termed CysLT1 [14]. The CysLT1 receptor is the molecular target of the “lukast” class of antileukotriene drugs currently marketed for asthma therapy, including montelukast, zafirlukast, and pranlukast; such compounds failed to block contractile responses induced equipotently by LTC4 and LTD4 in human pulmonary veins, and this second receptor was termed CysLT2 [15]. The dual antagonist BAYu9773 can antagonize the CysLT2 receptor experimentally, but currently marketed antileukotriene drugs do not block the actions of cys-LTs at this receptor, which may include endothelial activation and the production of specific cytokine subsets by mast cells, as well as effects on other organ systems. Human CysLT1 and CysLT2 receptors were both characterized at the molecular level in 1999–2000 [16–18] (Table 1). Both are classical G-protein-coupled receptors (GPCR) with seven putative transmembrane regions, and their functional activation involves calcium mobilization. The CysLT2 receptor polypeptide shows 31% amino acid identity to Cys-LT1. The molecular studies largely confirmed the previous pharmacological observations – at the CysLT1 receptor, LTD4 is approximately 10-fold more potent as an agonist of calcium mobilization than LTC4 or LTE4. At CysLT2 receptors, LTC4 and LTD4 are roughly equipotent, but both have lower potency for CysLT2 than LTD4 has for the CysLT1 receptor. The specificity of the “lukast” antagonists for CysLT1, and the dual antagonism of CysLT1 and CysLT2 by BAYu9773 were also confirmed by the molecular studies. There are distinct patterns

Brain, heart, spleen, leukocytes (e.g., monocytes), vascular endothelium

Brain, heart, kidney

Human bronchial fibroblasts

CysLT1

CysLT2

GPR17

Unidentified

Sampson AP Allergy Frontiers Antileukotriene drugs in asthma and allergic rhinitis

Cellular expression

Bronchial smooth muscle, mast cells, eosinophils, basophils, some T-cells

Receptor

Table 1 Cysteinyl-leukotriene receptors

LTC4 > LTD4 > LTE4 Uridine diphosphate LTC4 = LTD4 None

Montelukast

Montelukast Pranlukast Zafirlukast MK-571 Bay u9773 Bay u9773

LTD4 > LTC4 > LTE4

LTC4 = LTD4 >> LTE4 Bay u9773 (partial)

Antagonists

Agonists

Actions

Enhanced proliferation

Endothelial activation, bleomycin-induced airway fibrosis, interleukin-8 release Ischemic neural injury

Bronchoconstriction, eosinophilia, vascular leakage, Th2 cytokine synthesis, airway remodeling

References

[56]

[22]

[17,18,21,35,61]

[16,19–21,39, 41–45,54,60]

66 A.P. Sampson

Antileukotrienes in Asthma and Rhinitis

67

of tissue expression for CysLT1 and CysLT2 receptors. CysLT1 is found mainly in airway smooth muscle, spleen, peripheral blood leukocytes (notably eosinophils and basophils), and pulmonary macrophages [16,19,20]. In contrast, large amounts of CysLT2 mRNA are found in the heart (Purkinje fibers), brain, placenta, spleen and leukocytes, but little in the lung [17]. On grounds of structural homology, the CysLT receptors are classified as members of the nucleotide family of GPCRs that also includes purinergic (P2Y) receptors [21]. There is growing evidence that some members of this family are dual receptors, able to be activated both by cys-LTs and by nucleotides such as uridine diphosphate (UDP). The family also contains a number of orphan GPCRs, and one of these, known as GPR17, was recently identified as a dual CysLT/P2Y receptor [22]. GPR17 shows most activity in response to nanomolar concentrations of LTC4 and is also activated by micromolar concentrations of UDP. Intriguingly, GPR17 is expressed highly in brain and is associated with ischemic neural injury in a rat model; montelukast antagonizes the receptor and blocks the neural injury [22]. It is possible that further novel CysLT receptors will be identified and interactions between cys-LTs and nucleotide agonists may be functionally important in the inflamed airway.

Actions of cys-LTs in Asthma and Rhinitis Bronchoconstriction Leukotriene B4 has no bronchoconstrictor activity in normal or asthmatic human subjects [23], but the cys-LTs are the most potent bronchoconstrictor mediators yet identified. In normal and asthmatic subjects, LTC4 and LTD4 are 400- to 10,000fold more potent than histamine or methacholine, with a slower onset but a longer duration of action [24–26]. Inhaled LTE4 is 10-fold less potent than LTC4 or LTD4, but remains more potent than histamine. The bronchoconstrictor effects of cys-LTs are mediated by CysLT1 receptors.The cys-LTs appear to act equally on the central and peripheral airways. In asthmatic subjects, inhalation of cys-LTs may increase bronchial responsiveness to histamine or methacholine, with one report indicating increased histamine responsiveness up to seven days after LTE4 inhalation [27]. In normal subjects, evidence of an effect of cys-LTs on methacholine responsiveness is contradictory. Cysteinyl-LTs do not affect responsiveness to exercise challenge or inhalation of distilled water.

Vascular Effects In addition to bronchoconstriction, cys-LTs have a wide range of potent proinflammatory actions relevant to asthma and rhinitis, including effects on the vasculature. Cysteinyl-LTs directly increase endothelial permeability in human

68

A.P. Sampson

post-capillary venules in vitro [28]. In mice, gene deletion experiments demonstrate the importance of the CysLT1 receptor in acute vascular permeability increases, following IgE-dependent stimuli [29]. Unlike many other inflammatory autacoids, cys-LTs at high concentrations generally constrict arterioles in a number of organs; and in human skin, the wheal and flare are accompanied by a central pale area due to vasoconstriction at the injection site where the cys-LT concentrations are highest [30]. However, assessed by laser Doppler imaging, LTD4 markedly increases overall blood flow in human skin, mediated at least in part by secondary release of histamine [31]. Laser Doppler fluximetry also showed that LTD4 increases blood flow in the nasal mucosa, accompanied by increased nasal resistance and reduced nasal airflow [32]. It seems likely that leukotrienedependent increases in microvascular permeability contribute to edema in the allergic airway [33]. In addition to opening tight junctions between vascular endothelial cells, cysLTs promote leukocyte-endothelial interactions. In human umbilical vein endothelial cells (HUVEC), cys-LTs enhance the rolling of polymorphonuclear leukocytes along the endothelium, by increasing expression of P-selectin on both leukocyte and endothelial cell surfaces [34]. CysLT1 antagonists do not block the effect and this may be explained by the high expression of CysLT2 receptors on HUVECs [35]. Eosinophils overexpress a specific ligand for P-selectin that may produce selective endothelial adhesion of eosinophils relative to neutrophils [36].

Leukocyte Recruitment As well as on human bronchial smooth muscle, CysLT1 receptors are also expressed on a number of inflammatory cell-types, including mast cells, basophils and eosinophils [19,20]. In atopic asthmatic subjects, inhalation of LTE4 produces a 10-fold influx of eosinophils in the bronchial mucosa 4 h after inhalation, while there is no cellular response to concentrations of inhaled methacholine producing a similar degree of bronchoconstriction [37]. The eosinophilia persists for up to 6 weeks after a single LTE4 inhalation. Inhalation of LTD4 produces a modest increase in sputum eosinophils [38]. Consistent with the in vivo data, nanomolar concentrations of LTD4 cause selective migration of normal human eosinophils in vitro [39], although the magnitude of the effect is moderate compared to that induced by eosinophilotactic chemokines., migratory responses of eosinophils to LTD4 may be further enhanced in asthmatic subjects by in vivo priming by eosinophilopoietic cytokines such as IL-5 [40]. Cysteinyl-LTs may also promote airway eosinophilia by reducing eosinophil apoptosis [41] or by enhancing their proliferation in the bone marrow and their release into the circulation [42]. These proliferative, chemotactic, and antiapoptotic effects of cys-LTs on eosinophils are mediated by CysLT1 receptors [43].

Antileukotrienes in Asthma and Rhinitis

69

Other Inflammatory Actions The presence of CysLT1 receptors on other cell-types including mast cells, basophils, monocytes, dendritic cells, and activated T-cells suggests multiple roles of cys-LTs in allergic inflammation [44]. Mice rendered incapable of generating cys-LTs by deletion of the LTC4 synthase gene show reduced airway inflammation induced by inhaled allergen, with reductions in eosinophil counts, mast cell activation, Th2 cytokine production, and mucus gland hyperplasia [45]. Production of Th2 cytokines is also blocked in antigen-stimulated human mononuclear cells treated in vitro with the CysLT1 receptor antagonist pranlukast [46]. Nitric oxide (NO) is a key vasodilator mediator and a useful marker of inflammation [44]; blockade of CysLT1 receptors reduces exhaled NO in asthmatic children [47], although no effect is detectable in children with seasonal allergic rhinitis (SAR) [48]. In vitro, LTC4 and LTD4 increase mucus secretion in human bronchial mucosal explants [49], and reduce mucociliary clearance in human nasal epithelium [50]. The ability of cys-LTs to increase mucus secretion, blood flow, and resistance in the nasal airway complements the ability of histamine to cause profuse watery nasal secretions as well as itching and sneezing [51]. Together, cys-LTs and histamine effectively mimic allergic rhinitis symptoms.

Airway Remodeling It is increasingly recognized that airway remodeling – including the proliferation of bronchial smooth muscle cells and myofibroblasts and the deposition of subepithelial collagen – is an important feature of asthma and that cys-LTs may have key roles in these processes [52]. An early study in rats showed that the increase in bronchial responsiveness induced by inhaled antigen, is related to an increased mass of bronchial smooth muscle, and both these increases are blocked by a CysLT1 antagonist, suggesting a mitogenic effect of cys-LTs on smooth muscle [53]. In vitro, LTD4 greatly augments the proliferative effects of epidermal growth factor (EGF) on human airway smooth muscle (HASM) cells [54]. The proliferative effects may be mediated by CysLT1 receptors and involve modulation of the activity of insulin-like growth factor (IGF) [55]. Cys-LTs also markedly enhance the mitogenesis and proliferation of human bronchial fibroblasts induced by a range of growth factors; intriguingly, this effect is not Ca2+-dependent and is not reduced by antagonists of CysLT1, CysLT2, GPR17 or P2Y receptors, suggesting that a novel CysLT receptor is responsible [56]. LTC4 further induces collagenase expression in human lung fibroblast cells and in primary fibroblasts in patients with idiopathic pulmonary fibrosis [57], which may contribute to remodeling of extracellular matrix. The cysLTs are also reported to be potent mitogens for human airway epithelial cells [58], suggesting that they may be involved in epithelial repair processes. Studies that are more recent provide striking evidence of cys-LT involvement in airway fibrosis in mouse models. In an allergic mouse model, the CysLT1 antagonist

70

A.P. Sampson

montelukast had modest effects on airway inflammation (e.g., eosinophil counts) induced by ovalbumin, but entirely prevented the airway smooth muscle hyperplasia and airway fibrosis induced during 75 days of exposure to the antigen [59]. In a second study, when montelukast was introduced only after remodeling had been induced by ovalbumin exposure over a similar period, it was nevertheless able to reverse these changes completely over the following 90 days, while dexamethasone had no effect [60]. In a mouse model of interstitial pulmonary fibrosis induced by bleomycin, deletion of the LTC4 synthase gene confirmed that cys-LTs are essential for fibrosis to develop; however, in contrast to the allergic mouse, the profibrotic changes were dependent on CysLT2 receptors in this model, while CysLT1 receptors were antifibrotic [61]. Clinical studies are required to determine whether blockade of CysLT1 or CysLT2 receptors may prevent, reverse, or exacerbate airway fibrosis in asthma and other human airway diseases.

Leukotrienes in Biological Fluids Leukotrienes can be quantified in biological fluids including urine, sputum, nasal lavage fluid, bronchoalveolar (BAL) lavage fluid, and exhaled breath condensate (EBC) using radio- or enzyme-immunoassays, often requiring prior purification with solid-phase extraction, immunoaffinity columns, or high performance liquid chromatography [62]. Urinary LTE4 levels, are elevated in asthmatic subjects with acute severe asthma after correction for variable dilution using creatinine concentration, but not allergic rhinitis [63]; and in asthma the levels correlate with airflow limitation [64]. BAL fluid levels of LTC4 rise along with other mast cell mediators within 5 min of inhaled allergen challenge, and urinary LTE4 levels are elevated during both the early and late phase responses [65, 66]. BAL fluid LTC4 levels also increase markedly after aspirin challenge in susceptible subjects, and in these aspirin-intolerant subjects, levels of cys-LTs in BAL fluid and EBC and urinary LTE4 levels are persistently elevated even at baseline when compared to other asthmatics [67, 68], in whom baseline levels are usually indistinguishable from normal subjects. A number of studies also report elevated cys-LT levels in EBC in asthma [2]. In the nasal airway, lavage fluid LTC4 levels and urinary LTE4 levels are raised in patients with SAR, after laboratory allergen challenge or natural allergen exposure [69–72]. Respiratory syncvtial virus infection also increases nasal LTC4 levels [73].

Classes of Oral Antileukotriene Drug Compounds that target the leukotriene pathway can be divided into leukotriene synthesis inhibitors (LTSI) – which target enzymes of the leukotriene synthetic pathway, most notably inhibitors of 5-LO or FLAP – and leukotriene receptor antagonists (LTRA) which may target either LTB4 receptors (B-LTRA) or cys-LT receptors (cysLTRA) (Table 2). The only LTSI that is licensed for asthma therapy

Ono pharmaceuticals

AstraZeneca

OnonTM

AccolateTM

Pranlukast

Zafirlukast

CysLT1 antagonist

CysLT1 antagonist

CysLT1 antagonist

5-LO inhibitor

Type

Asthma, allergic rhinitis Asthma

Asthma, allergic rhinitis

Asthma

Indication

Adults and children >12 years: 20 mg bid Children 5–11 years: 10 mg bid

Adults: 10 mg nocte Children 6–14 years: 5 mg nocte Infants 2–5 years: 4 mg tablet nocte or 1–5 years: 4 mg granules nocte Adults: 225 mg bid

Adults and children >12 years: 600 mg qid

Dosages

Note: not all drugs or formulations are available in all countries and indications may also vary Sampson AP Allergy Frontiers Antileukotriene drugs in asthma and allergic rhinitis

a

Merck & Co.

SingulairTM

Montelukast

Critical Therapeutics Inc

Manufacturer

Zyflo

TM

Trade name

Zileuton

Generic name

Table 2 Oral antileukotriene drugsa

Headache, abdominal pain, C-S syndrome; dose interactions with food, theophylline, warfarin

Headache, abdominal pain, C-S syndrome

Abdominal pain, liver enzyme elevation, hepatotoxicity; dose interactions with theophylline, warfarin, propranolol Headache, abdominal pain, C-S syndrome

Adverse effects

Antileukotrienes in Asthma and Rhinitis 71

72

A.P. Sampson

is zileuton (Zyflo), and the only licensed LTRAs are the cysLTRAs montelukast (Singulair), zafirlukast (Accolate), and pranlukast (Onon) – all three of which are highly selective antagonists of the CysLT1 receptor, but not the CysLT2 receptor. It is not known whether the ability of zileuton to block LTB4 synthesis as well as that of LTC4 confers additional therapeutic benefit. The availability of zileuton is restricted to some countries and its clinical use is hindered by the requirement of monitoring of liver function due to a risk of hepatotoxicity. Its use is also restricted by low patient compliance resulting from the four times daily dose regimen, although slow-release preparations are being developed. The remainder of this review will therefore focus mainly on the cysLTRAs, two of which (pranlukast, montelukast) are also registered for use in allergic rhinitis.

Antileukotriene Drugs in Provocation Studies Allergen Bronchoprovocation The currently marketed cysLTRAs are representatives of a third generation of compounds that emerged in the early 1990s. They were licensed in many countries later in that decade, starting with pranlukast in Japan in 1995. All are potent and selective CysLT1 antagonists that are able to displace the dose-response curve for inhaled LTD4 to the right by about 200-fold [74–76]. A number of studies showed unexpected effectiveness of cysLTRAs in the allergen bronchoprovocation model, with the area under the curve (AUC) of the early airway response (EAR) being reduced by 75–80% compared to placebo [77, 78]. The remainder of the EAR is accounted for by histamine and PGD2, with IgE-activated mast cells being the likely source of all three mediators [79]. CysLTRAs also reduce the AUC of the late airway response (LAR) by about 50%, but have only a modest inhibitory effect on the increased numbers of sputum eosinophils and increased airway responsiveness that follows the LAR [80]. They may therefore act by blocking the bronchoconstrictor effects of cys-LTs released by eosinophils and other infiltrating leukocytes, rather than by preventing the chemoattraction of these leukotriene-generating cells.

Exercise and Cold Air Challenges CysLTRAs have also been investigated in challenges with exercise, cold air, and aspirin in susceptible subjects. The evidence for raised urinary LTE4 levels after exercise challenge is ambiguous, but cysLTRAs consistently reduce bronchoconstriction induced by exercise challenge or inhalation of cold dry air by approximately 30–60% in adults [81, 82] and children [83, 84]. In an 8-week study in adults, the protection against EIB afforded by montelukast was similar to that obtained by salmeterol. However, the efficacy of montelukast was sustained over the trial while that of salmeterol declined [85].

Antileukotrienes in Asthma and Rhinitis

73

Aspirin Challenge Approximately 10–15% of asthmatics bronchoconstrict in response to oral or inhaled challenge with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs can also trigger adverse rhinoconjunctival reactions in susceptible individuals, who have a high risk of nasal polyposis. Aspirin-intolerant patients are more likely to be female with onset usually in early middle age, and they often require significant glucocorticoid therapy for moderate-to-severe persistent asthma. As this is not eliminated by NSAID avoidance, the syndrome is best described as aspirin-exacerbated respiratory disease (AERD). The bronchoconstrictor and nasal responses are associated with cys-LT synthesis [86], probably triggered by inhibition by NSAIDs of endogenous PGE2 synthesis, which normally suppresses 5-LO pathway activity [87]. Aspirin-intolerant subjects also show chronically elevated urinary LTE4 levels, which may be associated with enhanced LTC4 synthase expression in the upper and lower airway eosinophils [88,89] and mast cell activation [90]. Bronchoconstriction induced by threshold doses of aspirin can be completely blocked by cysLTRAs [91], but cysLTRAs only partially block bronchial reactions induced by larger aspirin doses [92]. The 5-LO inhibitor zileuton also reduces aspirin-induced bronchospasm associated with reduced urinary LTE4 excretion and marked improvements in nasal symptoms [90]. In long-term studies in AERD, both a cysLTRA (montelukast) and the 5-LO inhibitor zileuton provided further improvements in lung function and symptom scores when added to existing therapy with inhaled and oral corticosteroids [93,94]. In a 4-week study, montelukast also improved nasal symptoms and reduced nasal reactions to intranasal aspirin [95]. Despite the mechanistic links between AERD and the leukotriene pathway, no studies exist that demonstrate that cysLTRAs are more effective in AERD than in other asthma phenotypes.

Efficacy of Antileukotriene Drugs in Asthma Acute Asthma A number of studies showed that oral cysLTRAs and 5-LO inhibitors could produce rapid improvements in baseline lung function of up to 30% in patients with stable, mild-to-moderate persistent asthma, suggesting an inherent basal airway tone in asthma driven by cys-LTs [96]. The bronchodilator effect is additive to that obtained with short-acting beta-2 agonists [97]. The bronchodilator effect is greater and occurs more rapidly when montelukast is given by the intravenous route [98], suggesting that intravenous cysLTRAs may be effective in status asthmaticus. A study in adult asthmatics with acute, severe asthma showed that intravenous montelukast added to standard therapy improved FEV1 after 10 min and at 2 h, with a lower requirement of beta-2 agonists and fewer treatment failures [99].

74

A.P. Sampson

Although not available for intravenous use, short courses of oral montelukast reduce acute healthcare utilization, symptoms and school absences in children aged 2–14 years with intermittent asthma, when treatment is instigated at the onset of an acute exacerbation or upper respiratory tract infection [100].

Chronic Asthma Many long-term studies in adults and children (aged 6–14 years) with mild-tomoderate persistent asthma have demonstrated that, cysLTRAs improve FEV1 and secondary outcomes [1, 2, 96]. Typically, oral cysLTRAs over 2–6 months produce 7–16% increases in FEV1, with 30–50% reductions in symptom scores, night time awakenings, use of beta-2 agonists or oral corticosteroids, acute healthcare contacts, and days lost from work/school [101–103]. Similar outcomes are seen with zileuton [104]. The benefits are observed in patients with or without concurrent inhaled corticosteroid therapy, and occur within hours or days.They are sustained over the duration of the trials, with a prompt return to baseline values on withdrawal of the cysLTRA. In a 12-month trial, oral montelukast therapy also reduced exacerbations and use of inhaled corticosteroids in children aged 2–5 years with intermittent asthma exacerbations associated with respiratory infection [105].

Anti-Inflammatory and Remodeling Effects CysLTRA has multiple anti-inflammatory effects in vitro and in animal models, including reductions in airway eosinophilia and the prevention of airway remodeling [59, 106]. In clinical trials, inflammatory markers are usually secondary to objective measures of lung function and subjective measures of disease severity, but multiple-dose studies of cysLTRAs consistently show modest (~30%) reductions in blood eosinophils in mild-moderate asthma and in SAR [48,107]. CysLTRAs also reduce exhaled NO in children with asthma, although not in SAR [48, 49]. The effect is truly anti-inflammatory and not simply due to bronchodilation, as it is not mimicked by a short-acting beta-2 agonist, while it appears to be masked by ICS [108]. The impact of cysLTRA therapy on aspects of airway remodeling such as subepithelial fibrosis and smooth muscle hyperplasia has not been investigated in clinical trials. However, a study in mild asthmatic subjects found that oral montelukast for eight weeks marginally reduced the numbers of bronchial mucosal myofibroblasts induced by repeated low-dose inhaled allergen challenge, although this did not reach significance compared to placebo treatment [109]. Evidence that a cysLTRA, but not a corticosteroid, can reverse established airway remodeling in mice makes such clinical studies a high research priority.

Antileukotrienes in Asthma and Rhinitis

75

Comparison with Other Asthma Therapies In adults with mild-to-moderate asthma, oral therapy with antileukotriene drugs has been reported to show improvements in lung function, beta-2 agonist use, and symptoms comparable to those obtained with sodium cromoglycate or oral theophylline [110,111]. The most important comparative studies however are those with inhaled corticosteroids (ICS) and long-acting beta-2 agonists (LABA). Well-designed studies in persistent asthma of all severities in children [112] as well as adults [107,113,114] indicate that cysLTRA is not as effective on the average in improving FEV1 as low-dose ICS, including fluticasone and beclomethasone (Fig. 2a), although the ICS is generally more effective on secondary outcomes. Nevertheless, the MOSAIC study in children aged 6-14 years with mild asthma failed to show statistically significant inferiority of montelukast to fluticasone in the number of rescue-free days [115]. In clinical trials, average responses to ICS may be skewed upwards by a small proportion (<10%) of steroid hyper-responders (FEV1 improvement >50%), with the majority of subjects showing a range of improvements similar to the LTRA [107] (Fig. 2b). Commensurate with their

Fig. 2 (a) Comparison of mean changes in forced expiratory volume in one second (FEV1) in adult chronic asthmatics treated for 12 weeks with oral montelukast (black circles; 10 mg once daily; n = 354), inhaled beclomethasone (black triangles; 200 mg twice daily by spacer; n = 233) or placebo (open squares) (n = 215). Dotted lines indicate patients switched from montelukast to placebo (n = 52) or beclomethasone to placebo (n = 43) for a further 3-week washout period

Fig. 2 (continued) (b) Distribution of treatment responses for FEV1. Hatched bars indicate patients receiving montelukast (10 mg once daily) and white bars those receiving inhaled beclomethasone (200 mg twice daily). From [107] with permission

Fig. 3 Difference in FEV1 response in an 8-week crossover trial of inhaled fluticasone (100 mg twice daily) and oral montelukast (5 or 10 mg once daily) in asthmatic children aged 6–17 years. Only 45% of children experienced an FEV1 improvement of 7.5% or greater, and of these, about one-quarter showed a better response to montelukast than to fluticasone. From [118] with permission

Antileukotrienes in Asthma and Rhinitis

77

respective molecular mechanisms, the onset of action of cysLTRAs is more rapid than ICS, often within the first day of treatment, but the benefits of ICS overtake those of the cysLTRA after 2–3 weeks. In longer-term “open extension” studies, which mimic real-world asthma, the efficacy of cysLTRAs may improve relative to ICS due to better patient compliance with the nonsteroidal drug [116]. However, a study of hospitalizations and healthcare costs for 1 year following initiation of therapy in a practice setting showed lower costs and fewer hospitalizations for fluticasone compared to zafirlukast [117]. Individual patients may nevertheless have differing experiences with these drugs. In a crossover study comparing 8 weeks of inhaled fluticasone and oral montelukast in asthmatic children aged 6–17 years, only about half the children responded to therapy. Of the responders, more were likely to respond to fluticasone than to oral montelukast. However, in a significant minority montelukast was the superior drug, with favorable response to fluticasone being associated with blood eosinophilia, exhaled NO and serum IgE levels, and favorable response to the cysLTRA being linked to younger age and shorter disease duration [118] (Fig. 3).

Add-on Therapy and Steroid-Tapering Trials The rationale of add-on therapy is the apparent inability of oral or inhaled corticosteroids to inhibit cys-LT synthesis in vivo in normal and asthmatic subjects, although most published studies are short-term [119–121]. CysLTRA may therefore provide additional benefit when combined with ICS or oral corticosteroids, particularly as a shallow dose-response curve provides only marginal improvements with increased ICS dosages. Addition of a second drug like salmeterol, theophylline or a cysLTRA may therefore be preferable to increasing the ICS dosage. Add-on therapy can be examined in three contexts: (1) adding a cysLTRA to ICS therapy as an alternative to maintaining or increasing the ICS dosage in poorlycontrolled asthma, (2) enabling the tapering of existing ICS dosage by adding a cysLTRA while maintaining good asthma control, and (3) comparison of cysLTRA plus ICS cotherapy against cotherapy with LABA plus ICS – typically salmeterol and fluticasone. Compared with low-dose beclomethasone alone, adding oral montelukast to therapy of patients with moderate asthma produced a modest improvement in FEV1 and consistent improvements in secondary outcomes [122]. In patients with severe asthma receiving high-dose ICS (>1600 mg/d of beclomethasone or equivalent), the addition of zafirlukast at double the standard dose (80 mg/d) similarly improved primary and secondary outcomes [123]. Similar results were seen when montelukast was added to budesonide in children [124], although it failed to provide additional benefit in a short-term study in very severe asthmatics already taking three controller medications [125]. In steroid dose-doubling studies, adding oral montelukast has been shown to be at least as effective as doubling the daily dose of budesonide from 800 to 1600 mg/d

78

A.P. Sampson

Fig. 4 In the COMPACT study, adult asthmatics inadequately controlled on 800 mg of budesonide daily who were randomized to receive oral montelukast (10 mg daily) in addition to budesonide (solid line) showed a more rapid improvement in morning peak expiratory flow (AM PEF) than those randomized to receive a doubled budesonide dose (1600 mg daily; dashed line). From [126] with permission

in mild-to-moderate adult asthmatics, across a wide range of measures including time of onset, morning PEF, symptom scores, night-time awakenings, beta-2 agonist use and asthma QoL [126, 127] (Fig. 4). The combination of montelukast and budesonide is superior to doubling the budesonide dose in asthmatics with or without comorbid SAR [128]. Tapering studies suggest that asthma control can be maintained by adding a cysLTRA, while reducing ICS dosage [129, 130]. In the second of these studies, the ICS dose was carefully tapered to the lowest possible to maintain control during the run-in period, and adding montelukast allowed a further 47% reduction compared to 30% in the placebo group. An updated Cochrane meta-analysis supports the view that cysLTRAs are effective as add-on therapy and as steroid-sparing agents, but summarized their effects on lung function as being modest [131]. Finally, a number of conflicting studies have compared the combination of LTRA plus ICS versus a LABA plus ICS in patients poorly controlled on ICS alone. In one 48-week study, 2000 uncontrolled asthmatics on 200 mg/d fluticasone were randomized to receive in addition either montelukast (10 mg/d) or salmeterol (100 mg/d) [132]; the combinations were equally effective on time to first asthma attack, asthma exacerbations, nocturnal awakenings, and asthma QoL, while the montelukast / fluticasone cotherapy was superior in reducing blood eosinophilia. The salmeterol / fluticasone combination was superior on lung function outcomes. Other studies of similar drug combinations also show better inflammatory marker outcomes with the LTRA/ICS combination and greater lung function improvements with the LABA/ICS combination [133–136]. The latter phenomenon may be related to the usual clinical trial entry criterion of reversibility with a short-acting

Antileukotrienes in Asthma and Rhinitis

79

beta-2 agonist; many asthmatics may not meet this criterion and it could therefore bias study populations towards patients most likely to show a strong bronchodilator response to a LABA. Overall, the differences between LTRA/ICS and LABA/ICS combinations may be clinically insignificant [137].

Efficacy of Antileukotriene Drugs in Allergic Rhinitis Monotherapy Cysteinyl-LTs mimic many of the features of allergic rhinitis, particularly congestion and rhinorrhea [3], with mast cells, eosinophils and basophils within the nasal mucosa all being likely sources of these mediators [72]. An early study of zafirlukast showed improvements in nasal congestion, and to a lesser extent rhinorrhoea and sneezing, in adult patients with acute SAR, with no effect on nasal itch or eye symptoms [138]. It was shown that zafirlukast reduced eosinophils in nasal lavage fluid and increased ciliary beat frequency in SAR patients [139], reduced symptoms and improved tolerability of a cat allergen challenge [140]. In a 6-week winter study, daytime and nighttime nasal symptoms, global evaluations, and quality of life were improved by montelukast compared to placebo in patients with perennial allergic rhinitis [141]. A meta-analysis confirmed that montelukast and antihistamines are equally effective as monotherapies when compared with placebo for SAR symptoms and quality of life, but that both are inferior to intranasal corticosteroids [142].

Combination Therapy Rhinitis symptoms, particularly itch, are also associated with histamine release, and a combination of the cysLTRA montelukast and the antihistamine loratadine was better than either drug alone in a 2-week springtime study in SAR patients for symptoms including itch, rhinorrhoea, and sneezing; the exception was nasal congestion in which the combination proved no better than montelukast alone [143]. An autumn (fall) study however showed only modest benefits from adding montelukast to loratadine on nasal symptom scores and secondary outcomes [144]. The combination of montelukast and the antihistamine cetirizine has been shown to be as effective as the intranasal corticosteroid mometasone in improving SAR, particularly in domiciliary measures of nasal peak flow and symptom scores [145] (Fig. 5). A meta-analysis of eight large studies in SAR and PAR confirms that combining montelukast with an antihistamine is well-tolerated and generally more effective than either drug-type given as monotherapy, and that in many cases the combination is as effective as nasal steroids [146]. The meta-analysis also points to

80

A.P. Sampson

Fig. 5 In 22 patients with seasonal allergic rhinitis (SAR), the combination of oral montelukast (10 mg) with the histamine H1 receptor antagonist cetirizine (10 mg) given once daily produced a significant reduction in total nasal symptom score similar to that produced by the intranasal corticosteroid mometasone furoate (200 mg once daily). From [145] with permission

the concomitant benefits of oral cysLTRA therapy in patients with comorbid asthma and allergic rhinitis, in line with the ARIA recommendations on treating allergic inflammation concomitantly in the upper and lower airways [147]

Safety, Compliance, and Adherence Antileukotriene drugs are generally well tolerated in clinical trials and in routine clinical practice [148–150], with headache being the most frequently reported adverse event in large-scale prescription-event monitoring studies [150]. The 5-LO inhibitor zileuton is associated with a 3.5% incidence of serum alanine aminotransferase levels rising above three times the upper limit of normal [104], usually within the first 2–3 months of treatment. Hepatic function tests are therefore recommended over the first year of zileuton treatment, but cysLTRA do not produce a similar incidence of hepatic enzyme changes. Rare severe hepatic reactions have been reported with zafirlukast [151], which also has pharmacokinetic interactions with food and with warfarin and theophylline that require dosage adjustments. Reports of a rare eosinophilic vasculitis (Churg–Strauss syndrome) emerging in patients initiated on cysLTRA therapy are usually accounted for by ill-advised concomitant reductions in systemic corticosteroid dosage that allow the unmasking of underlying eosinophilic disease [148, 152]. A similar phenomenon can occur with other antiasthma drugs [153].

Antileukotrienes in Asthma and Rhinitis

81

Variability in Clinical Response Asthma and allergic rhinitis are inherently variable in intensity overtime. There is a perception however, of an unusually high variability in clinical response to cysLTRA therapy, but this is not entirely justified by the evidence. In routine clinical practice, 66% of asthmatics report lung function improvements, with 8% reporting a dramatic improvement [149] Lung function improvements with montelukast follow a bell-shaped (Gaussian) distribution with no evidence of distinct populations of responders and nonresponders [107]. The distribution of responses is very similar to that seen with low-dose inhaled beclomethasone in the same patients. In individual patients, the clinical response to antileukotriene therapy nevertheless shows consistency overtime [154], suggesting a real biological basis for variability that may include genetic factors. Polymorphism in the 5-LO, LTC4 synthase and CysLTR2 genes has been linked to the clinical response to antileukotriene therapy in some studies [155–158] but not in all [159]. LTC4 synthase polymorphism is also linked with baseline lung function impairment in asthma [160] and allergic rhinitis susceptibility [161]. Genetic factors may also underlie the marked variability in bronchodilator response to beta-2 agonists and the predisposition of LABA to induce tolerance to short-acting beta-2 agonists used as rescue medication [162]. Overall, the heterogeneity of therapeutic response to antiasthma drugs is similar for glucocorticoids, beta-2 agonists, and antileukotriene drugs [154]. This heterogeneity reinforces the need for asthma management guidelines to be flexible to allow clinicians to tailor therapy appropriately to individual patients.

Summary Antileukotriene drugs were developed in the 1990s to block the synthesis or activity of the leukotriene family of lipid mediators, which has well-established roles as potent bronchoconstrictor agents with additional proinflammatory effects on blood vessels, mucus glands, and leukocytes. The most successful antileukotriene drugs are the cysteinyl-leukotriene type 1-receptor antagonists (cysLTRA) which became available for clinical use in asthma management in the late 1990s and for allergic rhinitis in many countries since 2003. CysLTRAs are safe and effective oral prophylactic medications that, depending on national guidelines, can be used as controller monotherapy or as second-line therapy added to inhaled corticosteroids. Their use seems well supported by scientific rationale and by clinical evidence in exercise-induced bronchoconstriction, in aspirin-exacerbated respiratory disease, and in patients with concomitant allergic rhinitis. Further research may identify additional asthma phenotypes or genotypes that predict good clinical response to antileukotriene drugs. Clinical studies are also required to determine whether antileukotriene drugs can modify chronic processes of airway remodeling.

82

A.P. Sampson

References 1. Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1874. 2. Montuschi P, Sala A, Dahlen SE, Folco G (2007) Pharmacological modulation of the leukotriene pathway in allergic airway disease. Drug Discov Today 12:404–412. 3. Peters-Golden M, Gleason MM, Togias A (2006) Cysteinyl-leukotrienes: multifunctional mediators in allergic rhinitis. Clin Exp Allergy 36:689–703. 4. Drazen JM, Israel E, O’Byrne PM (1999) Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 340:197–206. 5. Bruynzeel PL, Kok PT, Hamelink ML, Kijne AM, Verhagen J (1985) Exclusive leukotriene C4 synthesis by purified human eosinophils induced by opsonized zymosan. FEBS Lett 189:350-354. 6. Coffey MJ, Wilcoxen SE, Peters-Golden P (1994) Increases in 5-lipoxygenase activating protein expression account for enhanced capacity for 5-lipoxygenase metabolism that accompanies differentiation of peripheral blood monocytes into alveolar macrophages. Am J Respir Cell Mol Biol 11:153–158. 7. Freeland HS, Schleimer RP, Schulman ES, Lichtenstein LM, Peters SP (1988) Generation of leukotriene B4 by human lung fragments and purified human lung mast cells. Am Rev Respir Dis 138:389-394. 8. Jakobsson PJ, Steinhilber D, Odlander B, Radmark O, Claesson HE, Samuelsson B (1992) On the expression and regulation of 5-lipoxygenase in human lymphocytes. Proc Natl Acad Sci USA 89:3521-3525. 9. Behera AK, Kumar M, Matsuse H, Lockey RF, Mohapatra SS (1998) Respiratory syncytial virus induces the expression of 5-lipoxygenase and endothelin-1 in bronchial epithelial cells. Biochem Biophys Res Commun 251:704–709. 10. James AJ, Lackie PM, Cazaly AM, Sayers I, Penrose JF, Holgate ST, Sampson AP (2007) Human bronchial epithelial cells express an active and inducible biosynthetic pathway for leukotrienes B4 and C4. Clin Exp Allergy 37:880–892. 11. Medina JF, Barrios C, Funk CD, Larsson O, Haeggstrom J, Radmark O (1990) Human fibroblasts show expression of the leukotriene A4 hydrolase gene, which is increased after simianvirus-40 transformation. Eur J Biochem 191:27–31. 12. Sjostrom M, Jakobsson PJ, Heimburger M, Palmblad J, Haeggstrom JZ (2001) Human umbilical vein endothelial cells generate leukotriene C4 via microsomal glutathione S-transferase type 2 and express the CysLT1 receptor. Eur J Biochem 268:2578–2586. 13. James AJ, Penrose JF, Cazaly AM, Holgate ST, Sampson AP (2006) Human bronchial fibroblasts express the 5-lipoxygenase pathway. Respir Res 7:102. 14. Buckner CK, Krell RD, Laravuso RB, Coursin DB, Bernstein PR, Will JA (1986) Pharmacological evidence that human intralobar airways do not contain different receptors that mediate contractions to LTC4 and D4. J Pharmacol Exp Ther 237:558–562. 15. Labat C, Ortiz JL, Norel X, Gorenne I, Verley J, Abram TS, Cuthbert NJ, Tudhope SR, Norman P, Gardiner P (1992) A second cysteinyl leukotriene receptor in human lung. J Pharmacol Exp Ther 263:800–805. 16. Lynch KR, O’Neill GP, Liu Q, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z, Connolly BM, Bai C, Austin CP, Chateauneuf A, Stocco R, Greig GM, Kargman S, Hooks SB, Hosfield E, Williams DLJ, Ford-Hutchinson AW, Caskey CT, Evans JF (1999) Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399:789–793. 17. Heise CE, O’Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im DS, Stocco R, Bellefeuille JN, Abramovitz M, Cheng R, Williams DL, Zeng Z, Liu Q, Ma L, Clements MK, Coulombe N, Liu Y, Austin CP, George SR, O’Neill GP, Metters KM, Lynch KR, Evans JF (2000) Characterization of the human CysLT2 receptor. J Biol Chem 275:30531–30536.

Antileukotrienes in Asthma and Rhinitis

83

18. Takasaki J, Kamohara M, Matsumoto M, Saito T, Sugimoto T, Ohishi T, Ishii H, Ota T, Nishikawa T, Kawai Y, Masuho Y, Isogai T, Suzuki Y, Sugano S, Furuichi K (2000) The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT2 receptor. Biochem Biophys Res Commun 274:2 316–322. 19. Figueroa DJ, Breyer RM, Defoe SK, Kargman S, Daugherty BL, Waldburger K, Liu Q, Clements M, Zeng Z, O’Neill GP, Jones TR, Lynch KR, Austin CP, Evans JF (2001) Expression of the cys-LT1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med 163:226–233. 20. Gauvreau GM, Plitt JR, Baatjes A, MacGlashan DW (2005) Expression of functional cysleukotriene receptors by human basophils. J Allergy Clin Immunol 116:80–87. 21. Izumi T, Yokomizo T, Obinata H, Ogasawara H, Shimizu T (2002) Leukotriene receptors: classification, gene expression and signal transduction. J Biochem 132:1–6 22. Ciana P, Fumagalli M, Trincavelli ML, Verderio C, Rosa P, Lecca D, Ferrario S, Parravicini C, Capra V, Gelosa P, Guerrini U, Belcredito S, Cimino M, Sironi L, Tremoli E, Rovati GE, Martini C, Abbracchio MP (2006) The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J 25:4615–4627. 23. Sampson SE, Costello JF, Sampson AP (1997) The effect of inhaled leukotriene B4 in normal and in asthmatic subjects. Am J Respir Crit Care Med 155:1789–1792. 24. Weiss JW, Drazen JM, Coles N, McFadden ER, Lewis R, Weller P, Corey EJ, Austen KF (1982) Bronchoconstrictor effects of leukotriene C in humans. Science 216:196–198. 25. Griffin M, Weiss JW, Leitch AG, McFadden ER, Corey EJ, Austen KF, Drazen JM (1983) Effects of leukotriene D on the airways in asthma. N Engl J Med 308:436–439. 26. Adelroth E, Morris MM, Hargreave FE, O’Byrne PM (1986) Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls. N Engl J Med 315:480–484. 27. Arm JP, Spur BW, Lee TH (1988) The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects. J Allergy Clin Immunol 82:654–660. 28. Joris I, Majno G, Corey EJ, Lewis RA (1987) The mechanism of vascular leakage induced by leukotriene E4. Am J Pathol 126:19–24. 29. Beller TC, Friend DS, Maekawa A, Lam BK, Austen KF, Kanaoka Y (2004) Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis. Proc Natl Acad Sci USA 101:3047–3052. 30. Camp RD, Coutts AA, Greaves MW, Kay AB, Walport MJ (1983) Responses of human skin to intradermal injection of leukotrienes C4, D4 and B4. Br J Pharmacol 80:497–502. 31. Bisgaard H (1987) Vascular effects of LTD4 in human skin. J Invest Dermatol 88:109–114. 32. Bisgaard H, Olsson P, Bende M (1986) Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans. Clin Allergy 16:289–297. 33. Woodward DF, Weichman BM, Gill CA, Wasserman MA (1983) The effect of synthetic leukotrienes on tracheal microvascular permeability. Prostaglandins 25:131–142. 34. Pedersen KE, Bochner BS, Undem BJ (1987) Cysteinyl leukotrienes induce P-selectin expression in human endothelial cells via a non-CysLT1 receptor-mediated mechanism. J Pharmacol Exp Ther 281:655–662. 35. Sjostrom M, Johansson AS, Schroder O, Qiu H, Palmblad J, Haeggstrom JZ (2003) Dominant expression of the CysLT2 receptor accounts for calcium signaling by cys-leukotrienes in human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 23:e37–e41. 36. Symon FA, Lawrence MB, Williamson ML, Walsh GM, Watson SR, Wardlaw AJ (1996) Functional and structural characterization of the eosinophil P-selectin ligand. J Immunol 157:1711–1719. 37. Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH (1993) Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet 341:989–990. 38. Diamant Z, Hiltermann JT, Van Rensen EL, Callenbach PM, Veselic-Charvat M, Van der Veen H, Sont JK, Sterk PJ (1997) The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma. Am J Respir Crit Care Med 155:1247–1253.

84

A.P. Sampson

39. Spada CS, Nieves AL, Krauss AH, Woodward DF (1994) Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol 55:183–191. 40. Sehmi R, Wardlaw AJ, Cromwell O, Kurihara K, Waltmann P, Kay AB (1992) Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects. Blood 79:2952–2959. 41. Lee E, Robertson T, Smith J, Kilfeather S (2000) Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am J Respir Crit Care Med 161:1881–1886. 42. Braccioni F, Dorman SC, O’Byrne PM, Inman MD, Denburg JA, Parameswaran K, Baatjes AJ, Foley R, Gauvreau GM (2002) The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. J Allergy Clin Immunol 110:96–101. 43. Fregonese L, Silvestri M, Sabatini F, Rossi GA (2002) Cysteinyl leukotrienes induce human eosinophil locomotion and adhesion molecule expression via a CysLT1 receptor-mediated mechanism. Clin Exp Allergy 32:745–750. 44. Sampson AP, Pizzichini E, Bisgaard H (2003) Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation. J Allergy Clin Immunol 111 (Suppl 1):S49–S59. 45. Kim DC, Hsu FI, Barrett NA, Friend DS, Grenningloh R, Ho IC, Al-Garawi A, Lora JM, Lam BK, Austen KF, Kanaoka Y (2006) Cysteinyl leukotrienes regulate Th2 cell-dependent pulmonary inflammation. J Immunol 176:4440–4448. 46. Tohda Y, Nakahara H, Kubo H, Haraguchi R, Fukuoka M, Nakajima S (1999) Effects of ONO-1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma. Clin Exp Allergy 29:1532–1536. 47. Bisgaard H, Loland L, Oj JA (1999) NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 160:1227–1231. 48. Razi C, Bakirtas A, Harmanci K, Turktas I, Erbas D (2006) Effect of montelukast on symptoms and exhaled nitric oxide levels in 7- to 14-year-old children with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 97:767–774. 49. Coles SJ, Neill KH, Reid LM, Austen KF, Nii Y, Corey EJ, Lewis RA (1983) Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins 25:155–170. 50. Bisgaard H, Pedersen M (1987) SRS-A leukotrienes decrease the activity of human respiratory cilia. Clin Allergy 17:95–103. 51. Mygind N, Dahl R, Bisgaard H (2000) Leukotrienes, leukotriene receptor antagonists, and rhinitis. Allergy 55:421–424. 52. Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR (2003) Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol 111 (Suppl 1):S18–S34. 53. Wang CG, Du T, Xu LJ, and Martin JG (1993) Role of leukotriene D4 in allergen-induced increases in airway smooth muscle in the rat. Am Rev Respir Dis 148:413-417. 54. Panettieri RA, Tan EML, Ciocca V, Luttmann MA, Leonard TB, Hay DWP (1998) Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol 19:453–461. 55. Cohen P, Noveral JP, Bhala A, Nunn SE, Herrick DJ, Grunstein MM (1995) Leukotriene D4 facilitates airway smooth muscle cell proliferation via modulation of the IGF axis. Am J Physiol 269:L151–L157. 56. Yoshisue H, Kirkham-Brown J, Healy E, Holgate ST, Sampson AP, Davies DE (2007) Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts. J Allergy Clin Immunol 119:132–140. 57. Medina L, Perez Ramos J, Ramirez R, Selman M, Pardo A (1994) Leukotriene C4 upregulates collagenase expression and synthesis in human lung fibroblasts. Biochim Biophys Acta 1224:168–174.

Antileukotrienes in Asthma and Rhinitis

85

58. Leikauf GD, Claesson HE, Doupnik CA, Hybbinette S, Grafstrom RC (1990) Cysteinyl leukotrienes enhance growth of human airway epithelial cells. Am J Physiol 259: L255-L261. 59. Henderson WR, Tang LO, Chu SJ, Tsao SM, Chiang GK, Jones F, Jonas M, Pae C, Wang H, Chi EY (2002) A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med 165:108–116. 60. Henderson WR, Chiang GK, Tien YT, Chi EY (2006) Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med 173:718–728. 61. Beller TC, Maekawa A, Friend DS, Austen KF, Kanaoka Y (2004) Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J Biol Chem 279:46129–46134. 62. Westcott JY (1999) The measurement of leukotrienes in human fluids. Clin Rev Allergy Immunol 17:153–177. 63. Taylor GW, Taylor IK, Black PN, Maltby N, Fuller RW, Dollery CT (1989) Urinary leukotriene E4 after allergen challenge and in acute asthma and allergic rhinitis. Lancet 1:584–588. 64. Green SA, Malice MP, Tanaka W, Tozzi CA, Reiss TF (2004) Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax 59:100–104. 65. Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY (1990) Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis 142:112–119. 66. O’Sullivan S, Roquet A, Dahlen B, Dahlen S, Kumlin M (1998) Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions. Clin Exp Allergy 28:1332–1339. 67. Szczeklik A, Sladek K, Dworski R, Nizankowska E, Soja J, Sheller J, Oates J (1996) Bronchial aspirin challenge causes specific eicosanoid response in aspirin-sensitive asthmatics. Am J Respir Crit Care Med 154:1608–1614. 68. Sanak M, Kielbasa B, Bochenek G, Szczeklik A (2004) Exhaled eicosanoids following oral aspirin challenge in asthmatic patients. Clin Exp Allergy 34:1899–1904. 69. Creticos PS, Peters SP, Adkinson NFJ, Naclerio RM, Hayes EC, Norman PS, Lichtenstein LM (1984) Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N Engl J Med 310:1626–1630. 70. Miadonna A, Tedeschi A, Leggieri E, Lorini M, Folco G, Sala A, Qualizza R, Froldi M, Zanussi C (1987) Behavior and clinical relevance of histamine and leukotrienes C4 and B4 in grass pollen-induced rhinitis. Am Rev Respir Dis 136:357–362. 71. Volovitz B, Osur SL, Bernstein JM, Ogra PL (1988a) Leukotriene C4 release in upper respiratory mucosa during natural exposure to ragweed in ragweed-sensitive children. J Allergy Clin Immunol 82:414–418. 72. Higashi N, Taniguchi M, Mita H, Ishii T, Akiyama K (2003) Nasal blockage and urinary LTE4 concentration in patients with seasonal allergic rhinitis. Allergy 58:476–480. 73. Volovitz B, Welliver RC, De-Castro G, Krystofik DA, Ogra PL (1988b) The release of leukotrienes in the respiratory tract during infection with respiratory syncytial virus: role in obstructive airway disease. Pediatr Res 24:504–507. 74. Smith LJ, Geller S, Ebright L, Glass M, Thyrum PT (1990) Inhibition of leukotriene D4induced bronchoconstriction in normal subjects by the oral LTD4 receptor antagonist ICI 204,219. Am Rev Respir Dis 141:988–992. 75. Cheng JB (1992) Early efficacy data with a newer generation of LTD4 antagonists in antiasthma trials: early promise for a single mediator antagonist. Pulmon Pharmacol 5:77-80. 76. De Lepeleire I, Reiss TF, Rochette F, Botto A, Zhang J, Kundu S, Decramer M (1997) Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma. Clin Pharmacol Ther 61:83–6192. 77. Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery CT (1991) Effect of cysteinyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet 337:690–694.

86

A.P. Sampson

78. Findlay SR, Barden JM, Easley CB, Glass M (1992) Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol 89:1040–1045. 79. Roquet A, Dahlen B, Kumlin M, Ihre E, Anstren G, Binks S, Dahlen SE (1997) Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergeninduced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 155:1856–1863. 80. Diamant Z, Grootendorst DC, Veselic-Charvat M, Timmers MC, De Smet M, Leff JA, Seidenberg BA, Zwinderman AH, Peszek I, Sterk PJ (1999) The effect of montelukast (MK0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 29:42–51. 81. Finnerty JP, Wood-Baker R, Thomson H, Holgate ST (1992) Role of leukotrienes in exerciseinduced asthma: inhibitory effect of ICI 204219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis 145:746–749. 82. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, Dockhorn R, Kundu S, Zhang J, Seidenberg BC, Reiss TF (1998) Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 339:147–152. 83. Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, Knorr B (1998) Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 133:424–428. 84. Bisgaard H, Nielsen KG (2000) Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children. Am J Respir Crit Care Med 162:187–190. 85. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, Ghannam AF, DeLucca PT, Gormley GJ, Pearlman DS (2000) Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction: a randomized, double-blind trial. Exercise Study Group. Ann Intern Med 132:97–104. 86. Kumlin M, Dahlen B, Bjorck T, Zetterstrom O, Granstrom E, Dahlen SE (1992) Urinary excretion of leukotriene E4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4, and histamine in asthmatics. Am Rev Respir Dis 146:96–103. 87. Sestini P, Armetti L, Gambaro G, Pieroni MG, Refini RF, Sala A, Vaghi A, Folco GC, Bianco S, Robuschi M (1996) Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma. Am J Respir Crit Care Med 153:572–575. 88. Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen KF, Holgate ST, Sampson AP (1998) Overexpression of LTC4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 101:834–846. 89. Adamjee J, Suh YJ, Park HS, Choi JH, Penrose JF, Lam BK, Austen KF, Cazaly AM, Wilson SJ, Sampson AP (2006) Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J Pathol 209:392–399. 90. Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Rubin P, Cohn J, White MV, Igarashi Y, Kaliner MA, Drazen JM, Israel E (1994) Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. J Allergy Clin.Immunol 94:1046–1056. 91. Christie PE, Smith CM, Lee TH (1991) The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis 144:957–958. 92. Stevenson DD, Simon RA, Mathison DA, Christiansen SC (2000) Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics. Ann Allergy Asthma Immunol 85:477–482. 93. Dahlen B, Nizankowska E, Szczeklik A, Zetterstrom O, Bochenek G, Kumlin M, Mastalerz L, Pinis G, Swanson LJ, Boodhoo TI, Wright S, Dube LM, Dahlen SE (1998) Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 157:1187–1194.

Antileukotrienes in Asthma and Rhinitis

87

94. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, Lumry WR, Picado C, Stevenson DD, Bousquet J, Pauwels R, Holgate ST, Shahane A, Zhang J, Reiss TF, Szczeklik A (2002) Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 165:9–14. 95. Micheletto, Tognella S, Visconti M, Pomari C, Trevisan F, Dal Negro RW (2004) Montelukast 10 mg improves nasal function and nasal response to aspirin in ASA-sensitive asthmatics: a controlled study vs placebo. Allergy 59:289–294. 96. Holgate ST, Bradding P, Sampson AP (1996) Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol 98:1–13. 97. Gaddy JN, Margolskee DJ, Bush RK, Williams VC, Busse WW (1992) Bronchodilation with a potent and selective leukotriene D4 receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis 146:358–363. 98. Dockhorn RJ, Baumgartner RA, Leff JA, Noonan M, Vandormael K, Stricker W, Weinland DE, Reiss TF (2000) Comparison of the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax 55:260–265. 99. Camargo CA, Smithline HA, Malice MP, Green SA, Reiss TF (2003) A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 167:528–533. 100. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, Lee AJ, Turner J, Sant M (2007) Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 175:323–329. 101. Suissa S, Dennis R, Ernst P, Sheehy O, Wood Dauphinee S (1997) Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med 126:177–183. 102. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB (1998) Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 158:1213–1220. 103. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, Becker A (1998) Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 279:1181–1186. 104. Lazarus SC, Lee T, Kemp JP, Wenzel S, Dube LM, Ochs RF, Carpentier PJ, Lancaster JF (1998) Safety and clinical efficacy of zileuton in patients with chronic asthma. Am J Manag Care 4:841–848. 105. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P (2005) Montelukast reduces asthma exacerbations in 2-5-year-old children with intermittent asthma. Am J Respir Crit Care Med 171:315–322. 106. Peters-Golden M (2003) Do anti-leukotriene agents inhibit asthmatic inflammation? Clin Exp Allergy 33:721–724. 107. Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX, Seidenberg BC, Reiss TF (1999) Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med 130:487–495. 108. Buchvald F, Bisgaard H (2003) Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide. Ann Allergy Asthma Immunol 91:309–313. 109. Kelly MM, Chakir J, Vethanayagam D, Boulet LP, Laviolette M, Gauldie J, O’Byrne PM (2006) Montelukast treatment attenuates the increase in myofibroblasts following low-dose allergen challenge. Chest 130:741–753. 110. Nathan RA, Minkwitz MC, Bonuccelli CM (1999) Two first-line therapies in the treatment of mild asthma: use of peak flow variability as a predictor of effectiveness. Ann Allergy Asthma Immunol 82:497–503.

88

A.P. Sampson

111. Schwartz HJ, Petty T, Dube LM, Swanson LJ, Lancaster JF (1998) A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group. Arch Intern Med 158:141–148. 112. Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, V. M. Chinchilli VM, Lemanske RM, Strunk RC, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM (2006) Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 117:45–52. 113. Bleecker ER, Welch MJ, Weinstein SF, Kalberg C, Johnson M, Edwards L, Rickard KA (2000) Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma. J Allergy Clin Immunol 105:1123–1129. 114. Busse W, Raphael GD, Galant S, Kalberg C, Goode-Sellers S, Srebro S, Edwards L, Rickard K (2001) Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial. J Allergy Clin Immunol 107:461–468. 115. Garcia-Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P (2005) Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study. Pediatrics 116:360–369. 116. Williams B, Noonan G, Reiss TF, Knorr B, Guerra J, White R, Matz J (2001) Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older. Clin.Exp.Allergy 31:845–854. 117. Stempel, Meyer JW, Stanford RH, Yancey SW (2001) One-year claims analysis comparing inhaled fluticasone propionate with zafirlukast for the treatment of asthma. J Allergy Clin Immunol. 107:94–98. 118. Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, Zeiger RS, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM (2005) Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 115:233–242. 119. O’Shaughnessy KM, Wellings R, Gillies B, Fuller RW (1993) Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis 147:1472–1476. 120. Dworski R, Fitzgerald GA, Oates JA, Sheller JR (1994) Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med 149:953–959. 121. Gyllfors P, Dahlen SE, Kumlin M, Larsson K, Dahlen B (2006) Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate. J Allergy Clin Immunol 118:78–83. 122. Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet JC, Peszek I, Zhang Z, Reiss TF (1999) Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 160:1862–1868. 123. Virchow JC, Prasse A, Naya I, Summerton L, Harris A (2000) Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 162:578–585. 124. Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, Laessig W, Schuster A, Perez-Frias J, Sekerel BE, Menten J, Leff JA (2001) Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study. J Pediatr 138:694–698. 125. Robinson DS, Campbell D, Barnes PJ (2001) Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 357:2007–2011. 126. Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, Konstantopoulos S, Rojas R, Van Noord JA, Pons M, Gilles L, Leff JA (2003) Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 58:211–216.

Antileukotrienes in Asthma and Rhinitis

89

127. Barnes N, Laviolette M, Allen D, Flood-Page P, Hargreave F, Corris P, Tate H, Parker D, Pavord I (2007) Effects of montelukast compared to double dose budesonide on airway inflammation and asthma control. Respir Med 101:1652–1658. 128. Price DB, Swern A, Tozzi CA, Philip G, Polos P (2006) Effect of montelukast on lung function in asthma patients with allergic rhinitis: analysis from the COMPACT trial. Allergy 61:737–742. 129. Tamaoki J, Kondo M, Sakai N, Nakata J, Takemura H, Nagai A, Takizawa T, Konno K (1997) Leukotriene antagonist prevents exacerbation of asthma during reduction of highdose inhaled corticosteroid. Am J Respir Crit Care Med 155:1235–1240. 130. Lofdahl CG, Reiss TF, Leff JA, Israel E, Noonan MJ, Finn AF, Seidenberg BC, Capizzi T, Kundu S, Godard P (1999) Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. Br Med M 319:87–90. 131. Ducharme F, Schwartz Z, Hicks G, Kakuma R (2004) Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev (2):CD003133. 132. Bjermer L, Bisgaard H, Bousquet J, Fabbri LM, Greening AP, Haahtela T, Holgate ST, Picado C, Menten J, Dass SB, Leff JA, Polos PG (2003) Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. BMJ 327:891. 133. Nelson HS, Busse WW, Kerwin E, Church N, Emmett N, Rickard K, Knobil K (2000) Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 106:1088–1095. 134. Fish JE, Israel E, Murray JJ, Emmett E, Boone R, Yancey SW, Rickard KA (2001) Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 120:423–430. 135. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ (2001a) Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 119:1021–1026. 136. Currie GP, Lee DK, Haggart K, Bates CE, Lipworth BJ (2003) Effects of montelukast on surrogate inflammatory markers in corticosteroid-treated patients with asthma. Am J Respir Crit Care Med 167:1232–1238. 137. Currie G, Lee DK, Srivastava P (2005) Long-acting bronchodilator or leukotriene modifier as add-on therapy to inhaled corticosteroids in persistent asthma? Chest 128:2954–2962. 138. Donnelly AL, Glass M, Minkwitz MC, Casale TB (1995) The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med 151:1734-1739. 139. Phipatanakul W, Eggleston P, Conover-Walker M, Kesavanathan J, Sweitzer D, Wood R (2000) A randomized, double-blind, placebo-controlled trial of the effect of zafirlukast on upper and lower respiratory responses to cat challenge. J Allergy Clin Immunol 105:704–710. 140. Piatti G, Ceriotti L, Cavallaro G, Ambrosetti U, Mantovani M, Pistone A, Centanni S (2003) Effects of zafirlukast on bronchial asthma and allergic rhinitis. Pharmacol Res 47:541–547. 141. Patel P, Philip G, Yang W, Call R, Horak F, LaForce C, Gilles L, Garrett GC, Dass SB, Knorr BA, Reiss TF (2005) Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis. Ann Allergy Asthma Immunol 95:551–557. 142. Wilson AM, O’Byrne PM, Parameswaran K (2004) Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 116:338–344. 143. Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF, Wolfe JD, Reiss TF (2000) Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 105:917–922. 144. Nayak AS, Philip G, Lu S, Malice MP, Reiss TF (2002) Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol 88:592–600.

90

A.P. Sampson

145. Wilson AM, Orr LC, Sims EJ, Lipworth BJ (2001) Effects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotriene receptor antagonists in seasonal allergic rhinitis. Clin Exp Allergy 31:61–68. 146. Nayak A, Langdon RB (2007) Montelukast in the treatment of allergic rhinitis : an evidencebased review. Drugs 67:887–901. 147. Bousquet J (2002) The new ARIA guidelines: putting science into practice. Clin Exp Allergy Rev 2:38–43. 148. Garcia-Marcos L, Schuster A, Perez-Yarza E (2003) Benefit-risk assessment of antileukotrienes in the management of asthma. Drug Saf 26:483–518. 149. Barnes N, Thomas M, Price D, Tate H (2005) The national montelukast survey. J Allergy Clin Immunol 115:47–54. 150. Biswas P, Wilton L, Pearce G, Freemantle S, Shakir S, Mann RD (2001) Pharmacosurveillance and safety of the leukotriene receptor antagonist (LTRA), montelukast. Clin Exp Allergy Rev 1:300–304 151. Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ (2000) Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 133:964–968. 152. Price D (2000) Tolerability of montelukast. Drugs 59:35–42. 153. Martin RM, Wilton LV, Mann RD (1999) Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: retrospective analysis of 58 prescription-event monitoring cohort studies. Pharmacoepidemiol Drug Saf 8:179–189. 154. Drazen JM, Silverman RK, Lee TH (2000) Heterogeneity of therapeutic responses in asthma. Br Med Bull 56:1054–1070. 155. Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J (1999) Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 22:168–170. 156. Sampson AP, Siddiqui S, Buchanan D, Howarth PH, Holgate ST, Holloway JW, Sayers I (2000) Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 55 (Suppl 2):S28–S31. 157. Asano K, Shiomi T, Hasegawa N, Nakamura H, Kudo H, Matsuzaki T, Hakuno H, Fukunaga K, Suzuki Y, Kanazawa M, Yamaguchi K (2002) Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 12:565–570. 158. Klotsman M, York TP, Pillai SG, Vargas-Irwin C, Sharma SS, Van den Oord EJ, Anderson WH (2007) Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics 17:189–196. 159. Currie GP, Lima JJ, Sylvester JE, Lee DK, Cockburn WJ, Lipworth BJ (2003) Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma. Br J Clin Pharmacol 56:422–426. 160. Sayers I, Barton S, Rorke S, Beghe B, Hayward B, Van Eerdewegh P, Keith T, Clough JB, Ye S, Holloway JW, Sampson AP, Holgate AP (2003) Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma. Thorax 58 (5):417–424. 161. Eskandari HG, Unal M, Ozturk OG, Vayisoglu Y, Muslu N (2006) Leukotriene C4 synthase A-444C gene polymorphism in patients with allergic rhinitis. Otolaryngol Head Neck Surg 134:997–1000. 162. Jackson CM, Lipworth B (2004) Benefit-risk assessment of long-acting beta2-agonists in asthma. Drug Saf 27:243–270.

Mechanisms of Action of b2 Adrenoceptor Agonists Ian P. Hall and Ian Sayers

Introduction b2 adrenoceptor agonists have been the main stay bronchodilator agents used for the management of asthma for the last 50 years. These drugs have proven to be the most effective bronchodilators available. The first agent used widely in the management of asthma was isoprenaline (isoproterenol), a nonselective b adrenoceptor agonist. This was replaced by short acting b2 adrenoceptor selective agents, often called SABAs; the main agents used are salbutamol (albuterol) and terbutaline. More recently, long acting b2 agonists (LABAs), which have a prolonged duration of bronchodilator effect, have been developed, the major examples being formoterol and salmeterol. A number of new LABAs are currently in development or phase II/III clinical trials, including agents such as indacaterol. This chapter deals with the molecular pharmacology underlying the control of b2 adrenoceptor signalling.

Adrenoceptor Populations in the Airways Human airways predominantly express b2 adrenoceptors [1,2]. However, three different human b adrenoceptors, namely b1, b2, and b3 adrenoceptors, exist, with different physiological roles. The b1 adrenoceptor is responsible for predominantly mediating the cardiovascular effects of catecholamines, and the b3 adrenoceptor is expressed primarily in adipocytes and the cardiovascular system and is responsible for mediating metabolic and cardiovascular effects (see [3] for a review). A human b4 adrenoceptor has been hypothesized to exist, but, at present, the consensus view is that the pharmacological findings, which have been used to support the existence

I.P. Hall () and I. Sayers Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, NG7 2UH, UK e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_6, © Springer 2010

91

92

I.P. Hall and I. Sayers

of the putative b4 adrenoceptor, are likely to be due to actions at different conformational states of the other known human b adrenoceptors [4].

Molecular Genetics of the Human b2 Adrenoceptor The gene for the human b2 adrenoceptor is located on chromosome 5 q31–33 [5]. The b2 adrenoceptor gene (ADRB2) is an intronless gene, although interestingly at least one open reading frame is present in the 5¢ untranslated region of the gene: this codes for a short peptide also known as the b upstream peptide, or BUP [6, 7]. The human b2 adrenoceptor gene is relatively polymorphic, with two common nonsynonymous single nucleotide polymorphisms (SNPs), resulting in amino acid substitutions at codon 16 (Arg16Gly) and codon 27 (Gln27Glu). A rare polymorphism at codon 164 (Thr164Ile) has also been identified (Fig. 1). The promoter region for the gene also contains a number of SNPs including a SNP in the terminal codon of the 5¢ leader cistron (BUP), which may alter the ability of BUP to modulate translation [8, 9]. A full account of the effects of these polymorphisms can be found in volume 1, pages 205–225.

Structure–Function Relationships of the b2 Adrenoceptor The human b2 adrenoceptor belongs to the superfamily of G protein coupled receptors (GPCRs), typified by rhodopsin like structures with seven transmembrane spanning domains, an extracellular N terminus, and an intracellular C terminus

Arg:39% Glu:43%

Met: <0.001%

Ile: 3%

Fig. 1 Schematic of the human b2 adrenergic receptor with coding region polymorphisms shown. Allele frequencies for the nonsynonymous coding region SNPs are shown, derived from the UK population [56]. Figure adapted from [61]

93

Mechanisms of Action of b2 Adrenoceptor Agonists

[5,10]. Agonist binding is dependent upon the presence of key amino acid residues within the hydrophobic core of the receptor in the third, fourth, and fifth transmembrane spanning domains [10–13]. The third intracellular loop contains amphiphilic regions important for coupling the stimulatory G protein Gs. This third intracellular loop, together with key residues on the long cytoplasmic tail of the receptor, are important sites for receptor regulation by phosphorylation [11–16]. Following agonist binding to the receptor, downstreams signalling is dependent upon the binding of Gs to the receptor complex. Gs exists as heterotrimers of a and bg and subunits: following agonist binding, GDP is released from the a subunit of the complex, leading to the disassociation of the complex. The free a subunit of Gs is then able to stimulate adenylyl cyclase, which results in the elevation of cyclic AMP within the cell. Cyclic AMP, in turn, catalyses the disassociation of protein kinase A regulatory and catalytic subunits: the free catalytic subunit of protein kinase A then phosphorylates key downstream signalling proteins (reviewed in [17]) (Fig. 2). Thus, the activation of protein kinase A mediates the majority of physiological responses driven by the stimulation of this pathway. In addition to physiological effects, which are protein kinase A dependent, there is some evidence that cyclic AMP /protein kinase A independent effects may also contribute to signalling. For example, free Gsa may interact directly with calcium activated potassium channels (BKCa) to stimulate channel activity independent of protein kinase A induced phosphorylation, although the latter also contributes to b agonist induced increases in channel activity [18]. Hence, while there is a good

Beta 2 adrenoceptor agonist BKCa

PKA

Fig. 2 Mechanisms underlying downstream signalling from the b2 adrenoceptor. Adapted from [62]. See text for details. AC = adenylyl cyclase; BKCa = calcium activated potassium channel; PKA = Protein kinase A

94

I.P. Hall and I. Sayers

relationship between the magnitude of cell cyclic AMP responses and physiological responses in general, some inconsistencies can be observed, for example, when comparing the effects of agents such as forskolin, which is able to elevate cell cyclic AMP content independent of receptor activation [18]. In addition, at least in some transformed cell systems, there is evidence that cyclic AMP/protein kinase A independent actions on downstream signalling cascades may result through stimulation of alternative pathways including interactions with the inhibitory G protein Gi and effects on gene transcription activated by MAP kinase dependent signalling pathways [19]. However, many of the transformed cell systems used to detect these effects have a marked overexpression of the b2 adrenoceptor, and whether or not these effects are important in nontransformed cell systems, or in vivo, remains unclear. Although these cyclic AMP independent pathways may be important at least in some cell types for physiological responses, it is still the case that the vast majority of effects of b2 adrenoceptor agonist stimulation are driven by cyclic AMP/protein kinase dependent effects. This signal is also regulated by the breakdown of intracellular cyclic AMP. The only known mechanism which catalyses cyclic AMP breakdown is activation of phosphodiesterase isoenzymes within the cell. The most important class of these enzymes in airway smooth muscle appears to be the type 4 phosphodiesterases (PDE4), and in particular, a specific splice variant, PDE4D5, which appears to act as a key gate keeper regulating cell cyclic AMP levels [20, 21]. For example, although PDE4D is a minor component of total tissue PDE activity, and PDE4D5 an even smaller component, inhibition of PDE4D5 by siRNA approaches produces marked effects on cyclic AMP cascades following b2 adrenoceptor stimulation in airway smooth muscle, possibly, in part, related to the ability of the receptor complex to bind targeted PDE4D5 [21].

Distribution of b2 Adrenoceptor Expression The b2 adrenoceptor is widely expressed in the airways being present in airway smooth muscle, bronchial epithelial cells, and a number of inflammatory cells including mast cells and alveolar macrophages [22, 23]. Stimulation of the b2 adrenoceptor on airway smooth muscle results in cell relaxation. This is the most important effect of inhaled b2 agonists in the airways and is responsible for the bronchodilation observed following the administration of inhaled b2 adrenoceptor agonists. There are a number of potential mechanisms underlying the relaxant effect of b2 adrenoceptor agonists on airway smooth muscle: the most important of these are summarised in Table 1 (see also [24] for review). The role of b2 adrenoceptors on epithelial cells has not been studied extensively. Stimulation results in altered ciliary beat frequency and ion (e.g. Cl−) and water secretion, and may also modulate mediator release, though the importance of these mechanisms in vivo remains largely unexplored [25]. Stimulation of b2 adrenoceptors on

Mechanisms of Action of b2 Adrenoceptor Agonists

95

Table 1 Effects of b2 adrenoceptor agonists on airway smooth muscle Effects on contractile/relaxant signalling pathways: Inhibition of myosin light chain kinase (MLCK) activation Stimulation of Ca2+ uptake into sarcoplasmic reticulum Stimulation of Na+/K+ ATPase activity Inhibition of phosphatidylinositol 4,5 bisphosphate hydrolysis Inhibition of inositol trisphosphate induced Ca2+ release from intracellular stores Inhibition of Ca2+ entry through store and/or receptor operated channels Stimulation of Ca2+ activated K+ channels (BKCa) Other effects: Stimulation of gene transcription via CREB activation Inhibition of cell proliferation/migration

mast cells results in the inhibition of mediator release: however, interestingly, b2 agonists, at least in vitro, appear to increase IgE release from B cells. b2 adrenoceptors are also likely to regulate vascular permeability in the small vessels present in the airway wall, though the importance of this effect in vivo remains unclear [26].

Regulation of b2 Adrenoceptor Expression Both the expression and coupling of b2 adrenoceptors is closely regulated within the airways [27–33]. The number of receptors present at the cell surface is dependent upon the balance between new receptor formation due to increased transcriptional activity of the ADRB2 gene and receptor internalisation and breakdown. Increased transcription may be partly due to the stimulation of cyclic AMP response elements in the promoter of the ADRB2 gene. Increased receptor expression is also likely to be, in part, due to the regulation of mRNA stability by AU rich regions in the 3¢ untranslated region of the gene. In contrast, longer term receptor activation, at least in tissue culture models, results in a loss of responsiveness, initially due to phosphorylation of the receptor by both protein kinase A dependent and protein kinase A independent (beta adrenergic receptor kinase or BARK dependent) pathways. Both of these kinase mediated responses result in the phosphorylation of key residues on the receptor, which, in turn, alters receptor coupling. BARK is a member of a large family of receptor kinases, namely the GRKs or GPCR kinases. In the short term, b2 adrenoceptor phosphorylation leads to dissociation from down stream signalling: however, prolonged receptor stimulation leads to receptor internalisation. Once internalised, the receptor can be recycled to the cell membrane or targeted to the proteosome for degradation [32, 33]. While these effects can clearly be demonstrated in both transformed and nontransformed cell culture models, their importance in the more dynamic environment of the airway wall again remains less clear. Receptor downregulation can be easily demonstrated ex vivo in peripheral blood mononuclear cells (PBMC) [34], but has not unequivocally been demonstrated to date in vivo in structural cells in the human airway.

96

I.P. Hall and I. Sayers

b2 adrenoceptor expression and coupling can also be modulated by exposure to pro- and anti-inflammatory agents. Glucocorticoids have been shown to increase b2 adrenoceptor expression in a number of model systems [35], though the importance of this response in vivo in the human lung remains uncertain. In contrast, exposure to pro inflammatory mediators such as interleukin 1b, at least in the short term, results in reduced cyclic AMP responses to b2 adrenoceptor stimulation in cultured cell systems [36]. It has also been demonstrated in primary human airway myofibroblast culture systems that b2 adrenoceptor coupling is modulated by the extracellular matrix, with relatively smaller cyclic AMP responses to receptor stimulation when cells are grown in the presence of laminin compared with fibronectin [37]. This suggests that receptor coupling is controlled via integrin dependent adhesion mechanisms, an observation of particular interest, given the alterations in matrix composition seen following long term inflammation in the airway wall in chronic asthma. Transgenic mice studies have added insights into the role of b2 adrenoceptors in the airway. Mice with very high levels of overexpression of the human b2 adrenoceptor show, as perhaps might be expected, reduced bronchoconstrictor responses to spasmogens [38, 39]. However, interestingly, mice with lower levels of overexpression show enhanced rather than reduced bronchoconstrictor responses to cholinergic stimulation [40]. This counter-intuitive effect may be related to homeostatic mechanisms being brought into play, which result in increased expression of key proteins involved in contractile signalling pathways in airway myocytes (e.g. phospholipase C) or in altered receptor expression of bronchoconstrictor receptors such as the histamine H1 receptor [40, 41].

Pharmacology of b Adrenoceptor Agonists b2 adrenoceptor agonists are predominantly based on the structure of adrenaline. All agents currently in clinical usage are composed of a benzene ring with a side chain of two carbon atoms and either an amine or a substituted amine head. Positions 3 and 4 on the benzene ring can be substituted by hydroxyl groups (OH), in which case the molecule becomes a catecholamine. Substitution of these hydroxyl groups, in general, makes the compound less potent, but does make the agent relatively resistant to metabolic degradation by the enzyme catechol O methyltransferase (COMT). Substitutions on the a carbon atom block oxidation by monoamine oxidases (MAO). The pharmacological effects of adrenaline and noradrenaline are believed in vivo to be predominantly terminated by uptake into sympathetic nerve endings (uptake 1), though catecholamine uptake into other sympathetically innervated tissues (uptake 2) may also contribute to some extent. Oxidation by MAO occurs predominantly in sympathetic nerve endings, while degradation by COMT occurs predominantly in tissues. Exogenously administered b2 adrenoceptor agonists are conjugated with sulphates and glucuronides in the liver (and probably also the lung and gut wall), contributing to elimination (reviewed in [42]).

Mechanisms of Action of b2 Adrenoceptor Agonists

97

There are some important differences in the lipophilicity of different agonists, which may, in part, underlie the longer duration of action of some LABAs. For example, salmeterol is a relatively lipophilic molecule, resulting in extensive pooling in the plasma membrane following drug exposure: the long duration of action is also probably related to the long lipophilic tail of the molecule inserting into the receptor agonist binding pocket.

Clinical Pharmacology of SABAs and LABAs b2 adrenoceptor agonists, in clinical use, can be distinguished by their pharmacology in terms of duration of action and degree of agonism. As mentioned above, salbutamol (albuterol) and terbutaline are short acting agents (SABAs) with bronchodilator responses which reach a maximum within 1–2 min and last typically up to 4–6 h. In contrast, the long acting agents (LABAs) salmeterol and formoterol provide sustained bronchodilation over at least 12 h. These agents are frequently administered in combination inhalers, together with an inhaled corticosteroid. The new generation LABAs (such as indacaterol) have an even longer duration of bronchodilator effects [43]. These drugs can also be distinguished in terms of their pharmacology depending upon the degree of agonism at the cognate receptor. Thus, while terbutaline and formoterol are near full agonists compared to isoprenaline at the b2 adrenoceptor, salbutamol and, to an even greater extent, salmeterol are partial agonists at least in cell systems expressing the b2 adrenoceptor at physiological levels of expression [44]. The final point to consider is that salbutamol and formoterol exist as racemic mixtures (i.e., include both the R and S enantiomers), though the R enantiomer is the active component [45]. There have been concerns that the S-enantiomer may have detrimental effects rather than just being an ineffective inert component of the racemic mixture, though clinical evidence to support this idea is currently not available.

Clinical Effects b2 adrenoceptor agonists have two main effects on airway pharmacology in patients with asthma. Firstly, they provide short term bronchodilation, the extent of which is at least, in part, dependent on the degree of pre-existing bronchoconstriction. This effect is driven by relaxation of airway smooth muscle within the airway wall, with a resultant increase in airway calibre and hence, reduction in air flow limitation. The second effect of stimulation by b2 adrenoceptor agonists is to inhibit bronchoconstrictor responses mediated by challenge with a wide range of airway irritants such as histamine, methacholine, cold air, and exercise.

98

I.P. Hall and I. Sayers

Safety of SABAs and LABAs Despite the observations that b2 adrenoceptor agonists provide the most effective bronchodilators available in the treatment of asthma, there is a long history of concern over the use of these agents. These concerns originally arose because of epidemiological studies showing the association between the use of isoprenaline and increased risk of asthma death or severe asthma exacerbations in the 1960s, and subsequent studies suggesting similar effects with the shorter acting b adrenoceptor agonist fenoterol [46, 47]: The latter data resulted in the withdrawal of fenoterol from the market in a number of countries. More recently, the FDA placed a black box warning on LABAs in the USA following the early termination of a study examining the efficacy of salmeterol (the SMART study), in which a small excess of deaths or severe exacerbations was seen in the treatment arm [48]. There are a number of possible mechanisms whereby SABAs and/or LABAs could potentially have caused these effects. Firstly, while inhaled b2 selective agonists are predominantly active within airways, some systemic absorption occurs and a number of studies have shown effects on relevant systemic physiological end points such as heart rate, hypokalaemia, and tremor, all of which are dose related (see for example [49]). However, while these effects could potentially contribute to cardiovascular risk, particularly in patients with underlying cardiovascular disease, they would not explain the worsening of asthma control. Hence, attention has been concentrated on the possibility that tachyphylaxis (tolerance) to the effects of SABAs and LABAs may contribute to poorer control in at least some asthmatics [50]. Reduced responsiveness to SABAs and LABAs could potentially occur by alteration of their effectiveness in either (1) inducing bronchodilator effects or (2) in preventing bronchoconstriction. Both of these possibilities have been extensively studied. Although some studies have shown reduced bronchodilator responsiveness to acute administration of SABAs after a period of regular treatment with salmeterol or formoterol, in general, the effects observed have been small (see e.g. [51]) and of doubtful clinical significance. However, more pronounced effects on the degree of bronchoprotection seen against bronchoconstructer challenge have been observed in, a number of studies. Maximum bronchoprotection to constrictor challenge is observed with b2 adrenoceptor agonists in the first 24 h after commencing treatment: this is followed by a reduction in the amount of bronchoprotection provided [52]. However, the amount of bronchoprotection observed, though relatively reduced, is still greater than that observed with placebo. This, therefore, seems unlikely to be the explanation underlying the observational studies suggesting poorer outcome in asthmatics. It is clear that regular use of short acting b2 agonists is no more effective than ‘as required’ use of these agents [53] and hence, clinical guidelines for asthma, in general, do not recommend regular use of SABAs. However, the explanation for this difference, given the effectiveness of LABAs, is unclear, though it is conceivable that relatively rapid on/off effects at the receptor may be detrimental as com-

Mechanisms of Action of b2 Adrenoceptor Agonists

99

pared to the long term receptor stimulation observed with LABAs. One other possibility, which has been suggested as a possible explanation of the SMART data, is that compliance with inhaled steroid may be reduced in some patients taking LABAs, due to symptomatic relief with LABAs, a subsequent reduction in inhaled steroid usage, and a consequent loss in anti-inflammatory effects. There had been considerable attention recently paid to the possibility that b2 adrenoceptor polymorphism may contribute to either disease risk [54–56], disease severity [56], or treatment responses for patients on SABAs and LABAs. This is discussed in greater detail in volume 1, pages 205–225. From the clinical perspective, a large retrospective study and a subsequent prospective study on SABA usage suggested that in steroid naïve patients, individuals with the Arg16Arg genotype (approximately 15% of the Caucasian population), either failed to respond or deteriorated in terms of lung function parameters, symptoms scores, and relief medication usage while on regular treatment [57, 58] (Fig. 3). However, as discussed above, regular treatment with SABAs, particularly in steroid naïve patients, is not recommended currently under national asthma treatment guidelines such as those in use in the UK and USA and hence, while of academic interest, this effect is of limited clinical significance. A subsequent pilot study examining genotype and responses to LABAs suggested similar effects may be present in both steroid naïve patients and asthmatics taking inhaled corticosteroids [59]: however, a larger (retrospective) analysis of clinical trial data suggested no difference in outcome by genotype group in patients on combination LABA and corticosteroid treatment, implying the receptor polymorphism is unlikely alone to account for poorer treatment outcomes [60].

Fig. 3 Effects of regular and as required salbutamol (albuterol) on lung function by ADRB2 genotype for Arg16Gly. Adapted from [57] DAM PEF = change in morning peak expiratory flow

100

I.P. Hall and I. Sayers

Therefore, in summary, it appears that small numbers of individuals with asthma taking b2 adrenoceptor agonists may be at risk of deterioration of their disease and (very rarely) death. However, these effects have not been convincingly shown for currently used SABAs or LABAs in patients on regular inhaled corticosteroid treatment.

Summary The above review has dealt with the major mechanisms underlying the mode of action of b2 adrenoceptor agonists, and the modulation of these responses. This has been an active area of research over recent years, driven by the clinical importance of these agents and lingering concerns over safety. Over the next few years, a number of novel LABAs are likely to be introduced into clinical practice. This will undoubtedly lead to further evaluation of efficacy and safety issues: with this in mind, the profile of new agents in terms of their duration of action and degree of agonism should be carefully considered, as it is already clear from the data discussed above that not all LABAs are identical in terms of their pharmacology. Acknowledgements Work in the authors’ laboratory is supported by Asthma UK and the Medical Research Council.

References 1. JR Carstairs, AJ Nimmo, and PJ Barnes, (1985). Autoradiographic visualization of betaadrenoceptor subtypes in human lung. Am Rev Respir Dis, 132(3): p. 541–7. 2. F Qing, CG Rhodes, MJ Hayes, T Krausz, SW Fountain, T Jones, and JM Hughes, (1996). In vivo quantification of human pulmonary beta-adrenoceptor density using PET: Comparison with in vitro radioligand binding. J Nucl Med, 37(8): p. 1275–81. 3. B Rozec and C Gauthier, (2006). Beta3-adrenoceptors in the cardiovascular system: Putative roles in human pathologies. Pharmacol Ther, 111: p. 652–73. 4. JG Baker, IP Hall, and SJ Hill, (2003). Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. Mol Pharmacol, 64: p. 1357–69. 5. BK Kobilka, RA Dixon, T Frielle, HG Dohlman, MA Bolanowski, IS Sigal, TL Yang-Feng, U Francke, MG Caron, and RJ Lefkowitz, (1987). cDNA for the human beta 2-adrenergic receptor: A protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci USA, 84(1): p. 46–50. 6. AL Parola and BK Kobilka, (1994). The peptide product of a 5’ leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis. J Biol Chem, 269(6): p. 4497–505. 7. SE Johnatty, M Abdellatif, L Shimmin, RB Clark, and E Boerwinkle, (2002). Beta 2 adrenergic receptor 5’ haplotypes influence promoter activity. Br J Pharmacol, 137(8): p. 1213–6. 8. DW McGraw, SL Forbes, LA Kramer, and SB Liggett, (1998). Polymorphisms of the 5’ leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest, 102(11): p. 1927–32.

Mechanisms of Action of b2 Adrenoceptor Agonists

101

9. MG Scott, C Swan, AP Wheatley, and IP Hall, (1999). Identification of novel polymorphisms within the promoter region of the human beta2 adrenergic receptor gene. Br J Pharmacol, 126(4): p. 841–4. 10. PL Freddolino, MY Kalani, N Vaidehi, WB Floriano, SE Hall, RJ Trabanino, VW Kam, and WA Goddard, 3rd, (2004). Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists. Proc Natl Acad Sci USA, 101(9): p. 2736–41. 11. CD Strader, IS Sigal, MR Candelore, E Rands, WS Hill, and RA Dixon, (1988). Conserved aspartic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function. J Biol Chem, 263(21): p. 10267–71. 12. K Wieland, HM Zuurmond, C Krasel, AP Ijzerman, and MJ Lohse, (1996). Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor. Proc Natl Acad Sci USA, 93(17): p. 9276–81. 13. G Liapakis, JA Ballesteros, S Papachristou, WC Chan, X Chen, and JA Javitch, (2000). The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the beta 2-adrenergic receptor. J Biol Chem, 275(48): p. 3777 14. CD Strader, MR Candelore, WS Hill, IS Sigal, and RA Dixon, (1989). Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J Biol Chem, 264(23): p. 13572–8. 15. V Iyer, TM Tran, E Foster, W Dai, RB Clark, and BJ Knoll, (2006). Differential phosphorylation and dephosphorylation of beta2-adrenoceptor sites Ser262 and Ser355,356. Br J Pharmacol, 147(3): p. 249–59. 16. SB Liggett, M Bouvier, WP Hausdorff, B O’Dowd, MG Caron, and RJ Lefkowitz, (1989). Altered patterns of agonist-stimulated cAMP accumulation in cells expressing mutant beta 2-adrenergic receptors lacking phosphorylation sites. Mol Pharmacol, 36(4): p. 641–6. 17. SB Liggett, (2002). Update on current concepts of the molecular basis of beta2-adrenergic receptor signaling. J Allergy Clin Immunol, 110(6 Suppl): p. S223–7. 18. H Kume, IP Hall, RJ Washabau, K Takagi, and MI Kotlikoff, (1994). Beta-adrenergic agonists regulate Kca channels in airway smooth muscle by cAMP-dependent and -independent mechanisms. J Clin Invest, 93: p. 371–9 19. Y Daaka, LM Luttrell, and RJ Lefkowitz, (1997). Switching of the coupling of the beta2adrenergic receptor to different G proteins by protein kinase A. Nature, 390(6655): p. 88–91. 20. IR Le Jeune, M Shepherd, G Van Heeke, MD Houslay, and IP Hall, (2002). Cyclic AMPdependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter. J Biol Chem, 277(39): p. 35980–9. 21. CK Billington, IR Le Jeune, KW Young, and IP Hall, (2008). A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells. Am J Respir Cell Mol Biol, 38: p. 1–7. 22. G Marone, G Ambrosio, D Bonaduce, A Genovese, M Triggiani, and M Condorelli, (1984). Inhibition of IgE-mediated histamine release from human basophils and mast cells by fenoterol. Int Arch Allergy Appl Immunol, 74(4): p. 356–61. 23. SG Kelsen, O Anakwe, MO Aksoy, PJ Reddy, and N Dhanasekaran, (1997). IL-1 beta alters beta-adrenergic receptor adenylyl cyclase system function in human airway epithelial cells. Am J Physiol, 273(3 Pt 1): p. L694–700. 24. IP Hall, (2000). Second messengers, ion channels and pharmacology of airway smooth muscle. Eur Respir J, 15(6): p. 1120–7. 25. MO Aksoy, IA Mardini, Y Yang, W Bin, S Zhou, and SG Kelsen, (2002). Glucocorticoid effects on the beta-adrenergic receptor-adenylyl cyclase system of human airway epithelium. J Allergy Clin Immunol, 109: p. 491–7. 26. PB Bolton, P Lefevre, and DM McDonald, (1997). Salmeterol reduces early- and late-phase plasma leakage and leukocyte adhesion in rat airways. Am J Respir Crit Care Med, 155(4): p. 1428–35. 27. S Danner, M Frank, and MJ Lohse, (1998). Agonist regulation of human beta2-adrenergic receptor mRNA stability occurs via a specific AU-rich element . J Biol Chem, 273(6): p. 3223–9.

102

I.P. Hall and I. Sayers

28. K Subramaniam, K Chen, K Joseph, JR Raymond, and BG Tholanikunnel, (2004). The 3¢-untranslated region of the beta2-adrenergic receptor mRNA regulates receptor synthesis. J Biol Chem, 279(26): p. 27108–15. 29. S Collins, M Bouvier, MA Bolanowski, MG Caron, and RJ Lefkowitz, (1989). cAMP stimulates transcription of the beta 2-adrenergic receptor gene in response to short-term agonist exposure. Proc Natl Acad Sci USA, 86(13): p. 4853–7. 30. S Collins, J Altschmied, O Herbsman, MG Caron, PL Mellon, and RJ Lefkowitz, (1990). A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem, 265(31): p. 19330–5. 31. JC Mak, M Nishikawa, and PJ Barnes, (1995). Glucocorticosteroids increase beta 2-adrenergic receptor transcription in human lung. Am J Physiol, 268(1 Pt 1): p. L41–6. 32. SK Shenoy, PH McDonald, TA Kohout, and RJ Lefkowitz, (2001). Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science, 294(5545): p. 1307–13. 33. J Mialet-Perez, SA Green, WE Miller, and SB Liggett, (2004). A primate-dominant third glycosylation site of the beta2-adrenergic receptor routes receptors to degradation during agonist regulation. J Biol Chem, 279(37): p. 38603–7. 34. B Lipworth, GH Koppelman, AP Wheatley, et al., (2002) Beta2 adrenoceptor promoter polymorphisms: Extended haplotypes and functional effects in peripheral blood mononuclear cells. Thorax, 57: p. 61. 35. IM Adcock, K Maneechotesuwan, and O Usmani, (2002). Molecular interactions between glucocorticoids and long-acting beta2-agonists. J Allergy Clin Immunol, 110(6 Suppl): p. S261–8. 36. CK Billington, RM Pascual, ML Hawkins, RB Penn, and IP Hall, (2001). Interleukin-1ß and rhinovirus sensitize adenylyl cyclase in human airway smooth muscle cells. Am J Respir Cell Mol Biol, 24(5): p. 633–9. 37. AM Freyer, CK Billington, RB Penn, and IP Hall, (2004). Extracellular matrix modulates beta2-adrenergic receptor signalling in human airway smooth muscle cells. Am J Respir Cell Mol Biol, 31(4): p. 440–5. 38. DW McGraw, SL Forbes, JC Mak, DP Witte, PE Carrigan, GD Leikauf, and SB Liggett, (2000). Transgenic overexpression of beta(2)-adrenergic receptors in airway epithelial cells decreases bronchoconstriction. Am J Physiol Lung Cell Mol Physiol, 279: p. L379–89. 39. DW McGraw, SL Forbes, LA Kramer, DP Witte, CN Fortner, RJ Paul, and SB Liggett, (1999). Transgenic overexpression of beta(2)-adrenergic receptors in airway smooth muscle alters myocyte function and ablates bronchial hyperreactivity. J Biol Chem, 274: p. 32241–7. 40. DW McGraw, KF Almoosa, RJ Paul, BK Kobilka, and SB Liggett, (2003). Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox. J Clin Invest, 112: p. 619–26. 41. I Sayers, C Swan, and IP Hall, (2006). The effect of beta2-adrenoceptor agonists on phospholipase C (beta1) signalling in human airway smooth muscle cells. Eur J Pharmacol, 531: p. 9–12. 42. P Barnes, J Drazen, S Rennard, and N Thomson (eds), (2002). b2-adrenoceptor agonists. In: Asthma and COPD: basic mechanisms and clinical management. Elsevier Academic, London. 43. KM Beeh, E Derom, F Kanniess, R Cameron, M Higgins, and A van As, (2007). Indacaterol, a novel inhaled beta2-agonist, provides sustained 24-h bronchodilation in asthma. Eur Respir J, 29: p. 871–8. 44. M Johnson, (2006). Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol, 117(1): p. 18–24 45. CP Page and J Morley, (1999). Contrasting properties of albuterol stereoisomers. J Allergy Clin Immunol, 104(2 Pt 2): p. S31–41. 46. N Pearce, J Grainger, M Atkinson, J Crane, C Burgess, C Culling, H Windom, and R Beasley, (1990). Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977–1981. Thorax, 45: p. 170–5.

Mechanisms of Action of b2 Adrenoceptor Agonists

103

47. J Crane, N Pearce, A Flatt, C Burgess, R Jackson, T Kwong, M Ball, and R Beasley, (1989). Prescribed fenoterol and death from asthma in New Zealand, 1981–1983: Case-control study. Lancet, 1(8644): p. 917–22. 48. HS Nelson, ST Weiss, ER Bleecker, SW Yancey, and PM Dorinsky, (2006). The salmeterol multicenter asthma research trial: A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest, 129(1): p. 15–26. 49. AR Guhan, S Cooper, J Oborne, S Lewis, J Bennett, and AE Tattersfield, (2000). Systemic effects of formoterol and salmeterol: A dose-response comparison in healthy subjects. Thorax, 55: p. 650–6. 50. MR Sears, DR Taylor, CG Print, et al., (1990). Regular inhaled ß-agonist treatment in bronchial asthma. Lancet, 336: p. 1391. 51. BJ Lipworth, IP Hall, I Aziz, KS Tan, and A Wheatley, (1999). Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy. Clin Sci (Lond), 96(3): p. 253–9. 52. S Tan, IP Hall, J Dewar, E Dow, and B Lipworth, (1997). Association between beta 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet, 350(9083): p. 995–9. 53. CP van Schayck, E Dompeling, CLA van Herwaarden, et al., (1991). Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study. BMJ, 303: p. 1426. 54. DG Contopoulos-Ioannidis, EN Manoli, and JP Ioannidis, (2005). Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol, 115(5): p. 963–72. 55. A Thakkinstian, M McEvoy, C Minelli, P Gibson, B Hancox, D Duffy, J Thompson, I Hall, J Kaufman, TF Leung, PJ Helms, H Hakonarson, E Halpi, R Navon, and J Attia, (2005). Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: A HuGE review. Am J Epidemiol, 162(3): p. 201–11. 56. IP Hall, JD Blakey, KA Al Balushi, A Wheatley, I Sayers, ME Pembrey, SM Ring, WL McArdle, and DP Strachan, (2006). Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: A genetic association study. Lancet, 368(9537): p. 771–9. 57. E Israel, JM Drazen, SB Liggett, HA Boushey, RM Cherniack, VM Chinchilli, DM Cooper, JV Fahy, JE Fish, JG Ford, M Kraft, S Kunselman, SC Lazarus, RF Lemanske, RJ Martin, DE McLean, SP Peters, EK Silverman, CA Sorkness, SJ Szefler, ST Weiss, and CN Yandava, (2000). The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med, 162(1): p. 75–80. 58. E Israel, VM Chinchilli, JG Ford, HA Boushey, R Cherniack, TJ Craig, A Deykin, JK Fagan, JV Fahy, J Fish, M Kraft, SJ Kunselman, SC Lazarus, RF Lemanske, Jr., SB Liggett, RJ Martin, N Mitra, SP Peters, E Silverman, CA Sorkness, SJ Szefler, ME Wechsler, ST Weiss, and JM Drazen, (2004). Use of regularly scheduled albuterol treatment in asthma: Genotypestratified, randomised, placebo-controlled cross-over trial. Lancet, 364(9444): p. 1505–12. 59. ME Wechsler, E Lehman, SC Lazarus, RF Lemanske, Jr., HA Boushey, A Deykin, JV Fahy, CA Sorkness, VM Chinchilli, TJ Craig, E DiMango, M Kraft, F Leone, RJ Martin, SP Peters, SJ Szefler, W Liu, and E Israel, (2006). Beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med, 173(5): p. 519–26. 60. ER Bleecker, SW Yancey, LA Baitinger, LD Edwards, M Klotsman, WH Anderson, and PM Dorinsky, (2006). Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol, 118: p. 809–16. 61. E Reihsaus, M Innis, N MacIntyre, and SB Liggett, (1993). Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol, 8: p. 334–9. 62. CK Billington and RB Penn, (2003). Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res, 4: p. 2.

Alkylxanthines and Phosphodiesterase 4 Inhibitors for Allergic Diseases Mark A. Giembycz

Introduction Despite significant advances in our understanding of the pathogenesis of many allergic disorders, the etiology of allergy is still incompletely understood. However, both the World Allergy and World Health Organization [1] have identified and recognized the participation of immunoglobulin (Ig) E-driven mechanisms in many allergic diseases (Table 1). Since the incidence of allergy has reached epidemic proportions, it is very clear that drugs, which can prevent the overt and covert manifestations of allergic reactions and, ideally, suppress or even prevent the process of host sensitization can have a profound clinical and economic impact. While corticosteroids are considered the most effective antiallergic/anti-inflammatory drugs currently available, they are nonselective in action and not without adverse effects. Moreover, in diseases such as asthma, a significant proportion of patients who are treated with corticosteroids remain symptomatic [2]. Thus, new drugs with enhanced selectivity and improved side-effect profiles are clearly required. One group of drugs, which from a theoretical perspective, may exhibit powerful anti-inflammatory and immunomodulatory activity are inhibitors of certain of the cyclic nucleotide phosphodiesterase (PDE) isoenzymes that selectively degrade cyclic adenosine-3¢,5¢monophosphate (cAMP) and/or cyclic guanosine-3¢,5¢-monophosphate (cGMP) [3–9]. The prototype PDE inhibitors that have been used in the treatment of asthma for many years are the alkylxanthines of which theophylline is the most widely prescribed. The main beneficial activity of theophylline was originally attributed to its weak bronchodilator action. However, evidence accumulated in the 1990s suggested that this molecule might have anti-inflammatory activity at subbronchodilator doses [10–12]. These, somewhat surprising data fuelled the idea that theophylline and, socalled, “second generation” PDE inhibitors could act as bronchodilators and potential antiallergic and/or anti-inflammatory agents [7, 13–18]. M.A. Giembycz () Department of Pharmacology and Therapeutics, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1 e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_7, © Springer 2010

105

106 Table 1 Allergic diseases where IgEdriven mechanisms are implicated

M.A. Giembycz Asthma Atopic and contact dermatitis Rhinitis Eczema Sinusitis Hypersensitivity pneumonitis Extrinsic alveolitis Angioedema and anaphylaxis Certain forms of migraine and gastrointestinal disorders Urticaria

The rationale for developing new PDE inhibitors has stemmed primarily from the realization that PDEs represent a highly heterogeneous group of enzymes,which are differentially expressed across different cell types and specific functional responses are almost certainly regulated. Accordingly, it was rapidly appreciated that the selective inhibition of a particular PDE isoenzyme may discretely alter the function of cells expressing that variant, and theoretically, specific functional responses within the same cell. Given the prevalence of allergic diseases as a whole, the potential clinical reward for developing a novel class of steroid-sparing drugs is very apparent. With respect to allergy and allergic diseases, the most relevant enzyme family is known as PDE4 (see Table 2 for taxonomy). Indeed, many of the World’s major pharmaceutical companies have an active PDE4 research program have developed highly selective inhibitors, many of which are currently undergoing clinical trials for asthma and other allergic inflammatory disorders (Fig. 1, 1-12; Table 3). The purpose of this chapter is to introduce cyclic nucleotide PDEs in general and then describe the salient characteristics and tissue distribution of PDE4 across cells that participate in allergic inflammatory reactions. Potential sites where PDE4 inhibitors could act to alleviate the acute and chronic manifestations of allergic disease, including clinical trials data, form the final part of this chapter. Readers interested in the more general aspects of PDE biology are directed to recent reviews on this subject [3, 4, 19].

Generic Properties and Characteristics of Cyclic Nucleotide PDEs Cyclic nucleotide PDEs (E.C. 3.1.4.17) comprise a large group of enzymes whose sole function is to hydrolyze, and thereby inactivate the biologically active cyclic purines, cAMP and cGMP (Fig. 2). PDEs which act on cyclic pyrimidine monophosphates have also been described (see [20]), although investigators have tended to focus, almost exclusively, on the PDEs which hydrolyze cyclic purine nucleotides for which functionally important second messenger roles have unequivocally been established. A cyclic nucleotide PDE that hydrolyzed the 3¢-ribose phosphate bond of cAMP to the catalytically inactive 5¢-AMP was first identified in 1962 [21]. Since then, multiple families, and indeed, subfamilies of PDEs, which selectively act on cAMP and/or cGMP have been identified (see [3,4] for reviews). The PDEs that metabolize cyclic

Alkylxanthines and Phosphodiesterase 4 Inhibitors

107

Table 2 Properties and selective inhibitors of cyclic nucleotide phosphodiesterases Km ( mM) PDE family cAMP cGMP Selective inhibitors References 0.3–124 0.6–6 SCH 57801, KS-505a [142][143] 1 Ca2+/Calmodulinstimulated IC-224 [144] [145][146] 2 cGMP-stimulated 28–100 10–28 ENHA, Oxindole [147] BAY 60-7550 [144] IC933 [148] PDP 3 cGMP-inhibited 0.02–0.3 0.1–0.5 Siguazodan, SK&F [149][150] 95654 [151] Cilostamide [152] Cilostazol 4 cAMP-specific 1–10 >50 Rolipram, Ro 20-1724 [153,154][155] Cilomilast [156] Roflumilast [157] Piclamilast [158] 5 cGMP-binding 280 3–7 Zaprinast, Sildenafil [159][160] Vardenafil [161] Tadalafil [162] 6 Photoreceptor 600–700 15–17 None reported 7 Rolipram-insensitive, 0.01–0.5 NA BRL 50481, PF 332040 [163][164,165] cAMP-specific IC242 [166] 8 Rolipram-insensitive, 0.06 NA None reported cAMP-specific 9 Zaprinast-insensitive, 228 0.7–0.17 BAY 73-6691 [167] cGMP-specific 10 cAMP-inhibited (?) 0.22–1.1 13–14 None reported 11 Dual-selective 1–2 2–3 None reported NA reliable data not available

purine nucleotides comprise at least 11 distinct families and can be distinguished by a number of criteria including substrate specificity, kinetic properties, responsiveness to endogenous allosteric regulators, and susceptibility to inhibition by various compounds and in primary amino acid sequence (Table 3). Molecular biological studies have discovered that many PDEs are separate gene products and express multivariant regulatory domains linked to highly conserved homologous catalytic sequences located near the C-terminus of the protein. Members of one family share 20–25% sequence homology with members of another family. Furthermore, at least six out of the 11 gene families can be divided in to subfamilies that are 70–90% homologous. At the end of 2006, more than 22 PDE genes were unequivocally identified. For further information on the molecular diversity of PDE isoenzymes, interested readers are directed towards a number of comprehensive reviews [3, 4, 22–26]. A diagrammatic representation of the primary structure of cyclic purine PDEs is shown in Fig. 3. All mammalian PDEs essentially share the same structure: there is a central core located close to the C-terminus of the protein, which shares 25–35% homology between isoenzyme families and which features a highly conserved domain of some 270 amino acids. Studies performed in a number of laboratories indicate that this conserved region within the central core of all PDEs represents the

108

a

M.A. Giembycz

H 3C

O

OH H N

O

N

N

O

HN N

N

N N

N

N

N

O

S O

H3C

Cl

CH3

1 Arofylline

3 Cilomilast

2 Tofimilast OH CH3

Cl

N

O

O HO

O

N O

Cl

CH3

S

O

N

O

F

F

4 Tetomilast

O

N

O

NH

N

O

HN

CH4

CH3

6 ONO 6126

5 Roflumilast

F

N

N

Cl

O

N

O

O CH3

O Cl

CH3

9 IC-485

8 Ibudilast

7 AWD-12-281 (GSK 842470)

b O HN

O H N

O

O

H N O

NH2 O

N

O

O

O

H3C

HO

CH3

N

CH3 NH

CH3 O

CH3

CH3

N

R1 R2 O

N

N

Y

O

Z

CH3

10 Atizoram

H3C

11 Cipamfylline

H3C or

Z= O

NH2

H 3C O

O

or

CH3

OH O

P

OH

propionamide methyl propionate ethylphosphonic acid

12 CC-10004

Fig. 1 Chemical structures of PDE4 inhibitors which have been clinically evaluated in allergic diseases. The structure of CC-10004 has not been disclosed. Shown are predicted possibilities. Only small substitutions are tolerated at R1 and methyl and difluromethyl are tolerated candidates. Larger substitutions are tolerated at R2 and possibilities include cyclopropyl or cyclopentyl moieties. Y = O or H2. Z = propionamide, methyl propionate or ethylphosphonic acid. See text and Ref. [107] for further details

Arofylline Oglemilast (GRC 3886) Tofimilast (CP-325366) ONO 6126 Tetomilast (OPC 6535) Roflumilast Cilomilast (SB 207499) AWD-12-281 (GSK 842470) CC-10004 IC-485 Ibudilast Cipamfylline (BRL 61063) Atizoram (CP-80,633)

Almirall Glenmark Pfizer ONO Otsuka Nycomed GlaxoSmithKline GlaxoSmithKline Celgene ICOS MediciNova GlaxoSmithKline/Leo Pharma Pfizer

Data collated from Mealey & Bayes (2005)

Drug

Company

Table 3 Representative PDE4 inhibitors for inflammatory disorders

4 4 4 4 4 4 4 4 4 4 4 4 4

Isoenzyme selectivity Bronchitis Asthma, COPD Asthma Asthma, COPD COPD Asthma, COPD COPD Asthma, Atopic Dermatitis Asthma, Psoriasis, Atopic Dermatitis COPD Multiple sclerosis Atopic Dermatitis Atopic Dermatitis

Indication

Phase II/III Phase III Phase II Phase II Phase III Phase III Phase III Phase II Phase II Discontinued Phase II Phase II Discontinued

Development stage

Alkylxanthines and Phosphodiesterase 4 Inhibitors 109

110

M.A. Giembycz NH2

NH2 N

N

N

N N

N

PDE

N

N

cAMP

O

OH

H2O; Mg2+

O O

OH

5’-AMP

OH

HO

P HO

O

O P

O

HO

O

Fig. 2 CAMP hydrolysis by cyclic nucleotide phosphodiesterases

Allosteric/Small Molecule

cAMP cGMP

5’-AMP 5’-GMP

Phosphorylation Sites (eg ERK-2 at S579 in PDE4D3

Binding Site 2+

and S651 in PDE4D5)

(e.g. cGMP, Ca /calmodulin)

Phosphorylation Sites

(eg PKA at S54 in PDE4D3)

Targeting Domains (eg TAPAS-1 in PDE4A1)

Catalytic Domain Dimerisation Domains

Fig. 3 General structure of mammaliam cyclic purine PDEs. Limited proteolysis and protein sequencing suggest that all mammalian PDEs so far examined contain a conserved central core that features the catalytic site. This region of PDE proteins is flanked, through putative hinge regions, by highly heterologous C- and N-termini. These are believed to express regulatory domains, dimerisation motifs, phosphorylation sites, and sequence information which determine the subcellular localization of PDEs. See text for further details. TAPAS Tryptophan Anchoring Phosphatidic Acid Selective

catalytic site [27]. The central core of mammalian PDEs is linked via, so called, hinge regions to C- and N-terminal extensions (Fig. 3) which show relatively little sequence homology between PDE families [22]. This finding has led to the view that the nonconserved domains subserve regulatory functions of the protein [22]. Indeed, it is now appreciated that the N-termini of PDEs can feature binding sites for calmodulin (PDE1) and cGMP (PDEs 2, 5, 6, 10, 11) – so-called GAF domains1 [28], membrane-association domains (PDE3), subcellular targeting sequences (PDE4,

1 GAF and PAS [domains] are acronyms of the names of the first three groups of proteins identified to contain them, i.e. cGMP-regulated cyclic nucleotide phosphodiesterase, cyanobacterial Adenylyl cyclase and E. coli transcription factor, Fh1A (formate-hydrogen lyase), and Period circadian protein, Ah receptor nuclear translocator protein and Single minded protein, respectively.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

111

PDE7), phosphorylation sites (most PDEs) that control catalytic activity, and PAS1 domains (PDE8) – involved in ligand recognition and protein–protein interactions. Similarly, sequences at the C-terminus express dimerization motifs (most PDEs exist as dimers; [29–33]) and/or are substrates for phosphorylation (e.g., [34, 35]).

Phosphodiesterase 4 A cAMP-specific PDE that was inhibited by the alkoxybenzyl-substituted imidazolidone, Ro 20-1724, but largely unaffected by cGMP was originally purified from canine kidney [36, 37]. It is now appreciated that this was the first report of a member of a large family of similar proteins collectively known as PDE4 isoenzymes. Since that original description, PDE4s have been purified and partially characterized from a number of sources including human monocytes [38] and human leukocytes [39]. Human recombinant proteins have also been heterologously expressed and purified to facilitate the identification of selective inhibitors by high throughput screening [40]. Without apparent exception, PDE4 isoenzymes are acid proteins (pI = 4–6) that exclusively hydrolyze cAMP (Table 3). In 1989 Davies and colleagues isolated and cloned the Drosophila melanogaster “dunce” gene and found that it encoded a PDE of the PDE4 family. In the same year, four rat cDNA homologues [41–43] of the “dunce” cAMP PDE were identified, establishing a molecular basis for the observed heterogeneity of gene products within the PDE4 family. These clones represent transcripts of four different genes and are now named RNPDE4A, RNPDE4B, RNPDE4C, and RNPDE4D according to the nomenclature proposed by Beavo and colleagues (1994). Four human genes (A–D) have also been identified and many of their products studied in some detail (see [3, 4, 19]. An astonishing finding that emerged from the molecular cloning of PDE4 isoenzymes was the presence of mRNA transcripts of different sizes for each of the four variants (greater than 50 have been unequivocally identified at the time of writing) that are differentially expressed between tissues [3, 4, 23]. The basis for this profound heterogeneity of PDE4 isoenzymes is attributable to both alternative mRNA splicing and to the fact that PDE4 genes express multiple promoter regions, and therefore provide several potential start codons for the translation of the protein. Proteins encoded by each PDE4 gene may be either of the “short” or “long” form (see [3]). Structurally, long PDE4 isoforms have an N-terminal domain, two, so-called, upstream conserved regions (UCR1 and UCR2; they are thought to mediate dimerization of long PDE4s [32]), have a highly conserved catalytic centre and a unique C-terminus; in contrast, short PDE4 variants are truncated proteins that lack UCR1 [44].

Therapeutic Indications of PDE4 Inhibitors PDE4 inhibitors have been tested for efficacy in a number of immunological and immunodeficiency conditions including asthma, chronic obstructive pulmonary disease (COPD), Crohn’s disease, myasthenia gravis, atopic dermatitis, psoriasis, sys-

112

M.A. Giembycz Table 4 Established PDE isoenzyme profiles in human proinflammatory and immune cells implicated in allergic disorders Immune/proinflammatory cell PDE profile Mast cell 3, 4, 5, 7 Alveolar macrophage 1, 3, 4, 5, 7 T-Lymphocyte 1, 2, 3, 4, 5, 7, 8(?) B-lymphocyte 3, 4, 7 Eosinophil 4 Neutrophil 4, 7 Basophil 4, 7 Monocyte 1, 3, 4, 7 Platelet 1, 2, 3, 5 Epithelial cell 1, 2, 3, 4, 5, 7, 8 Endothelial cell 2, 3, 4, 5, 7 Dendritic cell 1, 3, 4, 7 Airway myocyte 1, 2, 3, 4, 5, 7, 8 Vascular myocyte 1, 2, 3, 4, 5, 7

temic lupus erythematosis, rheumatoid arthritis, diabetes and multiple sclerosis [45–49]. Asthma, COPD, and to a lesser extent, atopic dermatitis/psoriasis are indications where development of PDE4 inhibitors is most advanced (Table 3). The rationale for developing compounds that attenuate PDE4 activity is based on three critical findings: (1) PDE4 is abundant and the major regulator of cAMP metabolism in almost every proinflammatory and immune cell (Table 4); (2) PDE4 inhibitors suppress a myriad of in vitro responses such as cytokine generation, free radical generation, degranulation, IgE production, proliferation, lipid mediator and histamine generation, and chemotaxis; and (3) PDE4 inhibitors are efficacious in animal models of inflammation [7]. If these observations hold in humans then, conceptually, PDE4 inhibitors should demonstrate pleiotropic inhibitory activity across proinflammatory and immune cell function. A further prediction is that inhibition of PDE4 should potentiate the effects of endogenous anti-inflammatory agents that increase cAMP such as catecholamines, prostaglandin E2 and prostacyclin. Taken together, the preclinical pharmacology of these compounds provided a rational basis for the development of novel anti-inflammatory pharmaceuticals that may display steroid-like activity without associated adverse event.

Anti-inflammatory Effects of PDE Inhibitors In Vivo The actions of theophylline and PDE4 inhibitors upon acute (IgE-mediated) and chronic (proinflammatory/immunocompetent cell-mediated) consequences of allergen provocation in vivo have, in general, been documented in some detail and include studies of passive cutaneous anaphylaxis (PCA), cell infiltration into sites of inflammation, and microvascular leakage.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

113

IgE-Mediated Processes It seems unlikely that PDE inhibitors of any isoenzyme family reduce IgE levels in vivo. In humans, it is reported that ibudilast, which is an essentially nonselective PDE inhibitor [50] is without effect on IgE levels in asthmatic individuals [51]. Similarly, the elevated level of total serum IgE in a murine model of dermatitis caused by the repeated application of the hapten, 2,4,6-trinitro-1-chlorobenzene, is unaffected by oral administration of the PDE4 inhibitor, rolipram [52]. In contrast, PDE4 inhibitors exhibit efficacy at reducing PCA reactions in rats, mice, and guinea -pigs [53, 54]. Furthermore, rolipram is effective at reducing the infiltration of indium-labeled eosinophils into the skin of guinea pigs following a PCA reaction [55]. Collectively, these data imply that PDE4 inhibitors can suppress the degranulation of IgE-bearing leukocytes and, therefore, allergen-induced mediator release. Further support for this proposal derives from studies in sensitized guinea pigs where rolipram, administered intravenously, inhibits antigen – but not LTD4-induced bronchoconstriction [56]. Thus, rolipram preferentially exerts an inhibitory influence at the level of mast cells and basophils rather than exerting a direct antispasmogenic action at the level of airways smooth muscle [56].

Proinflammatory Cell Infiltration Intravenous injection of a low dose of theophylline into a guinea pig model of allergic asthma immediately prior to antigen prevents both the immediate bronchoconstriction and the late phase reaction (LPR) [57]. Qualitatively identical results were obtained in an allergic sheep and rabbit model [58]. Independent experiments conducted with sensitized guinea pigs and rats have demonstrated that theophylline suppresses pulmonary eosinophil, and in the case of the rat, neutrophil recruitment which is believed to be intimately associated with the development of the LPR [59–65]. In many of these studies, however, theophylline was administered acutely at a supra-therapeutic dose indicating that the observed effects may not be relevant to the clinical situation. In contrast, chronic treatment of guinea-pigs for seven days with therapeutically-relevant doses of theophylline is reported to effectively prevent PAF- and allergen-induced eosinophil recruitment [60, 66]. A large number of investigations (too many to describe individually herein) have evaluated the effect of PDE inhibitors on the infiltration of proinflammatory cells into the airways lumen, skin, and eye of guinea pigs, rats, and monkeys in response to a variety of dissimilar stimuli including allergen. For example, pretreatment of sensitized guinea pigs with zardaverine, a mixed PDE3/PDE4 inhibitor, markedly suppressed allergen-induced infiltration of eosinophils, macrophages, and neutrophils into the bronchoalveolar lavage (BAL) fluid to a level achieved with dexamethasone [67]. Comparable data has been reported for the PDE3/PDE4 inhibitor, benafentrine, on PAF- and allergen-induced pulmonary eosinophil recruitment in guinea pigs after chronic (6 days) dosing [60, 66]. Studies conducted more recently

114

M.A. Giembycz

with rolipram and second generation PDE4 inhibitors including cilomilast (3), roflumilast (5) and AWD 12-281 (7) have corroborated those findings both in the airways and in allergic cutaneous reactions [68–77]. Similarly, treatment of sensitized Cynomolgus monkeys with rolipram abrogates the pulmonary neutrophilia and eosinophilia, and airways hyperresponsiveness after multiple exposures to the antigen but is without effect on the immediate increase in airways resistance that follows acute antigen provocation [78]. Thus, these data are consistent with the findings that PDE4 inhibitors may be anti-inflammatory and act primarily to prevent the activation of immune cells in the lung rather than exerting an antispasmogenic or spasmolytic effect on the level of airways smooth muscle [56].

Microvascular Leakage and Edema It is well recognized that the microcirculation plays an important role in inflammatory reactions. Under normal conditions, the endothelium lining the postcapillary microvenules in the skin and bronchial circulation (capillaries in the pulmonary vasculature) is largely impermeable to blood cells and to macromolecules; but following a proinflammatory insult, localized arteriolar vasodilatation occurs with a consequent increase in blood flow. This effect is induced by the liberation of proinflammatory mediators such as histamine and tachykinins. An increase in capillary and microvenular pressure then ensues together with the liberation of other mediators such as leukotriene D4, which directly contract the microvenular endothelial cells. Together, these effects, by increasing microvenular permeability, permit the loss of plasmaproteins from the vascular compartment. Furthermore, the resulting increase in osmotic pressure due to loss of solute from the circulation leads to marked fluid exudation and edema. In guinea pigs, theophylline reduces plasma exudation into the trachea, bronchi, and BAL fluid, but its efficacy may depend upon the nature and strength of the leak-evoking stimulus [79–82]. With respect to PDE4 inhibitors, intravenous, oral, and intratracheal administration markedly attenuate PAF-induced microvascular leakage in both small and large airways, and into the BAL fluid of anaesthetized guinea pigs [81, 83, 84]. The finding that rolipram is active when given directly into the airways indicates an important local action in the lung, and highlights that systemic administration is not necessary for these compounds to exert an anti-inflammatory influence. This is an important observation, since the administration of PDE4 inhibitors by the inhaled route should reduce untoward side effects while maintaining efficacy. Svensjo and colleagues [85] reported that PDE4 and PDE3/PDE4 inhibitors attenuate the increase in microvascular permeability evoked by bradykinin in the hamster cheek pouch. Qualitatively identical results were obtained for the effect of rolipram, denbufylline, AWD12-281, cilomilast, and piclamilast on edema formation in the skin, and proinflammatory cytokine release evoked by

Alkylxanthines and Phosphodiesterase 4 Inhibitors

115

a variety of stimuli including arachidonic acid, croton oil, and various irritant haptens [52, 68, 73–75, 86–89].

Clinical Trials of Theophylline in Asthma Until relatively recently, the therapeutic efficacy of theophylline in asthma was attributed to its weak bronchodilator activity. However, while theophylline is an effective bronchodilator, there is now increasing evidence that this drug may also exert an immunomodulatory action at plasma concentrations that do not affect airways smooth muscle tone (reviewed in [90]). Several lines of investigation have lead to this conclusion. In essentially all studies, theophylline protects against the LPR following allergen provocation, implying that the emigration of proinflammatory and immunocompetent cells from the circulation into the lung and/or their subsequent activation is suppressed. Indeed, suppression of the LPR at nonbronchodilator doses (<10 mg/l) of theophylline is associated with a reduction in the typical increase in CD4+ and CD8+ T-lymphocytes. Theophylline also suppresses the activity of other proinflammatory and immune cells ex vivo including neutrophils and macrophages, which is positively correlated with the concentration of theophylline measured in the BAL fluid. Similar experiments have demonstrated that the number of activated eosinophils and CD4+ T-cells are reduced in allergic subjects given low dose theophylline, and that eosinophil accumulation in bronchial tissue in patients with atopic asthma is attenuated. All these changes are mirrored by improvements in lung function.

Clinical Trials of PDE4 Inhibitors in Asthma and Rhinitis Asthma PDE4 inhibitors have been shown to be effective in patients with exercise-induced asthma. Nieman and colleagues (1998) have reported the results of a randomized, placebo-controlled, double blind crossover trial with cilomilast in 27 patients with exercise-induced asthma. Subjects were randomized to receive cilomilast or placebo for 7 days followed by a 7 day washout and then the alternative treatment for 7 days. The primary efficacy variable was the maximum percentage decrease (MPD) in forced expiratory volume in 1 s (FEV1) in response to exercise. In the placebo group the mean fall in FEV1 after exercise was 32.9%, which was significantly greater than the deterioration in lung function seen when the same subjects received a single dose of cilomilast (23.6% reduction in FEV1). The improvement in lung function was incremental such that after 7 days of therapy, the MPD in FEV1 was further reduced to 21.8% [91]. There were also improvements in the

116

M.A. Giembycz

MPD in peak expiratory flow rate (PEFR), time to recovery after exercise, and percent protection against exercise-induced bronchoconstriction [91]. Similar data have been obtained with roflumilast. Sixteen patients with exerciseinduced asthma were recruited into a placebo-controlled, randomized double blind, two-period cross-over study where placebo or roflumilast (500 mg od) was administered in random order for 28 days [92]. FEV1 was measured before and repeatedly up to 12 min after the end of the exercise challenge. Blood was taken for determination of lipopolysaccharide (LPS)-induced tumor necrosis-a (TNFa) released ex vivo as a surrogate marker of inflammatory cell activation. At the end of the study the mean fall in FEV1 in response to exercise was significantly reduced (by 41%) when compared to placebo [92]. Similarly, the median TNFa concentration was reduced by 21% during roflumilast treatment whereas it remained constant under placebo [92], indicating that an anti-inflammatory plasma concentration of the drug had been achieved. Other trials of cilomilast in asthma have yielded equivocal results. In one of these, the results of a multicentre, placebo-controlled, double blind randomized parallel group study with cilomilast (5, 10 and 15 mg bid for 6 weeks) involving 283 patients taking inhaled corticosteroids concurrently was reported [93]. All patients had an FEV1 of approximately 66% as predicted, expressed a 12% or greater responsiveness to salbutamol, and had asthma that was inadequately controlled with inhaled corticosteroids [93]. Two hundred and sixty six patients completed the study. At the highest tolerated dose (15 mg bid) cilomilast as well as placebo, increased FEV1 from week 1 onwards and this effect was greater with the active treatment group [93]. However, the improvement in lung function failed to reach statistical significance at any time except at week 2 when the mean difference in trough FEV1 was 210 ml greater than in the placebo treatment group [93]. Improvements, relative to placebo, in forced expiratory flow at 25–75% of forced vital capacity (FEF25–75) and domiciliary PEFR were also detected; but again, statistical significance was not achieved. However, in the physicians’ global assessment, 59% of patients taking cilomilast (15 mg bid) were rated as “markedly improved” compared to 39% of patients given placebo, which was significant. Similarly, in the patients’ global assessment, 69% of patients in the active treatment group (15 mg bid) indicated that they were “markedly improved” compared to 41% of patients who received placebo [93]. An international (Germany, United Kingdom, France and South Africa), multicentre phase IIb double blind, parallel, 12 month efficacy, safety and tolerability study of cilomilast (10 and 15 mg bid) also evaluated 211 asthmatic patients between 19 and 70 years of age, which was an extension of three double blind randomized phase II studies of 4–6 weeks duration [94,95]. One hundred and fifty eight patients received cilomilast and the rest were given placebo. Inclusion criteria included a history of episodic wheezing for at least 6 months, an FEV1 ³45% and £90% of predicted for height, sex and weight, and responsiveness to salbutamol (³12%) at time of screening. Clinically relevant and statistically significant improvements above placebo were seen in forced vital capacity (FVC) and PEFR, which were sustained from week 1 to the end of month 12. A consistent improvement

Alkylxanthines and Phosphodiesterase 4 Inhibitors

117

in FEV1 was also noted but this did not reach statistical significance. Asthma symptom scores maintained in diaries also indicated a reduction in cough, wheeze, and breathlessness/chest tightness in the active treatment group when compared to placebo [94]. More encouraging data have been obtained with roflumilast. In particular, a trial in 23 subjects with mild asthma showed that roflumilast (250 or 500 mg od) given for 7–10 days reduced the early and late asthmatic reactions evoked by allergen challenge [96]. These are potentially exciting data as the suppression of LPR (43% in the 500 µg treatment group) indicates that the drug may have exerted a clinically relevant anti-inflammatory effect. Indeed, in many clinical trials of oral PDE4 inhibitors, a maximum level of lung function improvement is achieved within the first 2–4 weeks of treatment, implicating a nonbronchodilator mode of action. Further studies have also found that roflumilast improved FEV1 in subjects with mild to moderate asthma [97]; it also reduced allergen-induced AHR to histamine [98]. One study has also found that roflumilast is as effective as an inhaled corticosteroid at improving lung function [99]. In that study, 499 asthmatic patients were randomized to receive either roflumilast (500 mg od) or beclomethasone dipropionate (200 µg bid) through a metered-dose inhaler for 12 weeks. At the end of the study, both treatment groups had significant and comparable improvements in FEV1, FVC, and PEFR; asthma symptoms and b2-agonist use were also reduced. Finally, roflumilast has been shown to be effective in the treatment of allergic rhinitis [100], which supports the idea that PDE4 inhibitors may have utility in treating a variety of allergic [and nonallergic] inflammatory disorders.

Clinical Trials of PDE4 Inhibitors in Psoriasis and Atopic/ Contact Dermatitis Several selective and nonselective PDE inhibitors of varied structural classes have been evaluated in humans for efficacy in atopic dermatitis and/or psoriasis [101].

Rolipram and Rolipram Analogues Two small studies, conducted in the late 1970s, were designed to examine the ability of Ro 20-1724, applied topically, to improve psoriatic lesions [102]. In one of these, which involved 17 subjects, Ro-20,1724 or vehicle was applied as a cream (qid) under occlusion for 4 weeks, and the extent of the lesions assessed 2, 4 and 6 weeks after initiation of the study. Compared to vehicle, 75% of subjects at week 4 showed improvements in skin lesions with no obvious adverse events. In the second study, Ro 20-1724 (1%) was compared to the corticosteroid, triamcinolone acetonide cream, in 33 subjects. Again, lesions were improved in 77% of subjects, although the corticosteroid was more efficacious (94% improvement at week 4).

118

M.A. Giembycz

Cutaneous application of the archetypal PDE4 inhibitor, rolipram (0.5% and 1%; 20 min pretreatment) to eight volunteers has also shown to reduce erythema induced by Balsam of Peru, given topically, which contains the irritant cinnamic aldehyde [103]. Similar data was obtained with Ro 20,1724 [103]. Another rolipram analogue, atizoram (10), was evaluated in 20 subjects with atopic dermatitis [104]. In this double-blind, randomized study, atizoram (0.5%) or its petrolatum vehicle was applied as an ointment (bid) for 28 days on 200 cm2 lesional areas. A statistically significant and clinical-relevant reduction in all proinflammatory parameters (i.e., erythema, induration/papulation, excoriation) was noticed within three days of treatment, which was preserved throughout the duration of the trial. At the end of the study 16 of the 20 sites treated with azitoram showed improvements in proinflammatory parameters compared to only 3 of the 20 sites to which vehicle had been applied.

Xanthines Consistent with the data obtained with rolipram and Ro 20-1724, cutaneous application of caffeine and pentoxfylline (0.5% and 1%; 20 min pretreatment) has been shown to reduce erythema induced by Balsam of Peru, given topically [103]. Significantly, there was a positive correlation between the anti-inflammatory activity of these four PDE inhibitors and their ability to suppress PDE4 isolated from the HaCaT keratinocyte cell line [103]. In 2002, the results of a multinational and multicentre, placebo-controlled, double-blind, randomized, parallel group, proof-of-concept study with cipamfylline (11) was reported [105]. In this trial, 52 subjects with a diagnosis of atopic dermatitis were randomized to one of two treatment groups such that the effect of cipamfylline (1.5 mg/g) could be compared against vehicle and the moderately potent corticosteroid, hydrocortisone 17-butyrate (0.1%), applied as creams. Subjects were treated twice daily with a maximum application of 2 g/day for 14 days. Several inflammatory parameters were measured at the beginning of the study and at days 3, 7 and 14 including the degree of erythema, edema/papulation, oozing/crusting, excoriation and lichenification to provide a total severity score (TSS). The results of that trial demonstrated that cipamfylline was more effective than vehicle in reducing the TSS but was not as efficacious as hydrocortisone 17-butyrate [105]. Despite the topical application of cipamfylline, systemic exposure was recorded in 25% of subjects, which presumably precluded further trials at higher topical doses. In contrast, cipamfylline (2.5 mg/g) delivered topically as an ointment was not better than vehicle in reducing inflammation in an acute and chronic human model of contact dermatitis where sodium dodecylsulphate was used as irritant, and under experimental conditions where betamethasone 17-valerate was effective [106]. The reason for this discrepancy is unclear.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

119

Thalidomide Derivatives C-10004 (12) is a thalidomide derivative in Phase II clinical trials for a number of allergic conditions including psoriasis [107]. In Phase I studies, C-10004 given orally in single and multiple doses (10 mg and 20 mg) was well tolerated in healthy volunteers and had a mild adverse-effect profile [107]. A Phase IIa trial has also established that C-10004 (20 mg) reduced both symptoms of psoriasis in a small population of subjects and reduced epidermal thickness – a primary efficacy endpoint measure – although this was not of a magnitude required by the United States Food and Drug Administration [101]. However, in this trial, C-10004 was not well tolerated, with adverse events (nausea, dizziness, and diarrhea) mirroring those reported for other PDE4 inhibitors including cilomilast and roflumilast (see Section on Adverse Events).

Safety, Tolerability, Drug Metabolism and Pharmacokinetics of Theophylline and PDE4 Inhibitors: A Comparison Table 5 shows a comparison of the drug metabolism, pharmacokinetics (DMPK), and clinical safety of theophylline and PDE4 inhibitors for which information is available. Perhaps the most striking difference is in the pharmacokinetics, which has implications for patient compliance and the extent to which the plasma concentration requires monitoring. At bronchodilator doses, intra- and intersubject variability to theophylline together with a low therapeutic ratio poses a significant clinical problem requiring careful titration with routine plasma monitoring to avoid serious cardiac and CNS side effects [108]. This is a particular problem with smokers, as polycyclic aromatic hydrocarbons present in vapor phase of cigarette smoke are known to induce drug metabolizing enzymes including CYP1A1 and CYP1A2 [109–111]. As theophylline is principally metabolized by CYP1A2 [112,113], dose adjustments are often necessary to compensate for the increased clearance in cigarette smokers [114–116]. Age is another factor that has a marked effect on the pharmacokinetics of theophylline. Indeed, the clearance of theophylline decreases 15–28% in the elderly when compared to young adults, which probably reflects a decrease in the elimination of theophylline by CYP1A2 [117–119]. In contrast, the pharmacokinetics of cilomilast and roflumilast are linear, providing dose-proportional systemic exposure that is essentially unaffected by age and cigarette smoking status. This indicates that no dose adjustments will be necessary in elderly smoking subjects with COPD [108, 120, 121]. Despite producing bronchodilatation, theophylline is prone to cause adverse events. These are particularly pronounced when dosed to give plasma concentrations of 20 mg/l or greater, although these unwanted actions can be offset by gradually titrating the dose of theophylline until therapeutic levels are achieved [122].

120

M.A. Giembycz

In contrast, a major benefit of PDE4 inhibitors in clinical trials is their superior safety and tolerability profile over theophylline. Although nausea and vomiting are common with PDE4 inhibitors, this is usually of moderate severity and is reported to be self-limiting [123]. Moreover, PDE4 inhibitors are generally well tolerated in both short- and long-term dosing trials with a low incidence of adverse events; they have no action on adenosine receptors, and with the exception of headache, are devoid of adverse cardiovascular activity [120, 121]. Nevertheless, despite these improvements over theophylline, there are still major safety concerns with current second generations PDE4 inhibitors at the doses believed necessary to impart therapeutic benefit (see Section on Adverse Events). Another significant clinical problem is that theophylline has a high potential for drug interactions [120, 121]. Thus, in addition to CYP1A2, theophylline is also metabolized, albeit to a lesser extent, by CYP2E1 and CYP3A4. Accordingly, many drug interactions may occur including all of those indicated in Table 5. In contrast, PDE4 inhibitors have, in general, a far reduced propensity for drug interactions. With respect to cilomilast, none of the metabolic pathways largely involve cytochrome P450 enzymes (CYP1A2, CYP2D6, CYP3A4), which are most susceptible to competitive inhibition by other drugs [121]. Indeed, the only P450 enzyme implicated (CYP2C8), has few other substrates or inhibitors. Moreover, cilomilast does not inhibit any important hepatic cytochrome P450 enzymes in vitro [121]. The finding that, at steady state, cilomilast has no clinically meaningful effect on the pharmacokinetics of digoxin, theophylline, or prednisolone supports this data [121]. Conversely, neither theophylline nor Maalox Plus – an antacid commonly used in the elderly that contains salts of calcium, magnesium and/or aluminium that can alter the absorption or bioavailability of some drugs – had any significantly influence on the pharmacokinetics of cilomilast [121]. Similar results have been reported for roflumilast. Thus, taken together these data demonstrate that the two most clinically advanced PDE4 inhibitors are not contra-indicated with commonly prescribed medications for asthma and can be safely coadministered with these drugs.

Adverse Events of Theophylline and PDE4 Inhibitors Theophylline Theophylline has a very low therapeutic ratio. This undesirable property is a major cause for concern, as adverse events tend to occur when the plasma concentration exceeds 20 µg/ml (110 µM). The most common adverse events include nausea, vomiting, gastro-intestinal irritation, and headache (probably due to PDE4 inhibition – see below). Other more serious, side effects such as CNS stimulation, diuresis, and cardiac arrhythmias occur at higher doses and may be due to the ability of theophylline to act as an adenosine A1-receptor antagonist [122, 124]. Still higher plasma concentrations may precipitate convulsions and even death [122].

Alkylxanthines and Phosphodiesterase 4 Inhibitors

121

Table 5 A comparison of the mechanism of action, DMPK, safety and tolerability of theophylline and PDE4 inhibitors Theophylline PDE4 inhibitorsa • Selective inhibition of Mechanism of • Unclear (inhibition of PI-3Kd; PDE4 action histone acetylation status) • PDE inhibition only at high (>20 mg/l) doses DMPK Pharmacokinetics • Nonlinear • Linear providing dose • Significant intersubject proportional systemic variability affected by age, exposure smoking status and concomitant • Low intersubject variability medication necessitating plasma – no plasma monitoring monitoring required Absorption • Variable, depends on formulation • Oral formulations (od or bid) • tmax ~1–2 h Bioavailability • Variable, depends on formulation • >80%, unaffected by food or antacids Half life • 7–9 h • 7–16 h depending on inhibitor Volume of distribution • 500 ml/kg • Low • plasma protein binding ~56% • High Clearance • ~400 ml/h/kg • Low • Affected by genetic factors, cigarette smoking, coexisting pathology and drugs that affect hepatic metabolism Metabolism • ~90% metabolized by liver • Negligible first pass hepatic (CYP1A2) metabolism Drug interactions • High potential for drug • Low potential for drug interactions including interactions propafenone, mexiletine, • Can be taken with other enoxacin, ciprofloxacin, drugs prescribed for asthma cimetidine, propranolol, oral and COPD contraceptives, erythromycin, rifampicin, phenytoin, carbamazepine, phenobarbitone, isoprenaline, tobacco smoke Excretion • 10% excreted unchanged via the • Depends on inhibitor kidneys • None, accept in individuals Dosing adjustment • May be required in cigarette with moderate hepatic and smokers, the elderly, individuals severe renal impairment with liver disease and subjects • Contraindicated in subjects taking concomitant medication with severe hepatic • Contraindicated in individuals impairment with heart disease, seizure disorders and gastro-esophageal reflux. (continued)

122

M.A. Giembycz

Table 5 (continued) Clinical efficacy

Safety and tolerability

Theophylline

PDE4 inhibitorsa

• Effective in a subset of patients with COPD • Nonbronchodilator doses effective in asthma; steroid sparing • Serious cardiovascular and CNS side-effects • GI irritation, nausea, insomnia in 10–15% of patients

• Phase III clinical trials ongoing

• No cardiovascular or CNS side-effects • Headache, nausea, vomiting, arteriopathy(?)

a

Details refer to cilomilast and roflumilast, which are in late Phase III clinical trials

PDE4 Inhibitors Despite some encouraging data from Phase III studies in asthma, and the superior DMPK over theophylline, roflumilast and other PDE4 inhibitors are still hampered by a low therapeutic ratio. This limitation became clear early on in the development of these compounds with nausea, diarrhea, abdominal pain, vomiting, and dyspepsia being the most common adverse events reported (reviewed in [120, 121]). For example, the number of subjects failing to complete all controlled trials of cilomilast conducted by GSK due to an adverse event was positively dose-related with gastrointestinal disturbances being the most prevalent [125]. Unfortunately, these unwanted actions, which are mediated both locally (i.e., in the gastrointestinal tract) and centrally, can be accounted for by the ubiquitous distribution of PDE4 isoforms across many tissues, and represent an extension of the pharmacology of PDE4 inhibitors that is typical of first generation compounds such as rolipram. Documentation of serious toxicities resulting from the oral administration of PDE4 inhibitors is relatively sparse. However, the most worrying potential toxicity generic to PDE4 inhibitors is arteritis. This condition is characterized by inflammation, hemorrhage and necrosis of blood vessels, and is believed to be irreversible in animals. Mechanistically, arteritis is thought to result from hemodynamic changes produced by excessive and prolonged vasodilatation of specific vascular beds, although the means by which PDE4 inhibitors cause certain vessels to become targets of inflammation is unknown. In nonhuman primates, studies with PDE4 inhibitors generally have not identified pathologies, including arteritis, similar to those reported in other species used for toxicology [126,127]; this has lead to a view that arteriopathies maybe nonprimate-specific. Indeed, rats and dogs may have an increased susceptibility to drug-induced vascular lesions because of the common occurrence of arteriopathies in these species [128,129]. Consistent with this hypothesis, cilomilast is reported not to produce vascular lesions in primates whereas in rodents medial necrosis of mesenteric arteries is well documented [130]. However, a recent comprehensive toxicological study found that a PDE4 inhibitor, SCH 351591 produced in Cynomolgus monkeys,

Alkylxanthines and Phosphodiesterase 4 Inhibitors

123

acute to chronic inflammation of small to medium sized arteries in many tissues and organs [131]. These findings of arteriopathy in primates, which were previously thought to be resistant to toxicity, have serious implications for human risk, and it is noteworthy that Merck in 2003 abandoned development of their lead PDE4 inhibitor (licensed from Celltech Group) due to an incidence of colitis, raising the possibility that it was secondary to arteritis [132]. Moreover, as asthma is a chronic disease requiring – in many subjects with moderate to severe disease – long-term therapy, a wide margin of safety will be needed because toxicity cannot be adequately monitored. The major problem for the physician is that presentation of mesenteric ischemia is vague in humans and diagnostic tools are poor. Indeed, attempts by the pharmaceutical industry to develop biomarkers of arteritis to assist the development of PDE4 inhibitors have, to date, been unsuccessful. However, perhaps some comfort can be derived from the knowledge that no clinically relevant effects have been produced in patients treated for many years with bronchodilator doses of theophylline (which produce medial necrosis of mesenteric vessels in rats [133, 134]), as well as more selective PDE4 inhibitors including rolipram and denbufylline [130]. Other adverse events generic to PDE4 inhibitors and of potential concern based on margin of safety calculations consist of testicular toxicity – manifested as degeneration of the epithelium lining the seminiferous tubules – hypertrophy, and hyperplasia of the adrenal cortex. It also includes focal myocardial necrosis, erosion of the gastrointestinal mucosa and squamous cell hyperplasia of the nonglandular stomach, which is indicative of an irritant action of cilomilast on the gut [130, 135, 136]. However, it is currently believed that these findings do not have clinical relevance. Indeed, there is no evidence from the Phase II or Phase III trials conducted to date that cilomilast at a dose 15 mg (bid) produces these adverse effects in humans.

Concluding Remarks Many of the major pharmaceutical companies in the world have developed potent and novel “second generation” PDE4 inhibitors for the treatment of a number of allergic disorders (Table 3). There is abundant predictive evidence from preclinical studies that these new drugs demonstrate global anti-inflammatory activity with an improved therapeutic ratio [7, 121, 137, 138]. That said one must be cautious of this interpretation since only the acute effects of PDE4 inhibitors in animals have been demonstrated and whether they translate into a useful therapy in chronic human allergic diseases remains to be determined. Indeed, despite initial optimism, the disappointing results of a number of Phase III trials of PDE4 inhibitors indicate that dose-limiting adverse events are a major cause for concern and probably reflect an interaction with PDE4 expressed in “nontarget” tissues. An additional contributing factor also may lie in the knowledge that all PDE4 inhibitors currently in development, block PDE4D, which is believed to promote emesis [139–141].

124

M.A. Giembycz

Nevertheless, by 2010 it is likely that results from clinical trials will reveal whether optimism in the therapeutic potential of this class of compounds was justified. Acknowledgements The author is an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar and is funded by the Canadian Institutes of Health Research.

References 1. Asher I, Baena-Cagnani C, Boner A, Canonica GW, Chuchalin A, Custovic A, et al. World Allergy Organization guidelines for prevention of allergy and allergic asthma. Int Arch Allergy Immunol. 2004;135:83–92. 2. Lemiere C, Bai T, Balter M, Bayliff C, Becker A, Boulet LP, et al. Adult Asthma Consensus Guidelines Update 2003. Can Respir J. 2004;11:9A–18A. 3. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488–520. 4. Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther. 2006;109:366–398. 5. Houslay MD. The long and short of vascular smooth muscle phosphodiesterase-4 as a putative therapeutic target. Mol Pharmacol. 2005;68:563–567. 6. Houslay MD, Schafer P, Zhang KY. Phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10:1503–1519. 7. Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998;157:351–370. 8. Giembycz MA. Phosphodiesterase 4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. Proc Am Thor Soc. 2005;2:326–333. 9. Giembycz MA. Life after PDE4: overcoming adverse events with dual-specificity phosphodiesterase inhibitors. Curr Opin Pharmacol. 2005;5:238–244. 10. Ward AJ, McKenniff M, Evans JM, Page CP, Costello JF. Theophylline – an immunomodulatory role in asthma? Am Rev Respir Dis. 1993;147:518–523. 11. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Anti-inflammatory effects of lowdose oral theophylline in atopic asthma. Lancet. 1994;343:1006–1008. 12. Djukanovic R, Finnerty JP, Lee C, Wilson S, Madden J, Holgate ST. The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results. Eur Respir J. 1995;8:831–833. 13. Banner KH, Page CP. Theophylline and selective phosphodiesterase inhibitors as anti-inflammatory drugs in the treatment of bronchial asthma. Eur Respir J. 1995;8:996–1000. 14. Giembycz MA. Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here? Drugs. 2000;59:193–212. 15. Palfreyman MN, Souness JE. Phosphodiesterase type IV inhibitors. Prog Med Chem. 1996;33:1–52. 16. Dent G, Giembycz MA. Phosphodiesterase inhibitors: lily the Pink’s medicinal compound for asthma? Thorax. 1996;51:647–649. 17. Essayan DM. Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem Pharmacol. 1999;57:965–973. 18. Doherty AM. Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents. Curr Opin Chem Biol. 1999;3:466–473. 19. Cyclic nucleotide phosphodiesterases in health and disease. Beavo JA, Francis SH, Houslay MD (eds). Boca Raton: CRC Press; 2007. 20. Newton RP, Salih SG. Cyclic CMP phosphodiesterase: isolation, specificity and kinetic properties. Int J Biochem. 1986;18:743–752. 21. Butcher RW, Sutherland EW. Adenosine 3’, 5’-phosphate in biological materials. I. Purification and properties of cyclic 3’, 5’-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3’, 5’-phosphate in human urine. J Biol Chem. 1962;237:1244–1250.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

125

22. Conti M, Jin SL. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol. 1999;63:1–38. 23. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1–18. 24. Houslay MD. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol. 2001;69:249–315. 25. Soderling SH, Beavo JA. Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol. 2000;12:174–179. 26. Conti M. Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol Endocrinol. 2000;14:1317–1327. 27. Charbonneau H, Beier N, Walsh KA, Beavo JA. Identification of a conserved domain among cyclic nucleotide phosphodiesterases from diverse species. Proc Natl Acad Sci USA. 1986;83:9308–9312. 28. Martinez SE, Beavo JA, Hol WG. GAF domains: two-billion-year-old molecular awitches that bind cyclic nucleotides. Mol Interv. 2002;2:317–323. 29. Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG, et al. The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci USA. 2002;99:13260–13265. 30. Charbonneau H, Kumar S, Novack JP, Blumenthal DK, Griffin PR, Shabanowitz J, et al. Evidence for domain organization within the 61-kDa calmodulin-dependent cyclic nucleotide phosphodiesterase from bovine brain. Biochemistry. 1991;30:7931–7940. 31. Kovala T, Sanwal BD, Ball EH. Recombinant expression of a type IV, cAMP-specific phosphodiesterase: characterization and structure-function studies of deletion mutants. Biochemistry. 1997;36:2968–2976. 32. Richter W, Conti M. Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem. 2002;277:40212–40221. 33. Zoraghi R, Bessay EP, Corbin JD, Francis SH. Structural and functional features in human PDE5A1 regulatory domain that provide for allosteric cGMP binding, dimerization, and regulation. J Biol Chem. 2005;280:12051–12063. 34. Hoffmann R, Wilkinson IR, McCallum JF, Engels P, Houslay MD. cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J. 1998;333:139–149. 35. MacKenzie SJ, Baillie GS, McPhee I, Bolger GB, Houslay MD. ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. J Biol Chem. 2000;275:16609–16617. 36. Thompson WJ, Epstein PM, Strada SJ. Purification and characterization of high-affinity cyclic adenosine monophosphate phosphodiesterase from dog kidney. Biochemistry. 1979;18:5228–5237. 37. Epstein PM, Strada SJ, Sarada K, Thompson WJ. Catalytic and kinetic properties of purified high-affinity cyclic AMP phosphodiesterase from dog kidney. Arch Biochem Biophys. 1982;218:119–133. 38. Torphy TJ, DeWolf WE Jr, Green DW, Livi GP. Biochemical characteristics and cellular regulation of phosphodiesterase IV. Agents Actions Suppl. 1993;43:51–71. 39. Truong VH, Muller T. Isolation, biochemical characterization and N-terminal sequence of rolipram-sensitive cAMP phosphodiesterase from human mononuclear leukocytes. FEBS Lett. 1994;353:113–118. 40. Salanova M, Jin SC, Conti M. Heterologous expression and purification of recombinant rolipram-sensitive cyclic AMP-specific phosphodiesterases. Methods. 1998;14: 55–64. 41. Colicelli J, Birchmeier C, Michaeli T, O’Neill K, Riggs M, Wigler M. Isolation and characterization of a mammalian gene encoding a high-affinity cAMP phosphodiesterase. Proc Natl Acad Sci USA. 1989;86:3599–3603.

126

M.A. Giembycz

42. Swinnen JV, Joseph DR, Conti M. Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. Proc Natl Acad Sci USA. 1989;86:5325–5329. 43. Swinnen JV, Joseph DR, Conti M. The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP. Proc Natl Acad Sci USA. 1989;86: 8197–8201. 44. Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol. 1998;44:225–342. 45. Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs. 2002;11:1–13. 46. Sommer N, Martin R, McFarland HF, Quigley L, Cannella B, Raine CS, et al. Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol. 1997;79:54–61. 47. Moore CS, Earl N, Frenette R, Styhler A, Mancini JA, Nicholson DW, et al. Peripheral phosphodiesterase 4 inhibition produced by 4-[2-(3, 4-Bis-difluoromethoxyphenyl)-2-[4-(1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826, 141) prevents experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther. 2006;319:63–72. 48. Banner KH, Trevethick MA. PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci. 2004;25:430–436. 49. Aricha R, Feferman T, Souroujon MC, Fuchs S. Overexpression of phosphodiesterases in experimental autoimmune myasthenia gravis: suppression of disease by a phosphodiesterase inhibitor. FASEB J. 2006;20:374–376. 50. Souness JE, Villamil ME, Scott LC, Tomkinson A, Giembycz MA, Raeburn D. Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone. Br J Pharmacol. 1994;111:1081–1088. 51. Kawasaki A, Hoshino K, Osaki R, Mizushima Y, Yano S. Effect of ibudilast: a novel antiasthmatic agent, on airway hypersensitivity in bronchial asthma. J Asthma. 1992;29: 245–252. 52. Harada D, Tsukumo Y, Takashima Y, Manabe H. Effect of orally administered rolipram, a phosphodiesterase 4 inhibitor, on a mouse model of the dermatitis caused by 2, 4, 6-trinitro1-chlorobenzene (TNCB)-repeated application. Eur J Pharmacol. 2006;532:128–137. 53. Davies GE, Evans DP. Studies with two new phosphodiesterase inhibitors (ICI 58, 301 and ICI 63, 197) on anaphylaxis in guinea pigs, mice and rats. Int Arch Allergy Appl Immunol. 1973;45:467–478. 54. Broughton BJ, Chaplen P, Knowles P, Lunt E, Marshall SM, Pain DL, et al. Antiallergic activity of 2-phenyl-8-azapurin-6-ones. J Med Chem. 1975;18:1117–1122. 55. Teixeira MM, Rossi AG, Williams TJ, Hellewell PG. Effects of phosphodiesterase isoenzyme inhibitors on cutaneous inflammation in the guinea-pig. Br J Pharmacol. 1994;112: 332–340. 56. Howell RE, Sickels BD, Woeppel SL. Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. J Pharmacol Exp Ther. 1993;264:609–615. 57. Andersson P, Brange C, Sonmark B, Stahre G, Erjefalt I, Wieslander E, et al. Anti-anaphylactic and ant-inflammatory effects of xanthines in the lung. In: Andersson KE, Persson CG, editors. Antiasthma xanthines and adenosine. Amsterdam: Excerpta Medica; 1985. p. 187–192. 58. Ali S, Mustafa SJ, Metzger WJ. Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol. Agents Actions. 1992;37:168–170. 59. Gristwood RW, Llupia J, Fernandez AG, Berga P. Effects of theophylline compared with prednisolone on late phase airway leukocyte infiltration in guinea pigs. Int Arch Allergy Appl Immunol. 1991;94:293–294.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

127

60. Sanjar S, Aoki S, Kristersson A, Smith D, Morley J. Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitized guinea-pigs: the effect of anti-asthma drugs. Br J Pharmacol. 1990;99:679–686. 61. Tarayre JP, Aliaga M, Barbara M, Malfetes N, Vieu S, Tisne-Versailles J. Theophylline reduces pulmonary eosinophilia after various types of active anaphylactic shock in guineapigs. J Pharm Pharmacol. 1991;43:877–879. 62. Tarayre JP, Aliaga M, Barbara M, Tisseyre N, Vieu S, Tisne-Versailles J. Pharmacological modulation of a model of bronchial inflammation after aerosol-induced active anaphylactic shock in conscious guinea pigs. Int J Immunopharmacol. 1991;13:349–356. 63. Tarayre JP, Aliaga M, Barbara M, Tisseyre N, Vieu S, Tisne-Versailles J. Model of bronchial allergic inflammation in the brown Norway rat. Pharmacological modulation. Int J Immunopharmacol. 1992;14:847–855. 64. Manzini S, Perretti F, Abelli L, Evangelista S, Seeds EA, Page CP. Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs. Eur J Pharmacol. 1993;249:251–257. 65. Lagente V, Moodley I, Perrin S, Mottin G, Junien JL. Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung. Eur J Pharmacol. 1994;255:253–256. 66. Sanjar S, Aoki S, Boubekeur K, Chapman ID, Smith D, Kings MA, et al. Eosinophil accumulation in pulmonary airways of guinea-pigs induced by exposure to an aerosol of plateletactivating factor: effect of anti-asthma drugs. Br J Pharmacol. 1990;99:267–272. 67. Schudt C, Winder S, Eltze M, Kilian U, Beume R. Zardaverine: a cyclic AMP specific PDE III/IV inhibitor. Agents Actions Suppl. 1991;34:379–402. 68. Griswold DE, Webb EF, Badger AM, Gorycki PD, Levandoski PA, Barnette MA, et al. SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo. J Pharmacol Exp Ther. 1998;287:705–711. 69. Underwood DC, Osborn RR, Novak LB, Matthews JK, Newsholme SJ, Undem BJ, et al. Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram. J Pharmacol Exp Ther. 1993;266:306–313. 70. Underwood DC, Kotzer CJ, Bochnowicz S, Osborn RR, Luttmann MA, Hay DW, et al. Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther. 1994;270:250–259. 71. Underwood DC, Bochnowicz S, Osborn RR, Kotzer CJ, Luttmann MA, Hay DW, et al. Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. J Pharmacol Exp Ther. 1998;287:988–995. 72. Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther. 2001;297:280–290. 73. Baumer W, Gorr G, Hoppmann J, Ehinger AM, Ehinger B, Kietzmann M. Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12–281 on the inflammatory reaction in a model of allergic dermatitis. Eur J Pharmacol. 2002;446:195–200. 74. Baumer W, Gorr G, Hoppmann J, Ehinger AM, Rundfeldt C, Kietzmann M. AWD 12–281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis. J Pharm Pharmacol. 2003;55: 1107–1114. 75. Hoppmann J, Baumer W, Galetzka C, Hofgen N, Kietzmann M, Rundfeldt C. The phosphodiesterase 4 inhibitor AWD 12–281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice. J Pharm Pharmacol. 2005;57:1609–1617. 76. Kuss H, Hoefgen N, Johanssen S, Kronbach T, Rundfeldt C. In vivo efficacy in airway disease models of N-(3, 5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyo xylic acid amide (AWD 12–281), a selective phosphodiesterase 4 inhibitor for inhaled administration. J Pharmacol Exp Ther. 2003;307:373–385.

128

M.A. Giembycz

77. Draheim R, Egerland U, Rundfeldt C. Anti-inflammatory potential of the selective phosphodiesterase 4 inhibitor N-(3, 5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3yl]-gly oxylic acid amide (AWD 12–281), in human cell preparations. J Pharmacol Exp Ther. 2004;308:555–563. 78. Turner CR, Andresen CJ, Smith WB, Watson JW. Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am J Respir Crit Care Med. 1994;149:1153–1159. 79. Erjefalt I, Persson CG. Pharmacologic control of plasma exudation into tracheobronchial airways. Am Rev Respir Dis. 1991;143:1008–1014. 80. Boschetto P, Roberts NM, Rogers DF, Barnes PJ. Effect of antiasthma drugs on microvascular leakage in guinea pig airways. Am Rev Respir Dis. 1989;139:416–421. 81. Raeburn D, Karlsson JA. Effects of isoenzyme-selective inhibitors of cyclic nucleotide phosphodiesterase on microvascular leak in guinea pig airways in vivo. J Pharmacol Exp Ther. 1993;267:1147–1152. 82. Raeburn D, Woodman VR. Effect of theophylline administered intratracheally as a dry powder formulation on bronchospasm and airway microvascular leakage in the anesthetized guinea-pig. Pulm Pharmacol. 1994;7:243–249. 83. Ortiz JL, Cortijo J, Valles JM, Morcillo EJ. Rolipram inhibits PAF-induced airway microvascular leakage in guinea-pig: a comparison with milrinone and theophylline. Fundam Clin Pharmacol. 1992;6:247–249. 84. Raeburn D, Underwood SL, Lewis SA, Woodman VR, Battram CH, Tomkinson A, et al. Antiinflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. Br J Pharmacol. 1994;113:1423–1431. 85. Svensjo E, Andersson KE, Bouskela E, Cyrino FZ, Lindgren S. Effects of two vasodilatory phosphodiesterase inhibitors on bradykinin-induced permeability increase in the hamster cheek pouch. Agents Actions. 1993;39:35–41. 86. Crummey A, Harper GP, Boyle EA, Mangan FR. Inhibition of arachidonic acid-induced ear oedema as a model for assessing topical anti-inflammatory compounds. Agents Actions. 1987;20:69–76. 87. Krause W, Kuhne G. Anti-inflammatory activity of rolipram in a rat ear edema model. Arzneimittelforschung. 1994;44:163–165. 88. Ehinger AM, Gorr G, Hoppmann J, Telser E, Ehinger B, Kietzmann M. Effects of the phosphodiesterase 4 inhibitor RPR 73401 in a model of immunological inflammation. Eur J Pharmacol. 2000;392:93–99. 89. Baumer W, Seegers U, Braun M, Tschernig T, Kietzmann M. TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines. Br J Dermatol. 2004;151:823–830. 90. Spina D. Theophylline and PDE4 inhibitors in asthma. Curr Opin Pulm Med. 2003;9:57–64. 91. Nieman RB, Fisher BD, Amit O, Dockhorn RJ. SB207499 (Ariflo), a second generation, selective oral phosphodiesterase type 4 (PDE4) inhibitor, attenuates exercise-induced bronchoconstriction in patients with asthma. Am J Respir Crit Care Med. 2007;157:A413. 92. Timmer W, Leclerc V, Birraux G, Neuhauser M, Hatzelmann A, Bethke T, et al. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNFa ex vivo. J Clin Pharmacol. 2002;42:297–303. 93. Compton C, Cedar E, Nieman RB, Amit O, Langley SJ, Sapene M. Ariflo improves pulmonary function in patients with asthma: results of a study in patients taking inhaled corticosteroids. Am J Respir Crit Care Med. 1999;159:A522. 94. Compton CH, Duggan M, Cedar E, Nieman RB, Amit O, Tabona MV, et al. Ariflo efficacy in a 12-month study of patients with asthma. Am J Respir Crit Care Med. 2000;161:A505. 95. Compton CH, Duggan M, Cedar E, Tabona MV, Nieman RB, Amit O, et al. Safety of Ariflo in a 12-month study of patients with asthma. Am J Respir Crit Care Med. 2000;161:A200. 96. van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, et al. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol. 2005;116:292–298.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

129

97. Bateman ED, Izquierdo JL, Harnest U, Hofbauer P, Magyar P, Schmid-Wirlitsch C, et al. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol. 2006;96:679–686. 98. Louw C, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbroker D, Bardin PG (2007) Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge. Respiration (Epub) 99. Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy. 2006;61:72–78. 100. Schmidt BM, Kusma M, Feuring M, Timmer WE, Neuhauser M, Bethke T, et al. The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis. J Allergy Clin Immunol. 2001;108:530–536. 101. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17–26. 102. Stawiski MA, Rusin LJ, Burns TL, Weinstein GD, Voorhees JJ. Ro 20–1724: an agent that significantly improves psoriatic lesions in double-blind clinical trials. J Invest Dermatol. 1979;73:261–263. 103. Goyarts E, Mammone T, Muizzuddin N, Marenus K, Maes D. Correlation between in vitro cyclic adenosine monophosphate phosphodiesterase inhibition and in vivo anti-inflammatory effect. Skin Pharmacol Appl Skin Physiol. 2000;13:86–92. 104. Hanifin JM, Chan SC, Cheng JB, Tofte SJ, Henderson WR Jr, Kirby DS, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107:51–56. 105. Griffiths CE, Van Leent EJ, Gilbert M, Traulsen J. Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17-butyrate cream for the treatment of atopic dermatitis. Br J Dermatol. 2002;147:299–307. 106. Kucharekova M, Hornix M, Ashikaga T, T’kint S, de Jongh GJ, Schalkwijk J, et al. The effect of the PDE-4 inhibitor (cipamfylline) in two human models of irritant contact dermatitis. Arch Dermatol Res. 2003;295:29–32. 107. Khobzaoui M, Gutke HJ, Burnet M. CC-10004. Curr Opin Investig Drugs. 2005;6: 518–525. 108. Vignola AM. PDE4 inhibitors in COPD – a more selective approach to treatment. Respir Med. 2004;98:495–503. 109. Shimada T, Iwasaki M, Martin MV, Guengerich FP. Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. Cancer Res. 1989;49:3218–3228. 110. Campbell ME, Spielberg SP, Kalow W. A urinary metabolite ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther. 1987;42:157–165. 111. Vistisen K, Poulsen HE, Loft S. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis. 1992;13:1561–1568. 112. Fuhr U, Doehmer J, Battula N, Wolfel C, Kudla C, Keita Y, et al. Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Biochem Pharmacol. 1992;43:225–235. 113. Sarkar MA, Hunt C, Guzelian PS, Karnes HT. Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos. 1992;20:31–37. 114. Jusko WJ. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev. 1979;9:221–236. 115. Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced biotransformation of theophylline in marihuana and tobacco smokers. Clin Pharmacol Ther. 1978;24:405–410. 116. Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther. 1976;19:546–551. 117. Antal EJ, Kramer PA, Mercik SA, Chapron DJ, Lawson IR. Theophylline pharmacokinetics in advanced age. Br J Clin Pharmacol. 1981;12:637–645.

130

M.A. Giembycz

118. Ohnishi A, Kato M, Kojima J, Ushiama H, Yoneko M, Kawai H. Differential pharmacokinetics of theophylline in elderly patients. Drugs Aging. 2003;20:71–84. 119. Shin SG, Juan D, Rammohan M. Theophylline pharmacokinetics in normal elderly subjects. Clin Pharmacol Ther. 1988;44:522–530. 120. Giembycz MA. Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Arch Chest Dis. 2002;57:48–64. 121. Giembycz MA. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2001;10: 1361–1379. 122. Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med. 2003;167:813–818. 123. Compton CH, Gubb J, Nieman R, Edelson J, Amit O, Bakst A, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet. 2001;358:265–270. 124. Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci. 1980;1:129–132. 125. GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) – New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee Briefing Document. http:// www.fda.gov/ohrms/dockets/ac/03/briefing/3976B1_02_D-FDA-%20Tab%203.pdf 126. Larson JL, Pino MV, Geiger LE, Simeone CR. The toxicity of repeated exposures to rolipram, a type IV phosphodiesterase inhibitor, in rats. Pharmacol Toxicol. 1996;78:44–49. 127. Robertson DG, Reily MD, Albassam M, Dethloff LA. Metabonomic assessment of vasculitis in rats. Cardiovasc Toxicol. 2001;1:7–19. 128. Ruben Z, Deslex P, Nash G, Redmond NI, Poncet M, Dodd DC. Spontaneous disseminated panarteritis in laboratory beagle dogs in a toxicity study: a possible genetic predilection. Toxicol Pathol. 1989;17:145–152. 129. Bishop SP. Animal models of vasculitis. Toxicol Pathol. 1989;17:109–117. 130. GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) – New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee. Nonclinical Findings. http:// www.fda.gov/ohrms/dockets/ac/03/briefing/3976B1_01_C-Glaxo-Nonclinical%20Findings. pdf 131. Losco PE, Evans EW, Barat SA, Blackshear PE, Reyderman L, Fine JS, et al. The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys. Toxicol Pathol. 2004;32:295–308. 132. Data Monitor (2003) Press release: Merck discontinues development of PDE4 inhibitor compound. http://www.datamonitor.com/~90c3cffcaf0546f7ad089c97929631c8~/companies/company/?pid=E915DFB3-6FBF-4C67-AE8F-29EB1160FC4C&nid=816AB3F2982C-44B3-887C-3451D89A6362&type=NewsWire&article=1 133. Nyska A, Herbert RA, Chan PC, Haseman JK, Hailey JR. Theophylline-induced mesenteric periarteritis in F344/N rats. Arch Toxicol. 1998;72:731–737. 134. Collins JJ, Elwell MR, Lamb JC, Manus AG, Heath JE, Makovec GT. Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice. Fundam Appl Toxicol. 1988;11:472–484. 135. GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) – New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee. Clinical Pharmacology. http:// www.fda.gov/ohrms/dockets/ac/03/briefing/3976B1_01_D-Glaxo-Clinical%20Pharmacology.pdf 136. GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) – New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee. Preclinical Considerations. http://www.fda.gov/ohrms/dockets/ac/03/briefing/3976B1_02_F-FDA-Tab%205.pdf 137. Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, et al. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther. 1999;12:131–135. 138. Souness JE, Rao S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal. 1997;9:227–236.

Alkylxanthines and Phosphodiesterase 4 Inhibitors

131

139. Robichaud A, Stamatiou PB, Jin SL, Lachance N, MacDonald D, Laliberte F, et al. Deletion of phosphodiesterase 4D in mice shortens a2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest. 2002;110:1045–1052. 140. Giembycz MA. 4D or not 4D – the emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol Sci. 2002;23:548. 141. Hansen G, Jin S, Umetsu DT, Conti M. Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc Natl Acad Sci USA. 2000;97:6751–6756. 142. Ahn HS, Bercovici A, Boykow G, Bronnenkant A, Chackalamannil S, Chow J, et al. Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity. J Med Chem. 1997;40:2196–2210. 143. Ichimura M, Eiki R, Osawa K, Nakanishi S, Kase H. KS-505a, an isoform-selective inhibitor of calmodulin-dependent cyclic nucleotide phosphodiesterase. Biochem J. 1996;316:311–316. 144. Snyder PB, Esselstyn JM, Loughney K, Wolda SL, Florio VA. The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res. 2005;46:494–503. 145. Podzuweit T, Nennstiel P, Muller A. Isozyme selective inhibition of cGMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hydroxy-3-nonyl) adenine. Cell Signal. 1995;7:733–738. 146. Chambers RJ, Abrams K, Garceau NY, Kamath AV, Manley CM, Lilley SC, et al. A new chemical tool for exploring the physiological function of the PDE2 isozyme. Bioorg Med Chem Lett. 2006;16:307–310. 147. Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology. 2004;47:1081–1092. 148. Seybold J, Thomas D, Witzenrath M, Boral S, Hocke AC, Burger A, et al. Tumor necrosis factor-a-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability. Blood. 2005;105:3569–3576. 149. Murray KJ, England PJ, Hallam TJ, Maguire J, Moores K, Reeves ML, et al. The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function. Br J Pharmacol. 1990;99:612–616. 150. Murray KJ, Eden RJ, Dolan JS, Grimsditch DC, Stutchbury CA, Patel B, et al. The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function. Br J Pharmacol. 1992;107:463–470. 151. Hidaka H, Hayashi H, Kohri H, Kimura Y, Hosokawa T, Igawa T, et al. Selective inhibitor of platelet cyclic adenosine monophosphate phosphodiesterase, cilostamide, inhibits platelet aggregation. J Pharmacol Exp Ther. 1979;211:26–30. 152. Tanaka T, Ishikawa T, Hagiwara M, Onoda K, Itoh H, Hidaka H. Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle. Pharmacology. 1988;36:313–320. 153. Schwabe U, Miyake M, Ohga Y, Daly JW. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2pyrrolidone (ZK 62711): a potent inhibitor of adenosine cyclic 3’, 5’-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol. 1976;12:900–910. 154. Reeves ML, Leigh BK, England PJ. The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J. 1987;241:535–541. 155. Sheppard H, Tsien WH. Alterations in the hydrolytic activity, inhibitor sensitivity and molecular size of the rat erythrocyte cyclic AMP phosphodiesterase by calcium and hypertonic sodium chloride. J Cyclic Nucleotide Res. 1975;1:237–242. 156. Barnette MS, Christensen SB, Essayan DM, Grous M, Prabhakar U, Rush JA, et al. SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. J Pharmacol Exp Ther. 1998;284:420–426. 157. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;297:267–279.

132

M.A. Giembycz

158. Souness JE, Maslen C, Webber S, Foster M, Raeburn D, Palfreyman MN, et al. Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. Br J Pharmacol. 1995;115:39–46. 159. Lugnier C, Schoeffter P, Le Bec A, Strouthou E, Stoclet JC. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem Pharmacol. 1986;35:1743–1751. 160. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996;8:47–52. 161. Saenz de T, I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A, Lledo E, Korschen HG, Niewohner U, Haning H, Pages E, Bischoff E (2001) The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 13:282–290 162. Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM, et al. On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res. 2001;13:2–9. 163. Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, et al. Discovery of BRL 50481 [3-(N, N-dimethylsulfonamido)-4-methylnitrobenzene), a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophage and CD8+ T-lymphocytes. Mol Pharmacol. 2004;66:1679–1689. 164. Jones NA, Leport M, Holand T, Vos T, Morgan M, Fink M, et al. Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD. Pulm Pharmacol Ther. 2006;20:60–68. 165. Giembycz MA, Smith SJ. Phosphodiesterase 7 as a therapeutic target. Drugs Future. 2006;31:207–229. 166. Lee R, Wolda S, Moon E, Esselstyn J, Hertel C, Lerner A. PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP. Cell Signal. 2002;14:277–284. 167. Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol. 2005;68:1775–1781.

Glucocorticoid Insensitive Asthma Sally E. Wenzel

It has been understood for some time that, although the majority of patients with asthma respond well to corticosteroid (CS) therapy, a small subgroup exists in whom CSs either have no effect on asthma or its components, or in whom the dose required to cause an improvement, greatly exceeds the usual therapeutic range. As CSs are widely recognized as the most effective therapy currently available for asthma, a poor response to CSs may contribute to the development of severe asthma. However, GC insensitive asthma is not synonymous with difficult-to-treat asthma, as it has been recognized that child and adult asthmatics with a wide range of severity may exhibit a lower than expected response [1, 2]. Yet, it is the group of patients with difficult-totreat asthma, who are also refractory to treatment with CSs, who likely contribute to nearly 50% of the economic burden of the disease [3]. For many years, CS insensitivity was described as being related to a direct abnormality in the glucocorticoid (GC) pathway (i.e., receptor, translocation, transcription factor binding). However, it is now understood that GC insensitive asthma is likely to be much more complex than originally described, with numerous other factors also contributing to an absent or diminished CS response, which may have little to do with molecular pathways. After defining GC insensitivity, this review will describe the current understanding of four potential reasons for GC insensitivity. These include: (1) abnormal activation of the GC receptor and its nuclear inhibitory effects, (2) the presence of a “different” inflammatory process that may not respond to CS therapy, (3) the lack of any inflammatory process and (4) the presence of an inflammatory process in a region of the lung, poorly accessible to inhaled therapy. A fifth reason for GC insensitivity also exists, namely, non-adherence/compliance with CS medications. However, that reason for GC insensitivity will not be discussed further in this chapter. This chapter will conclude with a section on approaches to treatment of GC insensitive asthma (Table 1). The relative importance of each of these components to “GC insensitive asthma” is not yet known; but each subtype requires a different treatment approach. In fact, it is

S.E. Wenzel() University of Pittsburgh, NW 628 Montefiore, 3459 Fifth Ave., Pittsburgh, PA 15213, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_8, © Springer 2010

133

134

S.E. Wenzel

Table 1 Mechanisms of GC insensitivity 1. Abnormal activation of the GC receptor and its nuclear inhibitory effects 2. The presence of a “different” inflammatory process that may not respond to CS therapy 3. The lack of any inflammatory process 4. The presence of an inflammatory process in a region of the lung poorly accessible to inhaled therapy

likely that the classically associated reasons for GC insensitivity – those related to abnormalities in the GC pathway – occur in no more than 50% of the refractory asthma population [4–6]. These patients are more likely to have the hallmark of persistent eosinophilic/lymphocytic inflammation despite high dose steroids, but very few studies have evaluated the level of airway inflammation in association with GC insensitivity. For the remainder of this chapter, “GC” will be used to describe the glucocorticoid pathway and its molecular biology, while “CS” will always refer to corticosteroids in relation to asthma therapy.

Definition of GC Insensitive Asthma It is first important to define the term “GC insensitive asthma.” It is clear that this definition varies from study to study. However, “steroid resistance” was originally defined as the failure of an asthmatic patient to respond to high dose systemic/oral CS therapy. Specifically, patients were treated with methylprednisolone (40 mg) per day for 2 weeks and FEV1 response was determined. Those patients who failed to achieve a 15% improvement in FEV1 over that 2-week period were termed GC resistant [7,8]. What has become increasingly clear is that absolute GC resistance is quite uncommon. In fact, most people with a poor response to GCs rather have a rightward shift in the dose response to GC therapy, requiring higher (and often unacceptably high) doses of GCs before a therapeutic response is seen. These patients might better be termed “poorly sensitive” as opposed to “insensitive.” Unfortunately, in many studies undertaken more recently, the details of the level of GC responsiveness in the mechanistic studies are limited. Similarly, in many of the “GC pathway” studies, little description exists regarding the background inflammatory process of the patient-subject’s disease.

Abnormal Activation of the GC Receptor and its Nuclear Inhibitory Effects (Table 2) For many years, GC insensitive asthma was believed to be primarily due to a defect in GC receptors or their signaling mechanisms. One of the first identified abnormalities was the description of extremely rare individuals who lacked a functional GC receptor.

Glucocorticoid Insensitive Asthma

135

These individuals, labeled as “Type 2” GC resistance, were completely lacking in response to GCs at any level and in any tissue. These rare individuals not only did not benefit from GCs, but they also did not suffer the side effects of GCs. However, in studies by Sher and colleagues, these patients were believed to account for no more than 5% of the GC insensitive population [9]. In contrast, the majority of the GC insensitive patients were described to have a Type 1 defect, meaning that they suffered the consequences of GC therapy through side effects in other tissues/ organs, but did not achieve an anti-inflammatory response in the lung [10]. These patients had low GC binding affinities and the defect was described to occur primarily on T-lymphocytes and monocyte/macrophages [9]. Interestingly, very small numbers of these patients were actually studied for the level of lung inflammation before or after CS therapy; however, there appeared to be an increase in eosinophilic inflammation in these patients, and a lack of suppression of Th2 cytokines, including IL-4 and -5 [10]. In recent studies, the mechanisms for this Type 1 defect have been further evaluated, with different groups defining different mechanisms for the process. These mechanisms have recently been extensively reviewed by Ito, et al., although direct comparisons are often difficult due to the different peripheral blood systems used [11]. Interestingly, although rare studies have evaluated the responses of lung cells to CSs, the majority of mechanistic studies have evaluated peripheral blood mononuclear cell response, including the basal response to GC stimulation, the impact of co-stimulatory factors on GC responses and the effects of IL-2 and -4 in combination, or IL-13 alone to induce GC insensitivity [12]. The comparability of these different systems remains questionable, and cross verification with either severity of asthma or the presence of “uninhibited” inflammation is lacking. Several studies have attempted to address the mechanisms behind the ability of these cytokines to blunt the usual steroid suppressive effects. In no case does it appear to be secondary to defects in the structure of the receptor [11]. However, two general theories have been proposed. The first suggests that in GC insensitive asthma there is an increase in a particular splice variant of the GC receptor, known as glucocorticoid (GR)-b. This GR-b is an isoform of the GC receptor which normally binds GC, but in which the signaling responses are generally blunted as compared to the more common form of the receptor – the GR-a. GR-b is produced when the last exon of the GR gene is altered through alternative splicing to produce a protein with a truncated carboxyterminus. Several studies have shown an increase in expression of GR-b, particularly on airway T-cells and macrophages; however, other studies have not been able to demonstrate such an increase [13–15]. Of note, incubation of PBMCs with IL-2 and IL-4, while rendering them less GC sensitive, did not produce higher levels of GR-b expression [16]. Interestingly, while the finding of increased GR-b in GC insensitive asthma is controversial, it is clear that neutrophils express high levels of the GR-b isoform. As will be described later, neutrophils are present in higher numbers in severe, CS dependent asthma, and neutrophils are well known to be poorly responsive to CSs [17–19]. Another theory holds that this blunted response is due to interference by proinflammatory signaling molecules such as AP-1, NF-kB, which interfere with the

136

S.E. Wenzel

ability of GCs to prevent the translocation and binding of these molecules to the nucleus. Adcock and colleagues first observed that the GR in “steroid resistant” asthmatics did not bind to the DNA binding sites in the nucleus to the same degree that it did in steroid sensitive asthmatics. This diminished binding was suggested to be due to a diminished interaction of AP-1 with the GR in steroid resistant asthmatics, and an increase in AP-1 binding to DNA [20,21]. However, in that study, there was no difference in GR binding to other transcription factors, such as NF-kB. Subsequently, one of the components of AP-1, c-fos, was shown to be increased in biopsies from GC insensitive asthmatics, with overexpression of c-fos associated with diminished DNA binding [22]. Further studies have suggested that activation of the mitogen activated protein (MAP) kinase jun-kinase (JNK) – which can activate both c-fos and its counterpart, c-jun, contributing to increased AP-1 levels – is also increased in GC insensitive asthma [23]. Mechanistically, activation of T-cells through the T-cell receptor (TCR) (alone) is inhibited by dexamethasone through a c-fos AP-1 pathway. However, when T-cells are activated by co-stimulatory molecules in conjunction with TCR, dexamethasone is no longer able to suppress lymphocyte proliferation, and simultaneously, c-fos is not inhibited. However, when some MAP kinase pathways (although not JNK pathways) were inhibited in the presence of dexamethasone, T-cell resistance was reversed [24]. While increases in GR-beta were not observed in response to IL-2/IL-4 treatment of PBMCs, others have reported that IL-2/IL-4 treatment increases the activation of another MAP kinase – p38 MAP kinase. Inhibiting p38 MAP kinase appears to restore the GC sensitivity of these cells to GCs, at least when measuring inhibition of granulocyte macrophage colony stimulating factor production in response to lipopolysaccharide (LPS) [25]. Interestingly, in most cases, the mechanisms for GC insensitivity are evaluated at the level of nuclear translocation and GC response element (GRE) binding. This would imply that the majority of the GC resistance is due to diminished GRE binding. However, as previously noted by Ito, et al., it is likely that the majority of immunosuppressive effects of GCs are not due to transrepression, but rather due to inhibition of transactivation. The role that altered GC-DNA binding plays in GC insensitive asthma associated transactivation of inflammatory cytokine expression remains poorly understood. As previously noted, almost all reported studies on the molecular mechanisms of GC insensitive asthma have focused on PBMCs, sometimes differentiated into T-cells and monocyte/macrophages (Table 2). Recently, a specific class of t-cells, Table 2 Molecular mechanisms of GC insensitivity 1. Lack of GC receptor (Type 2 defect) 2. Low GC binding affinity with normal GC receptor numbers (Type 1 defect) (induced by IL-2, IL-4 and IL-13) a. Increase in GR-beta to GR-alpha ratio (not induced by cytokine exposure) b. Diminished binding of GR to pro-inflammatory transcription factors (c-fox, NF-kB) c. Increased activation of p38 MAP kinase d. Vitamin D dependent IL-10 deficiency e. Low histone deacetylase activity

Glucocorticoid Insensitive Asthma

137

Treg cells has been identified by their expression of the transcription factor Foxp3. These cells are believed to be regulatory of adaptive immune responses, particularly Th2 immune responses. A current theory suggests that deficiency in Treg cells contributes to a Th2 response in asthma. In that regard, a recent study suggested that GCs are normally sufficient to induce the expression of the Treg associated cytokine, IL-10 from isolated CD4(+) T-cells when incubated in the presence of vitamin D [26]. In patients with GC insensitive asthma, there was reduction in IL-10 production, which could be rescued by pretreatment of the cells with dexamethasone, followed by vitamin D. The authors proposed that the mechanism for this effect was through an inhibition of loss of the GC receptor in the presence of dexamethasone alone [27]. This observation of loss of GC receptor expression in the response to dexamethasone is consistent with anecdotal reports of progressive loss of GC responsiveness in patients with severe asthma (Wenzel, unpublished observations). Interestingly, the authors proceeded to administer oral vitamin D to three GC insensitive subjects and were able to show in vitro that IL-10 production was enhanced. Although the clinical significance of these findings remains to be determined, several additional studies recently have suggested that increasingly severe forms of asthma may be associated with vitamin D deficiency and/or related genetic abnormalities [28]. The final “molecular mechanism” for GC insensitivity relates to changes in the epigenetics of the chromatin and was first described in chronic obstructive pulmonary disease (COPD) [29]. The overall hypothesis is based on the concept that inflammatory and oxidative stresses alter the chromatin structure in such a way as to maintain high levels of gene transcription over time. In COPD, Barnes and colleagues reported that activation of the enzyme, histone deacetylase (HDAC) 2 was reduced. The authors proposed that HDAC inactivity allowed persistent histone acetylation, which kept the chromatin in an “on” or active arrangement. They proposed that this HDAC activation was poorly inhibited by CS therapy in COPD, especially in lung tissue and alveolar macrophages, explaining the relative steroid “resistance in that disease as compared to asthma” [30]. Subsequently, patients with severe asthma were also evaluated for levels of histone acetyltransferases and HDAC-2. Similar to COPD, PBMCs from severe asthma subjects appeared to have a decrease in HDAC2 activity, which was related to their level of GC insensitivity in an in vitro assay of LPS induced cytokine release [31, 32]. While theophylline was reported to reverse some of these effects on HDAC inhibition, a therapeutic trial of theophylline in GC insensitive patients has not yet been performed [33]. Further, the interaction of alterations in histone acetylation with other theories of GC insensitive asthma, specifically overactivity of JNK/AP-1 and/or high level activation of T-cells through TCR and co-stimulatory molecules remains to be investigated. In virtually all reported cases of GC insensitive asthma, a direct link to the level of eosinophilic inflammation, a hallmark for poorly controlled asthma, is absent. Therefore, it is difficult to determine whether the effect in PBMCs actually predicts the lack of suppression of inflammation. In fact, when patients are selected for treatment with CS based on their level of eosinophilic inflammation, the response

138

S.E. Wenzel

to CS therapy remains, albeit at higher doses, at least in severe asthma subjects [34, 35].Whether these higher doses overcome all or one specific molecular pathway described above remains to be determined.

GC Insensitivity Due to the Presence of a “Different” Inflammatory Process Although GC insensitivity typically conjures up cellular level responses and molecular biology, it is highly likely that a good percentage of GC insensitivity is due to differences in the disease itself. As has long been appreciated, asthma is a highly heterogeneous disease. More recently, investigations have determined that not only is it clinically heterogeneous, but pathologically heterogeneous as well. As the definition of asthma involves the mere presence of symptoms in the face of reversible airflow limitation, many obstructive airway diseases can “mimic” or be mistaken for asthma. These diseases or syndromes include various bronchiolitic syndromes, COPD-smoking asthma overlap, and post-infectious bronchiolitis. In addition, a group of “severe asthmatics” exists in whom the inflammation is predominantly neutrophilic [19, 36]. In most, if not all of these syndromes, classical Th2/eosinophilic inflammation is only minimally present, and neutrophils may be the most common inflammatory cell. As previously noted, neutrophils are highly resistant to CS, and in fact, appear to increase in the face of CS therapy. Several studies suggest that those individuals with more neutrophilic inflammation are likely to be relatively GC insensitive [17, 37, 38]. In these cases, the insensitivity is likely due to the basic lack of responsiveness of the particular type of inflammation or inflammatory cell, as compared to an abnormality in the GC receptor pathway. An area of intensive current investigation for GC insensitivity is the smoking asthmatic. Several groups have now reported that response to CS therapy is blunted in smoking asthmatics [39, 40]. Smoking asthmatics have a higher level of neutrophilic as compared to eosinophilic inflammation [38], which falls when smoking is discontinued. Interestingly, in that same study, CS responsiveness increased as neutrophil levels fell. Whether this neutrophilic inflammation contributes to a higher oxidative stress level is not yet clear; however, their FeNO levels are generally low [41].

GC Insensitivity Due to the Lack of Any Inflammatory Process In a smaller percentage of asthma subjects, very little migratory inflammatory cellrelated inflammation can be found despite an evaluation of many lung compartments [6,42,43]. These patients have been reported to be more often female and obese. An additional group may consist of patients who once had a very active inflammatory process, but in whom the disease has progressed to a state where the

Glucocorticoid Insensitive Asthma

139

inflammation has resolved, but poorly defined remodeling has occurred. This remodeling, in the form of epithelial abnormalities, smooth muscle hypertrophy/ hyperplasia or fibrotic/repair changes, could contribute to ongoing airway obstruction and symptoms in the absence of GC responsive elements. For instance, epithelial abnormalities in asthma have been shown to be moderately responsive to GCs [44]. Similarly, the subepithelial basement membrane, which is reported to be thicker in asthma, is only modestly impacted by CS treatment, even in high doses [45]. Whether these GC insensitive subjects might respond to therapies targeted towards a specific structural/remodeling element is not yet clear. However, those subjects with lower levels of eosinophilic inflammation are generally less symptomatic and at less risk of severe exacerbations than those with a “CS responsive” inflammation. Another group of asthmatics with lower than expected inflammation is the obese asthmatic [46]. Findings from a recent report suggested that an inverse relationship between FeNO and BMI exists, such that the higher the BMI, the lower the measurable inflammation. In that regard, a recent study compared the efficacy of an inhaled CS vs. a leukotriene receptor antagonist (LTRA) in obese asthmatics and reported that the relative efficacy of the CS was reduced as compared to the LTRA [47]. Finally, it is important to confirm the diagnosis of asthma. Vocal cord dysfunction can and has masqueraded as asthma – and particularly severe asthma – for many years and does not respond to CS therapy [48].

GC Insensitivity Due to the Presence of an Inflammatory Process in a Region of the Lung Poorly Accessible to Inhaled CS Therapy Identification of eosinophilic inflammation has traditionally been through sputum analysis or endobronchial biopsy. Additionally, exhaled nitric oxide (FeNO) has been proposed as a tool to identify patients with persistent eosinophilic inflammation [49,50]. In general, there are reasonable correlations of sputum or biopsy eosinophils with FeNO, even in patients on high doses of CS [50]. However, it is likely that neither is an adequate measure of eosinophilic (i.e., GC sensitive) inflammation in the distal lung. As noted in the previous section, up to 50% of severe asthma patients have low or no inflammation in these regions. In addition to having a disease that exists because of “non-inflammatory elements,” it is also possible that the inflammation exists beyond the reach of these more proximal airway approaches. In this regard, a systematic comparison of standard markers of inflammation in subjects with severe asthma comparing proximal to distal airways, revealed increased inflammation in the distal airway, as compared to the proximal airway [51]. Specifically, mast cells appeared to be dramatically increased in the distal lung, despite low levels in the proximal airways [52]. In a recent abstract, about 50% of severe asthma subjects previously identified as “non-eosinophilic” were found to have eosinophilic inflammation in the distal lung [53]. All these findings,

140

S.E. Wenzel

support a recent study in which alveolar nitric oxide was measured and compared to standard measures of FeNO in patients with refractory asthma. Although the proximal measures of FeNO were not increased, assessments of nitric oxide at higher flow rates, believed to measure more distal nitric oxide levels were found to be significantly higher in these patients. These alveolar NO levels correlated with lavage eosinophils, but not sputum or bronchial wash, supportive of a distal source [54]. While the reasons for these differences are not clear, it is likely that the majority of today’s inhaled CS, with larger particle sizes, do not reach the distal lung. If severe asthma persists in some patients because of a strong distal component to their disease, then treatment with inhaled CS could leave a large portion of the inflammation undetected-or under treated. This lack of delivery of CS to the small airways could cause some asthmatics to present with GC insensitive asthma based on inadequate delivery to the region of interest.

Approaches to Therapy in GC Insensitive Patients As noted earlier, GC insensitive asthma covers a range of patients, from mild to severe. Most therapeutic trials in GC insensitive asthma have focused on the severe patients, and often without any attempt to determine the “type” of GC insensitivity that is present. However, it can definitely be argued that before treating a patient with a cytotoxic drug, determining the type of GC insensitivity is very helpful. After confirming the diagnosis of asthma and evaluating adherence/compliance as best as one can (AM cortisol, pharamacy records, etc), determining: (1) the level of eosinophilic inflammation and later (2) the response to systemic steroids can give extremely helpful information. Eosinophilic inflammation can be measured in biopsy tissue, sputum and marginally, as FeNO [4, 50, 55]. Eosinophils in sputum may be the most robust indicator of airway eosinophils and strong support exists for the relationship between reduction in sputum eosinophils and improvement in asthma control [34,35]. If there is any indication of persistent eosinophilic inflammation, then a trial of systemic steroids is warranted. This can be done using the standard approach of 40 mg of prednisone or methylprednisolone for 2 weeks or as an injection of high doses of triamcinolone. If little improvement in FEV1 and reduction in eosinophils occurs, then the patient likely is poorly responsive to GC, but truly sensitive. Treatment may require daily oral steroids, or even in extreme cases, monthly injections of CSs. Although trials of cytotoxic agents including methotrexate and cyclosporine have been carried out, the additional benefits of these medications over CS alone is marginal. Unfortunately, no currently indicated asthma therapy has specifically evaluated its efficacy as steroid sparing in patients with persistent eosinophilic inflammation despite high dose CS therapy. If there is any indication that the inflammation is more persistent in the distal lung, then treatment with systemic medications, including LTRA, 5 lipoxygenase inhibitors, and even theophylline, in addition to systemic CS or fine particle aerosol corticosteroids may offer some benefit.

Glucocorticoid Insensitive Asthma

141

Patients with GC insensitive asthma because of cigarette smoking or obesity would be best advised to quit smoking and lose weight. However, in addition, there are data from small studies that LTRAs may offer some benefit in these patients [39,47]. In patients in whom no eosinophilic inflammation (anywhere) is found, but in whom a neutrophilic inflammation is noted, additional higher doses of CS are not likely to be helpful. An evaluation for esophageal reflux and appropriate treatment is indicated, as is an evaluation for infection. Anecdotally, a 5-lipoxygenase inhibitor may have some efficacy in these patients, as well.

Conclusions GC insensitive asthma describes a wide range of asthma patients and multiple mechanisms for the poor response. While intensive effort continues to understand the group of patients with GC insensitivity based on abnormalities in the GC pathway itself, many other mechanisms of GC insensitivity exist. For the clinician, it is important to differentiate one from the other to improve therapeutic options.

References 1. Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM, Lemanske RF, Jr., Strunk RC, Larsen G, Spahn JD, et al. Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 2006;117:45–52 2. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Fagan JK, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410–418 3. Chung KF, Godard P, Adelroth E, Ayres J, Barnes N, Barnes P, Bel E, Burney P, Chanez P, Connett G, et al. Difficult/therapy-resistant asthma: The need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. Ers task force on difficult/therapy-resistant asthma. European respiratory society. Eur Resp J 1999;13:1198–1208 4. Wenzel SE. Inflammation, leukotrienes and the pathogenesis of the late asthmatic response. Clin Exp Allergy 1999;29:1–3 5. Simpson JL, Scott RJ, Boyle MJ, Gibson PG. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am J Respir Crit Care Med 2005;172:559–565 6. Haldar P, Pavord ID. Noneosinophilic asthma: A distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007;119:1043–1052; quiz 1053–1044 7. Carmichael J, Paterson IC, Diaz P, Crompton GK, Kay AB, Grant IW. Corticosteroid resistance in chronic asthma. Br Med J (Clinical Research ed 1981;282:1419–1422 8. Woolcock AJ. Corticosteroid-resistant asthma. Definitions. Am J Respir Crit Care Med 1996;154:S45–S48 9. Sher ER, Leung DY, Surs W, Kam JC, Zieg G, Kamada AK, Szefler SJ. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Investig 1994;93:33–39 10. Leung DY, Martin RJ, Szefler SJ, Sher ER, Ying S, Kay AB, Hamid Q. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med 1995;181:33–40

142

S.E. Wenzel

11. Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006;117:522–543 12. Spahn JD, Szefler SJ, Surs W, Doherty DE, Nimmagadda SR, Leung DY. A novel action of il-13: Induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol 1996;157:2654–2659 13. Hamid QA, Wenzel SE, Hauk PJ, Tsicopoulos A, Wallaert B, Lafitte JJ, Chrousos GP, Szefler SJ, Leung DY. Increased glucocorticoid receptor beta in airway cells of glucocorticoidinsensitive asthma. Am J Respir Crit Care Med 1999;159:1600–1604 14. Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol 2000;105:943–950 15. Gagliardo R, Chanez P, Vignola AM, Bousquet J, Vachier I, Godard P, Bonsignore G, Demoly P, Mathieu M. Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma. Am J Respir Crit Care Med 2000;162:7–13 16. Torrego A, Pujols L, Roca-Ferrer J, Mullol J, Xaubet A, Picado C. Glucocorticoid receptor isoforms alpha and beta in in vitro cytokine-induced glucocorticoid insensitivity. Am J Respir Crit Care Med 2004;170:420–425 17. Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J Immunol 1995;154:4719–4725 18. Strickland I, Kisich K, Hauk PJ, Vottero A, Chrousos GP, Klemm DJ, Leung DY. High constitutive glucocorticoid receptor beta in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids. J Exp Med 2001;193:585–593 19. Wenzel SE, Szefler SJ, Leung DYM, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma: Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156:737–743 20. Adcock IM, Lane SJ, Brown CR, Peters MJ, Lee TH, Barnes PJ. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol 1995;154:3500–3505 21. Adcock IM, Lane SJ, Brown CR, Lee TH, Barnes PJ. Abnormal glucocorticoid receptoractivator protein 1 interaction in steroid-resistant asthma. J Exp Med 1995;182:1951–1958 22. Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee TH. Corticosteroidresistant bronchial asthma is associated with increased c-fos expression in monocytes and t lymphocytes. J Clin Investig 1998;102:2156–2164 23. Sousa AR, Lane SJ, Soh C, Lee TH. In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of jun n-terminal kinase and failure of prednisolone to inhibit jun n-terminal kinase phosphorylation. J Allergy Clin Immunol 1999;104:565–574 24. Tsitoura DC, Rothman PB. Enhancement of mek/erk signaling promotes glucocorticoid resistance in cd4+ t cells. J Clin Investig 2004;113:619–627 25. Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. P38 mitogenactivated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma. J Allergy Clin Immunol 2002;109:649–657 26. Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, et al. Reversing the defective induction of il-10-secreting regulatory t cells in glucocorticoid-resistant asthma patients. J Clin Investig 2006;116:146–155 27. Burnstein KL, Jewell CM, Cidlowski JA. Human glucocorticoid receptor cdna contains sequences sufficient for receptor down-regulation. J Biol Chem 1990;265:7284–7291 28. Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST. Association of vitamin d receptor gene polymorphisms with childhood and adult asthma. Am J Resp Crit Care Med 2004;170:1057–1065 29. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: Inactivation of histone deacetylase. Lancet 2004;363:731–733 30. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. New Engl J Med 2005;352:1967–1976

Glucocorticoid Insensitive Asthma

143

31. Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 2002;166:392–396 32. Hew M, Bhavsar P, Torrego A, Meah S, Khorasani N, Barnes PJ, Adcock I, Chung KF. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J R Crit Care Med 2006;174:134–141 33. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 2002;99:8921–8926 34. ten Brinke A, Sterk PJ, Masclee AA, Spinhoven P, Schmidt JT, Zwinderman AH, Rabe KF, Bel EH. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26:812–818 35. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: A randomised controlled trial. Lancet 2002;360:1715–1721 36. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999;160:1532–1539 37. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: Identification of a subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875–879 38. Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, McSharry CP, Thomson NC. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Resp Crit Care Med 2006;174:127–133 39. Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ, Deykin A, DiMango E, Fish JE, Ford JG, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Resp Crit Care Med 2007;175:783–790 40. Tomlinson JE, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 2005;60:282–287 41. McSharry CP, McKay IC, Chaudhuri R, Livingston E, Fraser I, Thomson NC. Short and longterm effects of cigarette smoking independently influence exhaled nitric oxide concentration in asthma. J Allergy Clin Immunol 2005;116:88–93 42. Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: Assessment and identification using induced sputum. Respirology 2006;11:54–61 43. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: Role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004;113:101–108 44. White SR, Dorscheid DR. Corticosteroid-induced apoptosis of airway epithelium: A potential mechanism for chronic airway epithelial damage in asthma. Chest 2002;122:278S–284S 45. Olivieri D, Chetta A, Del Donno M, Bertorelli G, Casalini A, Pesci A, Testi R, Foresi A. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: A placebo-controlled study. Am J Resp Crit Care Med 1997;155:1864–1871 46. Komakula S, Khatri S, Mermis J, Savill S, Haque S, Rojas M, Brown L, Teague GW, Holguin F. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Resp Res 2007;8:32 47. Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman JM. Influence of body mass index on the response to asthma controller agents. Eur Respir J 2006;27:495–503 48. Borer H, Hanni P, Schoenenberger RA. Vocal cord dysfunction: An important differential diagnosis of brittle asthma. Resp; Int Rev Thorac Dis 2001;68:318 49. Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: An observational study in adults with asthma. Clin Exp Allergy 2005;35:1175–1179

144

S.E. Wenzel

50. Silkoff PE, Lent AM, Busacker AA, Katial RK, Balzar S, Strand M, Wenzel SE. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. The J Allergy Clin Immunol 2005;116:1249–1255 51. Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002;20:254–259 52. Balzar S, Chu HW, Strand M, Wenzel S. Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am J Resp Crit Car Med 2005;171:431–439 53. Balkissoon RC, Balzar S, Rhodes D, Trudeau JB, Wenzel S. Eosinophils persist in the distal lung of severe asthma despite low numbers of proximal airways. 2006 ATS Annual Meeting, San Diego, CA, American Thoracic Society; 2006, p. A15 54. Berry M, Hargadon B, Morgan A, Shelley M, Richter J, Shaw D, Green RH, Brightling C, Wardlaw AJ, Pavord ID. Alveolar nitric oxide in adults with asthma: Evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005;25:986–991 55. Lemiere C, Ernst P, Olivenstein R, Yamauchi Y, Govindaraju K, Ludwig MS, Martin JG, Hamid Q. Airway inflammation assessed by invasive and noninvasive means in severe asthma: Eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol 2006;118:1033–1039

Recalcitrant Asthma Sharmilee M. Nyenhuis and William W. Busse

Introduction Asthma is increasing in both prevalence and severity throughout the world [1]. Asthma affects approximately 8% of the adult population and up to 20% of the pediatric population in North America, Europe, and Australia [2]. The majority of these patients have mild to moderate persistent asthma that can be well controlled by environmental control measures and appropriate use of controller and reliever medications. It is estimated, however, that 5–10% of patients with asthma have severe disease that is recalcitrant to typical treatment modalities, including, in some cases, the administration of systemic corticosteroids. These patients have the greatest impairment in lifestyles, highest morbidity, and a disproportionate amount of health care cost associated with this disease [3–5]. Women and minorities share these burdens disproportionately as well. Our understanding of the pathophysiology of this subset of asthma patients is poorly understood. Consequently, these patients need a careful evaluation to uncover risk factors and novel approaches to control the disease.

Definitions of Severe Asthma To more fully classify and identify severe asthma, a recognized and uniform definition is necessary. Rackemann published a working classification of asthma in 1921 in which he grouped patients into having “extrinsic” or “intrinsic” asthma [6]. “Extrinsic” asthma patients were likely to be allergic to environmental allergens;

S.M. Nyenhuis Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, Madison, WI USA W.W. Busse () Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_9, © Springer 2010

145

146

S.M. Nyenhuis and W.W. Busse

this linkage could usually be identified through the patient’s history and by allergen skin tests. These patients usually developed their asthma before 30 years of age, and their disease was more labile. Complications of “extrinsic” asthma were usually due to infections, malnutrition, or psychological factors. Those with “intrinsic” asthma tended to develop asthma after 40 years of age and have more severe disease with a less clear-cut allergic component. It was theorized that “intrinsic” asthma might be sensitive to the bacteria residing in places such as nose, sinuses, tonsils, and gums, but this has been difficult to prove and, to some extent, largely abandoned [6, 7]. In addition, other factors have been thought to play a role in “intrinsic” asthma such as infections (bacterial or viral), a reflex from upper airways (polypoid sinusitis), or psychological factors such as anxiety or fatigue. Other disease considerations, which should be made in “intrinsic” asthma, include emphysema, tumors, or foreign bodies. This clinical classification scheme acknowledges the relative contribution of allergic and nonallergic mechanisms to asthma pathogenesis and suggests that asthma is a heterogeneous disease. When classifying patients as having severe asthma, many factors need to be considered such as symptoms, medication use, pulmonary function abnormalities, bronchial hyper-responsiveness, features of inflammation, consequences of the disease, frequency and severity of exacerbations, response to treatment, and health impact status (Table 1). Various clinical definitions of severe asthma have been proposed through national and international guidelines, working groups, and workshops which incorporate the above factors [8]. An American Thoracic Society (ATS) sponsored Workshop made a comprehensive approach to establish a “working” definition of refractory asthma [9]. The definition was based on the medication requirements, asthma symptoms, frequency of asthma exacerbations, and degree of airflow limitations. Specifically, the definition required the need for patients to meet one of two major criteria (continuous high-dose inhaled corticosteroids or oral corticosteroids for > 50% of the previous year), and Table 1 Features to consider in defining severe asthma (from [8], with permission from Elsevier) 1. Symptoms Exacerbations • Frequency • Severity 2. Medication use Response to treatment or intensity of treatment required to control symptoms 3. Pulmonary functions 4. Bronchial responsiveness 5. Airway inflammation 6. Development of airway remodeling 7. Consequences of disease • Respiratory failure • Hospitalizations • Impaired quality of life

Recalcitrant Asthma

147

two of seven additional minor criteria (Table 2). The minor criteria include aspects of lung function, exacerbations, disease stability, and the use of one or more additional controller medications. In conjunction with these criteria, patients must have had other possible conditions excluded and adherence and exacerbation factors were fully considered [10]. This definition has recently been used by the NIH-sponsored Severe Asthma Research Program (SARP) which was established in 2000 to define the characteristics, mechanistic factors, potential approaches for study and treatment, and future research needs and directions of severe asthma [11]. SARP enrolled severe asthma patients across 8 centers in the United States who met the ATS Workshop criteria for severe asthma. Although, only 2 minor criteria (Table 2) were required to meet ATS criteria for severe disease, most of the severe asthma patients had 5–6 minor criteria present despite being on high doses of corticosteroids. In addition, the 2 minor criteria that best distinguished severe asthma from both mild and moderate asthma were ≥ 3 exacerbations requiring treatment with oral corticosteroids in the previous year and a history of endotracheal intubation. Therefore, with these findings from the SARP, the ATS Workshop definition has been shown to be helpful in classifying subjects with severe asthma, and establishes criteria to distinguish individuals with severe asthma [12].

Table 2 ATS Workshop Consensus Definition of Refractory Asthma (from [9], with permission)a,b Major characteristics In order to achieve control to a level of mild-moderate persistent asthma: 1. Treatment with continuous or near continuous (≥ 50% of year) oral corticosteroids 2. Requirement for treatment with high-dose inhaled corticosteroids: Drug Dose (µg/d) Dose (Puffs/d) a. Beclomethasone > 1,260 > 40 puffs (42 µg/inhalation dipropionate > 20 puffs (84 µg/inhalation b. Budesonide > 1,200 > 6 puffs c. Flunisolide > 2,000 > 8 puffs d. Fluticasone propionate > 880 > 8 puffs (110 µg), > 4 puffs (200 µg) e. Triamcinolone acetonide > 2,000 > 20 puffs Minor Characteristics 1. Requirement for daily treatment with a controller medication in addition to inhaled corticosteroids, for example, long-acting b-agonist, theophylline, or leukotriene antagonist 2. Asthma symptoms requiring short-acting b-agonist use on a daily or near daily basis 3. Persistent airway obstruction (FEV1 < 80% predicted; diurnal PEF variability > 20%) 4. One or more urgent care visit, for asthma per year 5. Three or more oral steroid “bursts” per year 6. Prompt deterioration with ≤ 25% reduction in oral or inhaled corticosteroid dose 7. Near fatal asthma event in the past a Requires that other conditions have been excluded, exacerbating factors treated, and patient felt to be generally adherent b Definition of refractory asthma requires one or both major criteria and two minor criteria

148

S.M. Nyenhuis and W.W. Busse

The European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA) was established to better understand the severe asthma, but it also addressed the need for a definition of severe asthma. The ENFUMOSA group developed common methodology that was applied to recruit a cohort of severe asthma patients and a control group of mild-moderate asthma patients who were controlled on low-moderate doses of inhaled corticosteroids (ICS) for comparison [13]. Criteria for severe asthma required that patients were diagnosed by an asthma specialist by 45 years of age, received daily ICS for at least one year, and had evidence of variable airflow obstruction. The study further divided the patients into levels of severity by inhaled corticosteroid treatment and asthma exacerbations in the past one year. Controlled asthma was defined as those with mild-moderate disease controlled on ≤ 1,000 mcg/day of beclomethasone (median dose 666 mcg/day) for at least 1 year and no asthma exacerbations over the past one year. Severe asthma was defined as patients using ≥ 1,200 mcg/day of beclomethasone (median dose 1773 mcg/day) and had at least one asthma exacerbation in the past one year [13]. In summary, these study groups defined severe asthma as patients with signs of ongoing poor asthma control despite the treatment with high doses of corticosteroids. Severe asthma may often be easily confused with “poorly controlled” and “brittle” asthma. “Poorly controlled” asthma may represent a transient state of disease, in which symptoms may be improved with standard approaches to therapy while severe asthma represents a disease that is not responsive to standard treatment despite aggressive attempts at management [10]. “Brittle asthma” is often thought by many as a specific asthma phenotype. The term was first used in 1977 to describe patients with asthma who manifest a wide and chaotic variation in peak expiratory flow (PEF) despite high doses of inhaled corticosteroids [14]. The PEF pattern identified in brittle asthmatics did not show an obvious repeating pattern and was distinct from the controlled patterns of PEF variation seen in patients with uncontrolled asthma (Fig. 1). This variability in PEF and the chaotic pattern has been identified as a risk factor of death from an acute severe asthma attack. The initial definitions/classifications of brittle asthma were not considered sufficiently specific and have undergone much recalculation. Ayres and colleagues developed a new classification of brittle asthma which divides these patients into two types [15]. Type 1 is characterized by persistent and chaotic variability in the peak flow (> 40% diurnal variation for > 50% of the time over a period of at least 150 days) despite aggressive medical therapy (e.g., ICS of at least 1,500 mcg of beclomethasone). Type 2 brittle asthma is characterized by sudden acute attacks occurring in less than three hours without an obvious trigger on a background of apparent normal airway function or well controlled asthma. The type 1 patient is more likely to be female (2.5F:1 M), usually ranging between 18 and 55 years of the age. Patients with type 2 brittle asthma apparently have no sex difference. Type 1 brittle asthma is associated with increased sensitization to common allergens such as Dermatophagoides pteronyssinus. Type 2 brittle asthma may be triggered by exposure to aeroallergens such as Alternaria leading to sudden and severe asthma attacks.

Recalcitrant Asthma

149

Fig. 1 Peak flow chart in a patient with type 1 brittle asthma before (open circles) and after (closed circles) treatment with continuous subcutaneous terbutaline. Brittle Asthma defined as a diurnal peak expiratory flow (PEF) variability of >40% (from [15], with permission)

Both types of patients often require hospital admissions but type 1 patients tend to use their health care resources more than type 2 patients. Type 1 brittle asthma often fails to respond to inhaled β2-agonists administered by nebulizer or longacting β2-agonists. The asthma attacks in the type 2 brittle variant appear not to be controlled or prevented by steroids, and often do not respond fully to inhaled β2-agonists. Patients who have had near fatal asthma attacks may have a poor perception of worsening airway function, a feature that may be pertinent in both type 1 and 2 brittle asthma [15, 16]. These patients have been found to have an impaired hypoxic drive when their lung function is normal, suggesting that during an acute exacerbation they may not have a normal ventilatory response [17]. This defect often leads to a reduced awareness of the severity of attacks and a subsequent delay in getting appropriate therapy.

Risk Factors for Severe Asthma Researchers have been trying to answer questions such as, “How does severe asthma develop?” and “What portends severe asthma?” To date, we have not been able to fully and satisfactorily answer these questions, but studies such as the Melbourne Epidemiological Study of Childhood Asthma will provide insight and more definitive answers to these questions in the near future. As asthma most commonly begins in infancy, age of onset appears to be the logical starting point to examine the natural history of asthma and the possible risk factors associated with severe and persistent asthma. The Melbourne Epidemiological Study is a large cohort of asthma, and control subjects who were enrolled at 7 years of age and

150

S.M. Nyenhuis and W.W. Busse Table 3 Predictors of persistence and severity of childhood asthma (from [19], with permission from Elsevier) More severe and frequent wheezing episodes during preschool age Onset during school age Family history of asthma and allergy Elevated serum IgE Early development of positive skin test results Early development of bronchial hyperresponsiveness Frequency of respiratory infections Lack of contact with older children Parenting difficulties Greater childhood psychological risk

have been followed for an additional 35 years [18]. Upon enrollment, the children were divided into 5 groups: (1) controlled, never wheezed; (2) mild wheezy bronchitis, fewer than 5 episodes; (3) wheezy bronchitis, 5 or more episodes; (4) asthma, not associated with infection; (5) severe asthma, onset before 3 years of age and persistent symptoms [19] [Table 3]. Over a 35 year period, the symptoms and FEV1 in each of these groups continued to reflect the differences found in the severity categorization. The more severe the asthma was at 7 years of age, the more likely it was to persist to 42 years of age. In addition, the reduced lung function at 7 years of age was associated with continuing symptoms in the adult life, and a reduction in the lung function continued. Furthermore, the presence of hay fever, eczema, or positive skin tests increased the risk of more severe asthma in adult life. From the Melbourne Epidemiological Study and other pediatric cohorts, the persistence and severity of asthma in adults has been found to be mainly dependent on the severity of asthma as a child. Other factors, though, may also play a role in the severity of asthma in adults. For example, chronic sensitization to indoor (dust mites, cats, and/or cockroaches) and outdoor allergens may also result in more severe and persistent asthma. Of the allergens that have been studied in this relationship, Alternaria appears to be associated with a reduction in FEV1 even in the absence of asthma symptoms [20]. Aspirin exacerbated respiratory disease is also an important category of adult asthma. This often develops in the third and fourth decades of life and is found more commonly in women. This phenotype is characterized by persistent rhinitis, which usually appears before the onset of asthma, aspirin sensitivity, and nasal polyps that usually appear after the onset of asthma. In a multicenter study, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR), severe or difficult-to-treat asthma patients had a lower post-bronchodilator FEV1 compared with patients with nonaspirin-sensitive asthma a finding that may be the result of airway remodeling [21]. Furthermore, these patients usually require inhaled or systemic corticosteroids to control their disease.

Recalcitrant Asthma

151

Not all adult asthma patients have a dramatic decline in lung function over time. The decline in FEV1 is proposed to be dependent on the severity of disease. The effect of inhaled corticosteroids on the deterioration of lung function has been studied and, thus far, ICS do prevent the loss of lung function [22]. The potential reasons for the deterioration in lung function are likely many, with airway remodeling being one possible contribution. Persistent inflammation and severity likely contribute to airway remodeling, which can increase airway obstruction in the absence of reversibility. In addition to airway remodeling, comorbid conditions such as tobacco use, allergen exposure, and bronchiectasis may contribute to the decline in lung function. Tobacco use may lead to chronic obstructive pulmonary disease. Prolonged allergen exposure, especially occupational agents like Western Red Cedar and diisocyanates, can cause irreversible changes in the airway [19]. Furthermore, bronchiectasis due to frequent infections or allergic bronchopulmonary aspergillosis can cause permanent loss of lung function and severe persistent asthma (Table 4). The risk factors of a disease are often divided into 2 groups: Genetic and environmental, that is, a gene-by environmental interaction. Taussig and colleagues have noted, the great variability and complexity of asthma suggest that the disease is not under the control of a typical Mendelian monogenic 2-allele locus, but that several major and minor loci are involved [23]. As several genes are most likely involved in asthma, the identification of risk factor genes for severe asthma is complex.

Genetic Risk Factors Several genetic polymorphisms have been found in relationship to asthma and asthma severity. These polymorphisms have been found not only associated with the pathogenesis of severe asthma but also involved in the response to the treatment and disease progression of asthma. IL-4 is a major cytokine responsible for B-cell class switching from immunoglobulin M (IgM) to immunoglobulin E (IgE). Mutations in the IL-4 gene and the IL-4 receptor have found a link to a loss of lung function and near-fatal events [24, 25].

Table 4 Predictors of persistence and severity of adult asthma (from [19], with permission from Elsevier) Continued exposure to allergens including occupational agents Older age of onset Presence of aspirin sensitivity Socioeconomic status Smoking Coexisting diseases, including COPD, bronchiectasis, and (rarely) α-1 antitrypsin deficiency or allergic bronchopulmonary aspergillosis

152

S.M. Nyenhuis and W.W. Busse

Specifically, a nucleotide substitution in the IL-4 gene promoter at position −589 has been identified and is present in approximately 27% of the Caucasian population [26]. This polymorphism has been associated with life-threatening asthma episodes and low FEV1 values in a Caucasian population [24, 25]. The gene encoding for the alpha subunit of the IL-4 (IL4RA) receptor also contains polymorphisms that have been associated with atopy and asthma. The nucleotide substitution occurs on the IL4RA receptor gene and has been found in 36% of Caucasians [27]. Sanford and colleagues found that the mutation in the IL4RA gene is a risk factor for reduced lung function in asthma but not of life-threatening asthma [24]. In addition, homozygosity of this mutation has also been associated with asthma subjects with severe disease, that is, FEV1 predicted < 60% [28]. Furthermore, the SARP study has suggested that polymorphisms in IL4RA are linked with both a high level of severe (intensive care unit/intubation) exacerbations and lower FEV1 [11]. ADAM33, another novel gene involved in the inflammatory response, has been found as a risk factor of asthma, bronchial hyperresponsiveness, and an accelerated decline in baseline lung function [29, 30]. ADAM33 is a disintegrin and metalloproteinase that is composed of multiple domains that allow the ADAM proteins to function in many cellular processes such as cell adhesion, proteolysis, signaling, proliferation, and differentiation. The expression of ADAM33 in vivo is increased in bronchial smooth muscle, myofibroblasts, and fibroblasts, thus, suggesting that this gene may play a role in the airway remodeling [31]. Furthermore, single nucleotide polymorphisms (SNPs) in ADAM33 are associated with a more rapid decline in FEV1 in asthma over a 20 year period in a Dutch population [32]. An inverse correlation exists between FEV1 values and ADAM33 protein levels in Korean asthma subjects [33]. Further investigations into the role that these gene polymorphisms play in the pathogenesis of severe asthma may provide novel treatments. β agonists exert their effect by binding to the β2-adrenergic receptor (β2AR) on airway smooth muscle to cause bronchial relaxation. Polymorphisms in the β2AR gene have been identified which may alter receptor function by changing the sensitivity, or regulation, of the receptor. The two most common polymorphisms of β2AR gene are Arg16Gly and Gln27Glu. Many studies have tried to evaluate the importance of these mutations to asthma susceptibility, phenotypes, and bronchial hyper-responsiveness [34]. Contopoulos-Ioannidis and colleagues compiled a meta-analysis to determine the strength of these polymorphisms with the aforementioned asthma characteristics [34]. The Gly16 allele of the β2AR gene probably doubled the risk of nocturnal asthma and modestly increased asthma severity when compared to the Arg16 allele. The modest increase in asthma severity may be associated with a greater frequency of nocturnal asthma. Neither the Gly16 nor the Glu27 allele contributed to asthma susceptibility or to the intensity of bronchial hyper-responsiveness. Whether polymorphisms of the (2AR gene decrease responsiveness to beta agonists and these changes that influence the outcomes are still controversial. Gender differences and asthma have always been of interest. A reversal of the prevalence of asthma between the two sexes occurs in adolescence when asthma becomes more prevalent in girls. More recently, the importance of sex in severe

Recalcitrant Asthma

153

asthma has been noted in TENOR and ENFUMOSA in which a striking prominence of females has emerged in severe asthma cohorts [15, 35]. The ENFUMOSA study also revealed a strong association with asthma exacerbations and the menstrual cycle with exacerbations occurring premenstrually [13]. In contrast, the SARP did not find women to be overly represented in the severe asthma group but did have similar findings with regard to the association between asthma exacerbations and menses [11]. Of note, both studies represent recruitment trials and not random sampling. Progesterone has been recognized to play a role in menstrual related asthma and can relax smooth muscle, thus contributing in the airway tone in women [36]. Furthermore, gonadotrophin releasing hormone (GnRH) may directly influence inflammatory responses in the airways. On the basis of these findings, a strong case can be made that further research should be undertaken to understand the factors that explain why women have more severe asthma.

Environmental Risk Factors Several environmental allergens have been studied, but a clear link to allergen exposure and asthma severity has not been fully ascertained. Asthma patients with Alternaria sensitization have a higher risk of severe asthma and death [9]. Rosenstreich and colleagues studied the role of cockroach allergy in inner-city children. The combination of both cockroach allergy and high level exposure was associated with more frequent hospitalizations for asthma and asthma impairment [37]. Such studies provide information on the link between allergen sensitization and exposure; further studies are needed to prove a “cause and effect” relationship between environmental allergens and asthma severity. The ENFUMOSA cohort was developed to better define the pathophysiology of chronic severe asthma and included both severe and mild-moderate asthma patients to identify differences that may suggest specific risk factors for severe disease. Although, atopy is identified as a strong risk factor of asthma development, the evidence from the ENFUMOSA study and the SARP indicated atopy is less apparent in severe disease [11, 13]. The ENFUMOSA subjects had reduced total serum IgE, fewer positive skin prick tests and RASTs to common allergens and the absence of a family history of allergy (Fig. 2). Furthermore, ENFUMOSA suggests that other environmental factors may be more important, such as infections and exposure to Aspergillus fumigatus and Alternaria [15].

Infections The coexistence of asthma and sinusitis is well appreciated with up to 50% of patients with sinus disease also carrying a diagnosis of asthma [38]. The SARP was formed to understand the mechanisms that contribute to severe asthma [39]. In severe asthma, a higher incidence of sinus disease was found in severe asthma. In other

154

S.M. Nyenhuis and W.W. Busse

Fig. 2 Percentage of positive skin-prick tests to common aeroallergens in asthmatic patients with well-controlled (hatched bars) or severe (open bars) asthma. # total number of subjects in each group with at least one positive reaction. Local 1 and Local 2 indicate the two most frequent allergens specific to the geographical region. *p < 0.05, (from [13], with permission)

studies, patients with severe asthma had prominent abnormalities on computed tomography (CT) scanning of the paranasal sinuses to suggest that sinonasal involvement may be a risk factor of asthma severity [40]. Ten Brinke and colleagues studied the relationship between sinonasal inflammation and bronchial mucosal inflammation in severe asthma [38]. Standard CT scans of the paranasal sinuses assessed mucosa thickness. Extensive disease was found in 24% of the severe asthma subjects (Table 5). Using different measurements to assess the bronchial inflammation, for example, sputum eosinophilia and exhaled nitric oxide (NO), they found a direct relationship between the sinonasal mucosa thickness and markers of bronchial inflammation (exhaled NO, blood eosinophils, and the % sputum eosinophils) (Table 6). Mechanisms by which sinus disease may exacerbate asthma are not established but include the enhancement of systemic airway inflammatory responses, direct deposition of inflammatory mediators and cytokines from the upper airways into the lower airways, and rhinobronchial reflexes [38]. The treatment of sinus disease in children and adults with severe or refractory asthma has led to better asthma control in these groups [41]. However, the linkage between sinusitis and asthma, particularly severe disease, is not established. Mycoplasma pneumoniae is a common cause of both upper and lower respiratory infection and can exacerbate asthma. This pathogen has been recovered from the

Recalcitrant Asthma

155

Table 5 Characteristics of patients with severe asthma with and without extensive sinus disease (from [38], with permission from Elsevier)

a

Age (y) Female sex (%) Age at onset of asthma (y)b Asthma duration (y)b Maintenance oral steroids (%) Nasal corticosteroids (%) Dose ICS (µg/d)b Smoking history (pack years)b History aspirin/NSAID sensitivityc Positive atopic status (%)

Extensive sinus disease (n = 21)

Limited sinus disease (n = 68)

p value

50.4 ± 14.8 61.9 35.0 (1.0–63) 12.0 (2–43) 38.1 57.1 1600 (1600–3600) 1 (0–10) 4/5 47.6

42.7 ± 13.1 69.1 11.5 (0.5–68) 23 (2–63) 26.9 30.9 1600 (1600–6400) 0 (0–10) 6/19 63.2

0.02 0.54 < 0.001 0.01 0.33 0.03 0.50 0.09 0.05 0.20

ICS. Inhaled corticosteroids, beclomethasone equivalent; NSAID, nonsteroidal anti-inflammatory drug a Mean ± SD b Median (range) c Only 24 patients were reported to have used these medications

Table 6 Comparison of physiologic and inflammatory parameters in patients with severe asthma with and without extensive sinus disease (from [38], with permission from Elsevier) Extensive sinus disease (n = 21) Baseline FEV1/VC (% predicted)a 70.2 ± 20.9 TLC (% predicted)a 102.8 ± 15.7 FRC (% predicred)a 132.1 ± 34.6 KCO (% predicted)a 80.9 ± 18.4 PC20 histamine (mg/mL)b 1.09 ± 2.4 Exhaled NO (ppb)c 27.1 (2–124) Blood eosinophils (109/L)c 0.44 (0.05–1.12) Sputum eosinophils (%)c 7.3 (0–59) VC, Slow inspiratory vital capacity; TLC, total lung capacity a Mean ± SD b Geometric mean ± SD (in doubling doses) c Median (range) FEV1: Forced Expiratory Volume in 1 second FRC: Functional Residual Capacity Kco: Diffusing Capacity NO: Nitric Oxide

Limited sinus disease (n = 68) p value 75.4 ± 21.5 97.5 ± 15.2 111.8 ± 33.9 94.3 ± 15.6 0.79 ± 2.8 8.5 (2–76) 0.17 (0.01–1.29) 0.7 (0–14)

0.33 0.19 0.03 0.006 0.63 0.002 < 0.001 0.007

upper and lower airways of patients with chronic stable asthma and has been proposed as a contributory factor to asthma severity [42]. In addition, Chlamydia pneumoniae has also been identified as a possible risk factor for severe asthma. In children, C. pneumoniae infections have been associated with asthma exacerbations [41].

156

S.M. Nyenhuis and W.W. Busse

The presence of this organism has been associated with persistent airflow limitation in nonatopic adult-onset asthma, disease severity and a poor clinical outcome, when detected in sputum and lung biopsies [43, 44]. There is also some evidence that infection with Chlamydia pneumonia is associated with asthma severity. Hahn and colleagues studied Chlamydiae in severe corticosteroid-dependent asthma patients and found treatment with macrolide antibiotics, such as clarithromycin or azithromycin, led to improved asthma control [41]. Further studies are needed to identify the exact role these infections play in asthma and its severity. Viral infections of the upper respiratory tract have long been recognized as one of the most important precipitants of acute severe exacerbation of asthma in children and adults [45]. Johnston and colleagues determined that 80–85% of school-aged children with wheezing episodes tested positive for a respiratory virus with, rhinovirus, the most common isolate [45]. Furthermore, Nicholson and colleagues demonstrated that approximately half of exacerbations in adults with asthma were associated with a viral infection [46]. Rhinoviruses (RV) are the cause of the common cold, but in the recent past, they were difficult to detect by standard virologic methods. With newer detection methods, such as reverse transcription polymerase chain reaction (RT-PCR), RV has been detected more frequently and are the predominant virus found in asthma exacerbations from a respiratory infection [45]. Respiratory viruses can have pro-inflammatory and immunomodulatory effects in the airways that could lead to asthma exacerbations [47]. When RV infects the epithelial cells of the airway, it initiates a cascade of events which inhibits viral replication and programmed cell death, and as a consequence effective viral elimination. In some asthma patients, there may be a defect in this process secondary to a deficiency in interferon-β production [44]. This deficiency can lead to the persistence of RV in the airways thus establishing a vicious cycle of pro-inflammatory responses that eventually causes tissue edema, lower airway obstruction, and heightened airway responsiveness. Furthermore, airway abnormalities from RV infection may last up to six months after an exacerbation in children. In infancy, an RV infection early in life is a strong predictor of subsequent wheezing, suggesting that RV might also be important in the pathogenesis and chronicity of asthma [44]. Studies have suggested that RV and its subsequent effects on the airway may also play a role in asthma severity. When RV infections occur in vivo, T helper-1 (Th1) responses are induced with the production of interferon-γ (IFN-γ). There is also evidence that some asthma patients have reduced Th1 production. In addition, decreases in IFN-γ production to dust mites may be related to asthma severity and persistence [48]. Brooks and colleagues further proposed that a defective Th1 response to RV could be associated with clinical features of greater asthma severity. Their results were consistent with their proposed findings as Th1 responses to RV, as measured by IFN-γ or IFNγ:IL-5 ratio, correlated with methacholine PC20 and FEV1, respectively. They also noted an association between measures of asthma severity and IFN-γ generation to be limited to RV and not occur with other mitogens or tetanus toxoid [49]. These findings suggest that respiratory viruses may also

Recalcitrant Asthma

157

play a role in asthma severity, and a defective Th1 response may be a factor. Additional research will have to be carried out to further characterize the role of RV in asthma severity.

Smoking Cigarette smoking contributes to the severity of asthma. Asthma patients who are smokers are more symptomatic and have more frequent and severe exacerbations as well as an accelerated decline in lung function [10]. Furthermore, when the efficacy of both inhaled and oral corticosteroids in tobacco users with asthma was investigated, smokers were less responsive to short-term inhaled corticosteroid treatment. More recently, Tomlinson and colleagues found that cigarette smokers with asthma were relatively insensitive to long-term administration of low-dose inhaled corticosteroid therapy as well [50]. Finally, Chaudhuri and colleagues found similar results but in patients treated with short-term high-dose oral corticosteroids [51]. The mechanisms of corticosteroid resistance in tobacco smokers are poorly understood, but several possibilities have been proposed. First, smokers with asthma have increased sputum neutrophils when compared with nonsmokers with asthma [51]. Airway neutrophilia has been associated with a poor response to inhaled corticosteroids. Second, there is a change in the glucocorticoid α:β receptor ratio which may be caused by elevated levels of tumor necrosis factor-␣, a growth factor, often found in smokers [51]. Finally, smokers have decreased histone deacetylase activity which is required for glucocorticoids to exert their maximal suppression of cytokine induction [52]. Without a full suppression of cytokine induction, there may be an increase in inflammatory gene expression that leads to a decrease in response to treatment [52].

Obesity A recent large-scale epidemiologic study of severe/difficult-to-treat patients with asthma (TENOR) suggested that the body mass index increases with greater severity of disease in adults [35]. In this cohort of severe/difficult-totreat asthma, 76% of the patients were obese or overweight. In the SARP cohort, patients with moderate asthma were equally as obese as patients in the severe asthma group, but this was not as large a group as TENOR [11]. Weight loss has been reported to improve lung volumes, but the relationship to airway obstruction, reactivity, and asthma symptoms has been more controversial [53, 54]. One must consider other comorbidities in this patient population, such as obstructive sleep apnea (OSA), as it may also affect overall lung function, and treat them as appropriate.

158

S.M. Nyenhuis and W.W. Busse

Gastroesophageal Reflux Disease (GERD) Gastroesophageal reflux disease (GERD) affects almost 20% of adults in the United States on a daily basis. The prevalence of GERD is much higher in asthma reaching approximately 75% of this population [55]. GERD is considered an inciting factor of asthma symptoms as well as exacerbations. Esophageal acid reflux can elicit respiratory responses by causing decreases in airflow and oxygen saturation, and increases in respiratory resistance, minute ventilation, and respiratory rate. There are several mechanisms of esophageal acid-induced bronchoconstriction including a vagally-mediated reflex, heightened bronchial reactivity, and microaspiration. Esophageal acid can also elicit airway neurogenic inflammatory responses with the release of substance P, tachykinins, nitric oxide, and other cytokines. In asthma, there are factors that may promote GERD such as autonomic dysregulation, increased thoracic pressure, diaphragm dysfunction, and medications [55]. Asthma subjects have the evidence of autonomic dysregulation which can lead to a heightened vagal responsive. This increased responsiveness could also result in decreased lower esophageal sphincter (LES) pressure and transient relaxation of the LES, which is a main mechanism of GERD [55]. Secondly, chronic airflow obstruction causes a greater negative pleural pressure to increase the pressure gradient between the thorax and the abdominal cavity to promote reflux. Thirdly, hyperinflation can cause geometric flattening of the diaphragm to relax the LES and subsequently allow acid reflux into the esophagus. Finally, asthma medications, theophylline, and inhaled β2-adrenergic agonist in some studies, have been noted to worsen GERD symptoms [55]. The significance of GERD to overall asthma management is still unresolved and further research is needed. A proposed management approach to GERD symptoms in adults with asthma includes a 3 month trial of high-dose proton pump inhibitor. If treatment failure occurs, a 24 hour esophageal pH test should be performed while monitoring symptoms. A precise link between GERD and a decline in asthma control is yet to be established as varying degrees of improvement in asthma have been observed with the treatment of GERD [41].

Adherence Problems with treatment adherence and hence apparent greater disease severity may be a factor in the loss of asthma control. It is no surprise that patients with the highest levels of adherence have significantly fewer exacerbations [56]. In addition, Milgrom and colleagues have suggested that poor control in children and adolescents is related to the adherence to corticosteroid therapy [57]. Prescription refills for ICS are approximately two to four canisters/year, implying that problems of adherence are not limited to severe asthma but occur across all severities [10]. Attempts to promote adherence to prescribed therapy should be made for all patients. If patients admit to poor adherence, the reasons should be established [56].

Recalcitrant Asthma

159

Table 7 Health Care Utilization Parameters in Psychiatric Cases and Noncases Among Patients with Severe Asthma (from [60], with permission)

Health Care Utilization Parameters

Cases

Noncases

(n = 21)

(n = 77)

n

%

n

%

p value

GP visits: ≥ 4 last year 15 71.4 23 29.9 0.02 Chest physician visits: ≥ 4 last year 17 81.0 60 77.9 0.78 Emergency visits: ≥ 2 last year 15 71.4 24 31.2 0.01 Exacerbations: ≥ 2 last yeara 12/13 92.3 29/51 56.9 0.02 Hospital admissions: ≥ 2 last year 4 19.0 4 5.2 0.04 Maintenance of oral corticosteroids 8 38.1 26 33.8 0.71 Ever ICU admission 3 14.3 8 10.4 0.62 Ever mechanical ventilation 3 14.3 2 2.6 0.03 Definition of abbreviations: GP = general practitioner; ICU = intensive care unit a For the exacerbation analysis, only the 64 patients without maintenance oral steroids were considered

Finally, if adherence is a concern, even after a thorough patient history and asthma education, an early morning cortisol level may be checked to ascertain the level of cortisol secretion for patients on oral corticosteroids [10]. Previously, psychologic problems have been associated with near-fatal asthma, but more extensive studies have not substantiated this relationship [10]. Studies have also suggested that psychologic disease is not more common in severe asthma compared to society in general [58–60]. However, patients with severe asthma, who frequently utilize health care, do exhibit more psychopathology (Table 7). The majority of the psychological abnormalities center on anxiety, depression, and a lack of trust for health care providers [61]. These psychological abnormalities often lead to noncompliance with medications, irregular follow-up, and suboptimal asthma management [60]. Other forms of psychopathology, such as bipolar disorder, personality disorders, and schizophrenia, have not been found to occur more often in patients with severe asthma [10].

Histological Features of Severe Asthma The role inflammation in the pathogenesis and pathophysiology of severe corticosteroiddependent asthma continues to be an area of study. Wenzel and colleagues have found differences in the inflammatory pattern among asthma patients on high-dose inhaled glucocorticoids compared wiht milder asthma and normal controls [1, 62] [Table 8]. Eosinophils were found to be most prominent in the moderate severe asthma subjects (not on glucocorticoids) compared with the normal controls and severe asthma subjects (p < 0.007). Furthermore, the airway tissue of severe asthma subjects dependent on high doses of glucocorticoids had a two-fold higher concentration of neutrophils compared

160

S.M. Nyenhuis and W.W. Busse

Table 8 BAL cell differentials among asthmatics on high dose glucocorticoids (severe asthma) when compared with milder asthmatics and normal controls (from [1], with permission) Group

Total Cells (×104)

Macrophages Lymphocytes Eosinophilsa Neutrophilsb (×104) (×103) (×103) (×103)

Normal (n = 6) 10.2 (7.9–11.8) 9.2 (7.1–10.9) 6.5 (4.8–10.0) 0 (0–0.3) 0.5 (0–1.5) Mild-moderate 10.0 (7.6–10.8) 7.8 (7.0–9.2) 3.0 (1.3–6.9) 2.3 (1.0–3.8) 1.0 (0–2.1) asthma (n = 12) Severe asthma 11.5 (8.2–21.3) 7.9 (6.6–17.2) 5.8 (3.9–16.7) 1.2 (0–2.1) 2.6 (1.2–8.7) (n = 14) All values given as median with interquartile range a Significant difference among the groups, p < 0.007 b Significant difference among the groups, p = 0.032 Table 9 Sputum characteristics of severe asthmatics when compared with normal controls and milder asthmatics (from [63], with permission)a Volume, ml TIC, × 106/ml Tmac, × 106/ml Tneu, × 106/ml Teos, × 106/ml Tsq, × 106/ml Macrophages, % Neutrophils, % Eosinophils, % Lymphocytes, % Squamous epithelium, % ECP, ng/ml

Normal

Mild asthma

Moderate asthma Severe asthma

2.9 (2.5–3.2) 0.67 (0.46–1.03) 0.43 (0.26–0.76) 0.22 (0.11–0.34) 0 (0–0) 0.20 (0.14–0.32) 71.7 (57.8–78.6) 27.7 (20.6–42.2) 0.0 (0.0–0.1) 0.2 (0.0–0.3) 22.5 (17.4–32.2)

2.9 (2.2–3.6) 1.10 (0.54–2.14) 0.66 (0.35–1.10) 0.25 (0.20–0.71) 0.03 (0.01–0.09)f 0.18 (0.10–0.31) 58.3 (47.7–66.1)g 35.4 (29.8–46.1) 4.2 (1.9–8.0)hi 0.2 (0.0–0.3) 18.8 (8.2–29.1)

2.6 (1.9–3.2) 1.36 (0.54–2.14) 0.55 (0.27–1.57) 0.64 (0.32–1.02) 0 (0–0.06) 0.17 (0.10–0.30) 49.9 (40.2–62.4) 48.9 (37.1–57.6) 0.5 (0–26) 0.0 (0.0–0.6) 13.9 (7.9–34.1)

2.7 (2.1–3.5) 1.87 (1.31–5.42)bc 0.53 (0.42–0.81) 1.20 (0.55–2.61)de 0.04 (0–0.33)g 0.20 (0.07–0.27) 33.1 (11.6–57.8)cd 53.0 (38.4–73.5)cg 4.5 (0.3–11.4)d 0.0 (0.0–0.3) 6.1 (2.5–46.1)

32.5 (7.5–84.5) 163.6 (90.2– 60.7 (29.6– 717)cj 163.6)b a IL-8, ng/ml 0.3 (0.2–0.6) 1.5 (0.4–2.6) 1.9 (1.5–2.7) 3.6 (2.3–5.8)de MPO, ng/ml 0 (0–2.5) 4.6 (0–23.2) 15.7 (4.2–32.4)e 26.0 (16.8–38.5)cd Definition of abbreviations: ECP = eosinophil cationic protein; IL-8 = interleukin-8; MPO = mycloperoxidase; Teos = total eosinophil count; TIC = total inflammatory cell count; Tmac = total macrophage count; Tneu = total neutrophil count; Tsq = total squamous epithelial cell count a Data shown as medians with 25–75 percentiles shown in parentheses b p < 0.01 compared with normal c p <0.05 compared with mild asthma d p < 0.001 compared with normal e p < 0.01 compared with mild asthma f p < 0.01 compared with normal g p < 0.05 compared with normal h p < 0.001 compared with normal i p < 0.05 compared with moderate asthma j p < 0.01 compared with moderate asthma 7.3 (0–24)

with moderate asthma group (not on glucocorticoids) and normal subjects. Jatakanon and colleagues have also detected higher concentrations of neutrophils in the sputum of severe asthma subjects when compared with normal subjects and milder asthma patients [63] [Table 9]. These findings suggest that in severe asthma

Recalcitrant Asthma

161

requiring high doses of glucocorticoids inflammation persists, particularly neutrophilic, which may be due to the severity of the disease, glucocorticoid treatment, or undefined factors [1]. Oral corticosteroids increase the number of neutrophils in biopsy tissues and lavage specimens while effectively eliminating eosinophils. Unlike eosinophils, neutrophils are resistant to treatment with glucocorticoids. However, leukotriene and superoxide production may inhibit of neutrophil apoptosis. Glucocorticoids may also reduce the eosinophil/lymphocyte driven process while leaving behind or even augmenting a neutrophil mediated process [1]. Severe asthma is, however, likely to be a heterogenous population. To further characterize the different histopathologic mechanisms in severe asthma, Wenzel and colleagues studied severe asthma patients dependent on glucocorticoids and separated them into two histopathologic groups: Eosinophils present (low to moderate concentration of eosinophils on endobronchial biopsy compared with normal controls) and eosinophil absence (nearly absent eosinophils on endobronchial biopsy) [62]. The low eosinophil group had a lower FEV1 % predicted (Tables 10 and 11). In contrast, the eosinophil positive subjects had a significantly higher incidence of respiratory failure and mechanical ventilation as well as thicker

Table 10 The physiologic characteristics of severe asthma patients dependent on glucocorticoids separated into two subgroups: (+) eosinophils and (–) eosinophils based on endobronchial biopsy (from [62], with permission) Eosinophil (−)a (n = 14)

Eosinophil (+)a (n = 20)

p value

FEV1, % pred 42 (33–58) 56 (34–66) 0.05 BD response, % 25 (12–50) 22 (15–35) 0.69 RV, % pred 191 (155–294) 210 (167–242) 0.95 Vtg, % pred 109 (93–150) 108 (393–131) 0.68 FVC/SVC 97 (89–100) 88 (71–94) 0.03 Definition of abbreviations: BD = bronchodilator; FVC/SVC = forced vital capacity/ slow vital capacity; RV = residual volume; Vtg = thoracic gas volume a Values are expressed as median (interquartile range)

Table 11 The clinical characteristics of severe asthma patients dependent on glucocorticoids separated into two subgroups: (+) eosinophils and (–) eosinophils based on endobronchial biopsy. (from [62], with permission)

a

Age, yr M/F Cauc/AA + Hisp Asthma duration, yra Steroid dose, mg/da Intubation (Y/N) a Values are mean ± SEM.

Eosinophil (−) (n = 14)

Eosinophil (+) (n = 20)

p value

28 ± 3 7/7 12/2 22 ± 3 27 ± 4 1/13

34 ± 3 8/12 16/4 19 ± 3 29 ± 5 12/8

0.22 0.68 0.67 0.51 0.85 0.004

162

S.M. Nyenhuis and W.W. Busse

sub-basement membrane (SBM). The FVC/SVC ratio, (as a potential indicator of airway collapse during forced expiration) was lower (indicating more collapse) in the eosinophil positive group (p = 0.03). These findings suggest that there are at least two different and distinct pathologic processes, based on the presence or absence of eosinophils, which present clinically and physiologically as “severe, refractory asthma”. This information may have implications for the treatment of not only severe asthma but also asthma of all severity.

Management of Severe Asthma When approaching a patient with recalcitrant asthma, there are at least four components to consider: (1) confirm the diagnosis of asthma, (2) evaluate and treat confounding or exacerbating factors, (3) evaluate possible asthma phenotypes, and (4) optimize the “standard” asthma pharmacotherapy [10] [Fig. 3]. Confirmation of the diagnosis of severe asthma includes an extensive history and physical examination, a set of full pulmonary function tests (pre- and post-bronchodilator spirometry, lung volumes, and diffusing capacity), total eosinophil count, allergy skin testing, serum IgE, and chest X-ray. Depending on the findings from the above testing, chest computed tomography scan, a standard methacholine challenge, and/or laryngoscopy may also be helpful. These diagnostic tests can help differentiate small changes related to interstitial disease and mixed obstructive/restrictive disease, as well as evaluate for allergic bronchopulmonary aspergillosis, emphysema, bronchiolitis obliterans, and vocal cord dysfunction (paradoxical adduction of the vocal cords during inspiration) [9]. Severe asthma should also be evaluated and treated for confounding/exacerbating factors as well. Diagnostic tests to identify these factors include: A pH probe to evaluate GERD; a sinus computed tomography to evaluate chronic sinusitis (bacterial/fungal), nasal/sinus polyps, or surgically amenable disease; a sleep study to evaluate for obstructive sleep apnea; allergy skin testing; and an early morning cortisol to evaluate compliance/adherence to oral corticosteroids [10]. Vocal cord dysfunction may coexist with asthma and may not only be in the differential diagnosis for asthma but also an exacerbating and coexisting factor. Once these confounding factors are identified, they should be treated as effectively as possible. Inhaled allergens (animal dander, pollens, and dust mites) can cause airway inflammation. Unfortunately, the evidence to suggest that avoidance of environmental triggers affects asthma control is varied [44]. Furthermore, adherence should be assessed often, including pill counts, prescription refills, direct questioning, or serological testing if the patient is on corticosteroids or theophylline [41]. Distinct phenotypes of severe asthma have begun to emerge. Further characterization of these phenotypes may lead to changes in treatment and approaches. For example, adult-onset asthma appears to be less involved with allergic reactions, making allergen avoidance unnecessary. In addition, aspirin sensitive asthma and

Recalcitrant Asthma

163

Fig. 3 Algorithm of possible strategies and recommendation for managing patients with difficult to control asthma despite maximum combination treatment. *Includes C pneumoniae and M pneumoniae. CF = cystic fibrosis. COPD = chronic obstructive pulmonary disease. CHF = chronic heart failure. ABPA = allergic bronchopulmonary aspergillosis (from [44], Reprinted with permission from Elsevier)

164

S.M. Nyenhuis and W.W. Busse

occupational-related asthma are additional phenotypes that might benefit from specific therapies, such as aspirin desensitization, use of 5-lipoxygenase inhibitors, and removal from occupational exposures [64]. Furthermore, an eosinophilic phenotype of severe asthma has been characterized by the presence of eosinophilic inflammation directly on sputum analysis or biopsy microscopy or indirectly on exhaled nitric oxide levels [64]. A predominance of eosinophils suggests that these patients may be more responsive to higher doses of corticosteroids or alternative inflammatory medications. Ten Brinke and colleagues studied the effect of parenteral corticosteroids in a small group of severe asthma patients with an eosinophilic phenotype [65]. Their findings suggest that aggressive anti-inflammatory treatment with parenteral corticosteroids (i.e. 120 mg intramuscular injection of triamcinolone) can result in improvements in post-bronchodilator FEV1 and a decreased use of rescue medication (Fig. 4). Finally, if there is limited evidence of inflammation histologically or diagnostically (normal exhaled nitric oxide levels), anti-inflammatory therapy may be less beneficial in this group of patients [64]. It is also important to establish whether patients with severe asthma are receiving adequate treatment. Undertreatment is consistently recognized in fatal and near fatal asthma and can be an important contributor to poor asthma control [41]. Standard treatment of severe asthma as outlined by The Global Initiative for Asthma (GINA), includes high-dose inhaled corticosteroids combined with a long-acting β2 agonist as the preferred add-on therapy [66]. Alternative therapies include 5-lipoxygenase inhibitors, cysteinyl leukotriene receptor antagonist, and sustained released theophylline which can be added onto the combination therapy [45]. Some patients may have persistent and refractory symptoms as well as poor lung function despite the use of high-dose ICS and long-acting β2 agonists. In this group, it is important to perform a trial of oral corticosteroid therapy. A clinical assessment along with spirometry before and after the treatment course can provide

Fig. 4 Effect of treatment with intramuscular triamcinolone (circles) or placebo (squares) on postbronchodilator Forced Expiratory Volume in 1 s (FEV1) (left panel) and on rescue medication score (right panel) in 22 patients with severe asthma. (Open symbols) Patients using corticosteroids on a daily basis. (Closed symbols) Patients not using oral corticosteroids on a daily basis. Lines represent median values (from [65], with permission)

Recalcitrant Asthma

165

useful information to the patient’s responsiveness to corticosteroid therapy [64]. If the patient does respond to an oral corticosteroid burst, titration to the lowest amount of oral corticosteroids to maintain control or stabilize symptoms should be undertaken. In a subset of patients with severe asthma, prolonged or chronic use of oral corticosteroids will be required; in these circumstances, the addition of a steroid sparing drug should be considered. A number of agents have been tried, including gold, cyclosporine, and methotrexate, all with limited benefit at best. Methotrexate has been the most studied steroid-sparing agent in asthma. A Cochrane review of the benefit of adding methotrexate to oral corticosteroids in steroid-dependent asthmatics evaluated the available, but conflicting, data in the current literature [67]. By performing a systematic review with a meta-analysis, the authors concluded that methotrexate may have a small steroid sparing effect, but the overall reduction in daily steroid use was not large enough to diminish steroid-associated adverse effects or offset the adverse effects of methotrexate. The decision to use methotrexate in any patient must be based on an individual assessment of the risks and benefits specific to that patient. Intravenous immunoglobulin (IVIG) has well appreciated anti-inflammatory and immunomodulatory properties and has been used in numerous disorders such as thrombocytopenia, Guillane-Barre syndrome, and Kawasaki’s disease [68]. In some studies, the use of high-dose intravenous human immunoglobulin in steroiddependent severe asthma has been shown efficacious in the reduction of oral corticosteroids and suppression of persistent inflammation [68, 69]. The variability in response as well as the cost and inconvenience of IVIG has prevented its widespread use in the treatment of steroid-dependent severe asthma [44].

New Approaches to Treatment of Severe Asthma Our increasing knowledge on the cellular mechanisms involved in asthma and a need for better asthma therapies have led to a focus on cellular and molecular targets in the treatment of severe asthma. Humanized monoclonal IgG1 blocking antibody directed to IgE (omalizumab) removes circulating and tissue IgE but also promotes the loss of high affinity IgE receptor on mast cells, basophils, and dendritic cells [44]. These effects decrease mast-cell activation and sensitivity to lead to a reduction in eosinophil influx and activation and finally the suppression of airway inflammation [See the Anti-IgE chapter by J. DeMore, this volume]. Several studies have shown omalizumab to be effective in the treatment of severe allergic asthma when symptoms are not controlled with standard therapies. The outcomes affected by omalizumab therapy include exacerbations, hospitalizations, symptoms, and asthma-specific quality of life [70]. Anti-IgE’s effectiveness in severe asthma, which is often nonatopic, is not fully defined and other targeted treatment options may need to be studied. Other approaches target cytokines that induce allergic airway, and include monoclonal antibodies to interleukin-5 (IL-5) and tumor necrosis factor-α (TNF-α). IL-5 is a

166

S.M. Nyenhuis and W.W. Busse

T helper (Th) type 2 cytokine involved in eosinophil production, activation, and survival. The presence of activated eosinophils is a cardinal feature of the allergic inflammation and is often found in severe asthma. The use of humanized monoclonal antibodies against IL-5 (mepolizumab) significantly reduces blood and sputum eosinophils, but only diminishes bone marrow and airway biopsy tissue approximately 50% in over 20 weeks of treatment [71]. Mepolizumab does not affect pulmonary responses to inhaled allergen and indexes of asthma control. Kips and colleagues, however, found a small, but significant improvement in FEV1 with a 0.3 mg/kg dose; no other clinical improvements were seen [72]. Despite its profound effect on blood and sputum eosinophils, mepolizumab has not produced striking changes in clinical outcomes in severe asthma. TNF-α has become a therapeutic target in a wide range of chronic inflammatory disorders including rheumatoid arthritis and Crohn’s disease. Given its effects on inflammation, TNF-α has also gathered interest in asthma. TNF-α has been shown to promote not only the recruitment of neutrophils but also eosinophils into the airways [73]. Howarth and colleagues found elevated levels of TNF-α in induced sputum from patients with steroid-dependent asthma [73]. Etanercept, a soluble TNF-α receptor-IgG1Fc fusion protein, has been evaluated in severe asthma in small prospective studies [71]. The results of these studies have shown promise by improving symptoms, lung function, asthma-related quality of life and airway hyper-responsiveness. Erin and colleagues conducted a double-blind, placebo-controlled trial with infliximab, a recombinant humanmurine chimeric monoclonal antibody, that specifically and potently binds and neutralizes soluble TNF-α and its membrane-bound precursor [74]. Infliximab was well tolerated and decreased exacerbations in moderate persistent asthma. Larger clinical trials with these promising anti-TNFα monoclonal antibodies in severe asthmatics are in progress to more fully define the role of TNF-α in asthma.

Conclusion Severe asthma may reflect only a small proportion of patients but, they account for the majority of the cost and morbidity of the disease. The pathophysiology, phenotypes, and effective treatment modalities of severe asthma are not well understood. Multi-center prospective cohorts such as SARP and ENFUMOSA provided a starting point to better define severe asthma, its risk factors, histopathology, and possible new therapies. Ongoing and future prospective cohorts will, hopefully, gather further insight into the pathophysiologic mechanisms of severe asthma and phenotypes that can then be used to determine novel biomarkers and more effective biologic therapies.

Recalcitrant Asthma

167

References 1. Wenzel SE, Szefler SJ, Leung DYM, Sloan SI, Rex MD, Martin RJ (1997) Bronchoscopic Evaluation of Severe Asthma. Am J Respir Crit Care Med 156:737–743 2. Burney P (1993) Epidemiology of asthma. Allergy 48:17–21 3. Serra-Batlles J, Plaza V, Morejon E, Comella A, Brugues J (1998) Costs of asthma according to the degree of severity. Eur Resp J 12:1322–1326 4. Antonicelli L, Bucca C, Neri M, De Benedetto F, Sabbatani P, Bonifazi F, Eichler H-g, Zhang Q, Yin DD (2004) Asthma severity and medical resource utilisation. Eur Resp J 23:723–729 5. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G (2002) Costs of asthma are correlated with severity: A 1-yr prospective study. Eur Resp J 19:61–67 6. Rackemann FM (1927) Studies in asthma: A clinical survey of 1,074 patients with asthma followed for two years. J Lab Clin Med 12:1185–1197 7. Walker IC (1918) A clinical study of 400 patients with bronchial asthma. Boston Med Surg J 179:288–293 8. Busse WW, Banks-Schlegel S, Wenzel SE (2000) Pathophysiology of severe asthma. J Allergy Clin Immunol 106:1033–1042 9. American Thoracic Society (2000) Proceeding of the ATS workshop on Refractory Asthma: Current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 162:2341–2351 10. Wenzel S (2005) Severe Asthma in Adults. Am J Respir Crit Care Med 172:149–160 11. Wenzel SE, Busse WW (2007) Severe asthma: Lessons from the Severe Asthma Research Program (SARP). J Allergy Clin Immunol 119:14–21 12. Chanez P, Wenzel SE, Anderson G, Anto JM, Bel EH, Boulet L-P, Brightling CE, Busse WW, Castro M, Dahlen B, Dahlen SE, Fabbri LM, Holgate ST, Humbert M, Gaga M, Joos GF, Levy B, Rabe KF, Sterk PJ, Wilson SJ, Vachier I (2007) Severe Asthma: What are the important questions? J Allergy Clin Immunol 119:1337–1348 13. ENFUMOSA study group (2003) The ENFUMOSA cross-sectional European multi-center study of the clinical phenotype of chronic severe asthma. Eur Respir J 22:470–477 14. Turner-Warwick M (1977) On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 71:73–86 15. Ayres JG, Miles JF, Barnes PJ (1998) Brittle Asthma. Thorax 53:315–321 16. Barnes PJ (1992) Poorly perceived asthma. Thorax 47:408–409 17. Town GI, Allan C (1989) Ventilatory responses to hypoxia and hypercapnea in asthmatics with previous respiratory failure. Aust NZ J Med 19:426–30 18. Phelan PD, Robertson CF, Olinsky A (2002) The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 109:189–194 19. Reed CE (2006) The natural history of asthma. J Allergy Clin Immunol 188:543–548 20. Sunyer J, Soriano J, Anto JM, Burgos F, Pereira A, Payo F, Martinez-Moratalla J, Ramos J (2000) Sensitization to individual allergens as risk factors for lower FEV1 in young adults. European Community Respiratory Health Survey. Int J Epidemiol 29:499–503 21. Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L (2005) Aspirin sensitivity and severity of asthma: Evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol 116:970–975 22. Dompleling E, van Schayck CP, van Grunsven PM, van Herwaardën CL, Akkermans R, Molema J, Folgering H, van Weel C (1993) Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids: A 4-year prospective study. Ann Intern Med 188:770–778 23. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD (2003) Tuscon Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol 111:661–675

168

S.M. Nyenhuis and W.W. Busse

24. Sanford AJ, Chagani T, Zhu S, Weir TD, Bai TR, Spinelli JJ, Fitzgerald JM, Behbehani NA, Tan WC, Paré PD (2000) Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 106:135–140 25. Burchard EG, Silvermann EK, Rosenwasser LJ, Borish L, Yandava C, Pillari A, Weiss ST, Hasday J, Lilly CM, Ford JG, Drazen JM (1999) Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma. Am J Respir Crit Care Med 160:919–922 26. Rosenwasser LJ, Klemm DJ, Dresback JK, Inamura H, Mascali JJ, Klinnert M, Borish L (1995) Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 25:74–78 27. Deichmann KA, Heinzmann A, Forster J, Dischinger S, Mehl C. Bruggenolte E, Hildebrandt F, Moseler M, Kuehr J (1998) Linkage and allelic association of atopy and markers flanking the IL4-receptor gene. Clin Exp Allergy 28:151–155 28. Rosa-Rosa L, Zimmermann N, Bernstein JA, Rothenberg ME, Khurana-Hershey GK (1999) The R576 IL-4 receptor a allele correlated with asthma severity. J Allergy Clin Immunol 104:1008–1014 29. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP (2002) Association of the ADAM-33 gene with asthma and bronchial hyper-responsiveness. Nature 418:426–430 30. Holgate ST, Davies DE, Powell RM, Holloway JW (2005) ADAM33: A newly identified gene in the pathogenesis of asthma. Immunol Allergy Clin North Am 25:655–669 31. Haitchi HM, Powell RM, Shaw TJ, Howarth PH, Wilson SJ, Wilson DI, Holgate ST, Davies DE (2005) ADAM33 expression in asthmatic airways and human embryonic lungs. Am J Respir Crit Care Med 171:958–965 32. Jongepier H, Boezen HM, Dijkstra A, Howards TD, Vonk JM, Koppelman GH, Zheng SL, Meyers DA, Bleecker ER, Postma DS (2004) Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy 34:757–760 33. Lee JY, Park SW, Chang HK, Kim HY, Rhim T, Lee JH, Jang AS, Koh ES, Park CS (2006) A disintegrin and Metalloproteinase 33 protein in patients with asthma: Relevance to airflow limitation. Am J Respir Crit Care Med 173:729–735 34. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JPA (2005) Meta-analysis of the association of b2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol 115:963–972 35. Dolan CM, Fraher KE, Bleecker ER, Borish L, Chipps B, Hayden ML, Weiss S, Zheng B, Johnson C, Wenzel S; TENOR Study Group (2004) Design and baseline characteristics of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study: A large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 92:32–39 36. Boggess KA, Williamson HO, Homm RJ (1990) Influence of the menstrual cycle on systemic disease. Obstet Gynecol Clin North Am 17:321–342 37. Rosenstreich DL, Eggleston P, Katan M, Baker D, Slavin RG, Gergen P, Mitchell H, McNiffMortimer K, Lynn H, Ownby D, Malveaux F (1997) The Role of Cockroach Allergy and Exposure to Cockroach Allergen in Causing Morbidity Among Inner-City Children with Asthma. N Engl J Med 33:1356–1363 38. ten Brinke A, Grootendorst DC, Schmidt JT, Bruïne Ft, van Buchem MA, Sterk PJ, Rabe KF, Bel EH (2002) Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol 109:621–626 39. Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, Calhoun WJ, Castro M, Chung KF, Clark MP, Dweik RA, Fitzpatrick AM, Gaston B, Hew M, Hussain I, Jarjour NN, Israek E, Levy BD, Murphy JR, Peters SP, Teague WG, Meyers DA,

Recalcitrant Asthma

40. 41. 42.

43.

44. 45. 46. 47. 48.

49.

50.

51.

52.

53.

54.

55. 56. 57. 58.

59.

169

Busse WW, Wenzel SE; National Heart, Lung, Blood Institute’s Severe Asthma Research Program (2007) Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program (SARP). J Allergy Clin Immunol 119:405–413 Bresciani M, Paradis L, Des RA, Vernhet H, Vacheir I, Godard P, Bousquet J, Chanez P (2001) Rhinosinusitis in severe asthma. J Allergy Clin Immunol 107:73–80 Stirling RG, Chung KF (2001) Severe Asthma: Definition and mechanisms. Allergy 56:825–840 Kraft M, Cassell GH, Henson JE, Watson H, Williamson J, Marmion BP, Gaydos CA, Martin RJ (1998) Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med 158:998–1001 ten Brinke A, van Dissel JT, Sterk PJ, Zwinderman AH, Rabe KF, Bel EH (2001) Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol 107:449–454 Holgate ST, Polosa R (2006) The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 368:780–793 Folkerts G, Busse WW, Nijkamp FP, Sorkness R, Gern JE (1998) Virus-induced Airway hyperresponsiveness and Asthma. Am J Respir Crit Care Med 157:1708–1720 Nicholson KG, Kent J, Ireland DC (1993) Respiratory viruses and exacerbation of asthma in adults. BMJ 307:982–986 Grunberg K, Sterk PJ (1999) Rhinivirus infections: Induction and modulation of airways inflammation in asthma. Clin Exp Allergy 29(S2):65–73 Smart JM, Horak E, Kemp AS, Robertson CF, Tand ML (2002) Polyclonal and allergeninduced cytokine responses in adults with asthma: Resolution of asthma is associated with normalization of IFN-gamma responses. J Allergy Clin Immunol 110:450–456 Brooks GD, Buchta KA, Swanson CA, Gern JE, Busse WW (2003) Rhinovirus-induced Interferon-g and Airway Responsivenss in Asthma. Am J Respir Crit Care Med 168:1091–1094 Tomlinson JEM, McMahon AD, Chaudhuri R, Thompmson JM, Wood SF, Thomson NC (2005) Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 60:282–287 Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC (2003) Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 168:1308–1311 Ito K, Lim J, Caramori G, Chung K, Barnes P, Adcock IM (2001) Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 15:1110–1112 Hakala K, Steniums-Aarniala B, Sovijarvi A (2000) Effects of weight loss on peak flow variability, airways obstruction, and lung volumes in obese patients with asthma. Chest 188:1315–1321 Aaron SD, Fergusson D, Dent R, Chen Y, Vandemheen KL, Dales RE (2004) Effect of weight reduction on respiratory functions and airway reactivity in obese women. Chest 125:2046–2052 Harding SM (1999) Gastroesophageal reflux and asthma: Insight into the association. J Allergy Clin Immunol 104:251–259. Chung KF, Godard P (1999) Difficult/therapy-resistant asthma. Eur Respir J 19:1198–1208 Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C (1996) Non-compliance and treatment failure in children with asthma. J Allergy Clin Immunol 98:1051–1057 Strunk RC, Mrazek DA, Fuhrmann GS, LaBrecque JF (1985) Physiologic and psychological characteristics associated with deaths due to asthma in childhood: A case-controlled study. JAMA 254:1193–1198 ten Brinke A, Ouwekerk ME, Bel EH, Spinhoven P (2001) Similar psychological characteristics in mild and severe asthma. J Psychosom Res 50:7–10

170

S.M. Nyenhuis and W.W. Busse

60. ten Brinke A, Ouwekerk ME, Zwinderman AH, Spinhoven P, Bel EH (2001) Psychopathlogy in patients with severe asthma is associated with increased health care utilization. Am J Respir Crit Care Med 163:1093–1096 61. Kolbe J, Fergusson W, Vamos M, Garrett J (2002) Case-control study of severe life threatening asthma (SLTA) in adults: Psychological factors. Thorax 57:317–322 62. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 160:1001–1008 63. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ (1999) Neutrophilic Inflammation in Severe Persistent Asthma. Am J Respir Crit Care Med 160:1532–1539 64. Wenzel, S and Szefler SS (2006) Managing severe asthma. J Allergy Clin Immunol 117:508–511 65. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH (2004) “Refractory” Eosinophilic Airway Inflammation in Severe Asthma. Am J Respir Crit Care Med 170:601–605 66. Global Initiative for Asthma. Global strategy for asthma management and prevention. A six part management program. NIH publication number 02-3659 http://www.ginathma.org 67. Davies H, Olson L, Gibson P (2000) Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Sys Rev 2:CD000391 68. Haque S, Boyce N, Thien FC, O’Hehir RE, Douglas J (2003) Role of intravenous immunoglobulin in severe steroid-dependent asthma. Intern Med J 33:341–344 69. Salmun LM, Barlan I, Wolf HM, Eibl M, Twarog FJ, Geha RS, Schneider LC (1999) Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: A double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 103:810–815 70. Niebauer K, Dewilde S, Fox-Rushby J, Revicki DA (2006) Impact of omalizumab on qualityof-life outcomes in patients with moderate-to-severe allergic asthma. Ann Allergy Asthma Immunol 96:316–326 71. O’Byrne PM (2006) Cytokines or Their Antagonists for the Treatment of Asthma. Chest 130:244–250 72. Kips JC, O’Connor BJ, Langley SJ, Woodcock A, Kerstjens HAM (2003) Effect of SCH55700, a humanized anti-human IL-5 antibody, in severe persistent asthma. Am J Respir Crit Care Med 167:1655–1659 73. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, Beckett P, Al Ali M, Chauhan A, Wilson SJ, Reynolds A, Davies DE, Holgate ST (2005) Tumour necrosis factor (TNFa) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60:1012–1018 74. Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, Zacharasiewisz AS, Turner J, Barnathan ES, Kon OM, Barnes PJ, Hansel TT (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-a in asthma. Am J Respir Crit Care Med 174:753–762

Mechanisms and Management of ExerciseInduced Bronchoconstriction John D. Brannan and Paul M. O’Byrne

Introduction The term “exercise-induced asthma” has been used to describe the transient narrowing of the airways and the subsequent increase in airway resistance, which can occur during, though more commonly following, vigorous exercise [1]. Exercise is a trigger for bronchoconstriction in individuals with asthma, but is not considered an independent risk factor for the development of asthma. The term “exercise-induced asthma” can be misleading and in some individuals, symptoms and airway narrowing can develop as a result of acute vigorous exercise in the absence of other clinically recognized symptoms of asthma [2]. Thus, the term exercise-induced bronchoconstriction (EIB) is now generally preferred to be a more accurate reflection of the underlying pathophysiology.

Epidemiology EIB can occur in the majority of individuals with symptoms of asthma [3]. The epidemiology of EIB has been confined to specific populations that are easier to study, such as in school children [4], athletes in high school [5] or college [6], summer and winter elite athletes [7–9] as well as army recruits [10]. The prevalence of EIB in the above populations has been reported to be between 7% and 50% depending on the type of sport and environment where the exercise is performed. Athletes in winter sports have generally been observed to have a higher prevalence of EIB than those engaged in summer sports. Longitudinal studies have demonstrated that the prevalence of EIB is increasing [11] and EIB is more common in urban environments

J.D. Brannan () and P.M. O’Byrne Firestone Institute for Respiratory Health and the Department of Medicine, Michael G DeGroot School of Medicine, McMaster University, 50 Charlton Ave, East, Room T3213, Hamilton, ON, Canada L8N 4A6 e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_10, © Springer 2010

171

172

J.D. Brannan and P.M. O’Byrne

than in rural environments [12]. Although associated with atopy [13], EIB can occur in those who are nonatopic [14]. An important observation from many of these studies is that up to 40% of individuals with EIB have not had a diagnosis of asthma and most have normal lung function prior to exercising. Thus, symptoms and lung function can be poor predictors of EIB in these individuals. Further, findings in epidemiological studies suggest that EIB may be a precursor for the development of persistent asthma [15]. A worldwide survey of asthma reported that in more than 10,000 individuals who were currently taking asthma medications or had symptoms in the previous year, nearly half reported exercise-induced symptoms, suggesting poor asthma control [16]. There is little information with regard to mortality related to EIB in either the general population or elite athletes. A retrospective analysis in North America over a 7-year period reviewed 61 asthma deaths that were closely associated to a sporting event or physical activity [17]. Many of these deaths occurred in individuals with mild asthma, while the majority (81%) occurred in individuals who were younger than 21 years of age. Almost 60% of deaths occurred in individuals who were considered elite or competitive level athletes. An important and yet disturbing finding was that 10% of deaths occurred in individuals with no known history of asthma or EIB.

Pathogenesis Early observations found that the intensity and duration of exercise as well as the temperature and humidity of the inspired air were important for the development of EIB [18]. During exercise, ventilation increases and the cooling and/or drying of the airways were considered important in causing exercise-induced airway narrowing. The osmotic and thermal effects of respiratory water loss are now thought to be the primary determinants for airway narrowing due to exercise [1]. This is supported by the finding that EIB is attenuated when the inspired air is more fully humidified and closer to body temperature and that EIB can occur when hot dry air is inspired [1]. The increase in the osmolarity of the airway surface is thought to result in the release of mediators of bronchoconstriction from inflammatory cells [19–21]. These mediators (e.g., leukotrienes, prostaglandins, histamine) then act via specific receptors on the bronchial smooth muscle to cause contraction and airway narrowing. Both airway inflammation and airway hyperresponsiveness (AHR) are important features of EIB. Early evidence using pharmacotherapy to inhibit EIB provided significant insight into the potential role of inflammation on the airway response to exercise. Inhaled b2 agonists were the first drugs to be shown to protect against EIB [22]. While confirming the beneficial effects of inhaled b2 agonists, it was later found that oral b2 agonists were not effective at protecting against EIB, even though they caused bronchodilation [23]. This suggested that the superior efficacy of an inhaled b2 agonist against EIB was due to an added benefit of acting directly on the airway surface.

Management of EIB

173

It was suggested that the ability of a b2 agonist to relax the airway smooth muscle and stabilize the mast cell provided an important duel mechanism for bronchoprotection [23]. This was supported by studies that demonstrated that sodium cromoglycate was also effective at inhibiting EIB, likely via inhibiting the release of mast cell mediators [24]. In addition, daily treatment with inhaled corticosteroids (ICS) reduced the severity of EIB, suggesting that airway inflammation was an important determinant of the presence and severity of EIB [25]. The involvement of inflammatory mediators such as the leukotrienes in sustaining airway narrowing due to exercise was later demonstrated using specific receptor antagonists for leukotrienes [26]. Direct evidence for airway inflammation in EIB has been provided by the finding of significantly more eosinophils in the sputum of asthmatics with EIB compared to those without EIB [27, 28]. Further, the severity of EIB is related to the number of eosinophils in both sputum and blood [27, 29]. There is also evidence that the levels of exhaled nitric oxide, a marker of nonspecific inflammation, are related to the airway response to exercise [30] and are associated with atopy [14]. There is increasing evidence that mast cell mediator release occurs in association with EIB. Studies attempting to measure mediators of bronchoconstriction have identified increases in arterial plasma histamine levels measured at the time of maximal airway narrowing to exercise [31]. Leukotriene E4 or the metabolite of prostaglandin D2, 9a, 11b-PGF2, a marker of mast cell release, are measured in urine [20, 21, 32] and sputum following EIB [33, 34]. An imbalance of bronchoconstricting leukotrienes and histamine compared to the bronchodilating mediator PGE2 after exercise has also been suggested [34]. While it has been shown that EIB is not a cause of eosinophilic airway inflammation [35], there may be an increased likelihood of airway injury as seen by the release of columnar epithelial cells in association with the severity of EIB [34]. Recently, it has been observed that nonasthmatics can release a variety of bronchoconstricting mediators following either exercise or surrogate tests that mimic EIB [36]. These observations have highlighted the importance of airway smooth muscle sensitivity in EIB. This has led to the suggestion that the development of EIB in elite athletes may be the result of chronic airway dehydration and airway damage due to regular high intensity exercise [37]. AHR to histamine or methacholine is often associated with airway narrowing due to exercise [29, 38]. However, in some cases, EIB can occur in the absence of AHR to either methacholine or histamine [4, 39]. It is known that a wide variety of mediators are involved in EIB and that leukotrienes are more potent at causing airway narrowing than methacholine or histamine [40]. This suggests that the airway smooth muscle in some individuals with EIB may be more sensitive to the bronchoconstricting effects of leukotrienes and other mediators. Allergen exposure has been shown to increase EIB. The percent fall in forced expiratory volume in 1 s (FEV1) after exercise in asthmatic children is more severe after allergen challenge [41]. The effect of allergen exposure on EIB is likely to be due to increases in airway sensitivity and the number of airway inflammatory cells (e.g., mast cells, eosinophils) following acute allergen exposure [42].

174

J.D. Brannan and P.M. O’Byrne

Clinical Manifestations The clinical presentations of EIB are the sudden onset of symptoms typical of asthma, such as wheeze, chest tightness, cough, and shortness of breath. Other nonspecific symptoms such as chest or abdominal pain, headaches, muscle cramps, fatigue, dizziness, poor exercise performance or “feeling out of shape” have also been described [43]. While those experiencing symptoms may seek medical assistance, it has been demonstrated that self reported symptoms are poor predictors of the presence or severity of EIB [6, 8]. A personal history or family history of asthma or allergic rhinitis may increase the likelihood of EIB [43]. EIB can occasionally occur during exercise itself and may be reflective of more severe EIB. However, bronchodilation can occur during exercise and last for 1–3 min following the cessation of exercise [44]. This is soon followed by bronchoconstriction with the maximum response seen 10–15 min after exercise, with spontaneous recovery of lung function often occurring by 60 min. In about 50% of the patients, the recovery from bronchoconstriction is followed by a refractory period, whereby there is a protective effect against further EIB if exercise is to be continued [45]. This protective effect usually lasts less than 4 h and is thought to involve the release of inhibitory prostaglandins in the airways [46, 47]. In some patients with very mild EIB, strenuous exercise may not cause clinically significant bronchoconstriction and the abnormal airway response to exercise is not reproducible.

Diagnosis As symptoms and lung function are poor predictors of the presence or severity of EIB, the use of exercise challenge testing is recommended to identify EIB [48, 49]. In addition, there has been a need for the development of a surrogate test for EIB as there are some limitations to laboratory exercise challenge testing [50, 51]. As previously described, the major factors that determine the severity of EIB are pulmonary ventilation reached and sustained during exercise and the water content and temperature of the inspired air. Thus, any exercise challenge must control the rate of water loss from the airways by monitoring the ventilation during exercise and controlling the water content of the inspired air. As a result, exercise challenges have been standardized and conventionally involve 6–8 min of exercise on a treadmill or cycle ergometer [52]. A source of compressed dry air is recommended to standardize the inhaled air during exercise and minimize the water content for effective airway drying. During the period of exercise, a suitable level of intensity is assessed by monitoring the heart rate so that 80–90% of the predicted maximum heart rate is reached and sustained for at least 4 min. However, it is recommended that ventilation, which is the provoking stimulus, also be measured during exercise to achieve a ventilation rate of at least 40–60% of the predicted maximum voluntary ventilation (MVV) [52].

Management of EIB

175

FEV1 should be the primary outcome variable to assess the airway response to exercise. As the maximum response often occurs 6–8 min following exercise, the FEV1 should be measured before and at regular intervals for at least 20–30 min following exercise [52, 53]. EIB is identified if a 10% fall in FEV1 in adults and a 15% fall in FEV1 in children occurs following exercise [52]. It has proved difficult to standardize exercise testing among laboratories. Further, the sensitivity of these laboratory-based exercise tests to identify EIB, even when the inspired air is cool and dry, has been reported to be only 65% in treated adult asthmatics [53] and even less, at 22%, when compared to field exercise tests [54]. The surrogate bronchial provocation tests, which have been developed through the understanding of the mechanism of EIB, provide some advantages in the identification of EIB [50, 51]. Ecuapnic voluntary hyperpnea (EVH) for 6 min at 80% of MVV using dry air containing 5% CO2 is more likely to achieve a greater sensitivity to identify airway narrowing compared to a progressive exercise challenge [55]. Higher ventilation rates are achieved more rapidly with EVH than a progressive exercise challenge [50]. However, while EVH tests are recommended for athletes with normal lung function, they should be used with caution, since falls in FEV1 of more than 50% can occur in known asthmatics. The recently developed doseresponse osmotic challenge tests have identified EIB in asthmatics and athletes, and can predict the severity of EIB in steroid naïve asthmatics [19, 56]. However, in a less clearly defined asthmatic population, AHR to methacholine and mannitol have demonstrated similar sensitivity [57]. The osmotic challenge tests can present a safe and less complex alternative for the identification of EIB that will respond to therapy [57, 58].

Differential Diagnosis Physiological dyspnea after exercise must be considered in patients with no evidence of EIB, particularly in those who derive no benefit from pretreatment with bronchodilators. Central airway obstruction, vocal cord dysfunction, laryngotracheomalacia, parenchymal pulmonary disease, gastroesophageal reflux, and heart failure should also be considered in adult patients who suffer from atypical exerciseinduced dyspnea (EID). The differential diagnosis is similar among children. In a retrospective review, treadmill exercise testing was performed on 142 children with EID, referred to a pediatric allergy and pulmonology clinic, who had no other signs of asthma or in whom treatment with b2 agonists had failed [59]. Symptoms of EID were reproduced in 117 children (82%). Among these, only 11 (9%) had EIB defined by the presence of symptoms and a >15% decrease in FEV1 from baseline following exercise. Other diagnoses included normal physiologic exercise limitation (63%), restrictive abnormalities (13%), vocal cord dysfunction (11%), laryngomalacia (2%), and hyperventilation and supraventricular tachycardia, each in one patient.

176

J.D. Brannan and P.M. O’Byrne

Management The combination of pharmacologic and nonpharmacologic intervention can be effective in preventing airway narrowing in the majority of patients with EIB. The major goal of this combination is to ensure that exercise is not avoided by patients with EIB. Asthmatics should exercise as much as desired, and should be encouraged by the fact that athletes, in spite of symptomatic asthma, have won Olympic medals and played professional sports. Improved understanding of the pathophysiology of EIB has resulted in general recommendations that can help reduce its severity. These measures are based upon observed relationships between the severity of bronchoconstriction and the following factors:

Pharmacological Treatment of EIB has been primarily studied in patients with EIB and underlying asthma. Therapeutic options for patients with EIB as the only manifestation of AHR are not well researched. In general, if EIB occurs frequently in patients with poorly controlled asthma, the most important strategy is to improve overall asthma control. ICS and leukotriene-modifying agents are often useful in this regard. Prophylactic treatment of EIB prior to exercise, using inhaled b2 agonists and/or cromolyn or nedocromil sodium or leukotriene antagonists, should be considered in all patients with EIB.

b2 Agonists Inhaled b2 agonists are the prophylaxis drug of choice to prevent and treat episodes of EIB in moderate to severe asthmatics. They are the most effective pharmacotherapy that can inhibit the severity of EIB. Two inhalations of a short acting b2 agonist (SABA) (e.g., salbutamol or turbutaline) or long acting b2 (LABA) (e.g., formoterol) should be taken 5–10 min before exercise. These have been shown to reduce the fall in FEV1 by 70–80% [53, 60]. LABAs have a longer duration of bronchoprotection than SABAs. However, the LABA salmeterol has a slower onset of action and needs to be taken at least 30 min before exercise [61]. Furthermore, salmeterol is less effective in reversing EIB. However, equipotent doses of terbutaline, formoterol, or salmeterol appear to be equally effective in providing shortterm control of EIB [62]. Patients with more severe asthma may require higher prophylactic doses of inhaled b2 agonists or the addition of cromolyn or nedocromil sodium [63]. It should also be noted that not all patients have experienced this superior protective effect with a b2 agonist and in these patients, other treatment strategies should be prescribed [64]. Children often present a difficult clinical situation by exercising vigorously

Management of EIB

177

and intermittently throughout the day without treatment prior to exercise. In this setting, LABA can provide protection against EIB for most of the day [65, 66]. However, regular use of both LABA and SABA provide less effective protection against EIB than the prophylactic use of b2 agonists [64, 67, 68] (Fig. 1). If patients forget to take prophylactic treatment for EIB or if they experience breakthrough symptoms despite treatment, bronchoconstriction should be treated with two to four inhalations of an inhaled b2 agonist. However, recovery using a standard dose of rescue bronchodilator may also be limited by daily b2 agonist therapy [64, 68]. Cromoglycates An alternative therapy is the prophylactic use of inhaled cromolyn or nedocromil sodium [69]. The bronchoprotective effect against EIB is immediate following inhalation. However, this protection does not extend beyond 2–3 h after treatment. As these drugs have a good safety profile and are well tolerated [69], it has been proposed that the dose administered could be titrated to suit the individual [70]. In exceptional situations like very high performance athletes or patients exercising in extreme conditions (e.g., very cold, dry air), the combination of four inhalations of

4.25 4.00 3.75 3.50 FEV1 3.25 (L) 3.00

Treatment Regular Pre-exercise

2.75

Placebo Salbutamol Placebo Salbutamol

2.50 2.25

exercise

2.00 post 0 pre Treatment

10

20

30

40

Placebo Placebo Salbutamol Salbutamol 50

60

Time Post Exercise (min)

Fig. 1 Mean forced expiratory volume in 1 s (FEV1) before and following a preexercise dose of 200 mcg of salbutamol or placebo followed by 5 min of constant work load exercise on a cycle ergometer in asthmatics with EIB. Exercise tests followed 7 days of regular treatment of 800 mcg per day of salbutamol and placebo. One week of regular treatment with salbutamol resulted in a decrease in baseline FEV1, more marked EIB, and decreased protective effect of salbutamol on EIB. From [67] with permission

178

J.D. Brannan and P.M. O’Byrne

a b2 agonist and four inhalations of cromoglycate is significantly more effective than either drug used alone [63]. Lower doses of nedocromil sodium are as effective as cromolyn sodium in protecting against EIB. However, they offer no clear advantage [69].

Inhaled Corticosteroids The most effective therapy to reduce the underlying pathology of asthma involves the use of ICS. While ICS may offer some improvement on EIB in the short-term [71], they will have a greater improvement over weeks to months by decreasing the magnitude of bronchoconstriction that occurs with a given workload [72, 73]. Crossover studies of 4-week treatment periods of 100, 200, and 400 mcg per day of the ICS budesonide demonstrated a dose-dependent reduction in the response to exercise in asthmatic children [74]. However, improvements in symptoms and lung function were not dose-dependent and were observed to plateau at the lowest doses. More recently, it was shown that higher doses of ciclesonide over 3 weeks were more effective against EIB than lower doses [71] (Fig. 2). It was also demonstrated that these higher doses were superior in attenuating the elevated level of eosinophils observed in persons with more severe EIB [75]. This evidence suggests that persons

80 70 60 FEV1

50

(% Fall) 40 30 20 10 0

40 µg pre

post

80 µg pre

post

106 µg pre

post

320 µg pre

post

Fig. 2 Individual data and the mean (SE) of the maximum decrease in FEV1 after exercise following 3 weeks treatment using four different doses of the inhaled corticosteroid ciclesonide (40, 80, 160, 320 mcg) in asthmatics with EIB. The maximum decrease in FEV1 was reduced in all treatment groups and in most individuals before (pre – open box) and following (post – closed box) 3 weeks of ciclesonide. The greatest inhibition was seen using the highest daily dose of 320 mcg. From [71] with permission

Management of EIB

179

with more severe EIB have more significant levels of airway inflammation and thus, may require a higher dose of ICS for effective inhibition of EIB. However, other studies in children have failed to demonstrate an ICS dosedependent reduction in EIB, with doses of 100–200 mcg of budesonide per day or doses of 200–500 mcg of fluticasone per day [72, 76, 77]. For these reasons, a therapeutic trial of ICS is a reasonable approach in patients with EIB. Furthermore, if an objective measurement of a patient’s response to ICS is required, an exercise test or a surrogate test for EIB should be considered, as EIB is one of the last features of asthma to be resolved using regular ICS [73]. The effects of combination therapy using inhaled b2 agonists with ICS against EIB have not been extensively studied. One study has demonstrated a superior protective effect of salmeterol and fluticasone in persons with moderate EIB compared to fluticasone alone [78]. However, in many patients, the addition of a LABA did not completely inhibit EIB after 4 weeks of therapy [64, 78].

Leukotriene-Modifying Agents Antileukotrienes provide a therapeutic alternative in the setting of chronic asthma complicated by EIB. Leukotrienes play a significant role in EIB by contributing to and sustaining the reduction in lung function [26] (Fig. 3). Thus, treatment with a

10 MK 571 5 0

FEV1 (% Change)

–5 –10 Placebo –15 –20 –25 0

3 5 7 9

15

20

25

30

35

40

45

Time Post Exercise (min)

Fig. 3 The first evidence to demonstrate in asthmatics that the leukotriene receptor antagonist MK-571 administered intravenously inhibits EIB. Studies using oral montelukast have since demonstrated a similar protective effect on EIB, attenuating the reduction in FEV1 following exercise and causing rapid recovery to preexercise FEV1 values. From [26] with permission

180

J.D. Brannan and P.M. O’Byrne

leukotriene modifying agent such as montelukast or an inhibitor of leukotriene synthesis such as a 5-lypoxygenase inhibitor can attenuate EIB [21, 79]. Protection against EIB is apparent even after a single dose of montelukast and recovery from post exercise bronchoconstriction is accelerated [80]. The long half-life of montelukast allows once-daily dosing to protect against EIB for up to 24 h [80]. Zileuton must be taken 4 times daily at present and while it demonstrates the same protection compared to montelukast, it has a shorter duration of action [79]. Leukotriene receptor antagonists appear superior to LABA when treating asthmatics with EIB, even in addition to regular ICS [81, 82]. In a blinded multicenter trial, asthmatics with EIB were randomly assigned to either montelukast or salmeterol for 8 weeks [83]. Therapy was protective within 3 days for both groups, however, tolerance to salmeterol developed. By 8 weeks, the bronchoprotective effect of montelukast had further improved. As previously mentioned, children with EIB can pose a therapeutic challenge, because they tend to exercise intermittently throughout the day and often neglect premedication with an inhaled b2 agonist. Leukotriene receptor antagonists are an effective option in this setting.

Histamine (H1) Antagonists Antihistamines have limited effectiveness in the treatment of EIB [84]. Limited protection has been reported in more severe EIB when exercise is at a higher intensity [85, 86], but not in mild EIB [87]. The combination of antihistamines and antileukotrienes had no significant additive effect in either adults [87] or children [88].

Dietary Modification Diets rich in omega-3 fatty acids (e.g., fish oil), which have demonstrated antiinflammatory activity, have not been conclusively demonstrated to be helpful in patients with asthma [89]. However, in athletes and asthmatics with EIB, there have been more promising results. In two randomized, double blind, crossover studies in athletes and asthmatics with mild EIB, 3 weeks of high dose fish oil supplementation significantly reduced the post exercise fall in FEV1 [32, 33]. This occurred in association with a reduction in LTE4 and PGD2 in the urine [32] and sputum [33] as well as IL-1b and TNF-a in blood [32] and sputum [33]. While no further improvement was seen in the preexercise FEV1 in this population with normal lung function, there was a reported decrease in the use of b2 agonist. This suggests that in asthmatics with mild EIB, a diet enriched with omega-3 fatty acids may provide some benefit. Other studies have demonstrated attenuation of EIB with low salt diets [90] or increased dietary ascorbic acid (Vitamin C) [91]. However, these studies have also investigated persons with mild EIB and thus, it may be difficult to extrapolate these findings to persons who have more severe EIB, as observed in studies assessing the efficacy of established asthma pharmacotherapies [53, 75].

Management of EIB

181

Other Therapies Other types of asthma therapy are not effective in protecting against EIB. Anticholinergics [92], oral b2 agonists [23], and methylxanthines [93], when used alone, are ineffective at inhibiting EIB in the majority of patients. Several other treatment approaches have been tested and they demonstrate a protective effect against EIB. Inhaled furosemide [94], prostaglandin E2 [95], indomethacin [96], and heparin [97] have been shown to protect against EIB. However, long-term clinical use of these compounds has not been directly compared with the prophylactic use of inhaled b2 agonists. For this reason, their role in clinical practice is unclear.

Nonpharmacological Avoiding exercise during periods of very cold weather, elevated airborne allergen, or high pollution, which may worsen EIB, should be recommended. Similarly, EIB is less severe when the inspired air is warmer and more humid. The use of a specially designed face mask to trap expired water and humidify the inspired air can be of significant benefit when exercising in cold environments and may provide added benefit when used together with a b2 agonist [98]. As previously described, a refractory period can occur and this has been used to recommend a warm up before exercise to prevent or minimize EIB. Exercising for 15 min at 60% of the maximum exercise intensity has been shown to reduce the severity of EIB, but will not inhibit the airway response [99]. However, it should be noted that nonsteroidal anti-inflammatory drugs can prevent any refractory period and thus, prevent any expected inhibition of EIB as a result of prior exercise [46].

Conclusion There are a variety of different approaches in choosing therapy to prevent EIB in the clinical setting. It is becoming increasingly clear that traditional clinical signs of asthma such as symptoms and lung function are poor predictors of the presence and severity of EIB. Thus, objective measures for EIB are useful in making informed decision to prescribe and monitor the benefits of therapy. In patients with uncontrolled asthma and those with persistent exercise-induced symptoms, treatment of the underlying inflammatory component of the disease using ICS is a first priority. If asthma is well controlled using ICS and EIB is the only manifestation of AHR, EIB should be treated prophylactically with inhaled b2 agonists or cromoglycates. Leukotriene-modifying agents are also effective and can be used in patients who refuse to take ICS because of unwanted side effects or fail to respond to ICS. b2 agonists remain the most effective treatment for acute episodes of EIB. Tolerance to the bronchoconstricting effects and the bronchodilator benefits of a b2 agonist

182

J.D. Brannan and P.M. O’Byrne

can occur with the frequent use of a b2 agonist, either with or without an ICS. Thus, using a cromolycate or leukotriene antagonist may be the best choice in this setting, as tolerance does not occur with regular use and side effects are minimal.

References 1. Anderson SD, Daviskas E (2000) The mechanism of exercise-induced asthma is. J Allergy Clin Immunol 106:453–459 2. Weiler JM, Bonini S, Coifman R, Craig T, Delgado L, Capao-Filipe M, Passali D, Randolph C, Storms W (2007) American Academy of Allergy, Asthma & Immunology Work Group Report: exercise-induced asthma. J Allergy Clin Immunol 119:1349–1358 3. McFadden ER Jr, Gilbert IA (1994) Exercise-induced asthma. N Engl J Med 330:1362–1367 4. Haby MM, Anderson SD, Peat JK, Mellis CM, Toelle BG, Woolcock AJ (1994) An exercise challenge protocol for epidemiological studies of asthma in children: comparison with histamine challenge. Eur Respir J 7:43–49 5. Kukafka DS, Lang DM, Porter S, Rogers J, Ciccolella D, Polansky M, D’Alonzo GE Jr (1998) Exercise-induced bronchospasm in high school athletes via a free running test: incidence and epidemiology. Chest 114:1613–1622 6. Thole RT, Sallis RE, Rubin AL, Smith GN (2001) Exercise-induced bronchospasm prevalence in collegiate cross-country runners. Med Sci Sports Exerc 33:1641–1646 7. Mannix ET, Farber MO, Palange P, Galassetti P, Manfredi F (1996) Exercise-induced asthma in figure skaters. Chest 109:312–315 8. Rundell KW, Im J, Mayers LB, Wilber RL, Szmedra L, Schmitz HR (2001) Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc 33:208–213 9. Wilber RL, Rundell KW, Szmedra L, Jenkinson DM, Im J, Drake SD (2000) Incidence of exercise-induced bronchospasm in Olympic winter sport athletes. Med Sci Sports Exerc 32:732–737 10. Nish WA, Schwietz LA (1992) Underdiagnosis of asthma in young adults presenting for USAF basic training. Ann Allergy 69:239–242 11. Addo-Yobo EO, Woodcock A, Allotey A, Baffoe-Bonnie B, Strachan D, Custovic A (2007) Exercise-induced bronchospasm and atopy in Ghana: two surveys ten years apart. PLoS Med 4:e70 12. Addo Yobo EO, Custovic A, Taggart SC, Asafo-Agyei AP, Woodcock A (1997) Exercise induced bronchospasm in Ghana: differences in prevalence between urban and rural schoolchildren. Thorax 52:161–165 13. Brutsche M, Britschgi D, Dayer E, Tschopp JM (1995) Exercise-induced bronchospasm (EIB) in relation to seasonal and perennial specific IgE in young adults. Allergy 50:905–909 14. Rouhos A, Ekroos H, Karjalainen J, Sarna S, Sovijarvi AR (2005) Exhaled nitric oxide and exercise-induced bronchoconstriction in young male conscripts: association only in atopics. Allergy 60:1493–1498 15. Jones A (1994) Asymptomatic bronchial hyperreactivity and the development of asthma and other respiratory tract illnesses in children. Thorax 49:757–761 16. Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, Weiss ST (2004) Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol 114:40–47 17. Becker JM, Rogers J, Rossini G, Mirchandani H, D’Alonzo GE Jr (2004) Asthma deaths during sports: report of a 7-year experience. J Allergy Clin Immunol 113:264–267 18. Anderson SD (1984) Is there a unifying hypothesis for exercise-induced asthma? J Allergy Clin Immunol 73:660–665

Management of EIB

183

19. Brannan JD, Koskela H, Anderson SD, Chew N (1998) Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma. Am J Respir Crit Care Med 158:1120–1126 20. O’Sullivan S, Roquet A, Dahlen B, Larsen F, Eklund A, Kumlin M, O’Byrne PM, Dahlen SE (1998) Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J 12:345–350 21. Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, Bronsky E, Guerreiro D, Hendeles L (1997) Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 52:1030–1035 22. Jones RS, Wharton MJ, Buston MH (1963) Place of physical exercise and bronchodilator drugs in the assessment of the asthmatic child. Arch Dis Child 38:539–545 23. Anderson SD, Seale JP, Rozea P, Bandler L, Theobald G, Lindsay DA (1976) Inhaled and oral salbutamol in exercise-induced asthma. Am Rev Respir Dis 114:493–500 24. Silverman M, Andrea T (1972) Time course of effect of disodium cromoglycate on exerciseinduced asthma. Arch Dis Child 47:419–422 25. Henriksen JM, Dahl R (1983) Effects of inhaled budesonide alone and in combination with low-dose terbutaline in children with exercise-induced asthma. Am Rev Respir Dis 128:993–997 26. Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O’Byrne PM (1990) Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med 323:1736–1739 27. Yoshikawa T, Shoji S, Fujii T, Kanazawa H, Kudoh S, Hirata K, Yoshikawa J (1998) Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma. Eur Respir J 12:879–884 28. Kivity S, Argaman A, Onn A, Shwartz Y, Man A, Greif J, Fireman E (2000) Eosinophil influx into the airways in patients with exercise-induced asthma. Respir Med 94:1200–1205 29. Koh YI, Choi S (2002) Blood eosinophil counts for the prediction of the severity of exerciseinduced bronchospasm in asthma. Respir Med 96:120–125 30. Scollo M, Zanconato S, Ongaro R, Zaramella C, Zacchello F, Baraldi E (2000) Exhaled nitric oxide and exercise-induced bronchoconstriction in asthmatic children. Am J Respir Crit Care Med 161:1047–1050 31. Anderson SD, Bye PT, Schoeffel RE, Seale JP, Taylor KM, Ferris L (1981) Arterial plasma histamine levels at rest, and during and after exercise in patients with asthma: effects of terbutaline aerosol. Thorax 36:259–267 32. Mickleborough TD, Murray RL, Ionescu AA, Lindley MR (2003) Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 168:1181–1189 33. Mickleborough TD, Lindley MR, Ionescu AA, Fly AD (2006) Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma. Chest 129:39–49 34. Hallstrand TS, Moody MW, Wurfel MM, Schwartz LB, Henderson WR Jr, Aitken ML (2005) Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med 172:679–686 35. Gauvreau GM, Ronnen GM, Watson RM, O’Byrne PM (2000) Exercise-induced bronchoconstriction does not cause eosinophilic airway inflammation or airway hyperresponsiveness in subjects with asthma. Am J Respir Crit Care Med 162:1302–1307 36. Anderson SD, Kippelen P (2005) Exercise-induced bronchoconstriction: pathogenesis. Curr Allergy Asthma Rep 5:116–122 37. Anderson SD, Kippelen P (2008) Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes. J Allergy Clin Immunol 122:225–235; quiz 236–227 38. Anderton RC, Cuff MT, Frith PA, Cockcroft DW, Morse JL, Jones NL, Hargreave FE (1979) Bronchial responsiveness to inhaled histamine and exercise. J Allergy Clin Immunol 63:315–320

184

J.D. Brannan and P.M. O’Byrne

39. Holzer K, Anderson SD, Douglass J (2002) Exercise in elite summer athletes: challenges for diagnosis. J Allergy Clin Immunol 110:374–380 40. O’Hickey SP, Arm JP, Rees PJ, Spur BW, Lee TH (1988) The relative responsiveness to inhaled leukotriene E4, methacholine and histamine in normal and asthmatic subjects. Eur Respir J 1:913–917 41. Mussaffi H, Springer C, Godfrey S (1986) Increased bronchial responsiveness to exercise and histamine after allergen challenge in children with asthma. J Allergy Clin Immunol 77:48–52 42. Gauvreau GM, Watson RM, O’Byrne PM (1999) Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 160:640–647 43. Storms WW (2003) Review of exercise-induced asthma. Med Sci Sports Exerc 35:1464–1470 44. Inman MD, Watson RM, Killian KJ, O’Byrne PM (1990) Methacholine airway responsiveness decreases during exercise in asthmatic subjects. Am Rev Respir Dis 141:1414–1417 45. Edmunds AT, Tooley M, Godfrey S (1978) The refractory period after exercise-induced asthma: its duration and relation to the severity of exercise. Am Rev Respir Dis 117:247–254 46. O’Byrne PM, Jones GL (1986) The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise. Am Rev Respir Dis 134:69–72 47. Manning PJ, Watson RM, O’Byrne PM (1993) Exercise-induced refractoriness in asthmatic subjects involves leukotriene and prostaglandin interdependent mechanisms. Am Rev Respir Dis 148:950–954 48. Rupp NT, Brudno DS, Guill MF (1993) The value of screening for risk of exercise-induced asthma in high school athletes. Ann Allergy 70:339–342 49. Hallstrand TS, Curtis JR, Koepsell TD, Martin DP, Schoene RB, Sullivan SD, Yorioka GN, Aitken ML (2002) Effectiveness of screening examinations to detect unrecognized exerciseinduced bronchoconstriction. J Pediatr 141:343–348 50. Anderson SD, Brannan JD (2003) Methods for “indirect” challenge tests including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols. Clin Rev Allergy Immunol 24:27–54 51. Rundell KW, Slee JB (2008) Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes. J Allergy Clin Immunol 122:238–246; quiz 247–238 52. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ (2000) Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 161:309–329 53. Anderson SD, Lambert S, Brannan JD, Wood RJ, Koskela H, Morton AR, Fitch KD (2001) Laboratory protocol for exercise asthma to evaluate salbutamol given by two devices. Med Sci Sports Exerc 33:893–900 54. Rundell KW, Wilber RL, Szmedra L, Jenkinson DM, Mayers LB, Im J (2000) Exerciseinduced asthma screening of elite athletes: field versus laboratory exercise challenge. Med Sci Sports Exerc 32:309–316 55. Rundell KW, Anderson SD, Spiering BA, Judelson DA (2004) Field exercise vs laboratory eucapnic voluntary hyperventilation to identify airway hyperresponsiveness in elite cold weather athletes. Chest 125:909–915 56. Holzer K, Anderson SD, Chan HK, Douglass J (2003) Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 167:534–537 57. Anderson SD, Charlton B, Weiler JM, Nichols S, Spector SL, Pearlman DS (2009) Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma. Respir Res 10:4 58. Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B (2005) The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res 6:144

Management of EIB

185

59. Abu-Hasan M, Tannous B, Weinberger M (2005) Exercise-induced dyspnea in children and adolescents: if not asthma then what? Ann Allergy Asthma Immunol 94:366–371 60. Patessio A, Podda A, Carone M, Trombetta N, Donner CF (1991) Protective effect and duration of action of formoterol aerosol on exercise-induced asthma. Eur Respir J 4:296–300 61. Anderson SD, Rodwell LT, Du Toit J, Young IH (1991) Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 100:1254–1260 62. Richter K, Janicki S, Jorres RA, Magnussen H (2002) Acute protection against exerciseinduced bronchoconstriction by formoterol, salmeterol and terbutaline. Eur Respir J 19:865–871 63. Latimer KM, O’Byrne PM, Morris MM, Roberts R, Hargreave FE (1983) Bronchoconstriction stimulated by airway cooling. Better protection with combined inhalation of terbutaline sulphate and cromolyn sodium than with either alone. Am Rev Respir Dis 128:440–443 64. Anderson SD, Caillaud C, Brannan JD (2006) Beta2-agonists and exercise-induced asthma. Clin Rev Allergy Immunol 31:163–180 65. Newnham DM, Ingram CG, Earnshaw J, Palmer JB, Dhillon DP (1993) Salmeterol provides prolonged protection against exercise-induced bronchoconstriction in a majority of subjects with mild, stable asthma. Respir Med 87:439–444 66. Vilsvik J, Ankerst J, Palmqvist M, Persson G, Schaanning J, Schwabe G, Johansson A (2001) Protection against cold air and exercise-induced bronchoconstriction while on regular treatment with Oxis. Respir Med 95:484–490 67. Inman MD, O’Byrne PM (1996) The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am J Respir Crit Care Med 153:65–69 68. Hancox RJ, Subbarao P, Kamada D, Watson RM, Hargreave FE, Inman MD (2002) Beta2agonist tolerance and exercise-induced bronchospasm. Am J Respir Crit Care Med 165:1068–1070 69. Kelly KD, Spooner CH, Rowe BH (2001) Nedocromil sodium versus sodium cromoglycate in treatment of exercise-induced bronchoconstriction: a systematic review. Eur Respir J 17:39–45 70. Anderson SD (2004) Single-dose agents in the prevention of exercise-induced asthma: a descriptive review. Treat Respir Med 3:365–379 71. Subbarao P, Duong M, Adelroth E, Otis J, Obminski G, Inman M, Pedersen S, O’Byrne PM (2006) Effect of ciclesonide dose and duration of therapy on exercise-induced bronchoconstriction in patients with asthma. J Allergy Clin Immunol 117:1008–1013 72. Jonasson G, Carlsen KH, Blomqvist P (1998) Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 12:1099–1104 73. Brannan JD, Koskela H, Anderson SD (2007) Monitoring asthma therapy using indirect bronchial provocation tests. Clin Respir J 1:3–15 74. Pedersen S, Hansen OR (1995) Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol 95:29–33 75. Duong M, Subbarao P, Adelroth E, Obminski G, Strinich T, Inman M, Pedersen S, O’Byrne PM (2008) Sputum eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma. Chest 133:404–411 76. Jonasson G, Carlsen KH, Hultquist C (2000) Low-dose budesonide improves exerciseinduced bronchospasm in schoolchildren. Pediatr Allergy Immunol 11:120–125 77. Hofstra WB, Neijens HJ, Duiverman EJ, Kouwenberg JM, Mulder PG, Kuethe MC, Sterk PJ (2000) Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma. Pediatr Pulmonol 29:415–423 78. Weiler JM, Nathan RA, Rupp NT, Kalberg CJ, Emmett A, Dorinsky PM (2005) Effect of fluticasone/salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma. Ann Allergy Asthma Immunol 94:65–72 79. Coreno A, Skowronski M, Kotaru C, McFadden ER Jr (2000) Comparative effects of longacting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma. J Allergy Clin Immunol 106:500–506

186

J.D. Brannan and P.M. O’Byrne

80. Pearlman DS, van Adelsberg J, Philip G, Tilles SA, Busse W, Hendeles L, Loeys T, Dass SB, Reiss TF (2006) Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast. Ann Allergy Asthma Immunol 97:98–104 81. Villaran C, O’Neill SJ, Helbling A, van Noord JA, Lee TH, Chuchalin AG, Langley SJ, Gunawardena KA, Suskovic S, Laurenzi M, Jasan J, Menten J, Leff JA (1999) Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group. J Allergy Clin Immunol 104:547–553 82. Storms W, Chervinsky P, Ghannam AF, Bird S, Hustad CM, Edelman JM (2004) A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge. Respir Med 98:1051–1062 83. Edelman JM, Turpin JA, Bronsky EA, Grossman J, Kemp JP, Ghannam AF, DeLucca PT, Gormley GJ, Pearlman DS (2000) Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Exercise Study Group. Ann Intern Med 132:97–104 84. Anderson SD, Brannan JD (2002) Exercise-induced asthma: is there still a case for histamine? J Allergy Clin Immunol 109:771–773 85. Patel KR (1984) Terfenadine in exercise induced asthma. Br Med J (Clin Res Ed) 288:1496–1497 86. Baki A, Orhan F (2002) The effect of loratadine in exercise-induced asthma. Arch Dis Child 86:38–39 87. Dahlen B, Roquet A, Inman MD, Karlsson O, Naya I, Anstren G, O’Byrne PM, Dahlen SE (2002) Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction. J Allergy Clin Immunol 109:789–793 88. Peroni DG, Piacentini GL, Pietrobelli A, Loiacono A, De Gasperi W, Sabbion A, Micciolo R, Boner AL (2002) The combination of single-dose montelukast and loratadine on exerciseinduced bronchospasm in children. Eur Respir J 20:104–107 89. Reisman J, Schachter HM, Dales RE, Tran K, Kourad K, Barnes D, Sampson M, Morrison A, Gaboury I, Blackman J (2006) Treating asthma with omega-3 fatty acids: where is the evidence? A systematic review. BMC Complement Altern Med 6:26 90. Mickleborough TD, Lindley MR, Ray S (2005) Dietary salt, airway inflammation, and diffusion capacity in exercise-induced asthma. Med Sci Sports Exerc 37:904–914 91. Tecklenburg SL, Mickleborough TD, Fly AD, Bai Y, Stager JM (2007) Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med 101:1770–1778 92. Poppius H, Sovijarvi AR, Tammilehto L (1986) Lack of protective effect of high-dose ipratropium on bronchoconstriction following exercise with cold air breathing in patients with mild asthma. Eur J Respir Dis 68:319–325 93. Ellis EF (1984) Inhibition of exercise-induced asthma by theophylline. J Allergy Clin Immunol 73:690–692 94. Bianco S, Vaghi A, Robuschi M, Pasargiklian M (1988) Prevention of exercise-induced bronchoconstriction by inhaled frusemide. Lancet 2:252–255 95. Melillo E, Woolley KL, Manning PJ, Watson RM, O’Byrne PM (1994) Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects. Am J Respir Crit Care Med 149:1138–1141 96. Shimizu T, Mochizuki H, Shigeta M, Morikawa A (1997) Effect of inhaled indomethacin on exercise-induced bronchoconstriction in children with asthma. Am J Respir Crit Care Med 155:170–173 97. Ahmed T, Gonzalez BJ, Danta I (1999) Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin. Am J Respir Crit Care Med 160:576–581 98. Millqvist E, Bengtsson U, Lowhagen O (2000) Combining a beta2-agonist with a face mask to prevent exercise-induced bronchoconstriction. Allergy 55:672–675 99. McKenzie DC, McLuckie SL, Stirling DR (1994) The protective effects of continuous and interval exercise in athletes with exercise-induced asthma. Med Sci Sports Exerc 26:951–956

Use of Theophylline and Sodium Cromoglycate in Adult Asthma Hironori Sagara, Kenya Kouyama, Takeshi Fukuda, and Sohei Makino

Introduction Sustained-release theophylline is frequently used in Japan to treat asthma. Theophylline has a long history as a therapeutic drug. In the early twentieth century, Plavec et al. reported that theophylline has a positive inotropic action on the myocardium. Since 1937, when Herrman et al. confirmed its effectiveness for asthma attacks, theophylline has been primarily considered a bronchodilator. In the 1970s and 1980s, theophylline was mainly used for the long-term management of asthma in the United States. Since the 1990s, the mainstay of treatment for asthma in the United States shifted to inhaled corticosteroids or inhaled corticosteroids plus long-acting inhaled b2 agonists (LABAs). The clinical positioning of theophylline was thus negatively affected. Since the latter part of the 1990s, however, evidence has accumulated that theophylline inhibits the airway inflammation characteristically found in asthma and can be used with inhaled corticosteroids to treat asthma. In this paper, we describe the clinical significance of sustained-release theophylline for the longterm management of asthma.

H. Sagara () and K. Kouyama Department of Respiratory Medicine, Dokkyo Medical University Koshigaya Hospital, Japan e-mail: [email protected] T. Fukuda Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Japan S. Makino Jobu Hospital for Respiratory Diseases, Japan

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_11, © Springer 2010

187

188

H. Sagara et al.

Properties of Sustained-Release Theophylline Pharmacological Properties of Theophylline Theophylline is metabolized by cytochrome P-450 enzyme systems in the liver. The rate of theophylline metabolism varies considerably among patients. The main metabolic pathways are demethylation and oxidation. Its metabolites are broadly distributed in the tissue and pass through the blood-brain barrier and placenta. The rates of protein binding range from 40 to 60%. In neonates with low serum albumin concentrations, elderly patients, and patients with cirrhosis, free theophylline concentrations may be higher than expected. Theophylline and its metabolites are excreted in the urine. The urinary excretion rate of unchanged theophylline is 10–15%. The urinary excretion rates of the main metabolites are about 50% for 1,3-dimethyl uric acid, 20% for 1-methyl uric acid, 15% for 3-methylxane, and less than 5% for 1-methyl xanthine. Generally, xanthine derivatives such as theophylline act on the central nervous system, heart, kidney, striated muscle, smooth muscle, and other organ systems. Theophylline most strongly acts on smooth muscle. Various actions, such as stimulation of the central nervous system, positive inotropic action, diuresis, cerebral vasoconstriction, and promotion of gastric-acid secretion can lead to side effects, depending on the dose and the response to theophylline. Theophylline acts primarily by phosphodiesterase inhibition and adenosine antagonism. Phosphodiesterase is a hydrolytic enzyme of cyclic adenosine monophosphate (AMP), which is produced from adenosine triphosphate by adenyl cyclase, and of cyclic guanosine monophosphate (GMP), which is produced from guanosine triphosphate by guanylate cyclase. The balance between the activities of these enzymes is regulated by intracellular concentrations of cyclic AMP and cyclic GMP. Theophylline inhibits phosphodiesterase, thereby elevating intracellular concentrations of cyclic AMP and relaxing airway smooth muscle. There are 11 phosphodiesterase isozymes, each with various subtypes [1,2]. Each isozyme has a characteristic tissue distribution. Phosphodiesterase 4 is mainly found in inflammatory cells such as eosinophils, mast cells, and T cells. Theophylline is basically considered to be a nonselective phosphodiesterase inhibitor. There are three types of adenosine receptors. Adenosine stimulates guanylate cyclase activity, contracts airway smooth muscle, and stimulates the release of histamine from mast cells. Theophylline is thought to nonselectively block adenosine receptors on the surface of the cells, thereby inhibiting airway-smooth-muscle contraction. However, theophylline-induced bronchodilation and anti-inflammatory activity cannot be explained solely by phosphodiesterase inhibition and adenosine antagonism. Various types of selective phosphodiesterase inhibitors are now being developed, and their clinical usefulness in patients with chronic obstructive pulmonary disease is being studied. However, these selective phosphodiesterase inhibitors have not been shown to be clearly superior to theophylline in terms of therapeutic

Use of Theophylline and Sodium Cromoglycate in Adult Asthma

189

activity or safety. Why theophylline is effective for asthma remains largely unknown [3] . Theophylline produces bronchodilation at serum drug concentrations from 5–15 mg mL−1 [4]. Theophylline alone is inferior to isoproterenol and adrenaline in terms of bronchodilation for asthma attacks [5]; bronchodilatory activity is additively enhanced by combining theophylline with b2 agonists [6,7].

Anti-Inflammatory Effects of Theophylline In 1994, Sullivan et al. reported that theophylline decreases activated eosinophil counts in the bronchial epithelium after allergen challenge in patients with asthma [8]. Attention subsequently focused on the anti-inflammatory effects of theophylline, and considerable progress has been made in understanding the mechanisms involved. The main mechanisms underlying the anti-inflammatory effects of theophylline are the augmentation of histone deacetylase activity (HDAC) and direct effects on eosinophils and other important inflammatory cells in asthmatic airways. Low concentrations of theophylline (below 2 mg mL−1) augment HDAC activity, inhibiting gene transcription activity. This mechanism is not involved in the anti-inflammatory activity of corticosteroids. Clinically, this independent mechanism of action is thought to underlie the complementation of the effects of inhaled corticosteroids by theophylline [9]. Theophylline induces apoptosis of eosinophils, whose survival is prolonged by interleukin-5 stimulation [10], and inhibits effector functions such as specific granular protein secretion caused by the stimulation of receptors on the surface of eosinophils [11]. The first essential step in the accumulation of eosinophils in asthmatic airways is the adherence of circulating eosinophils to endothelial cells. We previously reported that theophylline at clinically recommended and higher concentrations significantly inhibits the adhesiveness of eosinophils in blood and the expression of adhesive molecules on endothelial cells [12, 13]. On the other hand, the authors of this chapter and others have confirmed that corticosteroids do not directly influence eosinophil adhesion or the expression of adhesive molecules on endothelial cells [14, 15]. The inhibition of eosinophil adhesion by theophylline is thought to compensate for the inability of steroids to control this step in the establishment of eosinophilic airway inflammation [13]. Many clinical studies have shown that theophylline inhibits eosinophilic airway inflammation in patients with asthma [16–18]. This result was highly reproducible. In particular, the discontinuation of theophylline promotes eosinophil accumulation in the airways of patients with moderate, persistent asthma who are receiving inhaled corticosteroids [16]. Theophylline enhances the inhibitory effect of inhaled corticosteroids on eosinophilic inflammation in the majority of adults with asthma who are receiving a moderate dose of inhaled corticosteroids [17]. This finding shows that theophylline inhibits airway inflammation in patients with asthma who do not respond to steroids. In asthmatic airways, airway remodeling is believed to progress through the activation of fibroblasts induced by factors released from eosinophils, such as

190

H. Sagara et al.

transforming growth factor-b. Theophylline suppresses the proliferation of fibroblasts induced by transforming growth factor-b stimulation and the expression of type I collagen messenger RNA [19]. To our knowledge, no study has examined the effects of theophylline on remodeling clinically. Available evidence suggests that theophylline inhibits airway remodeling by acting on both eosinophils and fibroblasts, the sources of fibrosis-associated molecules in asthma. Theophylline also inhibits neutrophilic inflammation, which commonly occurs in severe asthma [20, 21]. Studies performed in Europe and North America have repeatedly shown that eosinophilic inflammation persists and eosinophils accumulate in the airways of some patients with severe asthma and who receive high-dose steroids [22, 23]. The results of our previous studies in Japanese patients with asthma support this finding [24]. The mechanism of inflammation is complex, involving neutrophils and eosinophils. Dr. Nagata et al. previously reported that neutrophils markedly induce the passage of eosinophils through the basement membrane by promoting CXC chemokine-induced neutrophil migration [25]. They also confirmed that such intercellular interactions are inhibited by clinical concentrations of theophylline [26]. Such effects may contribute to the action of theophylline in severe asthma, as described below.

Safety of Theophylline Generally, the optimal serum theophylline concentration is 5–15 mg mL−1, producing a given level of bronchodilation [3]. As described below, there is convincing evidence that a serum theophylline concentration of 8–10 mg mL−1 is useful for the long-term management of asthma. Guidelines for the prevention and management of asthma issued by the immunology and allergy research group of the Ministry of Health, Labor and Welfare recommend a serum theophylline concentration of 5–10 mg mL−1 for elderly patients. Side effects are likely to occur when the serum theophylline concentration exceeds 15 mg mL−1. Side effects include gastrointestinal symptoms such as nausea and vomiting, cardiac stimulation associated with tachycardias and arrhythmias, and central nervous symptoms such as restlessness and insomnia. Serious side effects such as convulsions can occur in elderly patients or in patients who concomitantly receive drugs that increase serum theophylline concentrations, as described below. In large studies of patients with asthma or chronic obstructive pulmonary disease who were 65 years or older, however, side effects occurred in 4.7% of the patients. The main side effects included gastrointestinal symptoms and palpitations; no patient had convulsions [27]. Theophylline is associated with cytochrome P-450-related drug interactions. Theophylline is a substrate of cytochrome P-450-IA2 (CYP1A2) and cytochrome P-450-IIIA4 (CYP3A4). Serum theophylline concentrations can increase when theophylline is used concomitantly with drugs that inhibit CYP1A2 and CYP3A4 activities, such as new quinolones, macrolides, diltiazem, and selective serotonin-reuptake inhibitors. In contrast, serum theophylline concentrations can decrease when theophylline is used concomitantly with drugs that promote CYP1A2 and CYP3A4 activities, such as rifampicin, phenytoin, and valproic acid. Side effects can also be caused by the excessive consumption of bever-

Use of Theophylline and Sodium Cromoglycate in Adult Asthma

191

ages containing caffeine, a xanthine derivative. Smoking elevates CYP1A2 activity and decreases serum theophylline concentrations. Most side effects can be avoided by monitoring serum theophylline concentrations. The dose of theophylline varies depending on the patient. In most average Japanese patients, serum theophylline concentrations of 5–15 mg mL−1 are obtained at a daily dose of 400 mg. If theophylline can be used safely and is confirmed to be effective, serum theophylline concentrations usually do not have to be measured in routine clinical practice.

Evidence Supporting the Effectiveness of Theophylline for the Long-Term Management of Asthma Evidence Supporting the Concurrent Use of Theophylline and Inhaled Corticosteroids Combination therapy with theophylline and inhaled corticosteroids is generally considered the standard of care for the long-term management of asthma. Japanese guidelines for the management and treatment of asthma recommend both drugs for the treatment of moderate or severe persistent asthma (step 3 or higher), but this regimen can also be used for mild persistent asthma (step 2). Inhaled corticosteroids and theophylline are thought to act on airway lesions in asthma through different mechanisms. In fact, evidence suggests that their clinical effects are additive. For example, some studies have compared the effectiveness of doubling the dose of inhaled corticosteroids with that of adding a low dose of sustained-release theophylline in patients with asthma unable to be controlled by moderate doses of inhaled corticosteroids. The improvement in asthmatic symptoms and respiratory function was equivalent or significantly better in the latter group [28–31]. Evans et al. found that the addition of theophylline in a dose producing a mean serum drug concentration of 8.0–8.9 mg mL−1 produced a greater improvement in airflow limitation than did doubling the dose of budesonide (Pulmicort®) in patients whose asthma was not adequately controlled by budesonide alone [28]. Ukena et al. reported that additional treatment with theophylline in a dose producing a mean serum drug concentration of 10 mg mL−1 in patients who are receiving inhaled corticosteroids is more clinically effective than doubling the dose of inhaled corticosteroids [29]. These results indicate that serum theophylline concentrations of 8–10 mg mL−1 are needed for sustained-release theophylline to be effective in patients with asthma poorly controlled by inhaled corticosteroids alone. As stated above, theophylline in a dose of 400 mg/day produces serum theophylline concentrations generally within the target range in most Japanese patients. However, a recent American study has reported that low-dose theophylline (300 mg/day) was more effective in improving symptoms in patients who were not receiving inhaled corticosteroids than in those who were concurrently receiving inhaled corticosteroids. Combined treatment with low-dose theophylline and inhaled corticosteroids improved pulmonary function, but did not significantly improve symptoms [32].

192

H. Sagara et al.

Adequate clinical effectiveness thus requires an appropriate dose of theophylline, providing optimal serum drug concentrations. In a study directly comparing the effects of theophylline, formoterol (an LABA), and zafirlukast (a leukotriene receptor antagonist) in adults with asthma who poorly responded to moderate dose of inhaled corticosteroids, the improvement in asthmatic symptoms was better in the formoterol group during the first month of treatment. Subsequently, however, the differences among the groups became smaller and were no longer significant after 3 months of treatment [33]. The rapid improvement in symptoms associated with LABAs is expected because of their potent bronchodilatory activity. In contrast to LABAs, both theophylline and leukotriene receptor antagonists have anti-inflammatory activity, which may contribute to an improvement in asthmatic symptoms after a certain period. The results described above showed that theophylline is useful for the long-term management of asthma. The addition of theophylline is a viable treatment option for persistent asthma, which cannot be controlled by inhaled corticosteroids alone because theophylline inhibits the chronic airway inflammation characteristically found in asthma and prevents airway remodeling. Asthma requires long-term medical treatment. Theophylline is far less expensive than inhaled corticosteroids, an important factor in ensuring continued treatment.

Evidence Supporting the Effectiveness of Theophylline for Severe Asthma In patients with severe asthma and are receiving oral steroids, the addition of theophylline significantly decreases symptom scores [34]. In contrast, the discontinuation of theophylline leads to exacerbations of asthma in a high proportion of patients [35]. High doses of inhaled corticosteroids and LABAs are generally used to treat severe asthma. However, a recent study reported that serum theophylline concentrations of 8–13 mg mL−1 significantly augmented salmeterol-induced bronchodilation in patients with severe asthma in whom the mean forced expiratory volume in 1 s was 57% of the predicted value [36]. The effectiveness of additional treatment with theophylline may be attributed to the fact that theophylline inhibits neutrophilic inflammation in severely asthmatic airways and interferes with the inflammatory mechanisms involving neutrophils and eosinophils, in addition to having bronchodilatory activity, as described above. Recent studies performed in the United States have shown that LABAs can have long-term negative effects on respiratory function and increase acute exacerbations of asthma, even in patients who concomitantly receive inhaled corticosteroids [37–39]. In patients for whom the asthma cannot be controlled by combination therapy with inhaled corticosteroids and LABAs and were repeatedly hospitalized because of a poor response to inhaled short-acting b2 agonists given on an emergency basis, baseline control status and the response to short-acting b2 agonists markedly improved after switching from LABAs to theophylline [40]. In contrast to LABAs, theophylline does not act through receptors on the surface of cells.

Use of Theophylline and Sodium Cromoglycate in Adult Asthma

193

Theoretically, a reduced response to theophylline with continued use of the drug (i.e., down-regulation) does not occur. In patients who do not respond well to LABAs, treatment regimens should be changed or theophylline should be given additionally. Taken together, currently available findings indicate that theophylline should be included in regimens for the long-term management of severe asthma, which cannot be controlled by high doses of inhaled corticosteroids and LABAs.

References 1. Fawett L, Baxedale R, Stacy R, et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family. PDE11A. Proc Natl Acad Sci USA 2000; 97: 3702–3707 2. De Boer J, Philpott AJ, van Amesterdam RG, et al. Human bronchial cyclic nucleotide phosphodiesterase isoenzymes Biochemical and pharmacological analysis using selective inhibitors. Br J Pharmacol 1992; 106: 1028–1034 3. Lipworth B. Phosphodiesterase type 4 inhibitors for asthma: a real Allergy. Asthma Immunol 2006; 96: 640–642 4. itenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N Engl J Med 1973; 289: 600–603 5. Rossing TH, Fanta CH, Goldstein DH, et al. Emergency therapy of asthma: Comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Ame Rev Respir Dis 1980; 122: 365–371 6. Rossing TH, Fanta CH, McFadden ER. A controlled trial of the use of single versus combined-drug therapy in the treatment of acute episodes of asthma. Am Rev Respir Dis 1981; 123: 190–194 7. Fanta CH, Rossing TH, McFadden ER, Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated? Am J Med 1986; 80: 5–l0 8. Sullivan P, Bekir S, Jaffar Z, et al. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994; 343: 1006–1008 9. Ito K, Sam Lim S, Caramori G, et al. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. PNAS 2002; 55: 8921–8926 10. Ohta K, Sawamoto S, Nakajima M, et al. The pro-longed survival of human eosinophils with inter-leukin-5 and its inhibition by theophylline via apoptosis. Clin Exp Allergy 1996; 26: l0–15 11. Spoeltsra FM, Berends C, Dijkhuizen B, et al. Effect of theophylline on CD1lb and L-selectin expression and density of eosinophils and neutrophils in vitro. Eur Respir J 1998; 12: 585–591 12. Choo JH, Nagata M, et al. Theophylline attenuates the adhesion of eosinophils to endothelial cells. Int Arch Allergy Immunol 2003; 131: 40–45 13. Nagata M. Differential effect of corticosteroids and theophylline on the adhesive interaction between eosinophils and endothelial cells. Allergol Int 2004; 53: 33–36 14. Kaiser J, Bickel CA, Bochner BS, et al. The effects of the potent glucocorticoid budesonide on adnesion of eosinophils to human vascular endothelial cells and endothelial expression of adhesion molecules. J Pharmacol Exp Ther 1993; 267: 45–49 15. Sutani A, Nagata M, et al. Dexamethasone does not modulate eosinophil adhesion to endothelial cells. Int Arch Allergy Immunol 2001; 125: 2–6 16. Minoguchi K, et al. Effect of theophylline with-drawl on airway inflammation in asthma. Clin Exp Allergy 1998; 28: 57–63 17. Aizawa H, et al. Once-daily theophylline reduces serum eosinophil cationic protein and eosinophil levels in induced sputum of asthmatics. Int Arch Allergy Immunol 2000; 121: 123–128

194

H. Sagara et al.

18. Lim S, et al. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001; 164: 273–276 19. Yano Y, Yoshida M, Hoshino S, et al. Anti-fibrotic effects of theophylline on lung fibroblasts. Biochem Biophys Res Comm 2006; 341: 684–690 20. Kraft M, Torvik JA, Trudeau JB, et al. Theophylline: potential anti-inflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996; 97: 1242–1246 21. Culpitt SV, de Matos C, Russell RE, et al. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 165: 1371–1376 22. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160: 1001–1008 23. The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003; 22: 470–477 24. Kikuchi S, Nagata M, Kikuchi I, et al. Association between neutrophilic and eosinophilic inflammation in patients with severe persistent asthma. Int Arch Allergy Immunol 2005; 137: 7–11 25. Kikuchi I, Kikuchi S, Kobayashi T, et al. Eosinophil trans-basement migration induced by IL-8 and neutrophils. Am J Respir Cell Mol Biol 2006; 34: 760–765 26. Kikuchi I, Kikuchi S, Kobayashi K, et al. Theophylline Attenuates the Neutrophil-Dependent Augmentation of Eosinophil Trans-Basement Membrane Migration. Int Arch Allergy Immunol 2005; 137 (accepted for publication) 27. Ohta K, Fukuchi Y, Grouse L, et al. A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD. Respir Med 2004; 98: 1016–1024 28. Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997; 337: 1412–1418 29. Ukena D, Harnest U, Sakalauskas R, et al. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 1997; 10: 2754–2760 30. Wang Y, Eang C, Lin K, et al. Comparison of inhaled corticosteroid combined with theophylline and double-dose inhaled corticosteroid in moderate to severe asthma. Respirology 2005; 10: 189–195 31. Shah AR, Sharples LD, Solanki RN, et al. Double-blind, randomized, controlled trial assessing controller medications in asthma. Respiration 2006; 73: 449–456 32. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelnkast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007; 175: 235–242 33. Yurdakul AS, Caliir HC, Tunctan B, et al. Comparison of second controller medications in addition to inhaled corticosteroid in patients with moderate asthma. Respir Med 2002; 96: 322–329 34. Nassif EG, Weinberger M, Thompson R, et al. The value of maintenance theophylline in steroid-dependent asthma. N Eng J Med 1981; 304: 71–75 35. Brenner M, Berkowitz R, Marshall N, et al. Need for theophylline in severe steroid-requiring asthmatics. Clinical Allergy 1988; 18: 143–150 36. Vatrella A, Ponticiello A, Pelaia G, et al. Bronchodilating effects of salmeterol, theophylline and their combination in patients with moderate to severe asthma. Pulm Pharmacol Ther 2005; 18: 89–92 37. Wechsler ME, Lehman E, Lazarus SC, et al. National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. beta-Adrener-gic receptor polymorphisms and response to salmeterol. Ame J Respir Crit Care Med 2006; 173: 519–526 38. Martinez FD. Safety of long-acting beta-agonists -an urgent need to clear the air. N Engl J Med 2005; 353: 2637–2639 39. Salpeter SR, Buckley NS, Ormiston TM, et al. Meta-analysis: effect of long-acting beta-ago-nists on severe asthma exacerbations and asthma-related deaths. Ann Int Med 2006; 144: 904–912 40. Weinberger M, Abu-Hasan M. Life-threatening asthma during treatment with salmeterol. N Engl J Med 2006; 355: 852–853

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma Giovanni Passalacqua and Giorgio Walter Canonica

Historical Context Allergen-specific immunotherapy (SIT) was introduced on an empirical basis about a century ago [1], with the erroneous rationale of vaccinating against “airborne toxins.” Despite this wrong conception, the subcutaneous injection (SCIT) of pollen extracts proved capable of reducing the symptoms of hay-fever, and SIT (also termed “vaccine”) became one of the cornerstones of allergy treatment. After the discovery of IgE [2], the mechanisms of SIT were investigated and its clinical efficacy was assessed in double blind placebo controlled trials [3]. From the 1960s until the end of the 1980s, there were no important changes in the practice of SIT that was invariantly given by SCIT, other than the introduction of the modified allergens or allergoids. In 1986, the British Committee for the Safety of Medicines (CSM)[4] reported 26 deaths due to SCIT and started a process of intense critical revision of this treatment, which led to the publication of the World Health Organization guidelines [5]. In these guidelines, indications, contraindications, risks, and benefits of SCIT were clearly stated, and SCIT was finally recognized as an effective treatment. Another important consequence of the CSM report was the strong impulse to search for safer modalities of immunotherapy. In this regard, the sublingual route (SLIT) was extensively studied and subsequently validated [5, 6]. SLIT can, therefore, be considered an important milestone in the history of SIT, since it really changed the clinical practice and originated an intense debate, which is still ongoing. Another revolution in the history of SIT was the discovery of Th1 and Th2 lymphocyte subsets [7], which allowed elucidating the mechanisms of action and, in turn, opened new research pathways such as the use of adjuvants. Few years later, the T regulatory cells were also described [8], leading to new immunotherapy approaches. In parallel to the clinical evolution, basic immunology techniques also

G. Passalacqua and G.W. Canonica () Allergy and Respiratory Diseases, Department of Internal Medicine, Padiglione Maragliano, L.go R. Benzi 10, 16132 Genoa, Italy e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_12, © Springer 2010

195

196

G. Passalacqua and G.W. Canonica

The future of Immunotherapy (SCIT/SLIT) INDICATIONS

Food allergy Latex Atopic dermatitis

Liposomes

PHARMACEUTICAL Biolistic injection FORM

Mucoadhesive substances

ADJUVANTS

RECOMBINANT/ ENGINEERED

Alum-alginates Bacterial wall derived DNA-adjuvants

Recombinant purified Hypoallergenic isoforms Peptides Chimeric proteins c-DNA GENIC VACCINATION Plasmids

Replicons Fig. 1 Novel approaches for specific immunotherapy

evolved rapidly and provided the instruments to design and build specific molecules, such as the recombinant and engineered allergens, for immunotherapy (Fig. 1).

Injection Immunotherapy Efficacy and Safety The SCIT is well established and its indications, contraindications, limits, and practical aspects have been well defined in numerous guidelines [5, 6, 9, 10]. In the last 5 years, some new articles on the clinical efficacy and safety of SCIT have been published, all confirming the clinical effect in rhinitis and asthma due to mites, grass, birch, and ragweed. Interestingly, two clinical studies, one evaluating symptoms upon exposure [11] and one evaluating the response to a nasal provocation test [12], demonstrated the dose-dependency of SCIT for clinical efficacy. Moreover, there are two meta-analyses of the efficacy of SCIT for both allergic asthma [13] and rhinitis [14], which clearly confirm the efficacy of the treatment on symptoms and use of rescue medications. Concerning the safety aspects, a randomized study with grass and birch vaccines [15] found that systemic reactions with SCIT occurred in 3.3% of the injections

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

197

with grass and 0.7% of the injections with birch. A postmarketing surveillance [16] reported a rate of systemic reactions of 0.9% of the total doses and 3.7% of patients, whereas another survey on grass pollen SCIT reported an occurrence of systemic reactions in 2% of patients [17]. A retrospective study [18] on 65 patients receiving multiple vaccines and rush IT reported 38% systemic reactions with one severe episode. It is noteworthy that an e-mail survey of more than 17,000 physicians in the USA [19] reported a high rate of errors in administration (wrong patient or wrong dose).

Mechanisms (Fig. 2) It is well known since many years that SCIT is associated with an increase in allergen-specific IgG antibodies, particularly in the IgG4 subclass. More recent studies have extended these observations, with a special attention toward the biological effects of IgG. These effects include the IgG-dependent ability of postimmunotherapy serum to inhibit the binding of allergen-IgE complexes to B-cells, the blocking of subsequent IgE-facilitated allergen presentation with the activation of allergen-specific T-lymphocytes, and the prevention of allergen-IgE dependent activation of peripheral basophils [20–22]. The effect of allergen-specific IgG may be explained either by competition for IgE-allergen binding or alternatively by an effect mediated via the inhibitory IgG receptor FcgRIII, which is coexpressed with IgE IL-4

APC

B-cell

Th2 ALLERGEN

Eosinophil

TGFb IL-10 CD4

IL-5

Allergic inflammation

SIT T reg

IL-10

SIT SIT

IgG Th1

IFN- γ

B-cell

Fig. 2 Putative mechanisms of action of immunotherapy. The solid red arrows indicate stimulation, the green dotted arrows indicate inhibition

198

G. Passalacqua and G.W. Canonica

FceRI on basophils, and inhibits post-IgE receptor signaling pathways following allergen binding [23, 24]. The allergic inflammation, typically accompanied by tissue eosinophilia, is regulated by Th2 lymphocytes that produce a distinct profile of cytokines. Studies over the past decade have confirmed the blunting of allergendriven Th2 responses, including reductions in IL-4, IL-13, IL-5, and IL-9, in the periphery and /or within the target organs [25–30]. These changes are associated with: a) immune deviation in favor of Th1 responses with an overproduction of IFNg and/or b) the emergence of a population of regulatory T-lymphocytes that produce the inhibitory cytokines IL-10 and/or TGFb [31–33]. It is hypothesized that these regulatory T-cells act directly to suppress allergen-specific Th2 responses. Alternatively, IL-10 is a known switch factor for IgG4 production [34], whereas TGFb favors IgA [35] and both of these antibody classes are increased in peripheral blood after SCIT [31].

Long-Lasting Effect and Prevention It is known since many years that injection immunotherapy maintains its beneficial effects for years after discontinuation. This long-term effect has been described in both open and controlled studies with a number of different allergens [36–43] (Table 1). The long-lasting effect has been reported to persist for 3–6 years, but a recent follow-up study in 23 children described a 6-years effect after the discontinuation of grass SCIT [42]. Interestingly, the same children were evaluated again after 12 years and persistence of a moderate beneficial effect was still identified [43]. In two large retrospective studies [44, 45], SCIT appeared to prevent the onset of new atopic sensitizations as determined by skin prick testing. This results confirmed those obtained previously in a small sample of monosesitized children [46]. In a large randomized, controlled, but not blinded, study of SCIT (the Preventative Allergy Treatment study, PAT), pollen immunotherapy reduced the risk of the onset of asthma in children who had allergic rhinitis and no asthma [47]. This preventive effect was observed to persist in the same patients for 2 years after the termination of SCIT [48].

Table 1 Long-lasting effect of subcutaneous immunotherapy Author (ref) Allergen Patients Duration sit Mosbech (36) Grass 2.5 years Grammer (37) Ragweed 61 adult/children 4 months Hedlin (38) Cat/dog 32 adult/chidren 3 years Des Roches (39) Mite 40 adult 1–4 years Ariano (40) Parietaria 35 adult 4 years Durham (41) Grass 52 adult 3–4 years Eng (43) Grass 25 children 3 years

Long-lasting effect 6 years 2 years 5 years 3 years 4 years 3 years 12 years

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

199

Sublingual Immunotherapy Efficacy and Safety SLIT is the natural evolution of the oral administration of allergens, proposed in the early 1970s and then abandoned [49]. The original rationale of the sublingual administration was to achieve an effective absorption of the allergen through the oral mucosa so that systemic side effects of the injections could be avoided or reduced. The rationale of the absorption was not supported by experimental data, but since the first controlled study [50], SLIT was found to be effective in reducing symptoms and medication intake. Nowadays, there are more than 50 randomized trials of SLIT (for review see [51, 52]), and several meta analyses of those studies [53–55]. A summary of the evolution of SLIT is depicted in Fig. 3. According to the literature, SLIT is effective in rhinitis and asthma due to the most common allergens, including mites, grasses, parietaria, ragweed, and olive. The clinical efficacy in rhinitis [55] and asthma [56] was also separately confirmed in pediatric patients in meta analyses. According to the evidence-based medicine rules [57], the meta analyses confer to SLIT a grade of evidence Ia and the recommendation for its clinical use is A. Nonetheless, the opponents of SLIT argue that meta analyses collect together small studies that are highly heterogeneous in design, doses, and evaluation parameters. This can be true, but in the more recent

1986, Scadding et al 1st DBPC trial

1970ties ORAL IT

1998: WHO SLIT is accepted

2001: ARIA document

1998, first Tablet SLIT

2004 1st META ANALYSIS

2005-2006: Large randomized controlled trials Studies on the mechanism of action

Fig. 3 The history of SLIT

1993. SLIT is Mentioned in an EAACI pos pap

1997, Tari, 1st pediatric trial

2004: Preventive effect Compliance

2005: SLIT in children below the age of 5

200

G. Passalacqua and G.W. Canonica

trials of sublingual immunotherapy for grass pollen-induced seasonal rhinitis, involving hundreds of patients, the magnitude of the effect, defined as the reduction in diary symptoms and rescue medication scores compared to placebo, was reported to vary from 24% to about 40% [58–61]. Moreover, in these studies, a clear doseresponse relationship was identified, similarly to SCIT. Of note is a recently published trial, which found that SLIT is not effective when utilized in a primary care setting [62]. This leads to concerns, mainly on the adequacy of patients’ choice made by GPs, rather than the efficacy of SLIT itself. There are few direct comparisons of SLIT versus SCIT. One double dummy study without the placebo group, conducted in grass pollen allergic patients, showed that the clinical efficacy of SLIT was equivalent to that of SCIT [63]. Another open comparative 12 months study in Alternaria tenuis allergic patients [64] found a significant clinical improvement in both groups (even greater with SLIT). There is also an open comparison between SLIT and SCIT in miteallergic patients [65], showing a better improvement with the subcutaneous route, especially for asthma symptoms, although SLIT well controlled rhinitis symptoms. This study is biased due to a clear imbalance between groups at the baseline, concerning asthma symptoms. Recently, a double-blind, doubledummy, placebo-controlled study compared SCIT and SLIT in birch pollinosis [66]. Symptoms and drug intake were reduced by about one third in the SLIT group and by half in the SCIT group, with no significant difference evident between treatments. However, there were six grade 3 and 4 reactions in the SCIT group and none in the SLIT group. The most relevant feature of SLIT is its safety, which still remains a concern with SCIT. In all the randomized controlled trials, SLIT was well-tolerated, the most frequent side effects being local (oral itching or swelling) or gastrointestinal (nausea, vomiting, diarrhea, and “stomach ache”). These side effects were generally described as either mild and self-limiting or manageable by a temporary dose reduction. The majority of these events were local, very mild, and self-resolving and systemic reactions were quite rare. It was suggested that the type and severity of adverse events are not directly related to the dose [67], but the more recent studies clearly showed that the rate of untoward effects, although these effects are mild, is dose dependent [68]. According to an extensive review of the literature, 17 serious adverse events (mainly asthma) were reported [69]. Two cases of anaphylaxis were recently reported, one with nonstandardized mixtures of allergens [70] and the other with a rush administration of latex extract [71]. Some postmarketing surveys in children and adults [72–76] are available (Table 2). Based on these large surveys, the overall rate of side effects was found to range between 3% and 18% of patients and was invariantly less than 1 reaction per 1,000 doses. Interestingly, the rate of adverse events in children below 5 years of age did not increase with respect to the other age classes [73, 76, 77]. This fact represents a relevant advantage, since, for SCIT, the age below 5 years is considered as a relative contraindication, due to the possible severity of the adverse events [5].

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma Table 2 Post-marketing surveillance studies on the safety of SLIT Author Average (ref) N pats Age range follow-up Allergens Di Rienzo 268 2–15 years 3 years 54% mites [69] 25% grass 6% parietaria 16% mixed Lombardi 98 >14 years 3 years 35% mites [72] 38% grass 23% parietaria 4% others Pajno [71] 354 5–15 years 3–4 years 42% mites 20% parietaria 11% grass 7% olive 20% mixed Agostinis 36 3–5 years 2 years Mites 19 [73] Grasses 17 62% mites Di Rienzo 70 3–5 years 2 years [70] 22% grass 12% parietaria 4% others

201

AE% of patients 3%

AE/1,000 doses

7.5%

0.5/1,000

6%

0.15/1,000

5%

0.07/1,000

5.6%

0.2/1,000

0.083/1,000

Mechanisms Until 5 years ago, only limited data were provided on the mechanism of action of SLIT, and these data were often controversial. In fact, in some studies, SLIT was associated with modest increases in IgG, transient increase in IgE, and suppression of eosinophil recruitment and activation in target organs [78–82]. Nonetheless, other studies failed to demonstrate changes in systemic T-cell, and cytokine response [83, 84] or local changes in the sublingual mucosa [79]. More recently, the investigation specifically focused on the Th1/Th2 balance and the role of Treg cells. Two studies reported an increased production of the regulatory cytokine IL-10 [85, 86] after SLIT and another study showed a reduction of the Th2 cytokine IL-13 [87]. Savolainen et al demonstrated in vitro that SLIT reduces the expression of IL-5 and enhances the expression of IL-10 in PBMC stimulated with the allergen [88]. Overall, the clinical effects of SLIT resemble those of SCIT, and the data available suggest that the mechanisms of action are partially similar. Nevertheless, a more detailed definition of the mechanisms of action of SLIT is mandatory and it will probably represent a major research field. Concerning the biodistribution of allergens in humans, the earliest studies conducted with the radiolabeled Par j 1 allergen and its allergoid [89] clearly showed that the direct absorption of the allergen through oral mucosa is absent or negligible. Moreover, it was shown that the allergen persists for hours in the mouth, even after

202

G. Passalacqua and G.W. Canonica

spitting or drinking. This suggests that the contact with the mucosa is crucial for the effect of SLIT. In fact, when the allergen is immediately swallowed (oral route), the clinical efficacy is poor or absent. In addition, it was consistently shown that the modified allergen, and not the native one, can be absorbed intact in small amounts in the bloodstream. These aspects were recently confirmed in allergic volunteers with the purified Der p 2 allergen and its allergoid [90]. This finding confirms that the biodistribution (no oral absorption, long persistence in the mouth, absorption of the intact allergoid) of allergens does not depend on the type of molecule.

Aspects Currently Under Investigation There are some aspects of SLIT that need further experimental support, although the existing data are favorable. One aspect is the ability of SLIT to prevent the onset of new sensitizations and the onset of asthma, similarly to SCIT [45, 47]. Recently, in an open randomized trial, involving more than 500 patients, the rate of occurrence of new sensitizations was found to be 5.8% in the active group and 38% in the control group (p < 0.001)[91]. In an observational cohort study, not designed to evaluate SLIT, it was shown that among monosensitized patients treated with SLIT, only about 10% developed new sensitizations after 3 years, whereas this percentage was around 40% in patients receiving only drugs without SLIT [92]. More importantly, a study by Novembre et al [93], performed on children, demonstrated that SLIT is capable of reducing the risk of asthma onset. In that study, 97 children with only rhinitis were subdivided into two groups, receiving either drugs or drugs plus SLIT for 3 years. In the active treatment group, asthma occurred in 6 the first year, 7 the second year, and 8 the third year. In the control group, the corresponding numbers were 6, 16 (P = 0.06), and 18 (P = 0.04). Another randomized open controlled trial [94] involved 216 children (age 5–17 years) suffering from allergic rhinitis, with or without intermittent asthma. They were randomly allocated 2:1 to drugs plus SLIT or drugs only, and followed for 3 years. One hundred and ninety-six patients were evaluated at 3 years, and the occurrence of persistent asthma was 2/130 (1.5%) in the SLIT group and 19/66 (30%) in the control group. Finally, the long-term effect, which is well ascertained for SCIT, has been so far demonstrated for SLIT in a single open and nonrandomized study [95]. Another important concern about SLIT is the adherence, because the treatment is self-managed by the patient. The problem of adherence was systematically addressed in three studies employing the method of unscheduled phone interviews. In the first study [96] involving 126 patients, the overall adherence was around 95%. In another study [97] conducted in more than 400 patients, the adherence rate at 3 and 6 months was greater than 90% in about 75% of the patients. A similar study was conducted in a population of 70 children, and the results on compliance did not differ from the above mentioned in adults [98]. In view of the increasing attention that is paid to the economic aspects of the treatment strategies nowadays, a cost-effectiveness assessment of SLIT is mandatory. A pharmaco-economic pilot study [99] in children

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

203

reported a substantial reduction in all outcome measures (exacerbations, visits, absence from school, drugs, and school and parental work loss) during SLIT. Another large study in adults, which utilized a formal pharmaco-economic model, showed that SLIT in pollinosis leads to remarkable economic savings in terms of direct and indirect costs when compared to drug treatment alone [100].

Future Developments The good safety profile of SLIT is likely to allow the expansion of its indications to conditions different from respiratory allergy. Indeed, a recent study [80] demonstrated that SLIT is clinically effective in the treatment of IgE-mediated hazelnut allergy. Positive results were also reported with SLIT in latex allergy [101–103]. Two randomized controlled trials of SLIT were conducted. The first one, on 12 children with latex allergy, reported a significant reduction of clinical symptoms at 12 months, accompanied by a decrease of symptoms related to cross-reacting foods [102]. The other randomized study [103] involved 35 adults with cutaneous and respiratory allergy to latex and it reported a significant improvement in both clinical manifestations after 12 years of SLIT. Finally, a randomized placebo-controlled trial conducted in 56 children with mite allergy and extrinsic atopic dermatitis, receiving SLIT for 18 months, described a significant reduction in the SCORAD (Fig. 4) and medication intake starting from month 9. The favorable effect was maintained until the end of SLIT, but was significant only in the mild and moderate form of the disease [104]. Another interesting aspect of SLIT is that the traditional slow updosing phase does not seem to be necessary. Indeed, there have been some reports with ultra rush (less than 2 h) updosing, showing that the rapid increase of the doses does not lead to an increase of side effects [105, 106]. A randomized trial compared the safety of the traditional updosing regimen with the no-updosing [107] regimen in 135 patients and found no difference in adverse events rate between the two groups. The most recent large randomized trials were all performed with the no-updosing regimen, and their results, in terms of safety, were as favorable as those of the studies involving the traditional route.

Novel Formulations and Routes of Administration One of the possibilities to improve SIT is to modify the pharmaceutical form of administration. In this method, liposomes are regarded as a promising route of delivery since they resemble biological membranes and can also act as adjuvants [108]. The use of liposomes to encapsulate allergens for SCIT has been proposed. A randomized DBPC study with a liposomal mite vaccine showed clinical efficacy

204

G. Passalacqua and G.W. Canonica SLIT (N=26)

Placebo (N= 22)

Δ SCORAD vs baseline

0 –2 –4 –6 –8

*

*

–10

*

*

–12

0

3

6

9

12

15

18

months Fig. 4 Double-blind, placebo-controlled study of SLIT for atopic dermatitis in 58 children. Change from baseline (delta SCORAD) in the two groups at the different time-points. The significant differences between groups are marked with an asterisk (from Ref. 104)

comparable to traditional vaccines as well as a good safety profile [109]. This treatment was also capable of reducing nonspecific bronchial hyperresponsiveness in mild asthmatics [110]. Another promising opportunity is represented by the needle-free epidermal administration of microparticles, the so-called “biolistic” administration. This route of delivery has been extensively studied for other kind of vaccinations [111], but only recently proposed for the delivery of allergens. So far, only a single study has been conducted on mice, showing that the biolistic administration is able to induce a Th1 skew [112]. Finally, in the case of mucosal administration of allergens, such as that of SLIT, potential improvement could result from the bioadhesive vehicles [113]. These mixtures of organic molecules prolong the time of persistence of the active principle on the mucosa and can enhance their immunogenicity. So far, no study has been performed on humans with bioadhesive molecules.

Immunotherapy with Adjuvants In immunology, adjuvants are classically non antigenic or non immunogenic substances, which, when coadministered with antigens, enhance their effects [114]. Thus, in the case of SIT, an effective adjuvant would allow the reduction in the amount of allergen to be administered.

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

205

Immunotherapy with Bacterial Adjuvants The traditional adjuvants used in experimental immunology are usually irritant or toxic and therefore, are not suitable for human use. For this reason, extensive researches were made to identify proper adjuvants to be given with allergens [115]. One of the most promising adjuvants is a mixture of phospholipids derived from the cell wall of the nonpathogen bacterium Salmonella Minnesota. This adjuvant is called monophosphoril-lipid A (MPLA). MPLA has been shown to be non toxic, well tolerated, and capable of inducing a pronounced Th1 response in animals [116] and humans [117]. A double-blind, placebocontrolled study was conducted on an injection SIT with grass pollen extract adjuvanted with MPLA [118], to be administered in only four injections. This study demonstrated a significant improvement in patients with allergic rhinitis, associated with immunological changes similar to those induced by traditional SCIT [119]. The same preparation was also tested, with favorable results, in children and adolescents, although the study was open and not controlled [120]. At present, the MPLA-adjuvanted immunotherapy is commercially available in several countries [121].

DNA-Adjuvanted Immunotherapy About 10 years ago, while attempting to vaccinate animals with the DNA encoding for the allergen, rather than with the allergen itself, it was noticed that the administration of DNA plasmids exerted a potent Th1-inducing effect [122]. The reasons for the adjuvant effect were identified as short repetitive sequences (CpG motifs) that are typical of the bacterial DNA [123]. These sequences, the so-called ISS-ODN (immunostimulatory sequences-oligodeoxynucleotide ), are typically recognized by the toll-like receptor 9, which is a component of the innate immunity [124] and activates the Th1 response to bacteria. It was immediately clear that ISS-ODN could represent a potent adjuvant for allergen immunotherapy [125], and a DNA conjugated allergen, Amb a 1, was prepared for human administration [126]. This injected adjuvanted allergen was shown able, in an exploratory study in humans, to effectively redirect the allergenspecific immune response toward the Th1 phenotype [127, 128]. Recently, a phase II, double-blind, placebo-controlled trial with the DNA-conjugated ragweed allergen, conducted in 25 adults with rhinitis, reported a significant clinical benefit (reduction of symptoms and medication intake), which was maintained for two pollen seasons after vaccination [129]. The DNA adjuvanted immunotherapy seemed to be well tolerated and no untoward effect was described.

206

G. Passalacqua and G.W. Canonica

Immunotherapy with Peptides The rationale behind this approach is that IgE recognizes the entire epitope of an allergen (i.e., conformational recognition), whereas antigen presenting cells and T cell receptors recognize the linear sequences. Thus, by giving, instead of the entire allergenic protein, only some peptides it is expected to obtain an immunogenic activity without the allergenic one. In fact, it was demonstrated in vitro that appropriate peptides derived from allergens were able to induce a functional inactivation of allergen-specific T helper cells [130–132]. The first attempts with this kind of SIT were made with mixtures of short peptides derived by the Fel d 1 allergen of cats [133–136], at a dose variable from 7.5 to 750 mcg per injection. Unfortunately, in the aforementioned human trials, despite some efficacy on symptoms and measurable immunological changes, there were unexpected severe adverse events [134, 136]. Subsequently, other mixtures of short and partially overlapping peptides were used and, in the more recent studies, [137, 138], there was a clear demonstration of clinical efficacy, with the reduction of symptoms upon cat exposure and the immunotherapy was well tolerated. A few small studies were also conducted with long peptides derived from the hymenoptera allergen Api m 1 [139–141], all showing a favorable immune response, despite the evaluation of clinical parameters only in one study [139].

Recombinant and Engineered Allergens The commercialized extracts for immunotherapy, although standardized, are heterogeneous mixtures of allergenic proteins and non-relevant components. In addition, there are numerous cross-reactivities within allergens. Thanks to the advances in molecular biology, it is now possible to synthesize many of the allergenic proteins, so that it would be also possible to vaccinate only with the relevant molecules. This is called “tailored immunotherapy.” There are numerous studies describing the characteristics and immunological effects of recombinant allergens [142], but their clinical application has only been carried out in the last 2 years. A randomized, controlled trial of recombinant birch allergens resulted in reduced skin test responses and the inhibition of basophil histamine release [143], whereas a trial of four recombinant grass allergens resulted in a decrease in seasonal symptoms and medication requirements compared to placebo treatment [144]. The molecular approach also offers the unique opportunity to synthesize allergens that are partly different from the naturally occurring ones (hypoallergenic isoforms). This can be achieved by numerous techniques such as site-directed mutagenesis [145], but the final goal is to maintain the immunogenicity of a vaccine, while reducing/avoiding the capacity to bind allergen-specific IgE, thereby reducing the risk of IgEdependent side effects. The most attractive perspective offered by genetic engineering is that of administering the genes encoding for the allergens instead of the allergens themselves.

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

207

This can be done using so-called replicons. Very recently, an effective vaccination with a replicons encoding for the major grass allergen was described in an animal model of allergy [146]. Molecular biology also allows building chimeric proteins that are a fusion of two or more different allergens. This has been done by constructing a fusion protein made by the Bet v 1 allergen, carrying the immunodominant peptides of Phl p 1 [147]. This construct has been shown immunologically effective in an animal model, but studies in humans are still lacking.

Concluding Remarks In the last 20 years, there has been an impressive blossoming of immunotherapy studies [148]. The most important novelty, from a clinical point of view, was the introduction of SLIT, which is now accepted as a viable alternative to injection immunotherapy. It is true that some points, such as the ideal patient, the extent of the long-lasting effect, and the preventative role [149], need to be better detailed for SLIT. These aspects will represent the clinical challenge for the near future. It is important to remind that though SLIT is easy to manage, the self-administration itself requires a careful instruction and a detailed follow-up of the patients. Its prescription must be made only by a specialist, after the establishment of a detailed diagnosis and the careful evaluation of the expected benefit/cost ratio. This certainly applies also to injection immunotherapy. In parallel to the clinical developments of SLIT, the mechanisms of specific desensitization were clarified in increasing detail [150]. This prompted the exploration of new opportunities, such as the use of bacterial and DNA adjuvants, peptides [151], and recombinant/engineered allergens. Although these approaches are still at the beginning stages in humans, they represent the frontier for the immediate future. Looking far ahead, the ultimate approach to immunotherapy is likely to be the “internal vaccination” via the administration of genes encoding for the allergens.

References 1. Noon L (1911) Prophylactic inoculation against hay fever. Lancet 1:1572–3. 2. Johansson SG (2006) The discovery of immunoglobulin E. Allergy Asthma Proc 27(2 Suppl 1): S3–6. 3. Frankland A (1965) Preseasonal injection treatment in hay fever using aqueous extracts. Int Arch Allergy Appl Immunol 28(1):1–11. 4. Committee on the safety of medicines (1986) CSM update. Desensitizing vaccines. Br Med J 293:948. 5. World Health Organization Position Paper (1998) Allergen immunotherapy: therapeutical vaccines for allergic diseases. Bousquet J, Lockey R, Malling HJ edts Allergy 53(suppl 72): 3–13. 6. Bousquet J, Van Cauwenberge P (2001) Allergic rhinitis and its impact on asthma (ARIA) WHO Position Paper. J Allergy Clin Immunol 108(5 Part 2):S147–334

208

G. Passalacqua and G.W. Canonica

7. Del Prete GF, De Carli M, Mastromauro C, Biagiotti R, Macchia D, Falagiani P, Ricci M, Romagnani S (1991) Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest 88:346–50. 8. Romagnani S (2006) Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders? Allergy 61(1):3–14. 9. Joint task force for practical parameters (2003) Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma and Immunology. American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 90(1 Suppl 1):1–40. 10. Alvarez-Cuesta E, Canonica GW, Durham S, Malling HJ, Valovirta E (2006) Standards for practical allergen-specific immunotherapy. Allergy 61(Suppl 82):1–20 11. Frew AJ, Powell RJ, Corrigan CJ, Durham SR; UK Immunotherapy Study Group (2006) Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 117:319–25. 12. Nanda A, O’connor M, Anand M, Dreskin SC, Zhang L, Hines B et al (2004) Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract. J Allergy Clin Immunol 114:1339–44. 13. Abramson M, Puy R, Weiner JM (2003) Allergen immunotherapy for asthma. Cochrane Database Syst Rev: CD001186 14. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S (2007) Allergen injection immunotherapy for seasonal allergic rhinitis. The Cochrane Database Syst Rev Issue 1. 15. Winther L, Malling HJ, Mosbech H (2000) Allergen-specific immunotherapy in birch- and grass-pollen-allergic rhinitis. II. Side-effects. Allergy 55:827–35 16. Moreno C, Cuesta-Herranz J, Fernandez-Tavora L, Alvarez-Cuesta E (2004) Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases. Clin Exp Allergy 34:527–31 17. Arifhodzic N, Behbehani N, Duwaisan AR, Al-Mosawi M, Khan M (2003) Safety of subcutaneous specific immunotherapy with pollen allergen extracts for respiratory allergy. Int Arch Allergy Immunol 132:258–62 18. Harvey SM, Laurie S, Hilton K, Khan DA (2004) Safety of rush immunotherapy to multiple aeroallergens in an adult population. Ann Allergy Asthma Immunol 92:414–9 19. Aaronson DW, Gandhi TK (2004) Incorrect allergy injections: allergists’ experiences and recommendations for prevention. J Allergy Clin Immunol 113:1117–21 20. Garcia BE, Sanz ML, Gato JJ, Fernandez J, Oehling A (1993) IgG4 blocking effect on the release of antigen-specific histamine. J Investig Allergol Clin Immunol 3:26–33. 21. Van Neerven RJ, Wikborg T, Lund G, Jacobsen B, Brinch-Nielsen A, Arnved J, Ipsen H (1999) Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. J Immunol 163: 2944–52. 22. Wachholz PA, Soni NK, Till SJ, Durham SR (2003) Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J Allergy Clin Immunol 112:915–22. 23. Strait RT, Morris SC, Finkelman FD (2006) IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcgammaRIIb cross-linking. J Clin Invest 116:833–41. 24. Zhu D, Kepley CL, Zhang M, Zhang K, Saxon A (2002) A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nat Med 8:518–21 25. Varney VA, Hamid QA, Gaga M, Ying S, Jacobson M, Frew AJ et al (1993) Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergeninduced late-phase cutaneous responses. J Clin Invest 92:644–51. 26. Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS et al (1996) Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

27.

28.

29.

30.

31.

32.

33. 34. 35.

36. 37.

38. 39.

40.

41. 42. 43.

44.

209

eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. J Allergy Clin Immunol 97:1356–65. Jutel M, Pichler WJ, Skrbic D, Urwyler A, Dahinden C, Muller UR (1995) Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. J Immunol 154:4187–94. Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U, Schenk S et al (1997) Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin Exp Allergy 27:1007–15 Klimek L, Dormann D, Jarman ER, Cromwell O, Riechelmann H, Reske-Kunz AB (1999) Short-term preseasonal birch pollen allergoid immunotherapy influences symptoms, specific nasal provocation and cytokine levels in nasal secretions, but not peripheral T-cell responses, in patients with allergic rhinitis. Clin Exp Allergy 29:1326–35. Wachholz PA, Nouri-Aria KT, Wilson DR, Walker SM, Verhoef A, Till SJ, Durham SR (2002) Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1:Th2 cytokine ratios. Immunology 105:56–62 Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA (2003) IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 33:1205–14. Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK (2004) Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 172:3252–9. Francis JN, Till SJ, Durham SR (2003) Induction of IL-10 + CD4 + CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol 111:1255–61. Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY (1998) IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 160:3555–61. Zan H, Cerutti A, Dramitinos P, Schaffer A, Casali P (1998) CD40 engagement triggers switching to IgA1 and IgA2 in human B cells through induction of endogenous TGF-beta: evidence for TGF-beta but not IL-10-dependent direct S mu-- > S alpha and sequential S mu-- > S gamma, S gamma-- > S alpha DNA recombination. J Immunol 161:5217–25. Mosbech H, Østerballe O (1998) Does the effect of immunotherapy last after termination of treatment? Follow-up study in patients with grass pollen rhinitis. Allergy 53:523–9. Grammer LC, Shaughnessy MA, Suszko IM, Shaughnessy JJ, Patterson R (1984) Persistence of efficacy after a brief course of polymerized ragweed allergen: a controlled study. J Allergy Clin Immunol 87:484–9. Hedlin G, Hheilborn H, Lilja G (1995) Long-term follow-up of patients treated with a threeyear course of cat or dog immunotherapy. J Allergy Clin Immunol 57:879–85. Des-Roches A, Paradis L, Knani J et al (1996) Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of efficacy of immunotherapy after its cessation. Allergy 51:430–4. Ariano R, Augeri M, Kroon L, Passalacqua G, Canonica GW (1999) Long term allergoid immunotherapy to Parietaria: clinical and immunological effects in a double blind trial. Allergy 54:313–19. Durham SR, Walker SM, Varga EM (1999) Long term clinical efficacy of grass pollen immunotherapy. N Eng J Med 341:468–75. Eng PA, Reihold M, Gnem HPE (2002) Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy 57:306–12. Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP (2006) Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 61: 198–201. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S (2001) Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy 31:1392–7.

210

G. Passalacqua and G.W. Canonica

45. Purello-D’Ambrosio F, Gangemi S, Merendino RA, Isola S, Puccinelli P, Parmiani S (2001) Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy 31:1295–302. 46. Des Roches A, Paradis L, Menardo JL, Bouges S, Daures JP, Bousquet J (1997) Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 99(4):450–3 47. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen L, Koivikko A, Koller DY, Niggemann B, Norberg LA, Urbanek R, Valovirta E, Wahn U (2002) Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PATstudy). J Allergy Clin Immunol 109:251–6 48. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S, Høst A (2006) Five-year follow up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 61:865–9 49. EAACI Position Paper on local immunotherapy (1998) Malling HJ edt Allergy 53:933–44. 50. Scadding K, Brostoff J (1986) Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy 16:483–91 51. Passalacqua G, Canonica GW (2006) Sublingual immunotherapy: update 2006. Curr Opin Allergy Clin Immunol 6(6):449–54. 52. Passalacqua G, Durham SR (2007) ARIA update: allergen immunotherapy. J Allergy Clin Immunol 119:881–91. 53. Wilson DR, Torres L, Durham SR (2005) Sublingual immunotherapy for allergic rhinitis. Allergy 60:3–8 54. Calamita Z, Saconato H, Bronhara Pelà A, Nagib Atallah A (2006) Efficacy of Sublingual immunotherapy in asthma. Systematic review of randomized clinical trials. Allergy 61:1162–72. 55. Penagos M, Compalati E, Tarantini F, Baena Cagnani R, Huerta Lopez J, Passalacqua G, Canonica GW (2006) Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in children. Meta analysis of randomized controlled trials. Ann Allergy Asthma Immunol 97:141–8 56. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE, Orozco S, Pedroza A, Canonica GW (2008) Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest 133(3):599–609 57. Shekelle PG, Woolf SH, Eccles M, Grimshaw J (1999) Clinical guidelines: developing guidelines. BMJ 318:593–6 58. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S (2006) Sublingual immunotherapy with once-daily grass-allergen tablets: a randomised controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 117:802–9. 59. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, Rivas MF, Ribel M, Durham SR (2006) Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 118:434–40. 60. Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A, Andre C, de Beaumont O, Melac M (2007) Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 120:1338–45. 61. Wahn U, Tabar A, KunaP, Halken S, Montagut A, De Beaumont O (2009) Efficacy and safety of 5 grass pollen subllingualimmunotherapy in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 123:160–166 62. Roder E, Berger MY, Hop WC, Bernsen RM, de Groot H, Gerth van Wijk R (2007) Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. J Allergy Clin Immunol 119:892–8. 63. Quirino T, Iemoli E, Siciliani E, Parmiani S (1996) Sublingual vs injective immunotherapy in grass pollen allergic patients: a double blind double dummy study. Clin Exp Allergy 26:1253–61 64. Bernardis P, Agnoletto M, Puccinelli P, Parmiani S, Pozzan M (1996) Injective VS sublingual immunotherapy in Alternaria tenuis allergic patients. J Invest Allergol Clin Immunol 6:55–62.

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

211

65. Mungan D, Misirligil Z, Gurbuz L (1999) Comparison of the efficacy of subcutaneous and sublingual immunotherapy in mite sensitive patients with rhinitis and asthma: a placebo controlled study. Ann Allergy Asthma Immunol 82:485–90 66. Khinchi MS, Poulsen LK, Carat F, Andrè C, Hansen AB, Malling H-J (2004) Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy. A randomized placebo controlled, double blind, double dummy study. Allergy 59:33–44 67. Gidaro G, Marcucci F, Sensi L, Frati F, Incorvaia C, Ciprandi G (2005) The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy 35:565–71. 68. Kleine-Tebbe J, Ribel M, Herold DA (2006) Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Allergy 61:181–4. 69. Cox LS, Linnemann DL, Nolte H, Weldon D, Finegold I, Nelson HS (2006) Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 117:1021–35. 70. Dunsky EH, Goldstein FM, Dvorin J, Belecanech GA (2006) Anaphylaxis to sublingual immunotherapy. Allergy 61:1235 71. Antico A, Pagani M, Crema A (2006) Anaphylaxis by latex sublingual immunotherapy. Allergy 61:1236 72. Di Rienzo V, Pagani A, Parmiani S, Passalacqua G, Canonica GW (1999) Post-marketing surveillance study on the safety of sublingual immunotherapy in children Allergy 54:1110–3 73. Di Rienzo V, Musarra A, Sambugaro R, Minelli M, Pecora S, Canonica GW, Passalacqua G (2005) Post marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy 35:560–4. 74. Pajno GB, Peroni DG, Vita D, Pietrobelli A, Parmiani S, Boner AL (2003) Safety of Sublingual immunotherapy in children with asthma. Paediatr Drugs 5:777–81 75. Lombardi C, Gargioni S, Melchiorri A, Tiri P, Falagiani P, Canonica GW, Passalacqua G (2001) Safety of sublingual immunotherapy with monomeric allergoid in adults: multicenter post-marketing surveillance study. Allergy 56:989–92. 76. Agostinis F, Tellarini L, Falagiani P, Canonica GW, Passalacqua G (2005) Safety of SLIT in very young children. Allergy 60(1):133. 77. Fiocchi A, Pajno G, La Grutta S, PezzutoF, Incorvaia C, Sensi L, Marcucci F, Frati F (2005) Safety of SLI T in children aged 3 to 7 years. Ann Allergy Asthma Immunol 95:254–8. 78. Bufe A, Ziegler-Kirbach E, Stoeckmann E, Heidemann P, Gehlhar K (2004) Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study. Allergy 59:498–504. 79. Lima MT, Wilson D, Pitkin L (2002) Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy 32:507–14 80. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, Castello JV, Alonso R, de Mateo JA, Cerda-Trias T, San Miguel-Moncin Mdel M, Monzon S, Garcia M, Palacios R, CisteroBahima A (2005) Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 116:1073–9. 81. Bahceciler NN, Arikan C, Taylor A, Akdis M, Blaser K, Barlan IB, Akdis CA (2005) Impact of sublingual immunotherapy on specific antibody levels in asthmatic children allergic to house dust mites. Int Arch Allergy Immunol 136:287–94. 82. Marcucci F, Sensi L, Di Cara G, Salvatori S, Bernini M, Pecora S, Burastero SE (2005) Threeyear follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing sub-lingual immunotherapy. Pediatr Allergy Immunol 16:519–26. 83. Rolinck-Werninghaus C, Kopp M, Liebke C, Lange J, Wahn U, Niggemann B (2005) Lack of detectable alterations in immune responses during sublingual immunotherapy in children with seasonal allergic rhinoconjunctivitis to grass pollen. Int Arch Allergy Immunol 136:134–41. 84. Dehlink E, Eiwegger T, Gerstmayr M, Kampl E, Bohle B, Chen KW, Vrtala S, Urbanek S, Szepfalusi Z (2006) Absence of systemic immunologic changes during dose build-up phase and early maintenance period in effective specific sublingual immunotherapy in children. Clin Exp Allergy 36:32–9.

212

G. Passalacqua and G.W. Canonica

85. Cosmi L, Santarlasci V, Angeli R, Liotta F, Maggi L, Forsali F, Rossi O, Falagiani P, Riva G, Romagnani S,Annunziato E, Maggi E (2006) Sublingual immunotherapy with Dermatophagoides monomeric allergoid down-regulates allergen-specific immunoglobulin E and increases both interferon-gamma- and interleukin-10-production. Clin Exp Allergy 36:261–72. 86. Ciprandi G, Fenoglio D, Cirillo I, Vizzaccaro A, Ferrera A, Tosca MA, Puppo F (2005) Induction of interleukin 10 by sublingual immunotherapy for house dust mites: a preliminary report. Ann Allergy Asthma Immunol 95:38–44. 87. Ippoliti F, De Sanctis W, Volterrani A (2003) Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol 14:216–21 88. Savolainen J, Jacobsen L, Valovirta E (2006) Sublingual immunotherapy in children modulates allergen induced in vitro expression of cytokine mRNA in PBMC. Allergy 61:1184–90 89. Bagnasco M, Passalacqua G, Villa G (2001) Pharmacokinetics of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers. Clin Exp Allergy 31:54–60. 90. Bagnasco M, Altrinetti V, Pesce G, Caputo M, Mistrello G, Falagiani P, Canonica GW, Passalacqua G (2005) Pharmacokinetics of radioalbelled Der p2 allergen and monomeric allergoid in allergic volunteers. Int Arch Allergy Immunol 138:197–202. 91. Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G (2004) Randomized controlled open study of SLIT for respiratory allergy in real life: clinical efficacy and more. Allergy 59:1205–10. 92. Marogna M, Massolo A, Zanon P, Berra D, Chiodini E, Canonica GW, Passalacqua G (2006) The type of sensitizing allergen affects the evolution of respiratory allergy. Allergy 61:1209–15. 93. Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M (2004) Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 114:851–7. 94. Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco AD, Canonica GW, Passalacqua G, Tripodi S (2008) Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol 101(2):206–11. 95. Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L, Canonica GW, Passalacqua G (2003) Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a ten year prospective study. Clin Exp Allergy 33: 206–10 96. Lombardi C, Gani F, Landi M, Falagiani P, Bruno M, Canonica GW, Passalacqua G (2004) Quantitative assessment of the adherence to sublingual immunotherapy. J Allergy Clin Immunol 113:1219–20. 97. Passalacqua G, Musarra A, Pecora S, Amoroso S, Antonicelli L, Cadario G, Di Gioacchino M, Lombardi C, Ridolo E, Sacerdoti G, Schiavino D, Senna G. (2006) Quantitative assessment of the compliance with a simplified SLIT regimen in real life. J Allergy Clin Immunol 117(4):946–8. 98. Passalacqua G, Musarra A, Pecora S, Amoroso S, Antonicelli L, Cadario G, Gioacchino MD, Lombardi C, Ridolo E, Sacerdoti G, Schiavino D, Senna G (2007) Quantitative assessment of the compliance with a once-daily sublingual immunotherapy regimen in children. Pediatr Allergy Immunol 18(1):58–62. 99. Berto P, Bassi M, Incorvaia C, Frati F, Puccinelli P, Giaquinto C, Cantarutti L, Ortolani C (2005) Cost effectiveness of sublingual immunotherapy in children with allergic rhinitis and asthma. Allerg Immunol (Paris) 37(8):303–8. 100. Berto P, Passalacqua G, Crimi N, Frati F, Ortolani C, Senna G, Canonica GW; Italian SPAI Study Group (2006) Economic evaluation of sublingual immunotherapy vs symptomatic treatment in adults with pollen-induced respiratory allergy: the Sublingual Immunotherapy Pollen Allergy Italy (SPAI) study. Ann Allergy Asthma Immunol. 97(5): 615–21.

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

213

101. Cistero Bahima A, Sastre J, Enrique E, Fernandez M, Alonso R, Quirce S, Gandarias B, Parmiani S, Rico P (2004) Tolerance and effects on skin reactivity to latex of sublingual rush immunotherapy with a latex extract. J Investig Allergol Clin Immunol 14(1): 17–25. 102. Bernardini R, Campodonico P, Burastero S, Azzari C, Novembre E, Pucci N, Massai C, De Martino M, Vierucci A (2006) Sublingual immunotherapy with a latex extract in paediatric patients: a double-blind, placebo-controlled study. Curr Med Res Opin 22(8):1515–22. 103. Nettis E, Colanardi MC, Soccio AL, Marcandrea M, Pinto L, Ferrannini A, Tursi A, Vacca A. (2007) Double-blind, placebo-controlled study of sublingual immunotherapy in patients with latex-induced urticaria: a 12-month study. Br J Dermatol 156(4):674–81. 104. Pajno G, Vita D, Caminiti L, Barberio G, Lombardo A, Canonica GW, Passalacqua G (2007) Sublingual immunotherapy in mite-senisitized children with atopic dermatitis. J Allergy Clin Immunol 120:164–170. 105. Rossi R, Monasterolo RE (2005) A pilot study of feasibility of ultra-rush (20–25 minutes) sublingual-swallow immunotherapy in 679 patients (699 sessions) with allergic rhinitis and/ or asthma. Int J Immunopathol Pharmacol 18(2):277–85. 106. Tripodi S, Di Rienzo Businco A, Benincori N, Scala G, Pingitore G (2005) Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children. Int Arch Allergy Immunol 139:149–152. 107. Rodriguez F, Boquete M, Ibanez MD, de la Torre-Martinez F, Tabar AI (2006) Once daily sublingual immunotherapy without updosing – A new treatment schedule. Int Arch Allergy Immunol 140:321–6. 108. Sehra S, Chugh L, Gangal SV (1998) Polarized TH1 responses by liposome-entrapped allergen and its potential in immunotherapy of allergic disorders. Clin Exp Allergy 28(12):1530–7. 109. Basomba A, Tabar AI, de Rojas DH, Garcia BE, Alamar R, Olaguibel JM, del Prado JM, Martin S, Rico P (2002) Allergen vaccination with a liposome-encapsulated extract of Dermatophagoides pteronyssinus: a randomized, double-blind, placebo-controlled trial in asthmatic patients. J Allergy Clin Immunol 109:943–8. 110. Alvarez MJ, Echechipia S, Garcia B, Tabar AI, Martin S, Rico P, Olaguibel JM (2002) Liposome-entrapped D. pteronyssinus vaccination in mild asthma patients: effect of 1-year double-blind, placebo-controlled trial on inflammation, bronchial hyperresponsiveness and immediate and late bronchial responses to the allergen. Clin Exp Allergy 32(11):1574–82. 111. Trimble C, Lin CT, Hung CF, Pai S, Juang J, He L, Gillison M, Pardoll D, Wu L, Wu TC (2003) Comparison of the CD8+ T cell responses and antitumor effects generated by DNA vaccine administered through gene gun, biojector, and syringe.Vaccine 21:4036–42. 112. Kendall M, Mitchell TJ, Costigan G, Armitage M, Lenzo JC, Thomas JA, von Garnier C, Zosky GR, Turner DJ, Stumbles PA, Sly PD, Holt PG, Thomas WR (2006) Downregulation of IgE antibody and allergic responses in the lung by epidermal biolistic microparticle delivery. J Allergy Clin Immunol 117(2):275–82. 113. Jalava K, Eko FO, Riedmann E, Lubitz W (2003) Bacterial ghosts as carrier and targeting systems for mucosal antigen delivery. Expert Rev Vaccines 2(1):45–51. 114. Crameri R, Rhyner C (2006) Novel vaccines and adjuvants for allergen-specific immunotherapy. Curr Opin Immunol 18(6):761–8. 115. Francis JN, Durham SR (2004) Adjuvants for allergen immunotherapy: experimental results and clinical perspectives. Curr Opin Allergy Clin Immunol 4(6):543–8. 116. Wheeler AW, Marshall JS, Ulrich JT (2001) A Th1-inducing adjuvant, MPL, enhances antibody profiles in experimental animals suggesting it has the potential to improve the efficacy of allergy vaccines. Int Arch Allergy Immunol 126(2):135–9. 117. Puggioni F, Durham SR and Francis JN (2005) Monophosphoryl lipid A (MPL)* promotes allergen-induced immune deviation in favour of Th1 responses. Allergy 60:678–84. 118. Drachenberg KJ, Wheeler A, Stubner P, Horak F (2001) A well tolerated grass pollen specific allergy vaccine containing a novel adjuvant MPL reduces allergy symptoms after only four preseasonal injections. Allergy 56:498–505.

214

G. Passalacqua and G.W. Canonica

119. Mothes N, Heinzkill M, Drachenberg KJ (2003) Allergen-specific immunotherapy with a monophosphoryl lipid A-adjuvanted vaccine: reduced seasonally boosted immunoglobulin E production and inhibition of basophil histamine release by therapy-induced blocking antibodies. Clin Exp Allergy 33:1198–208. 120. Drachenberg KJ, Heinzkill M, Urban E, Woroniecki SR (2003) Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents. Allergol Immunopathol (Madr) 31(5):270–7. 121. Patel P, Salapatek AM (2006) Pollinex Quattro: a novel and well-tolerated, ultra short-course allergy vaccine. Expert Rev Vaccines 5(5):617–29. 122. Raz E, Tighe H, Sato Y (1996) Preferential induction of a Th1 response and inhibition of IgE formation by plasmid DNA immunization. Proc Natl Acad Sci 93:5141–47 123. Sato Y, Roman M, Tighe H (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 272:352–4 124. Hemmi A, Takeuchi O, Kawai T (2000) A toll like receptor recognizes bacterial DNA. Nature 408:740–5. 125. Broide D, Raz E (1999) DNA-Based immunization for asthma. Int Arch Allergy Immunol 118:453–6. 126. Horner AA, Takabayashi K, Zubeldia JM, Raz E (2002) Immunostimulatory DNA based therapeutics for experimental and clinical allergy. Allergy 57:24–9. 127. Creticos PS, Eiden JJ, Broide DH, Balcer-Whaley S, Schroeder JT, Khattignavong A (2002) Immunotherapy with immunostimulatory oligonucleotides linked to purified ragweed Amb a1 allergen: effects on antibody production, nasal allergen provocation, and ragweed seasonal rhinitis. J Allergy Clin Immunol 109:743–4 128. Simons FE, Shikishima Y, Van Nest G, Eiden JJ, Hayglass KT (2004) Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 113:1144–51. 129. Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ, Broide D; Immune Tolerance Network Group (2006) Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355:1445–55. 130. O’Hehir R, Aguilar B, Schmidt TJ (1991) Functional inactivation of dermatophagoides spp reactive human T cell clones. Clin Exp Allergy 21:208–15. 131. Hoyne GF, Askonas BA, Hetzel C, Thomas WR, Lamb JR (1996) Regulation of house dust mite response by intranasaly administered peptides. Int Immunol 8:335–42. 132. Marcotte G, Braun CM, Norman PS, Nicodemus C, Kagey-Sobotka S, Lichtenstein N (1998) Effects of peptide therapy on ex vivo T cell responses. J Allergy Clin Immunol 101:506–13. 133. Norman P, Ohman JJ, Long A, Creticos P, Gefter M, Shaked Z (1996) Treatment of cat allergy with T cell reactive peptides. Am J Respir Crit Care Med 154:1623–8. 134. Simons FE, Imada M, Li Y, Watson WT, HayGlass KT (1996) Fel d 1 peptides. Effect on skin test and cytokine synthesis in cat allergic patients. Int Immunol 8:1937–45. 135. Pene J, Desroches A, Paradis L, Lebel B, Farce M, Nicodemus CF, Bousquet J (1998) Immunotherapy with Fel d 1 peptides decreases IL-4 release by peripheral blood T cells of patients allergic to cats. J Allergy Clin Immunol 102(4):571–8. 136. Maguire P, Nicodemus C, Robinson D, Aaronson D, Umetsu DT (1999) The safety and efficacy of ALLERVAX CAT in cat allergic patients. Clin Immunol 93:222–31. 137. Oldfield WL, Larchè M, Kay AB (2002) A double blind placebo controlled study of shortpeptides derived from Fel d 1 in cat allergic subjects. Lancet 360:47–53. 138. Alexander C, Tarzi M, Larche M, Kay AB (2005) The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects. Allergy 60:1269–74. 139. Muller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, Blaser K (1998) Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces spe-

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma

140.

141.

142. 143. 144.

145. 146.

147.

148. 149. 150. 151.

215

cific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol 101(6):747–54. Fellrath JM, Kettner A, Dufour N, Frigerio C, Schneeberger D, Leimgruber A (2003) Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a phase I trial. J Allergy Clin Immunol 111:854–61. Tarzi M, Klunker S, Texier C, Verhoef A, Stapel SO, Akdis CA (2006) Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy. Clin Exp Allergy 36:465–74. Valenta R, Niederberger V (2007) Recombinant allergens for immunotherapy. J Allergy Clin Immunol 119(4):826–30. Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O (2005) Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 116:608–13. Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, Valent P, Reisinger J, Pelzmann M, Hayek B, Kronqvist M, Gafvelin G, Gronlund H, Purohit A, Suck R, Fiebig H, Cromwell O, Pauli G, van Hage-Hamsten M, Valenta R (2004) Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci USA 101(Suppl 2): 14677–82. Valenta R, Kraft D (2002) From allergen structure to new forms of allergen-specific immunotherapy. Curr Opin Immunol 14:718–27. Gabler M, Scheiblhofer S, Kern K, Leitner WW, Stoecklinger A, Hauser-Kronberger C, Alinger B, Lechner B, Prinz M, Vrtala S, Valenta R, Thalhamer J, Weiss R (2006) Immunization with a low-dose replicon DNA vaccine encoding Phl p 5 effectively prevents allergic sensitization. J Allergy Clin Immunol 118(3):734–41. Wild C, Wallner M, Hufnagl K, Fuchs H, Hoffmann-Sommergruber K, Breiteneder H, Scheiner O, Ferreira F, Wiedermann U (2007) A recombinant allergen chimer as novel mucosal vaccine candidate for prevention of multi-sensitivities. Allergy 62(1):33–41. Nelson H (2007) Allergen immunotherapy. Where is it now. J Allergy Clin Immunol 119:769–77. Pajno GB (2007) Sublingual immunotherapy: the optimism and the issues. J Allergy Clin Immunol 119:899–901. Akdis M, Akdis CA (2007) Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 119(4):780–9. Larchè M (2007) Peptide immunotherapy for allergic diseases. Allergy 62(3):325–31.

Sublingual Immunotherapy in Allergic Rhinitis and Asthma Paul Potter

Introduction Since the recognition and approval of sublingual immunotherapy (SLIT) by the World Health Organization and the European Association of Allergy and Clinical Immunology in 1998 [1, 2], there was been a worldwide interest in the use of this treatment for allergic diseases. Sublingual immunotherapy has been shown to be effective in rhinitis and asthma; it is extremely safe and unlike subcutaneous immunotherapy, represents a form of immunotherapy which can be used beyond the specialized allergy centers. Sublingual immunotherapy involves the daily administration of incremental amounts of a purified allergen, which is held under the tongue for 2 min and then swallowed. Optimal dosing regimens are still being explored, but typically doses are increased over 4 weeks to reach a maintenance dose, which is continued on alternate days for a 3 year period. The allergen may be administered as drops, as an oral spray, or as a rapidly dissolving tablet. Sublingual immunotherapy (SLIT) has been found to be effective for seasonal allergic rhinitis and in certain children with asthma. This review will consider current knowledge of the immunological changes which have been observed in patients undergoing SLIT, the clinical evidence of efficacy and safety of SLIT in allergic rhinitis and asthma and the current indications and limitations of its use in children and adults.

P. Potter () Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, George Street, Mowbray, Cape Town 7700, South Africa e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_13, © Springer 2010

217

218

P. Potter

Mechanisms During sublingual immunotherapy, patients achieve a state of tolerance or unresponsiveness to the allergens administered. Clinical observations and recent studies indicate that a state of long term tolerance may be occurring in phases which may be related to dosing and frequency of administration of the allergen. There is currently some debate as to whether SLIT activates the same immunological mechanisms, to induce tolerance to the allergen, as that occurs during subcutaneous immunotherapy (SIT). It is evident from the route of administration of the vaccine that Fc Epsilon bearing dendritic cells in the oral mucosa, which are not present in subcutaneous tissues, are involved in SLIT, but not in SIT. Clinically, an early phase of oral tolerance is achieved within weeks of initiating SLIT. Patients who initially react to the sublingual drops with oral itching for about 30 min after exposure report that the oral itching goes away within a few weeks and higher oral doses are tolerated without local clinical effects. The oral tolerance, so achieved, occurs before any appreciable tolerance to allergen exposure is perceived in end organs such as the nose, or the airways. Once they have achieved oral tolerance, patients may report early onset of tolerance in the end organ. This was typically observed in patients receiving preseasonal SLIT for pollen allergies within 3 months of initiating SLIT [3]. A similar acquisition of significant protection and tolerance to latex allergen [4] has been reported within 3 months of SLIT. Long lasting tolerance is achieved after 2–4 years of SLIT typically for perennial allergies (e.g., house dust mites), manifesting as asthma and/or rhinitis, and also for seasonal allergies. Tolerance is maintained for as long as 10 years after SLIT has been discontinued [5]. There are no published sequential long-term studies, which provide information on what happens immunologically during these phases of tolerance. Several cross sectional studies have been published, reporting changes in mediators, immunoglobulins, cytokines, and surface markers. These studies have been done at different time points, studying different molecules, in variable populations, receiving different allergen extracts, with different dosing schedules and in differing end organ diseases. Immunological changes observed to occur during SLIT are summarized in Table 1. In studies where the immunological changes observed during SLIT have been compared directly with patients in a parallel group receiving SIT, the immune responses to SIT appear to be stronger [9,10]. In the first instance immunological changes have been observed in the end organs of allergy, particularly the nose. Early reports that SLIT down regulates the expression of adhesion molecules on the nasal and conjunctival epithelial cells by Passalacqua et al. in 1998 [11, 12] have been confirmed by Silvestri et al. [13] in the studies of the expression of ICAM I in nasal epithelial cells. In the studies of Ippoliti [7], falls in serum ECP and IL-13 are clearly demonstrated. In the studies of Marcucci et al. [8], SLIT prevented the observed increase in nasal tryptase after allergen challenge, and a fall in allergen specific IgE, without any change in nasal ECP.

Sublingual Immunotherapy in Allergic Rhinitis and Asthma

219

Table 1 Immunological changes observed during sublingual immunotherapy A

Early (6 months)

B

Intermediate (10–12 months)

C

Later (>18 months)

• • • • • • • • • •

Fall in serum ECP [7] Fall in IL-13 [7] Increased PHA stimulated IL-12 [6] Increased Der p 1 stimulated IFNg [6] Fall in nasal allergen Specific IgE [8] Reduction in nasal tryptase levels [8] Increase in IL-10 [18] Reduction in late phase SPT responses (p = <0.003) [9] Increase in IgG4/IgE ratios (p = 0.05) [9] Fall in ICAM-I expression in nasal epithelial cells [10,12,13] • Reduction in methacholine responsiveness [10]

Lima [9] has reported a significant increase in IgG4/IgE ratios in certain patients receiving SLIT for over 18 months. The induction of “blocking” IgG antibodies has been reviewed by Wachholz and Durham [14] in patients undergoing SIT. It has been modulated that the induction of IgG antibodies with blocking activity may have a protective role, not only through the inhibition of allergen induced IgE mediated release of inflammatory mediators, but also through the inhibition of IgE facilitated antigen presentation to T cells. In most studies, although allergen specific IgE levels have not been influenced by SLIT, allergen specific IgG was shown to increase in studies by Tari et al. [15]. Allergen specific IgG4 increases are usually only observed after several months of immunotherapy and while some have considered these increases to be a para phenomenon following exposure to higher doses of allergen, further studies are required to understand whether they contribute to the development of tolerance in patients receiving SLIT. Although several clinical studies have shown a rapid onset of oral tolerance within months of the initiation of SLIT, there are no published immunological studies of this early period to explain this early tolerance development. It is probable that an alteration of certain TH2 responses occurs early at a cytokine level, reducing mast cell priming necessary for mediator release. At a systemic level, mechanisms for the induction of immunological tolerance are more likely to be related to changes in the regulatory T cell network. Although a reduction in late phase responses to allergen has been demonstrated in SLIT patients by Lima et al., a complete shift from a TH2 to a TH1 response to allergen has not been consistently shown to accompany successful immunotherapy, as evidenced by a persistence in IgE levels and an elevation in IgG4 levels during successful immunotherapy. The importance of IL-10+ CD4+ CD25+ T cells in the peripheral blood playing a regulatory role in allergic and nonallergic subjects requires further study in patients undergoing SLIT. IL-10 is a major regulatory cytokine of inflammatory responses and acts as a general inhibitor of both TH1 and TH2 cells in vitro and in vivo [16].

220

P. Potter

IL-10 promotes IgG4 while TGF switches B cells toward IgA promoting IgA antibody production. For successful SIT induction of cells of the CD4+ CD25 type secreting IL-10 and TGF-B is essential for the suppression of allergen induced immune responses. Oral administration of antigens typically generates TGF B secreting T cells (Tr1/ Th3), which localize to the target organ and suppress inflammation in the local microenvironment [16]. Animal studies at the Pasteur Institute (Paris), Ben Mohamed L et al. [17] have shown that sublingual delivery of lipoproteins results in stronger systemic responses in lymph nodes and in the spleen than subcutaneous administration, without adjuvant. The mucosal route resulted in preferential induction of gamma interferon producing cells and of IgG2a antibodies, compared to the dominant IL-4 and IgG, responses from the subcutaneous route. However, using sublingual allergen immunotherapy, the presence of systemic immune effects on IgG4/IgE ratios (p = 0.05) and reduction in late phase SPT responses (p = 0.003) were not accompanied by changes in the sublingual epithelium or lamina propria for CD3+ cells, CD1a cells, CD68+ cells, or IL-2mRNA [9]. Oral dendritic cells have higher levels of FcER expression when compared with skin dendritic cells and activation of this receptor leads to secretion of IL-10 in monocytes. This unique environment in the oral mucosa contributes significantly to inflammatory suppression via the oral route. Its importance in SLIT remains to be explored. If allergens are given in high doses in a noninflammatory environment where there is a no co-stimulation by accessory molecules, immunological “suppression” rather than immune “activation” is favored Recently, the role of suppressive cytokines such as IL-10 and TGF-B as key molecules in the maintenance of peripheral tolerance has been highlighted. IL-10 enhances IgG4 and TGF-B enhances IgA secretion, while IgE production is suppressed by these cytokines. Allergens entering the mucosal surfaces are regulated by both IL-10 and TGF-B. Oral administration of antigen induces antigen specific TGF-B secreting T cells (Tr1/Th3), which localize to the target organ and suppress inflammation in the local environment. For bee venom SIT, Adkis et al. have found that an early increase in IL-10 (within a month) and an increase in TGF-B within 1 year correlates well with successful treatment and recently an increase in IL-10 was shown to accompany successful sublingual immunotherapy [18]. Pharmacokinetics of sublingual immunotherapy have been investigated by Bagnusco et al. [19] using 123I labeled purified parietaria allergen (Par j 1) and sequential scintiscans, plasma radioactivity, and plasma chromatographs. It was found that allergen was retained up to 40 h in the oral mucosa and that native allergen could not be detected in the bloodstream after swallowing. Oral dendritic cells “retain” allergen and Fc Epsilon receptor bearing cells in the oral mucosa of allergic subjects, which may be important in the induction of tolerance during SLIT. Further, long-term sequential studies are required to understand the immunological mechanisms underlying successful sublingual immunotherapy. The application of

Sublingual Immunotherapy in Allergic Rhinitis and Asthma

221

recent knowledge in peripheral tolerance mechanisms may well facilitate the development of more potent and effective sublingual vaccines [20].

Clinical Evidence of Efficacy SLIT is commercially available and used routinely in Europe, parts of the Middle East, Malaysia, Southern Africa, and in South America. In a recent update, Passalacqua and Canonica [21] reported on the clinical results of 36 double blind placebo controlled studies, which have been conducted on SLIT to date. Nine new studies [22–30] had been published between 2004 and 2006. All of the studies confirmed that SLIT was effective in reducing the symptoms of rhinoconjunctivitis and when present, also concomitant asthma. In the recent large placebo controlled study by Niu et al. (2006) [22] the clinical efficacy of SLIT in asthmatic children with mite allergy was also confirmed. An important meta analysis of Wilson et al. (2005) [31] confirmed that sublingual immunotherapy was effective and safe for allergic rhinitis and highlighted the paucity of studies on SLIT in asthma and particularly in children. A new meta analysis of 10 pediatric studies has confirmed that SLIT is effective in reducing the rescue medication and symptom scores in children [32], compared with placebo. In a review, comparing the clinical efficacy and safety of subcutaneous and sublingual immunotherapy, Malling [33] drew attention to the importance of using clearly defined selection criteria, extracts, dosing schedules, and outcome variables. Very few studies meet such criteria for direct comparison. The first methodologically optimal comparison between sublingual and subcutaneous immunotherapy evaluated over 2 years was reported by Khinchi et al. 2004 [34]. Despite a number of dropouts in this study of 71 subjects no significant difference in symptom and medication scores was observed among the groups using a commercial birch pollen extract as the allergen. The cumulative dose in the SLIT treated patients was 175 times the dose given subcutaneously in the first year. This study also drew attention to the importance in taking into consideration the pollen load in such a study. In the patients on SLIT, a reduction of 50% was observed, but in view of small numbers assessment of the statistical difference between SLIT and SLIT treated groups was not possible. The World Allergy Organization (WAO) has stressed the importance of conducting methodologically sound studies in a recent WAO document [35]. In a new ARIA document (Allergic Rhinitis and its Impact on Asthma group, in co-operation with Ga2LEN (Global allergy and asthma European Network). Passalacqua and Durham have also conducted an update on allergen immunotherapy in which the evidence for efficacy, safety, and additional effects of sublingual immunotherapy is reviewed [36]. Clinical efficacy has been confirmed for SLIT for rhinitis for most of the common allergens including grasses, trees, ragweed, parietaria, and mites. For asthma a 2 year course of SLIT significantly reduced the severity of bronchial hyperresponsiveness [37].

222

P. Potter

Since the meta analysis of Wilson [31], further studies have confirmed the efficacy of SLIT in children with allergies to grass pollen [38,39] and house dust mites [40]. SLIT is highly suitable for children for long term use because it is less invasive than subcutaneous injections. In a long term study of SLIT in children by Rienzo [5], the prevalence of asthma was greatly reduced 4–5 years after discontinuation of the vaccine. The long term benefit may be particularly important in children with more severe symptoms [40].

New Dosing Regimes Although sublingual immunotherapy has been proven to be safe and efficacious for allergic conjunctivitis and in asthma optimal dosing regimens are still being explored. It is conventionally accepted that treatment doses up to 375 times of those used in subcutaneous immunotherapy are necessary for efficacy, but it is unclear if a time dose-response relationship exists. The frequency of SLIT administration may be crucial to its efficacy, and possibly more so than the cumulative dose. This hypothesis has been recently evaluated in an open study by Bordignon and Burasten [41] in which 64 patients with birch or grass pollen were studied using different regimes over a 2 year period. Some subjects received their immunotherapy drops 3 times daily. It was found that in patients who received their sublingual drops more frequently (3 × daily), the number of administrations correlated with the efficacy of SLIT as measured by antihistamine use. There was no increase in adverse effects and skin prick reactivity was modulated parallel to increased frequency of SLIT use. It was suggested that multiple daily doses may provide a much greater impact on the overall allergen absorption through the oral mucosa than the concentration of the allergen or its cumulative amount. Using this regime an induction phase of administration is avoided. Further studies are needed to compare such regimes with the usual “high dose” SLIT administration regimes. Availability of a new dissolving tablet form of SLIT also opens up greater possibilities of the wider use of SLIT, because of its stability, simplicity of administration and easiness of storage. Strategies to enhance the allergen presentation to local dendritic cells, e.g., by regulatory T cells should be intensified [42].

Economic Evaluation Few data are available on the pharmacoeconomic aspects of sublingual immunotherapy. In a new study by Bertho et al. (2006) [43] costs, clinical outcomes, and cost effectiveness of SLIT plus pharmacotherapy was compared with pharmacotherapy alone using data on approximately 2,000 patients. From both perspectives SLIT was less expensive and more effective than pharmacotherapy alone.

Sublingual Immunotherapy in Allergic Rhinitis and Asthma

223

Safety There is good evidence to support the excellent safety profile of SLIT. In more than 20 years of clinical trials and commercial usage no or fatal event has ever been reported [44]. Pooled safety data has been reviewed again by Canonica [45] in 2006. In the pooled data from 472 adults published by Andre et al. [46], adverse occurred in 39% of individuals receiving active SLIT and 23% in the placebo groups. Adverse events were minor non-specific and mild systemic reactions and there were never any anaphylactic reactions. The main reason for stopping therapy in the few patients who dropped out (14 on active and 10 on placebo) was repeated buccal and abdominal discomfort. The most frequent side effect of SLIT was oral itching and swelling, which disappears within a few weeks. The gastrointestinal events appear to be dose related, but also disappear with time as tolerance is achieved. Seventeen systemic reactions have however been recently reported, including 2 cases of anaphylaxis [47, 48] when using non-standardised extracts [47] or a rush administration of a latex extract [48]

Psychological Stress and Response to SLIT Psychological stress has recently been shown to play a role in atopy and to also affect the response to immune modulating therapies such as vaccinations with microbial agents. In a new study by Ippoliti et al. (2006) of 40 children with asthma undergoing SLIT, there was a higher prevalence of psychosocial stressing factors (divorced/absent parents, low income households, nonworking parents) among stressed children. All clinical parameters and ECP concentration improved after SLIT in all patients, but greater improvements in symptom score, peak expiratory flow, and ECP occurred in the nonstressed patients. Stress evaluation is a useful prognostic factor in immunotherapy, as it may also have a bearing on adherence to medications, particularly over the long term. It should, however, also be borne in mind that on chronic allergic illness can also in its own right result in chronic stress for the patients if untreated. Sublingual immunotherapy has great potential to improve the quality of life of such patients [49].

Future Directions Since the efficacy and safety of sublingual immunotherapy has been confirmed in numerous DBPC trials [22–30] and meta analysis [32], and according to a Cochrane review discussed in this chapter [31], this form of therapy holds great promise for the future. Further research is required to determine optimal dosing and studies confirming efficacy of the new tablet formulations [50] are extremely important. Further studies on different tablet formulations are in progress. In the future, vaccine preparation strategies will focus on the use of biological or systemic adjuvants, which would improve the continuous allergen release and

224

P. Potter

presentation to oral Langerhans cells. These may include regulatory T cell adjuvants. Further research is also required as to how to best select patients for sublingual immunotherapy and whether mixtures of allergens would have any efficacy in sublingual immunotherapy vaccines, since only about 20% of allergic subjects are monosensitive, and efficacy has only been confirmed to date for SLIT using monovalent vaccines. For the purposes of marketing and registration it is also important that larger multicentre studies are conducted around the world to test efficacy and applicability of specific vaccines to allergy sufferers around the world. This is particularly important because of the potential for SLIT to be administered also by nonallergy specialists to allergy sufferers in the developing world, where there is a paucity of allergy expertise, but an increase in the prevalence in allergic disease, which parallels those that observed in the developed nations of the world.

References 1. Malling HJ, Abreu-Noguera J, Alvaraz-Cresta E. Local immunotherapy. Allergy 1998; 53: 933–944 2. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases (A WHO position paper). Allergy 1998; 53 (Suppl 44): 1–42 3. Gozallo F, Martin S, Rico P, Alvarez E, Cortes C. Clinical efficacy and tolerance of 2 year Lolium Perenne sublingual immunotherapy. Allergol and Immunopathol 1997; 25(5): 219–227 4. Patriarca G, Nucera E, Pollestrini E, et al. Sublingual desensitization: a new approach to the latex allergy problem. Anesth Anal 2002; 95(4): 956–960 5. Di Rienzo V, Marcucci F, Pucinilli P, et al. Long lasting effects of sublingual immunotherapy with asthma due to house dust mites: a 10 year prospective study. Clin Exp Allergy 2003; 33: 206–210 6. Arikan C, Bahceciler N, Deniz G, Adkis M, Akkok T, Adkis C, Burlan I. Bacillus Calmette Guérin induced IL-12 did not additionally improve clinical and immunologic parameters in asthmatic children treated with sublingual immunotherapy. Clin Exp Allergy 2004; 3: 398–405 7. Ippoliti F, De Santos W, Volterrani A, et al. Immunomodulation during sublingual immunotherapy in allergic children. Paed Allergy Immunol 2003; 14(3): 216–221 8. Marcucci F, Sensi L, Frati F, et al. Effects on inflammation parameters of a double blind, placebo controlled one-year course of SLIT in children monosensitised to mites. Allergy 2003; 58(7): 657–662 9. Lima MT, Wilson D, Petkin L, et al. Grass pollen sublingual immunotherapy for seasonal conjunctivitis. Clin Exp Allergy 2002; 32: 507–514 10. Silvestri M, Spaldarossa D, Buttistini E, et al. Changes in inflammatory and clinical parameters and in bronchial hyperreactivity in asthmatic children sensitised to house dust mites following SLIT. J Invest Allergol Clin Immunol 2002; 12: 52–59 11. Passalacqua G, Albano M, Fregonese L, et al. Randomised clinical trial of local allergoid immunotherapy on allergic inflammation in mite induced rhinoconjunctivitis. Lancet 1998; 351: 629–632 12. Passalacqua G, Albano M, Riccio AM, et al. Clinical and immunological effects of a risk sublingual immunotherapy to Parietaria species: a double bind placebo controlled trial. J Allergy Clin Immunol 1999; 104: 964–968

Sublingual Immunotherapy in Allergic Rhinitis and Asthma

225

13. Silvestri M, Spallarossa D, Battistini E, et al. Changes in inflammatory and clinical parameters and in bronchial hyperactivity in asthmatic children sensitised to house dust mites following sublingual immunotherapy. J Investig Allergol Clin Immunol 2002; 12: 52–59 14. Wachholz P, Durham S. Mechanisms of immunotherapy IgG revisited. Curr Opin Allergy Immunol 2004; 4: 313–318 15. Tari MG, Marciano M, Monti G, et al. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mites: a double blind study. Allergol Immunopath 1990; 18: 277–284 16. Adkis M, Schmidt-Weber C, Jutel M, Adkis L, Blaser K. Mechanisms of allergen immunotherapy. Allergy Clin Immunol Int J World Allergy Org 2004; 16: 65–69 17. Ben Mohamed L, Belkard Y, Loing E, Brahimi K, et al. Systemic immune responses induced by mucosal administration of lipo peptides without adjuvant. Eur J Immunol 2002; 32(8): 2274–2281 18. Ciprandi G, Fenoglio D, Cirilli I, Vizzacaro A, Ferreira A, Tosca MA. Induction of interleukin 10 by sublingual immunotherapy for house dust mites: a preliminary report. Ann Allergy Asthma Immunol 2005; 95: 38–44 19. Bagnusco M, Manani G, Passalacqua G, Motta C, Falagiani P. Absorption and distributions kinetics of the major parietaria judaica allergen (Par j 1) administered by non-injectable routes in healthy human beings. J Allergy Clin Immunol 1997; 100: 122–129 20. Jutel M, Adkis M, Blaser K, Adkis CA. Mechanisms of allergen specific immunotherapy: T cell tolerance and more. Allergy 2006; 61: 796–807 21. Passalacqua G, Canonica G. Sublingual immunotherapy: update 2006. Curr Opin Allergy Clin Immunol 2006; 6: 449–454 22. Tonnel AB, Scherpereel A, Douay B, et al. Allergic rhinitis due to house dust mites: evaluation of the efficacy of specific sublingual immunotherapy. Allergy 2004; 59: 491–497 23. Bufe A, Ziegler-Kirbach E, Stoeckmann E, et al. Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study. Allergy 2004; 59: 498–504 24. Smith H, White P, Annita I, et al. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol 2004; 114: 831–837 25. Rolinck-Werninghaus C, Wolf H, Liebke C, et al. A prospective, randomized double-blind, placebo-controlled multicentre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen. Allergy 2004; 59: 1285–1293 26. Bowen T, Greenbaum J, Charbonneau Y, et al. Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Ann Allergy Asthma Immunol 2004; 93: 425–430 27. Dahl R, Stender H, Rak S. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy 2006; 61: 185–190 28. Niu CK, Chen WY, Huang JL, et al. Efficacy of sublingual immunotherapy with high-dose mite extracts in asthma: a multicentre, double-blind, randomized and placebo-controlled study in Taiwan. Respir Med 2006; 100: 1374–1383 29. Passalacqua G, Pasquali M, Ariano R, et al. Randomized double blind controlled study with sublingual carbamylated allergoid in mild rhinitis due to mites. Allergy 2006; 61: 849–854 30. Durham SR, Yang WH, Pedersen MR, et al. Sublingual immunotherapy with once-daily grass-allergen tablets: a randomised controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 117: 802–809 31. Wilson DR, Torres L, Durham SR. Sublingual immunotherapy for allergic rhinitis. Allergy 2005; 60: 3–8 32. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, Canonica GW. Meta analysis of sublingual immunotherapy in pediatric patients. Ann Allergy Asthma Immunol 2006; 97: 141–148 33. Malling HR. Comparison of the clinical efficacy and safety of subcutaneous and sublingual immunotherapy: methodological approaches and experimental results. Current Opin Allergy Clin Immunol 2004; 4: 539–542

226

P. Potter

34. Khinchi MS, Poulsen LK, Carat F, et al. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, doubleblind, double-dummy study. Allergy 2004; 59: 45–53 35. Canonica W, Baena-Cagnani C, Bousquet J, Bousquet JP, Lockey RF, Malling HJ, Passalacqua G, Potter PC, Valovirta E. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. Statement of a WAO – World Allergy Organization Task Force. Allergy 2007; 62: 316–324 36. Passalacqua G, Durham S. In corporation with the Global Allergy and Asthma and European Network (Ga2Len) (2007). Allergic Rhinitis and its impact on asthma: Update on allergen immunotherapy. J Allergy Clin Immunol 119: 881–891. 37. Pajno GB, Passalacqua G, Vita D, Parmiani S, Barbeiro G. Sublingual immunotherapy abrogates seasonal bronchial hyperresponsiveness in children with parietaria induced respiratory allergy: a randomized controlled trial. Allergy 2004; 59(8): 883–887 38. Novembre E, Galli E, Landi F, Caffarelli C, Piffen M, De ME. Co-seasonal sublingual immunotherapy reduces the development of asthma in children with allergic conjunctivitis. J Allergy Clin Immunol 2004; 114: 851–857 39. Bufe A, Ziegler-Kirbach E, Stoeckman E, Heidermann P, Gehlhar K, Hollard Letz T. Efficacy of sublingual swallow immunotherapy in children with severe grass pollen symptoms: a double blind placebo controlled study. Allergy 2004; 59: 498–504 40. Marcucci F, Sensi L, Di GG, Salvatori S, Bernini M, Pecora S, et al. Three year follow up of clinical and inflammation parameters in children monosensitised to mites undergoing sublingual immunotherapy. Paediatr Allergy Immunol 2005; 16: 519–526 41. Bordignon V, Burastero SE. Multiple daily administration of low dose sublingual immunotherapy in allergic rhinoconjunctivitis. Ann Allergy Asthma Immunol 2006; 97: 158–163 42. Reider N. High dose sublingual immunotherapy: too much of the good! Ann Allergy 2006; 97: 125 43. Berto P, Passalacqua G, Crimi N, Frati F, Ortolani M, Senna G, Canonica GW. Ann Allergy Asthma Immunol 2006; 97: 615–621 44. Passalacqua G, Guerra L, Pasquali M, Lombard C, Canonica GW. Efficacy and safety of sublingual immunotherapy. Ann Allergy Asthma Immunol 2004; 93: 3–12 45. Canonica GW, Passalacqua G. Sublingual immunotherapy in the treatment of adult allergic patients. Allergy 2006; 61 (Suppl 81): 20–23 46. Ippoliti F, De Santos W, Volteranni A, Caritario N, Frattolillo D, Lucarelli S, Frediani S, Frediani T. Psychological stress affects response to sublingual immunotherapy in asthmatic children allergic to house dust mite. Paediatr Allergy Immunol 2006; 17: 337–345 47. Dunsky EH, Goldstein FM, Dvorin J, Bela-Canech G. Anaphylaxis to sublingual immunotherapy. Allergy 2006; 61: 1235. 48. Antico A, Pagan M, Crema A. Anaphylaxis by sublingual immunotherapy. Allergy 2006; 61: 1236. 49. Potter PC, Thomas H, Terblanche L. Quality of life as a monitoring index and global score as an outcome index in sublingual immunotherapy for allergic rhinitis. Curr Allergy Clin Immunol 2006; 19(3): 161 50. Didier A, Melac M, Combebias A, Andre C. Efficacy and safety of sublingual immunotherapy tablets in grass pollen rhinoconjunctivitis. J Allergy Clin Immunol 2006; 117: 721 (abstract)

Anti-IgE in Allergic Airway Diseases: Indications and Applications Jennifer Preston DeMore and William W. Busse

Introduction: Role of IgE and Anti-IgE Molecules IgE plays a role in both the initial sensitization to antigen and the subsequent effects upon repeat exposure. For sensitization, inhaled antigen is ingested by antigen presenting dendritic cells that line the airway, and then processed and presented to antigen-specific T cells. The subsequent production of cytokines stimulates B cells to produce antigen-specific IgE, which then binds to the surface of mast cells and basophils via the high-affinity receptor for IgE, namely FceRI [1] (Fig. 1a). Upon repeat exposure to an inhaled antigen, there is cross-linking of IgE bound to the surface of mast cells and basophils. This interaction signals mast cells and basophils to degranulate, releasing mediators such as histamine, prostaglandin, and leukotrienes, and to stimulate chemokine and cytokine production. These mediators cause an early or acute phase reaction and, under some circumstances, can lead to a late-phase reaction. IgE is an immunoglobulin that consists of a variable and constant region. The variable region is the area that binds to the antigen. Within the constant region, CHe3 contains the binding sites for the two different receptors, FceRI and FceRII (Fig. 2). Given the biological effects of IgE, a novel mechanism to treat allergic disease, including asthma, would be to block IgE and its actions. However, an antibody to IgE could either stimulate or block this molecule. The antibody could stimulate IgE if IgE were already bound to receptors on mast cells and basophils. If the antibody is subsequently attached to the bound IgE, it could cause the cross-linking of at least two IgE molecules with subsequent degranulation. Depending on the degree of degranulation, this response may result in an acute allergic reaction. However, if an antibody could block IgE from attaching to its receptors on mast cells and basophils, degranulation could be prevented. Omalizumab is such a molecule; it is an anti-IgE antibody that binds to IgE regardless of IgE specificity.

J.P. DeMore () and W.W. Busse University of Wisconsin School of Medicine and Public Health, J5/219 CSC-2454, 600 Highland Avenue, Madison, WI 53792, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_14, © Springer 2010

227

228

J.P. DeMore and W.W. Busse

Fig. 1 Pathophysiology of asthma: Aeroallergens initially interact with the immune system when they are taken up by dendritic cells (a). This process occurs by phagocytosis and may be enhanced after initial sensitization by the binding of allergen-specific IgE to high-affinity receptors (FceRIs) on the surface of dendritic cells. Dendritic cells process the allergen, bound to major-histocompatibility-

Anti-IgE in Allergic Airway Diseases: Indications and Applications

229

Fig. 2 Mechanism of action of human anti-IgE: Anti-IgE neutralizes IgE by binding to the constant region 3 of the IgE heavy chain at a site (inset CHe3, green circle) that overlaps the binding sties for both Fc epsilon receptor I (FceRI, white square) and FceRII or CD 23 (yellow square). This prevents IgE from binding to its receptors. Anti-IgE and IgE form trimers and hexamers that may “sweep” away allergens (a). Anti-IgE reduces IgE receptors on basophils and mast cells (c) as well as dendritic cells (d). Its effects on CD23, on B cells bearing membrane bound IgE (mIgE) (e), and on the differentiation of IgE producing plasma cells are unknown. (Adapted from Annual Review of Medicine, with permission ([2], p. C-1))

Fig. 1 (continued) complex (MHC) molecules, and present it to T cells. T cells are stimulated by the interaction of MHC-bound antigen with surface T-cell receptors, causing T-cell proliferation and the subsequent release of cytokines. These cytokines stimulate B cells to become plasma cells that produce IgE. B cells express low-affinity Fce receptors (FceRIIs); interaction of IgE with these receptors may influence B-cell differentiation and regulation of IgE synthesis. IgE produced by plasma cells binds to the surface of mast cells and basophils and, when cross-linked by allergen, induces degranulation and the release of inflammatory mediators. This process results clinically in an acute asthma attack. Omalizumab is a monoclonal anti-IgE antibody that binds to the Fc region of the IgE molecule (b). In so doing, Omalizumab prevents IgE from binding to cell-surface receptors. Omalizumab is unable to bind to IgE molecules that are already bound to FceRIs; as a result, it cannot induce anaphylaxis. Reduced binding of IgE to FceRIs on mast cells and basophils inhibits degranulation and the release of inflammatory mediators. There is also a marked downregulation of FceRIs. Reduced IgE binding to FceRI on dendritic cells may reduce the ability of these cells to process antigen efficiently. Reduced IgE binding to FceRII on B cells is thought to alter B-cell differentiation and the regulation of IgE synthesis. All these effects may contribute to the prevention of acute exacerbations of asthma. (Adapted from New England Journal of Medicine, with permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved ([1], p. 2690))

230

J.P. DeMore and W.W. Busse

It attaches to the IgE molecule in the CHe3 region, which is the same region that contains the binding sites for FceRI and FceRII. Omalizumab does not bind to IgA or IgG. Once Omalizumab is bound to IgE, the resulting complex is blocked from binding to either FceRI or FceRII receptors. It is thought that a conformational change takes place on the IgE molecule to prevent binding to receptors, but IgE can still bind another Omalizumab molecule for a total of 2 Omalizumab molecules/IgE molecule [2] (Figs. 1b and 2). Two antibodies were initially developed as anti-IgE molecules. Omalizumab was the antibody chosen for further development. Omalizumab, approved for use in moderate-to-severe asthma in the United States, is also known as rhuMAb-E25, rhuMab, or Xolair, and is a recombinant humanized monoclonal anti-IgE antibody of mouse origin. To produce Omalizumab, mice are immunized with human IgE, and their B cells are harvested and fused with myeloma cells, whereby a hybridoma is produced. The antibody is then humanized by grafting the light chains onto a human IgG1 molecule. The origin of the molecule is 95% human and 5% murine [2].

Proof of Concept of Omalizumab Actions in Asthma Boulet et al. [3] conducted a multicenter, randomized, double-blind, parallel group study, in which 20 allergic asthmatic subjects received either intravenous Omalizumab or placebo. They then underwent an inhaled antigen challenge to testvthe action of anti-IgE. The concentration of allergen that provoked a 15% fall in FEV1 during the early asthmatic response was first determined. Subjects in the Omalizumab group required a double dose of allergen to cause a 15% fall in FEV1 compared to baseline values, indicating a blockage of IgE actions [3]. Subsequently, Fahy et al. [4] studied 19 allergic asthmatic subjects in a randomized, double-blind, parallel group study. After 9 weeks of anti-IgE treatment or placebo, the effects of allergen inhalation on the early- and late-phase response to inhaled antigen were measured. When the subjects received Omalizumab, there was a significant increase in the dose of allergen needed to induce an early response, and both the early- and late-phase falls in FEV1 were significantly reduced [4]. Both studies demonstrated that Omalizumab blocks the allergic airway response to inhaled antigen, and as a consequence, may be an effective treatment for asthma by reducing the allergic airway response to allergen.

Clinical Efficacy in Allergic Asthma Omalizumab was initially studied in moderate-to-severe asthmatic patients in a phase I study [5]. Once the safety and tolerance in humans was determined, a phase II doubleblinded, placebo-controlled, multicenter study was conducted, involving 317 subjects who required inhaled corticosteroids (ICSs) or oral corticosteroids for asthma treatment.

Anti-IgE in Allergic Airway Diseases: Indications and Applications

231

In that study, the subjects received either intravenous placebo or low-dose or highdose Omalizumab. Those treated with Omalizumab showed improved asthma symptom scores and a decrease in ICSs and beta-agonist use without a loss of asthma symptom control, an improved quality of life, and a trend toward the ability to discontinue oral corticosteroid use [6].

Design of Studies Cochrane Database of Systematic Reviews examined the efficacy of anti-IgE in subjects with chronic asthma. This review pooled data from 14 randomized controlled trials and totaled 3,143 mild-to-severe allergic asthmatic subjects. The inclusion criteria for the studies included a positive skin test to a perennial aeroallergen and serum IgE levels greater than 30 and lesser than 700 to 1,300 IU/mL. Seven studies examined anti-IgE therapy as an adjunct to either inhaled or oral corticosteroid use. These studies used a run-in phase, during which the corticosteroid dose was titrated to the minimal amount of medication necessary to maintain symptom control, referred to as the “stable steroid phase.” After Omalizumab treatment for a period of 12—28 weeks, some studies tried to further taper the corticosteroid doses of their subjects, adding a steroid tapering phase to the trial [7].

Asthma Exacerbations The Cochrane Review found that the frequency of asthma exacerbations reduced with Omalizumab use. Both the number of subjects experiencing an asthma exacerbation as well as the number of exacerbations experienced reduced. The reduction in frequency of asthma exacerbations was also seen despite the taper of ICSs [7–12]. Even subjects with severe asthma experienced fewer exacerbations on Omalizumab treatment as well as a reduction in the number of severe exacerbations [11]. Hospitalizations for asthma also significantly reduced [8–10]. In adults on Omalizumab, the duration of an asthma exacerbation was reduced to 7.8 days compared to the average duration of 12.7 days in the placebo-treated group [8]. In children, Omalizumab did not reduce the duration of the exacerbation. [10].

Inhaled Corticosteroids During the steroid tapering phase, the endpoint dose of ICS was reduced. In the Omalizumab-treated groups, a greater reduction in ICSs was noted when compared to the placebo group. This effect was seen in both adults and children [8–12]. In adults, the Omalizumab-treated group was able to reduce their dose of ICSs by 75%

232

J.P. DeMore and W.W. Busse

compared to 50% by the placebo-treated group [8]. Of note, the placebo-treated group also had quite a high percentage of individuals who were able to reduce their corticosteroid dose as well. Using a pooled analysis, the Cochrane Database found that the subjects on Omalizumab were able to decrease their ICSs by a mean value of 119 mcg/day which, though relatively small, was still a significant reduction when compared to placebo [7]. Studies also determined the frequency of a complete withdrawal of ICSs. Adults and children who took Omalizumab were more likely than placebo-treated subjects to discontinue ICS use completely [8–12]. Overall, treatment with Omalizumab allowed for a reduction or total discontinuation of ICSs in some asthmatic subjects.

The Effect of Omalizumab on Other Medication Use, Including Beta-2 Agonists and Oral Corticosteroids Subjects who received Omalizumab also required less rescue beta-2 agonist use [8–12]. Pooled analysis found the reduction in rescue medication to be 0.63 and 0.74 puff/day in the steroid-stable and steroid-taper phases, respectively. No significant differences were seen in the reduction or withdrawal of oral steroids between the Omalizumab and placebo groups. In addition, a study examined a subgroup of subjects taking leukotriene receptor antagonists and found no additional effect to Omalizumab [7].

Lung Function There has been no consistent effect of Omalizumab on lung function. No differences in morning peak expiratory flow or FEV1 end of treatment values were noted between Omalizumab-treated and placebo-treated groups. However, two trials did note small, but not clinically significant, changes with Omalizumab on baseline FEV1 values [11, 12].

Quality of Life Assessment of asthma-related quality of life was performed using the Asthma Quality of Life Questionnaire (AQLQ) at different phases throughout two of the 52-week trials. For those receiving Omalizumab, there were statistically significant improvements in all domains as well as the overall AQLQ score. The domains addressed included activity limitations, emotions, environmental exposure, and symptoms. Furthermore, the AQLQ improvement was clinically significant in a higher proportion of subjects in the Omalizumab-treated groups. Improvement was also found during the reduction of ICSs [13, 14].

Anti-IgE in Allergic Airway Diseases: Indications and Applications

233

Severe Asthma Patients with severe asthma require either high doses of ICSs with long-acting beta-2 agonist or daily oral corticosteroids. Holgate et al. [15] investigated the effect of Omalizumab on severe asthmatic subjects on high-dose ICSs; more subjects in the Omalizumab group were able to significantly reduce their ICS dose. In addition, Omalizumab-treated subjects had fewer asthma exacerbations, but this effect did not reach statistical significance [15]. Humbert et al. also examined the effect of Omalizumab on severe asthmatic subjects. These subjects had a recent history of an exacerbation. The Omalizumab-treated group experienced less asthma exacerbations, fewer severe exacerbations, and a lower rate of emergency room visits [11].

Children Children with allergic asthma have also been found to benefit from treatment with Omalizumab. Milgrom et al. [10] evaluated children, 6–12 years of age, with moderate-to-severe allergic asthma. Compared to placebo treatment, more children who received Omalizumab were able to reduce their ICS dose, have a greater reduction in their ICS dose, and experience fewer asthma exacerbations. Asthma symptom scores and spirometry were relatively unaffected by active treatment. There was also a trend for children in the treatment group to miss fewer days of school [10]. A greater number of subjects treated with Omalizumab had clinically relevant improvements in their quality of life scores using the Pediatric AQLQ, limited to the domains of activities and overall quality of life [16]. Children who were treated with Omalizumab for a total of 52 weeks tolerated the medication well, with the same frequency of adverse events as those who received the placebo [17].

Predictors of Response to Omalizumab In the studies to evaluate the effects on asthma, some subjects have shown either minimal or no response to Omalizumab. Given this variability, it would be beneficial to know which patients are more likely to benefit from this treatment. Bousquet et al. [18] used two randomized, double-blind, placebo-controlled trials to retrospectively determine the predictors of response to Omalizumab. The best predictor of a positive response to Omalizumab was an emergency asthma treatment in the past year, which was defined as a hospital or emergency room visit or an urgent doctor visit. Subjects with FEV1 of less than 65% predicted or receiving a high dose of ICS (equivalent to budesonide > 800 mg/day) were also more likely to respond to treatment. Baseline values of IgE were not found to predict a subject’s response to Omalizumab [18] (Fig. 3).

234

J.P. DeMore and W.W. Busse

Fig. 3 Venn diagram of odds ratios (corresponding 95% CIs) for response with Omalizumab relative to placebo for the composite definition of response, according to three high-severity baseline covariates. (Adapted from Chest, with permission conveyed through Copyright Clearance Center, Inc. ([18], p. 1384))

Asthma Guidelines The National Asthma Education and Prevention Program Expert Panel (NAEPP) Report 3 addresses the use of anti-IgE therapy in asthma patients and recommends that practitioners consider anti-IgE as adjunctive therapy for patients, with severe persistent asthma and documented allergic disease, who are inadequately controlled on high dose ICSs and long-acting beta-agonist, i.e., step 5 or 6 therapy. In addition, patients who require oral corticosteroids, i.e., step 6, may also benefit from anti-IgE therapy (evidence B). The NAEPP asthma guidelines also state that patients, who are on step 4, have underlying allergies, and are on medium doses of ICSs and longacting beta-agonist may also benefit from anti-IgE therapy in order to avoid the need for larger doses of corticosteroids. However, this recommendation lacks comparator trials and is considered evidence D [19] (Fig. 4).

Allergic Rhinitis Allergic rhinitis is also an IgE-mediated disease that significantly impairs quality of life as well as productivity in school and work. Subjects with a history of ragweed-induced seasonal allergic rhinitis were enrolled and randomly given one of

Anti-IgE in Allergic Airway Diseases: Indications and Applications

235

Fig. 4 National Asthma Education and Prevention Program Expert Panel (NAEPP) Report 3 addresses the use of anti-IgE therapy as an adjunct in asthma patients, with severe persistent asthma and allergies, who are inadequately controlled on high-dose inhaled corticosteroids and long-acting beta-agonist or who require oral corticosteroids. (Adapted from [19], pending publication)

three doses of Omalizumab or placebo. Treatment was started prior to and continued through the ragweed pollination season. Subjects who received a 300 mg dose of Omalizumab experienced significantly less nasal and ocular symptoms and also needed less amounts of rescue antihistamine medication. Furthermore, rhinitisspecific quality of life scores improved even during the peak time of ragweed pollination. Serum values of lower free IgE levels also correlated with less severe nasal symptoms and need for rescue antihistamines [20]. A similar level of symptom control and reduction in rescue medication was seen in subjects, who were treated with Omalizumab, with seasonal allergic rhinitis to birch pollen. [21]. Patients with perennial allergic rhinitis may also benefit from Omalizumab. Over 16 weeks of treatment, subjects experienced a lower severity of nasal scores, reduced need for rescue antihistamine use, and improved rhinoconjunctivitisspecific quality of life. The nasal severity score was graded on a four-point scale from none to severe, based on the following four symptoms: sneezing, itchy, runny and stuffy nose [22]. An update of the pharmacologic treatment of allergic rhinitis by the Allergic Rhinitis and its Impact on Asthma (ARIA) Workshop Report has proposed that there exists level A evidence for anti-IgE treatment use in both seasonal and perennial rhinitis in adults as well as children [23].

236

J.P. DeMore and W.W. Busse

Allergic rhinitis is very common in patients with asthma and, if present, may also complicate the management of asthma. There is evidence that by controlling symptoms of allergic rhinitis, asthma control may also improve. The shared pathogenesis of these two conditions and the shared upper and lower airway make targeting both diseases with one treatment an ideal concept in the approach to treatment [24]. Patients with allergic asthma and concomitant persistent allergic rhinitis were studied in the SOLAR trial. Subjects who received Omalizumab as add-on therapy experienced fewer asthma exacerbations and had a clinically significant improvement in both the AQLQ and the Rhinitis Quality of Life Questionnaire (RQLQ). However, the use of rescue medications, both short-acting beta-agonists and antihistamines, was similar between the groups [12].

Mechanism of Action of Anti-IgE Anti-IgE inhibits the binding of IgE to effector cells by attachment to circulating free IgE molecules. IgE molecules that are bound to anti-IgE are unable to bind to the receptors on the effector cells. Milgrom et al. [6] demonstrate the reduction in free IgE through the administration of intravenous Omalizumab to occur 1 h after dosing [6]. Besides inhibiting IgE binding on cells to FceRI receptors, Omalizumab also decreases the number of high-affinity FceRI receptors. When FceRI is on the cell surface, it is either bound to IgE, stabilizing the receptor to remain on the surface, or is internalized and degraded. If no IgE is bound to the receptor, it is internalized, degraded, and not available for IgE binding. This reduction in receptors was noted by MacGlashan and colleagues on basophils of subjects treated with Omalizumab [25]. The reduction in receptor density was significant with mean values at baseline of 220,000, going to 8,300 /basophil following treatment. When basophils from patients treated with Omalizumab were subsequently challenged with allergen, histamine release was reduced by 90% [25]. The receptors on mast cells were also reduced with the administration of Omalizumab. The reduction of FceRI on mast cells occurred later than that observed with basophils, but the effects lasted longer due to the greater lifespan of mast cells [26]. Precursor dendritic cells, both subsets 1 and 2, are an earlier developmental stage of dendritic cells, and differentiate into dendritic cells upon migration into tissues. Precursor dendritic cells subsets 1 and 2 are associated with Th1 and Th2 immunologic responses, respectively. Both these dendritic cell subsets show a reduction of surface FceRI expression following Omalizumab use. A tenfold decrease in free IgE corresponded to a 42 and 54% decrease in FceRI on precursor dendritic cells subsets 1 and 2, respectively [27]. The reduction of IgE on these effector cells may diminish the patient’s response to an allergen as there is less antigen uptake. Allergen cannot be processed by the dendritic cell and presented to cells; consequently, this effect by Omalizumab could reduce IgE production and affect the ongoing sensitization to allergens.

Anti-IgE in Allergic Airway Diseases: Indications and Applications

237

Omalizumab may also affect B cells, reducing the expression of the low-affinity receptor, FceRII. With a decrease in circulating IgE, IgE binding to FceRII is also reduced and this effect is thought to subsequently affect B cell differentiation into plasma cells. With this FceRII alteration in expression, IgE synthesis is thought to subsequently decline [1]. Omalizumab has other anti-inflammatory effects as well. Djukanovic et al. [28] found reductions in IgE-bearing cells in the airway mucosa biopsies and significant decreases in the mean percentage of sputum eosinophils with Omalizumab treatment. This decrease was coupled with a decrease in the submucosal cells of B lymphocytes, IL-4 staining cells as well as CD3+, CD4+, and CD8+ T lymphocytes. No improvement was observed in airway hyperresponsiveness with methacholine. However, all subjects had mild asthma. In addition to reducing serum-free IgE, Omalizumab decreases IgE in the airway mucosa of asthma subjects [28]. Noga et al. [29], who previously found a decrease in circulating IL-13, also noted further anti-inflammatory effects with Omalizumab treatment. To further investigate the underlying mechanism, they found that the Omalizumab-treated group had increased Annexin V, a marker of eosinophil apoptosis, decreased GM-CSF+ lymphocytes as well as experienced a reduction in IL-2+ and IL-13+ lymphocytes with subsequent downregulation of cytokines IL-2 and IL-13. No differences were seen in IL-5, IFN-g, or TNF-a. Their findings suggest that the reduction in both tissue and circulating eosinophils caused by Omalizumab may occur by promoting apoptosis along with a reduction of GM-CSF, which normally supports eosinophil viability. The reduction in IL-2 is likely to affect the proliferation and activity of eosinophils. It is of interest that IL-5, which is an important growth factor for eosinophils, was unaffected by Omalizumab [29].

Pharmacokinetics of Omalizumab A dose-related decrease in circulating free IgE levels occurs with Omalizumab treatment. The clinical efficacy of Omalizumab has been shown to occur when free IgE levels are less than 10 IU/mL. To achieve this effect on IgE in the treated patient, the recommended dose schedule is 0.016 mg/kg/IU of serum IgE. Dosing is dependent on the weight of the patient and the initial total IgE level [30, 31] (Fig. 5). As Omalizumab is an IgG1 molecule, its serum half-life is 26 days, which is longer than IgE. When Omalizumab binds to IgE, the amount of total IgE increases, but the amount of free IgE decreases. With the administration of Omalizumab, there is an initial increase in total IgE. Currently, the measurement of free IgE is only a research tool and not available to assess treatment response. If patients experience a treatment interruption of less than 1 year, the dosing of Omalizumab should be based on the initial IgE prior to starting therapy, as total serum IgE changes with treatment.

238

J.P. DeMore and W.W. Busse

Fig. 5 Dosing schedule for subcutaneously administered Omalizumab, according to the baseline serum IgE level and body weight. The recommended dose is 0.016 mg/kg of body weight per international unit of IgE every 4 weeks, administered subcutaneously at either 4-week (italic) or 2-week (roman) intervals for adults and adolescents (persons 12 years of age and older) with allergic asthma. Dashes indicate that no dose should be prescribed. (Adapted from New England Journal of Medicine, with permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved ([1], p. 2692))

The onset of action of Omalizumab depends on the route of administration. When given intravenously, a reduction in free IgE occurs within 1 h of Omalizumab administration [6]. When Omalizumab is given subcutaneously, 4 weeks are required for a significant reduction in the free IgE level [20]. The peak serum concentration of Omalizumab is seen 7–8 days after administration. Bousquet et al. [18] examined the time for a clinical response to Omalizumab. Of the patients who experienced improvement at 16 weeks of treatment, 61% showed some benefit by 4 weeks from initiating treatment. Of those benefiting from Omalizumab, 87% had an effect at 12 weeks. Based on these findings, the investigators recommend continuing treatment for at least 12 weeks to assess whether benefit will occur [18]. With the discontinuation of anti-IgE therapy, IgE levels return to their prior levels. Patients do not experience a “rebound” effect with a further elevated IgE. In fact, some patients had IgE levels below their pretreatment level when evaluated 1 year after the discontinuation of Omalizumab treatment. The basophils from these patients also showed a reduction of FceRI compared to their pretreatment levels, but histamine release to antigen had returned to baseline values by 1 year [32].

Safety of Omalizumab The safety of Omalizumab has been examined in a number of clinical trials. Pooled data from the Cochrane Database found that the only statistically significant difference in adverse events was an increase in injection site reactions compared to placebo with the subcutaneous administration [7].

Anti-IgE in Allergic Airway Diseases: Indications and Applications

239

However, concerns have been raised recently that Omalizumab may cause anaphylaxis in some patients. In premarketing clinical trials, the incidence of anaphylaxis was three patients out of 3,507 or less than 0.1%. Since the approval by Food and Drug Administration in the United States, postmarketing data were collected until December 2005; during this time, 48 case reports of anaphylaxis were made. The estimated number of patients treated with Omalizumab by this time was 39,500, which gave a frequency of anaphylaxis of 0.1%. The case definition of anaphylaxis by the Food and Drug Administration was skin or mucosal tissue involvement with airway compromise, or a reduced blood pressure, with or without associated symptoms. A temporal relationship with Omalizumab administration, with no other identifiable cause, was needed to suggest a cause-and-effect relationship. The associated symptoms included bronchospasm, hypotension, syncope, urticaria, angioedema of the throat or tongue, dyspnea, cough, chest tightness, cutaneous angioedema, and generalized pruritus. The characteristics found in these case reports suggested that 71% of the patients with anaphylaxis experienced the onset of symptoms within 2 h of administration, while 13% of the reactions occurred up to 24 h later. Forty percent of the reported reactions occurred after the first dose of Omalizumab, while some reactions occurred following 2 years of therapy. Of the patients who experienced anaphylaxis to Omalizumab and were reported to have had a subsequent dosing, 56% experienced a repeat episode of anaphylaxis. Out of the symptoms noted with these reports of anaphylaxis, 96% of the cases had pulmonary involvement, such as bronchospasm, dyspnea, cough, or chest tightness. Thirteen percent were reported to experience hypotension or syncope. Some patients required oxygen or parenteral medications for treatment. Of these patients, 15% required hospitalization [33]. Due to concerns raised by these reports of anaphylaxis, the Food and Drug Administration in the United States recommended a boxed warning to the product. They also recommended that patients should be observed for 2 h after the administration of Omalizumab. These points are under consideration.

Neoplasms Premarketing data had noted an elevated incidence of neoplasm in patients receiving Omalizumab. In the treatment group, 25 neoplasms were found in 20 of the 4,127 Omalizumab-treated patients for an incidence of 0.48%. In the control group, five neoplasms were found in five of 2,236 patients treated, at an incidence of 0.22%. In the treatment group, these tumors were diagnosed soon after Omalizumab was initiated and varied both in cell type and location, with no single type of neoplasm being more prevalent. The incidence of different types of neoplasm was comparable to the general population. A blinded review by independent oncologists found no link between Omalizumab treatment and neoplasm. An epidemiological study to follow the long-term effects of Omalizumab is currently underway [34].

240

J.P. DeMore and W.W. Busse

Immune Complex and Antibodies A theoretical concern of immune complex disease exists as IgE binds to anti-IgE; however, there has been no evidence of immune complex deposition or immune complex disease in the clinical trials. As IgE binds to anti-IgE, trimers or cyclic hexamers are formed. The cyclic hexamers that are formed are the size of naturally occurring IgM molecule and do not cause serum sickness or affect renal glomeruli. These immune complexes do not fix complement and are cleared by a low-avidity interaction between Fc gamma receptors of leukocytes and the reticuloendothelial system in the hepatic sinusoids [35]. Another concern was the development of antibodies to Omalizumab. In premarketing trials, only one subject developed IgG and IgA anti-Omalizumab antibodies; they resolved when re-evaluated 11 weeks later. This subject had received Omalizumab via an inhalation route. Subjects who received the drug via intravenous or subcutaneous route have not developed anti-Omalizumab antibodies [35].

Helminth Infection With the depletion of IgE during Omalizumab therapy, another concern was the enhanced susceptibility to parasitic infections. In premarketing trials, including 3,678 patients with 1,934 patient years, one helminth infection, namely pinworm, was reported. Since the approval of Omalizumab, there have been no spontaneous postmarketing reports of helminth infection in an estimated 39,000 patients [35]. To investigate the risk of intestinal helminth infection with Omalizumab treatment, a randomized, double-blind, placebo-controlled trial was conducted for 1 year with 137 patients, who were at high risk for parasite infection, in Brazil. Of those who experienced at least one infection, 50% were in the treatment group, while 41% were in the placebo group. Cruz et al. found a tendency toward an increased incidence of infection, but this tendency was not statistically significant. Compared to the placebo-treated group, subjects treated with Omalizumab had no difference in the time, severity, and morbidity of the infection or the response to treatment [36].

Thrombocytopenia In monkeys, thrombocytopenia occurred with supertherapeutic doses of Omalizumab. In comparison with adult monkeys, juvenile monkeys were more susceptible to a decrease in platelets at the same dose of Omalizumab. Premarketing trials showed that subjects had a decrease in platelet counts, but these declines were still within normal ranges and not necessarily associated with bleeding events.

Anti-IgE in Allergic Airway Diseases: Indications and Applications

241

From postmarketing experience, one patient was reported to have severe thrombocytopenia, but as this was voluntarily reported, the true incidence of such reactions are unclear in comparison with the total number of patients who received this medication [35, 36].

Summary Anti-IgE therapy is a novel treatment for allergic airway diseases. Omalizumab was initially shown to affect early- and late-phase responses with antigen challenges. Clinical efficacy was demonstrated in both asthma and allergic rhinitis and in both adults and children in numerous well-designed, randomized, double-blind, placebocontrolled studies. The pharmacokinetics of Omalizumab have been examined and the safety of the medication has been studied. Further studies have helped elucidate the mechanism of action of Omalizumab and led to an insight into the pathophysiology of asthma.

References 1. Strunk RC, Bloomberg GR (2006) Omalizumab for asthma. N Engl J Med 354: 2689–95 2. Avila PC (2007) Does anti-IgE therapy help in asthma? Efficacy and controversies. Annu Rev Med 58: 36.1–19 3. Boulet LP, Chapman KR, Cote J, Kaira S, Bhagat R, Swystun VA, Laviolette M, Cleland LD, Deschesnes F, Su JQ, DeVault A, Fick RB Jr, Cockcroft DW (1997) Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am J Respir Crit Care Med 155: 1835–40 4. Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, Fick RB Jr, Boushey HA (1997) The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 155: 1828–34 5. Corren J, Froehlich J, Schoenhoff M, Spectgor S, Rachelefsky G, Schanker H, Patnaik M, Siegel S (1996) Phase I study of anti-IgE recombinant humanized monoclonal antibody rhuMAB-E25 (E25) in adults with moderate to severe asthma. J Allergy Clin Immunol 97: 245 6. Milgrom H, Fick RB Jr, Su JQ, Reimann JD, Bush RK, Watrous ML, Metzger WJ (1999) Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 341: 1966–73 7. Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH (2006) Anti-IgE for chronic asthma in adults and children (Review). Cochrane Database of Systematic Reviews Issue 2. Art No: CD003559. DOI 10.1002/14651858.CD003559.pub3 8. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A, Gupta N (2001) Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 108: 184–90 9. Solèr M, Matz J, Townley R, Buhl R, O’Brien J, Fox H, Thirlwell J, Gupta N, Della Cioppa G (2001) The anti-IgE antibody Omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 18: 254–61 10. Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, Taylor AF, Rohane P (2001) Treatment of childhood asthma with anti-Immunoglobulin E antibody (Omalizumab). Pediatrics 108: 36

242

J.P. DeMore and W.W. Busse

11. Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, Beeh K-M, Ramos S, Canonica GW, Hedgecock S, Fox H, Blogg M, Surrey K (2005) Benefits of Omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 60: 309–16 12. Vignola AM, Humbert M, Bousquet J, Boulet L-P, Hedgecock S, Blogg M, Fox H, Surrey K (2004) Efficacy and tolerability of anti-immunoglobulin E therapy with Omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 59: 709–17 13. Finn A, Gross G, van Bavel J, Lee T, Windom H, Everhard F, Fowler-Taylor A, Liu J, Gupta N (2003) Omalizumab improves asthma-related quality of life in patients with severe allergic asthma. J Allergy Clin Immunol 111: 278–84 14. Buhl R, Hanf G, Solèr M, Bensch G, Wolfe J, Everhard F, Champain K, Fox H, Thirlwell J (2002) The anti-IgE antibody Omalizumab improves asthma-related quality of life in patients with allergic asthma. Eur Respir J 20: 1088–94 15. Holgate ST, Chuchalin AG, Hébert J, Lötvall, Persson GB, Chung KF, Bousquet J, Kerstjens HA, Fox H, Thirlwell J, Della Cioppa G (2004) Efficacy and safety of a recombinant antiimmunoglobulin E antibody (Omalizumab) in severe allergic asthma. Clin Exp Allergy 34: 632–8 16. Lemanske RF, Nayak A, McAlary M, Everhard F, Fowler-Taylor A, Gupta N (2002) Omalizumab improves asthma-related quality of life in children with allergic asthma. Pediatrics 110: 55 17. Berger W, Gupta N, McAlary M, Fowler-Taylor A (2003) Evaluation of long-term safety of the anti-IgE antibody, Omalizumab, in children with allergic asthma. Ann Allergy Asthma Immunol 91: 182–8 18. Bousquet J, Wenzel S, Holgate S, Lumry W, Freeman P, Fox H (2004) Predicting response to Omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest 125: 1378–86 19. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Management of Asthma (2007) Draft, National Institutes of Health, National Heart, Lung and Blood Institute 20. Casale TB, Condemi J, LaForce C, Nayak A, Rowe M, Watrous M, McAlary M, FowlerTaylor A, Racine A, Gupta N, Fick R, Cioppa GD (2001) Effect of Omalizumab on symptoms of seasonal allergic rhinitis. JAMA 286: 2956–67 21. Adelroth E, Rak S, Haahtela T, Aasand G, Rosenhall L, Zetterstrom O, Byrne A, Champain K, Thirlwell J, Cioppa G, Sandstrõm T (2000) Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 106: 253–9 22. Chervinsky P, Casale T, Townley R, Tripathy I, Hedgecock S, Fowler-Taylor A, Shen H, Fox H (2003) Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol 91: 160–7 23. Bousquet J, van Cauwenberge P, Aït Khaled N, Bachert C, Baena-Cagnani CE, Bouchard J, Bunnag C, Canonica GW, Carlsen KH, Chen YZ, Cruz AA, Custovic A, Demoly P, Dubakiene R, Durham S, Fokkens W, Howarth P, Kemp J, Kowalski ML, Kvedariene V, Lipworth B, Lockey R, Lund V, Mavale-Manuel S, Meltzer EO, Mullol J, Naclerio R, Nekam K, Ohta K, Papadopoulos N, Passalacqua G, Pawankar R, Popov T, Potter P, Price D, Scadding G, Simons FER, Spicak V, Valovirta E, Wang DY, Yawn B, Yusuf O (2006) Pharmacologic and anti-IgE treatment of allergic rhinitis ARIA update. Allergy 61: 1086–96 24. Thomas M (2006) Allergic rhinitis: evidence for impact on asthma. BMC Pulm Med 6: S4 25. MacGlashan Jr DW, Bochner BS, Adelman DC, Jardieu PM, Togias A, McKenzie-White J, Sterbinsky SA, Hamilton RG, Lichtenstein LM (1997) Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 158: 1438–45 26. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S (2004) Omalizumab-induced reductions in mast cell FceRI expression and function. J Allergy Clin Immunol 114: 527–30 27. Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB (2003) Omalizumab treatment downregulates dendritic cell FceRI expression. J Allergy Clin Immunol 112: 1147–54

Anti-IgE in Allergic Airway Diseases: Indications and Applications

243

28. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthew J, Busse WW, Holgate ST, Fahy JV (2004) Effects of treatment with anti-immunoglobulin E antibody Omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 170: 583–93 29. Noga O, Hanf G, Brachmann I, Klucken AC, Kleine-Tebbe J, Rosseau S, Kunkel G, Suttorp N, Seybold J (2006) Effect of Omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J Allergy Clin Immunol 117: 1493–9 30. Casale TB (2001) Anti-immunoglobulin E (Omalizumab) therapy in seasonal allergic rhinitis. Am J Respir Crit Care Med 164: S18–21 31. Hochhaus G, Brookman L, Fox H, Johnson C, Matthews J, Ren S, Deniz Y (2003) Pharmacodynamics of Omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med Res Opin 19: 491–8 32. Saini SS, MacGlashan DW Jr, Sterbinsky SA, Togias A, Adelman DC, Lichtenstein LM, Bochner BS (1999) Down-regulation of human basophil IgE and Fc epsilon RI alpha surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo. J Immunol 162: 5624–30 33. http://www.fda.gov/cder/drug/InfoSheets/HCP/OmalizumabHCP.html 34. Deniz YM, Gupta N (2005) Safety and tolerability of Omalizumab (xolair) a recombinant humanized monoclonal anti-IgE antibody. Clin Rev Allergy Immunol 29: 31–48 35. Xolair (Omalizumab) for subcutaneous use package insert. (June 2003, code revision April 2006) Genentech, Inc and Novartis Pharmaceutical Corporation 36. Cruz AA, Lima F, Sarinho E, Ayre G, Martin C, Fox H, Cooper PJ (2007) Safety of antiimmunoglobulin E therapy with Omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy 37: 197–207 37. http://www.fda.gov/cder/biologics/review/omalgen062003r1.pdf

Drug Delivery Devices and Propellants Bruce K. Rubin and James B. Fink

Introduction Topical delivery of medications to the airway as medical aerosols is the first line treatment of asthma. Medical aerosols are produced by a range of devices and each device has its own characteristics, method of operation, and target patient population. Aerosol delivery can be a challenge as the structure of the airways is designed to minimize lung penetration of many aerosols found in the air around us; from dust and pollen to airborne pathogens. The smaller the airway, the greater the flow turbulence and therefore, the greater the volume of particles filtered. Thus, delivery of medical aerosols to children is often an order of magnitude less than adults [1]. This challenge is greater in asthma when there is airflow limitation, inflammation, excess mucus secretion, and airway remodeling [2]. Patient education for proper device use is as critical as proper device selection for effective therapy [3,4]. In this chapter, we discuss the characteristics of aerosol devices and the best techniques for aerosol delivery in patients with asthma.

Aerosol Characteristics An aerosol is a group of particles suspended in air. The lower the terminal settling velocity, the more stable the aerosol and the longer it remains in suspension. The settling velocity depends on both the particle size and density. Aerosol particle size

B.K. Rubin () Jessie Ball duPont Professor and Chairman of the Department of Pediatrics, Professor of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23219, USA e-mail: [email protected] J.B. Fink Independent Consultant, San Mateo, CF, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_15, © Springer 2010

245

246

B.K. Rubin and J.B. Fink

is usually reported as the mass median aerodynamic diameter (MMAD). For a uniformly spherical particle, this is defined as the particle diameter multiplied by the square root of the particle density. Because particles are non-uniform in density and shape, they are usually sized by their settling behavior on a series of baffles in a cascade impactor, yielding information about the MMAD and the particle size distribution or geometric standard deviation (GSD). The smaller the GSD, the greater the proportion of particles that will cluster around the MMAD. By convention, a GSD of less than 1.22 is called a monodisperse. Pressurized meter dosed inhalers (pMDI) and dry power inhalers (DPI) generally have a smaller GSD than that produced by jet nebulization [5]. Until recently, monodisperse aerosols have only been available for investigational use or for radioisotope studies of deposition. However, newer clinical devices produce a near monodisperse size distribution of particles. This could allow the targeting of particles to specific parts of the airway [6]. Because of variation in GSD, devices that generate similar MMAD may have different respirable mass, or volume percent of particles between 0.5 and 5 µm MMAD multiplied by the amount of aerosol inhaled at the mouthpiece. When a spacer or holding chamber is not used, up to 80% of the total emitted dose of a chlorofluorocarbon (CFC) powered inhaler deposits in the oral pharynx, leading to swallowing of medication, GI absorption, increased systemic effects, and loss of medication available to the lung. Oral pharyngeal deposition has been associated with thrush or laryngeal dysfunction with inhaled corticosteroids (ICS). Extremely fine particles, less than 0.5 µm MMAD, are so light that they may not sediment in the airway and can be exhaled. However, nanoparticles, less than 0.01 µm, such as those generated in the smoke of cigarettes, have the greatest penetration and retention in the lungs. Inertial impaction, gravitational sedimentation, and diffusion are the three major mechanisms of aerosol deposition and are particle size dependent. Inertial impaction is flow dependent and is the primary mechanism for deposition of particles larger than 3 µm. With high inspiratory flow, there is an increased tendency for even smaller particles to impact and deposit in the airway, while slow inspiratory flow allows larger particles to pass through the upper airways, into the lungs. The longer an aerosol particle resides in the airway, the greater the likelihood that it will deposit by sedimentation. It is for this reason that breath holding for 5–10 seconds is recommended after inhaling [7]. Diffusion primarily affects particles so small that Brownian motion is a greater influence on particle movement than gravity. Brownian movement results in both collision and coalescence of particles with both the surface of the airway and with other particles. The ability of a device to produce appropriately sized particles is a function of both how the device is designed as well as how the device is used. For example, spontaneous breathing results in 30% greater deposition of aerosol from a jet nebulizer than positive pressure breaths delivered by intermittent positive pressure ventilation or mechanical ventilation with the same nebulizer [8].

Drug Delivery Devices and Propellants

247

Aerosol Devices Aerosol device delivery has been reviewed by a panel of the American College of Chest Physicians [9]. In this evidence-based review, it was determined that for most patients with asthma, nebulizers, DPI, and pMDI were equally effective in delivering aerosolized short-acting beta agonists if the device is used appropriately by the patient. Although equally effective, there are significant differences in the ability of patients to use these devices as well as differences in costs, convenience, portability, and particle generation characteristics.

Inhalers Dry Powder Inhalers (DPI) Concerns about the environmental impact of propellants used in pMDI have resulted in an increase in the development of new DPI devices. DPIs have the advantage of being small, portable, and intrinsically breath activated, with the medication delivered when inhalation begins. In early DPIs, the medication was milled to a respirable size (2–3 µm), loosely bound to a much larger carrier such as lactose, and sealed in capsules, which were punctured at the time of administration. Use of a large particle carrier makes it easier to store the medication in a form that can be “disaggregated” with a patient’s inspiratory effort during inspiration. Capsules and blister packets are used to store and protect the powder from ambient humidity. Alternatively, powder can be packed into cakes that act as a bulk reservoir, from which a single dose is then scraped at the time of administration. Once a capsule, packet, or cake is exposed to ambient humidity or humidity from exhaled breath caused by breathing back into the device, the powder clumps within milliseconds, resulting in reduced emitted doses [10]. If large enough, the powder clumping can reduce the delivery of doses that follow. Once the medication is scraped from a cake reservoir or liberated from a capsule or blister pack, it needs to be dispersed into an aerosol cloud. This can be done passively with energy provided by the patient or actively with energy provided by the device. Most DPIs used for asthma therapy are passive, meaning that the energy to disaggregate the powder comes from the patient’s inspiratory force, with the emitted dose varying with patient effort [11]. Thus, a tight seal is needed on the mouthpiece to produce an adequate inspiratory flow, and flow can be compromised during an acute asthma attack. The inspiratory flow required for optimal disaggregating can range from 15 to 90 LPM. Effective flow for the Diskus is at least 30 LPM, while higher resistance devices like the Turbuhaler (AstraZeneca) or the Spiriva Handihaler (Pfizer) require 60 LPM or more [12].

248

B.K. Rubin and J.B. Fink

There are some DPI devices that can actively disaggregate and disperse the medication as a fine aerosol into a holding chamber, similar to those used for pMDI. The first of these was the Nektar powder delivery system for the administration of inhaled insulin (Exubera, Pfizer Pharmaceuticals) [13]. This type of active DPI tends to be more expensive than passive devices, and will not be initially available for asthma medications.

Pressurized Metered Dose Inhalers (pMDI) Pressurized MDI were first developed in the 1950s by the Riker Company, now part of 3 M [14]. They used a metering device to “puff” a specific amount of medication from a multiple dose canister. Each canister has a reservoir that contains propellants, surfactants/dispersing agents, and a small amount of active drug. The traditional asthma “puffers” are the primary means of aerosol medication delivery worldwide and use of the pMDI with the valved holding chamber (VHC) is often considered the standard, by which other aerosol delivery devices are judged. The pMDI is one of the most cost-effective devices for inhaled medication delivery. It is conveniently light weight, portable, and multidose, and can be stored in any orientation without leakage. It will reliably provide consistent dosing during the canister life. Few changes were made to the traditional pMDI until the mandate to seek new, more environmentally friendly propellants [15]. Within the stratosphere, ozone is concentrated, protecting the surface from ultraviolet radiation. Once released, CFCs rise to the stratosphere, where they are gradually broken down by ultraviolet light and this depletes the stratospheric ozone. Pressurized MDIs have historically used the chlorofluorocarbons trichlorofluoromethane (CFC-11) and dichlorodifluoromethane (CFC-12) as propellants, both of which are potent ozone-depleting substances. The Montreal protocol was adopted to reduce the emission of fluorocarbons into the atmosphere, creating a requirement to develop alternative propellants to the traditional CFC-11 and CFC-12 used for pMDI in the early 1950s. The FDA announced that after 31 December 2008, the production and sale of single ingredient CFC pMDIs must cease. Hydrofluoralkene HFA134a (tetrafluroethane) is a substitute for CFC-12. It has a much lower potential for ozone depletion and is an acceptable alternative for CFCs under the Montreal protocol. HFA carrier pMDIs require a different metering valve with a smaller aperture, producing a finer particle size for many medications. The particle size is decreased for some lipophilic corticosteroids that dissolve into a solution in HFA134a. In some cases, the new valves can reduce the particle size from greater than 4 µm MMAD to about 1.2 µm, as is the case with beclomethasone dipropionate (BDP) [16]. Some steroids do not dissolve in the HFA carrier and so, the particle size for medications such as budesonide or fluticasone are about the same as that of CFCs [17], and albuterol HFA does not have a smaller particle size than CFC. Most HFA pMDI are less affected by changes in temperature, and emit

Drug Delivery Devices and Propellants

249

aerosol at a lower velocity, tending to reduce pharyngeal deposition [18]. It is probable that a change to HFA devices will require us to reexamine the age-related dose equivalence of CFC pMDIs [19]. One of the disadvantages of pMDI is that it is hard to tell how much medication remains in the canister. While some pMDI have an overfill of 10–15% of the nominal fill, the amount of drug emitted after the number of doses on the label can vary, alternating between the label dose and no dose at all [20]. Unfortunately, the residual carrier agents and propellants continue to make an audible sound and plume with each actuation; long after medication delivery has been compromised. In the past, some manufacturers had suggested that the amount of medication remaining in the canister could be ascertained by floating the canister in a bowl of water, but it has been shown that this is not only an unreliable method but also that water entering the valve stem can alter performance of the pMDI for subsequent doses [20]. The best alternative is to use a dose counter similar to that used in DPI so that patients will know how many doses remain within the canister. Beginning in 2006, all new pMDI that are introduced in the US market have been required to have a built-in dose counter. In the absence of a dose counter, the best way of determining how much medication remains is to keep a running count of doses used for rescue drugs taken on an as-needed basis. For medications like ICS that are taken on a consistent basis, patients should be instructed to calculate in advance the number of actuations and the number of puffs per day and to indicate directly on pMDI exactly when the canister is to be discarded. In reality, most patients do not do this, and are at risk of using their pMDI beyond their ability to provide consistent dosing. Environmental factors such as temperature can also contribute to inconsistent doses. CFC inhaler activation rapidly drops the canister temperature as the gas expands. As temperature of the canister drops, so does the emitted dose of the CFC pMDI [21]. This is why the pMDI canister should be warmed to hand temperature before use and patients should wait for 20 seconds between each activation. This may not be as great a problem with HFA propelled pMDI canisters.

Breath Activated pMDI Breath activated pMDI have an inspiratory flow trigger that activates on inhalation only. This eliminates many problems with poor hand breath coordination, such as inhaling before or after the dose is emitted [22]. Because inspiratory flow is needed to activate these devices, the ability of a patient to use the device is age dependent. Maxair (pirbuterol) by 3-M (St. Paul, MN) and albuterol HPA (Teva) are available with the Autohaler and in Europe, the Easyhaler (Baker Norton Co., Eire) is available as a breath activated pMDI, with a triggering inspiratory flow required of about 30 LPM. An after-market device, the MD Turbo (TEAM Pharmaceuticals, Morrisville, NC) allows most pMDI with original boot from the manufacturer to be inserted in a device that provides breath actuation and a dose counter.

250

B.K. Rubin and J.B. Fink

Venturi Type Jet Nebulizers (JN) Small volume nebulizers (SVNs) typically use the Venturi principle to generate aerosol. A jet of compressed gas is directed over a tube, drawing fluid from a reservoir and shearing the fluid into particles that are driven against a baffle, or the internal wall of the nebulizer. This causes large particles to impact and return to the reservoir, while smaller particles continue with the gas stream toward the patient. The efficiency of the SVN depends on the gas flow and the pressure driving the nebulizer. Higher flows generally produce smaller particles [23]. Typical home nebulizers use a gas source between 10 and 35 psi, while 50 psi is commonly used in hospitals. The requirement for a compressed gas source limits device portability. With few exceptions, medical compressors are relatively heavy and require mains electricity to operate, limiting portability. Several small battery-operated VN have been introduced and they can also be operated from 12 V or mains power sources. The SVNs available in the market have a wide range of efficiency, particle size, and output rate [24]. The amount of medication remaining in the nebulizer cup at the end of nebulization or at the start of sputtering is referred to as the nebulizer residual volume and this ranges from 0.5 to 1.8 mL [25]. Thus, greater the residual volume and smaller the initial fill volume, lesser the amount of medication available for nebulization and inhalation. The fill volume is particularly important for nebulizers that have a large residual volume. Medication should be placed in the nebulizer cup in unit doses. Nebulizers should be inhaled from an upright position as tilting the nebulizer cups can cause spillage, loss of medication, and ineffective nebulization. Nebulization should stop once the cup begins to sputter.

Breath Activated Nebulizers Breath actuated nebulizers only produce aerosol during inspiration, with no loss between inspirations. Negative pressure at the start of inhalation drops a valve into place to allow nebulization to begin and stop when each inhalation is complete. These have the advantage of requiring smaller fill volumes because there is less medication lost, but often they take longer to completely nebulize a charge.

Large Volume Nebulizers (LVN) Large volume nebulizers have been used primarily for continuous nebulization of beta agonist bronchodilators in the emergency department or intensive care unit. LVNs have a greater reservoir volume to allow aerosol to be generated for extended periods of time, although this may not be therapeutically advantageous [26].

Drug Delivery Devices and Propellants

251

Ultrasonic Nebulization UN uses a vibrating piezoelectric crystal to produce cavitation in a reservoir containing a liquid formulation, producing standing waves that generate aerosols. Particle size and output rates vary with frequency and amplitude [27]. One of the advantages of UN is that a large volume of solution can be aerosolized in a relatively short period of time, but medications in suspension are poorly nebulized [28]. It can be difficult to detect when the piezoelectric crystal is cracked, caked with dry medication, or otherwise inoperable. Some crystals can become very hot through the process of vibrating and denature heat-sensitive medications, especially proteins. UNs are usually more expensive than other delivery devices. UNs are no more efficient at medication delivery than other devices and so, their use is not recommended for delivering therapeutic aerosols to ambulatory patients.

Vibrating Mesh Nebulizers (VM) VM nebulizers generate aerosols by pushing or drawing fluid through a mesh containing more than 1,000 apertures. Liquid medication passes from the reservoir through the mesh and is transformed into discrete particles. VM nebulizers use a piezo-ceramic element to vibrate the mesh containing the apertures, but the VM typically operates at less than 10% of the frequency and power consumption of the standard UN used in the clinical setting, reducing the heat transferred to the formulation. Unlike UN, which does not effectively nebulize suspensions, the VM can nebulize any suspension as long as it can physically pass through the aperture. The particle size generated by the VM is directly related to the diameter of the aperture through which the medications pass [29]. The VM nebulizers are more efficient than jet or UN nebulizers, with less residual drug remaining in the nebulizer after administration is complete, making this the most efficient commercially available liquid aerosol generation technology. This is offset by the price, which is more than that of standard nebulizer systems.

Other New Nebulizer Technologies There are promising nebulizer technologies in development. The Respimat (Boehringer Ingelheim) has been released in Europe as a hand-held multi-dose nebulizer, used to deliver tiotropium [30]. Aerosol generation through the use of electrostatic charge (Ventaira, Columbus, Ohio) has been shown to produce small, almost monodisperse particles. Another technology, which incorporates the rapid vaporization of molecules, including proteins, appears to produce highly respirable small particles.

252

B.K. Rubin and J.B. Fink

Accessory Devices Accessory devices have been developed to enhance the function of aerosol delivery devices. These include spacers, valved holding chambers (VHC), actuation enablers, and dose counters. The pMDI is designed to operate with the actuator/ boot provided by the manufacturer. Accessory devices with “universal” actuators, that do not allow the use of the manufacturer’s actuator/boot, may have great variability in performance depending on the pMDI, drug, or propellant used [31].

Spacers A spacer is a simple tube or chamber that is placed at the end of the actuator boot letting the pMDI aerosol cloud expand and mature, reducing the speed of the aerosol plume, and allowing larger particles to evaporate or rain out before reaching the patient. Spacers can be as simple as a piece of tubing, a toilet paper roll, or a large plastic drink bottle that has been cleaned and a second hole added [32]. At their best, spacers can reduce pharyngeal deposition up to 9%. They also provide some protection from loss of aerosol when the pMDI is actuated immediately before inspiration. Unlike VHC, spacers do not improve coordination problems such as patient exhaling during the actuation of the pMDI. Some spacers are so small or poorly designed that there is a significant reduction in medication inhaled. In general, a spacer that has less than 100 mL of internal volume will reduce the available inhaled mass of drug from the pMDI [33].

Valved Holding Chambers (VHC) VHC are a great improvement over the spacer. VHC have a one-way valve that prevents medication loss if the patient exhales into the device. VHC also allow a patient to dissociate the coordination of medication inhalation with actuation. Several seconds of delay between actuation and inhalation of the medication will not appreciably reduce the amount of medication available to the lungs [34] The placement of the valve between the chamber and the patient’s airway also serves to further reduce pharyngeal deposition by two orders of magnitude compared to the pMDI alone (0.9% vs. 90%), and one order of magnitude over simple spacers (0.9% vs. 9%), thus, reducing side effects. VHC can also increase the available drug for inhalation by up to fivefold compared to the pMDI alone. The most effective VHC are either metal coated or made of electrostatic resistant plastics that carry little charge [35]. Desirable characteristics of VHC include a size large enough to allow the aerosol to develop and remain as a cloud until inhalation, an easy to open inhalation valve,

Drug Delivery Devices and Propellants

253

the ability to accept a variety of pMDI boots into the device, a clear and straight aerosol flow path that decreases precipitation of aerosol within the device, construction using materials that are electrostatically reduced, and, of critical importance, a comfortable interface, either a mouthpiece or a mask, between the device and the patient [36].

Masks A variety of masks have been used for VHC; some of these are masks designed to be used for anesthesia or resuscitation, some have been adapted from adult use for children, while others have been specifically designed for inhalation using a VHC. The best masks have a low dead space, fit comfortably on the child’s face, and make a complete seal with a minimal amount of pressure [37]. For the child’s comfort, some masks incorporate an exhalation valve. However, the ability to make a complete and comfortable seal is most important. We can ensure that the mask is sealed on the face if we observe the VHC inhalation valve opening and closing with breathing.

Activation Enablers Accessory devices have been designed to fit around the boot that holds the pMDI canister, making it easier to press and actuate the pMDI. These can be useful for elderly patients with arthritis or with poor grip strength, who find it difficult to actuate the canister.

Special Uses Neonatal and Pediatric Aerosol Therapy The smaller diameter of upper and lower airways in infants and children result in a greater percentage of particle impact in this range [38]. In addition, preferential nose breathing filters aerosol from inspired gas, reducing the mass of drug available for pulmonary deposition. There are few indications for administering asthma medication to neonates because asthma is not a neonatal disease. Asthma is also uncommon in infants in the first year of life, and during this period, asthma may not respond well to medications. Children under the age of 3 years are usually not able to make a good seal on a mouthpiece and inhale on command. For toddlers, it is best that medications be delivered

254

B.K. Rubin and J.B. Fink

using a device that can be combined with a comfortable, closely fitting mask. Nowadays, that would mean using a nebulizer or pMDI and VHC with a mask. The crying and struggling child or infant has a short and high flow inhalation and a long exhalation, especially when screaming. This dramatically decreases the amount of medication in the lower respiratory tract and so, aerosol medication should not be given to a child who is upset, fighting the delivery device, or crying [39]. The face mask or mouthpiece appears to be equally effective when using a nebulizer [40], but mouthpiece delivery is superior when using a pMDI and holding chamber, and a mouthpiece should be used for most children 3 years of age and older. Medication should never be given by “blow-by”; that is using a mouthpiece that is not in the child’s mouth or a mask that is held some distance in front of the face. Almost no blow-by medication makes it into the lungs [41]. Most children who are old enough to drink from a straw are able to place the device mouthpiece directly in their mouth. When aerosols are given using a mouthpiece, it is important that the patient breathes in slowly and deeply and that the tubing should not increase turbulence as may happen with corrugated tubing. If a child can use a mouthpiece effectively, there should be no reason for them to routinely take asthma medication through a nebulizer. Guidelines from the Global Initiative for Asthma (GINA), a collaboration of the National Heart, Lung, and Blood Institute (United States) and the World Health Organization [42], recommend a pMDI with VHC plus face mask for infants, a pMDI with VHC plus mouthpiece for children 4–6 years of age, and a DPI, breathactuated pMDI, or pMDI with VHC for children 6 years and older.

Emergency Department Aerosol Delivery for Acute Asthma The goal of asthma therapy in the emergency department (ED) is to quickly reverse bronchospasm, improve airflow, and provide effective anti-inflammatory therapy. Fairly high doses of aerosol beta agonists are often administered with or without anticholinergic bronchodilators. Although there have been small studies that suggest that high doses of ICS can be nearly as effective as systemic corticosteroids for patients with acute asthma [43], there is little to recommend ICS as a substitute for systemic corticosteroids, given the high doses that are needed. On the other hand, although subcutaneous or intravenous beta agonists are effective in treating acute asthma, they are no more effective than the same medications given by aerosol and there is an unacceptably high risk of side affects when beta agonists are administered systemically. It has been shown that bronchodilators given by pMDI and VHC are at least as effective as medication administered by jet nebulizers in the ED [44]. Although patients with mild acute asthma may obtain benefit using a DPI, this is not recommended for patients with decreased inspiratory flow. In patients with stable asthma, 4 inhalations of albuterol (440 µg nominal dose in the US; 500 µg nominal dose in the rest of the world) is therapeutically equivalent to 2.5 mg by nebulization.

Drug Delivery Devices and Propellants

255

However, during acute asthma it may be necessary to initially increase the number of inhalations or the nebulized dose to achieve adequate bronchodilatation. With a higher initial dose of inhaled medications, bronchodilators are likely to be administered less frequently. The optimal dose and frequency of aerosol medication administration during acute moderate-to-severe asthma has not been established, and this is likely to be different for patients at different ages, with different durations of symptoms, and other mediations taken, such as ICS. Beta agonist bronchodilators can also be delivered by continuous nebulization by placing 10–20 mg of albuterol per hour in a large volume nebulizer (LVN) and administering this for extended periods of time (8–24 hours) [45]. Randomized controlled trials comparing continuous nebulization with intermittent lower dose nebulization or frequent inhalation of a pMDI with a VHC have not been reported. If continuous nebulization is used, it should be given with a comfortable and closely fitting mask because holding a mouthpiece in place for extended periods can be tiring during acute asthma. The mask must be vented in order to prevent re-breathing and carbon dioxide retention. The benefits of continuous nebulization decrease as the systemic anti-inflammatory drugs take effect. We recommend that if continuous nebulization is used in acute asthma, patients should be closely monitored for tremor and tachycardia, and should be evaluated frequently with the goal of returning them to intermittent pMDI and VHC as soon as possible. Data do not support the use of continuous nebulized bronchodilator therapy for patients with mild-to-moderate acute asthma.

Care of Devices Jet Nebulizer Maintenance JN should be routinely cleaned and should not have medication or nebulizer solution in them after treatment is completed, as this can be a reservoir for bacteria or fungus [46]. The nebulizer should be routinely checked for leaks and cracks. Older nebulizers tend to degrade over time [47].

VHC Maintenance VHC need to be checked to be sure that there are no objects that have entered the chamber during transport. Clear chambers make it easier to detect if there are foreign objects. The valve should be periodically examined to make sure it is not torn or stuck. This is particularly important for VHC where the valves are pegged (e.g. Optichamber) rather than using pliant flaps (e.g. Aerochamber). The mask should also be checked to make sure it is not torn and that it sits correctly on the holding chamber. VHC should be periodically washed with a mild liquid detergent.

256

B.K. Rubin and J.B. Fink

DPI and pMDI Maintenance DPI need to be kept dry when they are not being used. The dose counter needs to be checked regularly. The mouth orifice needs to remain clean at all times. Once activated, the DPI should not be flipped as this will cause dumping of medication. Pressurized MDIs need to sit completely in the boot before activation. If not properly placed in the boot or if the canister does not go with the boot, this can compromise medication delivery. The canister should be replaced once per month. The boot should also be kept clean and free from foreign objects at all times.

Patient Education One of the most important factors in the effectiveness of asthma medications is adherence to scheduled use. Nonadherence to prescribed ICS is a risk factor for acute severe and fatal asthma. Even during monitored clinical trials, full adherence to prescribed asthma therapy is estimated to be no more than 50% [48]. One of the most common reasons for nonadherence is the patient being unaware of the correct use of the device or the medication. A good way to ensure adherence is to teach the patient the correct use of medication, minimize the number of drugs and different frequencies of administration of their inhaled drugs, emphasize using the most important drug, reduce medication costs (financial and time), and suggest administration during those times in the day when they are performing routine activities, such as before brushing teeth. The use of medication and devices should be reviewed at every office visit and if there are questions, device use should be directly observed. The keys to good adherence are patient and caregiver education, and making medication use important, easy, and a routine part of the patient’s lifestyle [4].

References 1. Rubin BK, Fink JB. Aerosol therapy for children. Resp Care Clinics N Am 2001;7:175–213. 2. Sangwan S, Agosti JM, Bauer LA, et al. Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion. J Aerosol Med 2001;14:185–95. 3. Fink JB, Rubin BK. Problems with inhaler use: A call for improved clinician and patient education. Resp Care 2005;50:1360–75. 4. Rubin BK. What does it mean when a patient says, “My asthma medication isn’t working?” Chest 2004;126:972–981. 5. Reisner C, Katial RK, Bartelson BB. Buchmeir A, Rosenwasser LJ, Nelson HS. Characterization of aerosol output from various nebulizer/compressor combinations. Ann Allergy Asthma Immunol 2001;86:566–74. 6. Bennett WD, Brown JS, Zeman KL, Hu SC, Scheuch G, Sommerer K. Targeting delivery of aerosols to different lung regions. J Aerosol Med 2002;15:179–88. 7. Darquenne C, Paiva M, Prisk GK. Effect of gravity on aerosol dispersion and deposition in the human lung after periods of breath holding. J Appl Physiol 2000;89:1787–92.

Drug Delivery Devices and Propellants

257

8. Dolovich MB, Killian D, Wolff RK, Obminski G, Newhouse MT. Pulmonary aerosol deposition in chronic bronchitis: intermittent positive pressure breathing vs. quiet breathing. Am Rev Resp Dis 1977;115:397–402. 9. Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, Smaldone GC, Guyatt G. Device selection and outcomes of aerosol therapy: Evidence-based guidelines. Chest 2005; 127:335–371. 10. Meakin BJ, Cainey J, Woodcock PM. Effect of exposure to humidity on terbutaline delivery from turbohaler dry powder inhalation devices. Eur Respir J 1993;6:760–761. 11. Hindle M, Byron PR. Dose emissions from marketed dry powder inhalers. Int J Pharm 1995;116:169–177. 12. Bisgaard H et al. Inspiratory flow rate through the Diskus/Accuhaler inhaler and Turbuhaler inhaler in children with asthma. J Aerosol Med 1995;8:100. 13. Selam JL. Inhaled insulin for the treatment of diabetes: projects and devices. Expert Opin Pharmacother 2003;4:1373–1377. 14. Thiel CG. From Susie’s question to CFC free: an inventor’s perspective on forty years of MDI development and regulation. In: Dalby RN, Byron P, Farr SY, editors. Respiratory drug delivery V. Buffalo Grove: Interpharm Press; 1996:115–123. 15. Montreal Protocol, September 16, 1987, S. Treaty Doc. No. 10, 100th Cong., 1st sess., 26 I. L. M. 1541 (1987) found at http://www.unep.org/ozone/Montreal-Protocol/MontrealProtocol2000.shtml 16. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler. J Aerosol Med 2005;18:379–85. 17. Lasserson TJ, Cates CK, Jones AB, Steele EH, White J. Fluticasone versus HFAbeclomethasone dipropionate for chronic asthma in adults and children. Cochrane Database Syst Rev 2006;19(2):CD005309. 18. Kobayashi Y, Yasuba H, Kudou M, Hamada K, Kita H. Esophageal candidiasis as a side effect of inhaled fluticasone propionate dry powder: recovery by switching over to hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP). Int J Clin Pharmacol Ther 2006;44: 193–97. 19. Anhoj J, Thorsson L, Bisgaard H. Lung deposition of inhaled drugs increases with age. Am J Resp Crit Care Med 2000;162:1819–22. 20. Rubin BK, Durotoye L. How do patients determine that their metered-dose inhaler is empty? Chest. 2004;126:1134–37. 21. Williams RO 3 rd, Barron MK. Influence of temperature on the emitted dose of an oral metered dose inhaler. Drug Dev Ind Pharm 1998;24:1043–1048. 22. Hampson NB, Mueller MP. Reduction in patient timing errors using a breath-activated metered dose inhaler. Chest 1994;106:462–465. 23. Coates AL, MacNeish CF, Meisner D, Kelemen S, Thibert R, MacDonald J, Vadas E. The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols. Chest 1997;111:1206–12. 24. Hess D, Fisher D, Williams P, Pooler S, Kacmarek RM. Medication nebulizer performance. Effects of diluent volume, nebulizer flow, and nebulizer brand. Chest 1996; 110:498-505. 25. Ho SL, Coates AL. Effect of dead volume on the efficiency and the cost to deliver medications in cystic fibrosis with four disposable nebulizers. Can Respir J 1999;6:253–260. 26. Rodrigo GJ. Inhaled therapy for acute adult asthma. Curr Opin Allergy Clin Immunol 2003;3:169–75. 27. Katial RK, Reisner C, Buchmeier A, Bartelson BB, Nelson HS. Comparison of three commercial ultrasonic nebulizers. Ann Allergy Asthma Immunol 2000;84:255–61. 28. Nakanishi AN, Lamb BM, Foster CF, Rubin BK. Ultrasonic nebulization of albuterol is no more effective than jet nebulization for the treatment of acute asthma in children. Chest 1997;111:1505–08. 29. Dhand R. Nebulizers that use a vibrating mesh or plate with multiple apertures to generate aerosol. Respir Care 2002;47:1406–16.

258

B.K. Rubin and J.B. Fink

30. Hochrainer D, Holz H, Kreher C, Scaffidi L, Spallek M, Wachtel H. Comparison of the aerosol velocity and spray duration of Respimat Soft Mist inhaler and pressurized metered dose inhalers. J Aerosol Med 2005;18:273–82. 31. Berry J, Heimbecher S, Hart JL, Sequeira J. Influence of the metering chamber volume and actuator design on the aerodynamic particle size of a metered dose inhaler. Drug Dev Ind Pharm 2003;29:865–76. 32. Zar HJ, Asmus MJ, Weinberg EG. A 500-ml plastic bottle: An effective spacer for children with asthma. Pediatr Allergy Immunol 2002;13:217–22. 33. Dolovich MA, MacIntyre NR, Anderson PJ, et al. Consensus statement: aerosols and delivery devices. American Association for Respiratory Care. Respir Care 2000;45:589–96. 34. Barry PW, O’Callaghan C. The effect of delay, multiple actuations and spacer static charge on the in vitro delivery of budesonide from the Nebuhaler. Br J Clin Pharmacol 1995;40:76–8. 35. Wildhaber JH. High percentage lung delivery in children from detergent-treated spacers. Pediatr Pulmonol 2000;29:389–393. 36. Rubin BK, Fink JB. Optimizing aerosol delivery by pressurized metered dose inhalers. Resp Care 2005;50:1191–97. 37. Shah SA, Berlinski AB, Rubin BK. Force-dependent static dead space of face masks used with holding chambers. Respir Care 2006;51:140–4. 38. Rubin BK, Fink JB. The delivery of inhaled medication to the young child. Pediatr Clin N Am 2003;50:1–15. 39. Iles R, Lister P, Edmunds AT. Crying significantly reduces absorption of aerosolised drug in infants. Arch Dis Child 1999;81:163–65. 40. Lowenthal D, Kattan M. Facemasks versus mouthpieces for aerosol treatment of asthmatic children. Pediatric Pulmon 1992;14:192–96. 41. Rubin BK. Bye-bye, blow-by. Resp Care 2007 August (in press). 42. GINA Global Strategy for Asthma Management and Prevention. Updated 2003. NIH Publication NO 02-3659. 43. Nakanishi AK, Klasner AK, Rubin BK. A randomized controlled trial of inhaled flunisolide in the management of acute asthma in children. Chest 2003;124:790–94. 44. Cates CJ, Rowe BH. Holding chambers versus nebulisers for beta-agonist treatment of acute asthma (Cochrane Review). In: The Cochrane Library, 2000; Issue 2 (CD000052). Oxford: Update Software). 45. Colacone A et al. Continuous nebulization of albuterol (salbutamol) in acute asthma. Chest 1990;97:693–697. 46. Hamill RJ, Houston ED, Georghiu PR, Wright CE, Koza MA, Cadle RM, et al. An outbreak of Burkholderia cepacia respiratory tract colonization and infection associated with nebulized albuterol therapy. Ann Intern Med 1995;122:762–766 47. Standaert TA, Morlin GL, Williams-Warren J, Joy P, Pepe MS, Weber A, Ramsey BW. Effects of repetitive use and cleaning techniques of disposable jet nebulizers on aerosol generation. Chest 1998;114:577–86 48. Rubin BK. Adherence to asthma therapy: The “blocked receptor”. Pediatr Pulmonol 2004;37:36–37.

Update on the Management of Atopic Dermatitis/Eczema Sherrif F. Ibrahim, Anna De Benedetto, and Lisa A. Beck

Introduction Atopic dermatitis (AD) is a common chronic inflammatory skin disease that affects patients of all ages. The etiology is multifactorial, resulting from complex interactions of the immune system, environmental stimuli, and susceptibility genes. The prevalence of AD is increasing in industrialized nations, with as estimates as high as 20% of children and 3% of adults [1]. The financial and psychosocial cost of the disease is substantial [2]. Several studies have shown that AD in children is associated with a reduction in quality of life for patients as well as their families which is beyond that of other chronic diseases of childhood such as asthma, diabetes, and cystic fibrosis [3–5]. The treatment of moderate to severe atopic dermatitis continues to be frustrating because of the lack of efficacy of most therapies and the chronicity of the disease. There are also potential side effects with most therapies – whether topical or systemic – and these risks must be weighed against the therapeutic benefit to the patient. Because the natural history of AD involves periods of waxing and waning severity, treatment plans are often dynamic and must change accordingly to reflect disease activity. Combination therapy is the rule, as the disease itself is the final manifestation of many contributing environmental and host factors. Commonly, trials of several different treatment modalities coupled with environmental measures are necessary before an effective, individualized regiman is achieved. The diagnostic criteria and pathophysiology of AD have been well described elsewhere [1, 7, 8]. This chapter will present the general approach to the patient with AD, including basic practice guidelines for all patients, as well as a review of many of the available topical and systemic agents. When possible, evidence

S.F. Ibrahim, A. De Benedetto, and L.A. Beck () Departments of Dermatology and Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., 697, Rochester, NY 14642, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_16, © Springer 2010

259

260

S.F. Ibrahim et al.

will be presented that may support one treatment choice over another as well as a discussion of the impact that recent research may have on future treatment options.

Basic Approach to Therapy Treatment of AD regardless of extent of involvement must address general good skin care practice as well as the education of the patient and care providers on the natural history of AD, environmental control measures, screening and treatment of associated atopic diseases (rhinitis, asthma, eosinophilic esophagitis, food allergy, and conjunctivitis), psychosocial support, and adjustment of expectations from various treatment approaches. The cornerstones of treatment involve emollients and other means of skin hydration to address the profound xerosis classically seen with the disease, as well as identification and avoidance of trigger factors. Further treatment decisions are based on severity, and typically include the addition of topical glucocorticoids and/or topical calcineurin inhibitors. In the case of moderate to severe AD, a systemic treatment option is often considered, and may only be needed for short periods of time to control flares. More recently, it has become increasingly evident that control of skin infections is critical for the successful management of this disease [9]. The development of AD is multifaceted, with each patient having specific triggers and necessitating treatment regimens that are highly individualized. Although topical steroids have historically carried the bulk of the therapeutic burden, the approach to treatment of AD patients should utilize combination therapy to address the multiple components (pruritus, inflammation, colonization/ infection) of the disease.

Avoidance of Exacerbating Factors Exacerbating factors in AD include irritants and allergens – the latter typically evoking IgE-mediated inflammation. It is believed among patients with AD, that there are two forms of the disease – the more common “extrinsic” form (affecting 70–80% of patients) that is associated with IgE-mediated sensitivity to common allergens, and an “intrinsic” form (affecting 20–30% of patients) that develops in patients with normal IgE levels [10]. Allergen testing by skin prick and serum radioallergosorbent tests (RAST) can be helpful in the evaluation of AD patients. Up to 30% of children with moderate to severe AD may have underlying food allergy. Avoidance of foods implicated in either controlled challenges as well as in food allergen-specific CAP-RASTs have resulted in clinical improvement for some patients [11]. It is important to distinguish food intolerance from true food

Update on the Management of Atopic Dermatitis/Eczema

261

allergy. Up to 25% of adults report having a food allergy, although the prevalence of IgE mediated disease in double-blind, placebo-controlled studies indicates this figure is less than 5% in adults and approximately 6% in children under 3 years of age [12–14]. The most common food allergens are milk, eggs, peanuts, tree nuts, soy, fish, and wheat [15]. Clinical reactions to food in AD subjects include worsening of dermatitis – particularly in sensitized infants – either alone or associated with typical immediate-type allergic reactions such as urticaria, pruritis, gastrointestinal symptoms, or anaphylaxis. Several clinical studies have shown that elimination of relevant food allergens can lead to clinical improvement of the dermatitis [16, 17]. A large, controlled study in high-risk infants demonstrated that extensively versus partially hydrolyzed casein formula reduced AD severity by 50% in the first year of life [18, 19]. Interestingly, children with AD are often found to have positive skin tests for peanut despite being peanut naïve, and almost half of these peanut naïve children develop skin symptoms on oral peanut challenge [20]. This situation poses a challenge for counselling of parents as far as dietary restrictions and avoidance of foods are concerned. Because peanut allergy can theoretically be fatal without prior sensitization, the American College of Allergy recommends avoidance of peanut products before 3 years of age [21]. Ramesh has provided a recent thorough review of food allergy in children (Fig. 1) [13].

BASIC SKIN CARE: Irritant / Allergen Avoidance and Skin Hydration

Control of skin infection / colonization

Anti-itch therapy

Systemic Rxs Immunosuppressive Therapy

Topical Rxs Corticosteroids or Cakineurin Inhibitors

Dry skin

Mild

Moderate

Biologics

Severe

Recalcitrant

Disease State

Fig. 1 Basic approach to the management of atopic dermatitis. Combination therapy is the mainstay of AD treatment. Milder cases can be controlled with emollient use and topical agents alone, while more advanced disease requires systemic therapy. Frequently, patients will require systemic therapy for defined periods of time during flares of AD. Control of skin colonization and infection by bacteria as well as anti-itch treatment are critical to limit the progression of the disease

262

S.F. Ibrahim et al.

Although children can outgrow good allergies, they may become sensitized to inhaled allergens as they become older [10, 22]. The avoidance of aeroallergens such as house dust mite has proven effective in relieving symptoms in some, but not all studies. It is likely that most AD patients are polyallergic, with reactivity to multiple aeroallergens, microbial antigens, as well as self-antigens [10]. The deficiency in epithelial barrier function seen in AD patients probably allows easy access for multiple allergens to encounter immune system players and drives the characteristic Th2 response. The resultant polyallergic state may explain why elimination or reduction of one or more allergens does not always lead to significant clinical improvements. There are numerous reports on the use of specific immunotherapy in the management of respiratory hypersensitivity conditions such as allergic rhinitis and asthma [23]. This approach is thought to induce allergen-specific tolerance by introducing the known allergen either sublingually or subcutaneously at increasing doses. There is growing evidence supporting the efficacy of this approach in subjects with AD. Werfel et al, demonstrated that sublingual immunotherapy improves dermatitis in atopic patients who are mono-sensitized to a specific allergen, and can reduce the need for topical corticosteroids [22]. Recent reviews by Novak and Bussman et al have examined the role of specific immunotherapy as it pertains to AD [24, 25]. Further refinement in immunotherapy and well-designed trials will undoubtedly clarify its role and utility in the management of atopic dermatitis. Beyond food and environmental allergies, several reports have demonstrated that contact (type IV) allergy may also play a role in the skin manifestations observed in patients with atopic dermatitis [26]. Although there has been some controversy in the role of patch testing in AD patients, multiple studies have shown high rates of positive patch test readings in atopic patients [27, 28]. Therefore, it is worthwhile to evaluate AD subjects with recalcitrant disease to determine if contact allergens are also contributing to their skin disease. This is often difficult, as patch testing requires large areas of clear skin (preferably on the back) in order to adequately perform and interpret the test. As a general rule, most clinicians suggest that AD subjects just avoid exposure to the most frequent contact allergens such as metals, fragrances, dyes, and neomycin sulfate [27, 29].

Topical Treatments Emollients A feature observed in all AD patients is the loss of an effective skin barrier which, among other things, results in increased transepidermal water loss (TEWL), dry skin (xerosis), and in some, ichthyosis [30]. Defects in barrier function lead to greater exposure to environmental allergens, irritants, and likely play a role in AD subjects’ susceptibility to microbial colonization and infection. The extent of barrier

Update on the Management of Atopic Dermatitis/Eczema

263

dysfunction has been shown to correlate with the degree of inflammation [31]. Furthermore, barrier dysfunction may also lead to systemic allergic responses such as airway hyperreactivity and progression along the atopic march [32]. Proper skin hydration can be maintained with regular application of emollients (i.e. creams or ointments) throughout the day, as well as the use of soaps with minimal defatting activity and a neutral pH [33]. Branda et al performed a study correlating irritation from several commonly used household soaps, and found that Dove™ products had the lowest scores on a normalized irritation index [34]. Although scientific data supporting the use of emollients is limited, one study has shown they have a steroid-sparing effect in mild to moderate AD [35]. Another study demonstrated that emollients containing ceramide, a lipid that is expressed at reduced levels in the epithelium from AD subjects, was more effective than placebo in children with recalcitrant the epithelium from AD [36]. In July 2003, the compound MAS063D (Atopiclair™ in the US, Zarzenda™ in the EU) was approved as a prescription medical device by the US Food and Drug Administration (FDA) to relieve the symptoms of AD and allergic contact dermatitis. This is a steroid-free cream whose main components are hyaluronic acid, a glycosaminoglycan found in normal connective tissue and known to induce tissue hydration; Vitis vinifera (common grape vine), which has anti-oxidants and anti-protease activity; telmesteine, which reduces free radicals formation and theoretically may protect against oxidizing agents that may contribute to epithelial damage. The rationale for using MAS063D in AD therapy is to protect AD skin from insult by free radicals and skin-damaging enzymes, and to improve barrier function by moisturizing the skin. However, only a few studies have been conducted to evaluate the safety and benefits of this compound in the management of AD and none of them have elucidated the mechanism by which it has its effect [37, 38]. Recently, the FDA has approved another nonsteroidal topical called MimyX Cream™ (Stiefel Laboratories, Inc, Coral Gables, FL) for the management of burning and itching associated with AD and other dermatitis for both adult and pediatric patients. The approval was based on data from safety and efficacy studies showing the moisturizer was equivalent to currently marketed products for reducing post-procedure (e.g. laser, photodynamic therapy) symptoms [39]. The major constituent in MimyX™ is N-palmitoylethanolamide, a fatty acid that has been reported to be deficient in AD subjects, and is a ligand for the cannabinoid receptor, CB2 [40]. Topical cannabinoid agonists have been shown to be effective and well-tolerated therapies for refractory pruritus, suggesting that N-palmitoylethanolamide and other related agents may be useful for treatment of itch [41]. Pilot studies in patients with AD have been promising; however, larger controlled trials will be needed to better characterize their efficacy and mode of action [42]. The filament aggregating protein called filaggrin, is an essential player in the formation of the cornified cell layer and maintenance of skin barrier function. Recent genetic studies have shown that null mutations in the gene encoding filaggrin are a strong and highly reproducible predisposing factor in the development of AD in European and Asian cohorts [43]. Howell et al demonstrated that filaggrin expression is reduced in acute AD lesions compared to nonlesional skin, indicating that patients may also have an acquired defect. They also demonstrated that differentiated keratinocytes, cultured in

264

S.F. Ibrahim et al.

the presence of IL-4 and IL-13 had reduced filaggrin expression, suggesting that Th2 cytokines present in AD lesions may be responsible for the reduced filaggrin observed. This is another mechanism by which the barrier can become dysfunctional [44].

Topical Steroids Topical glucocorticoids have been the mainstay of therapy in the treatment of atopic dermatitis for over 40 years. They are rated on a scale from I to VII based on their relative potency in a cutaneous vasoconstrictor assay, with class I steroids being the most potent agents. Steroid class has been shown to correlate with clinical efficacy and side effects [46]. The utility of topical steroids has been demonstrated in a number of studies [46–50]. A meta-analysis of 83 randomized, vehicle-controlled studies demonstrated that 80% of patients treated with topical steroids for less than one month reported a positive response (good or better on a symptom scale) [51]. Unfortunately, side effects are tightly linked with potency and include skin atrophy or thinning, striae and acneiform eruptions [52]. As a general rule, mid to high potency agents should be used with caution on the face, flexural, and genital areas in most subjects or anywhere on the body in small children. Systemic adverse effects from topical steroids such as suppression of the hypothalamic-pituitary-adrenal axis (HPA) and Cushing’s syndrome are uncommon. Ellison et al have shown that HPA suppression was rare in pediatric subjects with moderate to severe AD, even after several years of regular use of mild to moderate potency topical steroids [53]. However, HPA suppression was found in those receiving potent topical glucocorticoids, or both topical and systemic steroids. Within this latter group, the authors identified a subgroup of AD patients with HPA suppression but no clinical improvement, implying that some patients may have glucocorticoid resistance that occurs only in the skin, and that this resistance may be inherent to disease pathophysiology [53]. Similarly, recent studies in AD subjects have shown a blunted HPA axis response with a low dose dexamethasone suppression test when compared to non-atopic controls [54, 55]. The authors speculated that a hyporeactive HPA could explain the link between atopic diseases and stress. Nevertheless, short courses of Class IV steroids are safe for up to 4 weeks in infants and young children based on the lack of demonstrable systemic effects [56]. Therefore topical corticosteroids, while effective, are limited in their use by their side effect profiles. This is of greater concern in subjects with AD, as their disease typically recurs in the same locations. Surprisingly, given their widespread use, it is unclear what the best application frequency is for topical steroids. There is no clear evidence to support the use of twice-daily over once-daily application [51, 57, 58]. It may therefore be reasonable to use once-daily corticosteroids initially in the treatment of AD patients.

Update on the Management of Atopic Dermatitis/Eczema

265

Several reports suggest that intermittent application of topical steroids may be useful as a preventative strategy. In one study, application of 0.1% betamethasone valerate on unaffected skin twice weekly prevented subsequent flares at that site [59]. This effect may at least in part be due to a reduction in Staphylococcus aureus colonization which has been observed with topical steroid use [60].

Topical Calcineurin Inhibitors The topical calcineurin inhibitors (TCI), pimecrolimus and tacrolimus, are approved for the treatment of mild-to-moderate and moderate-to-severe AD, respectively. By inhibiting calcineurin, they prevent the translocation of the transcription factor, nuclear factor of activated T cells (NFAT) from the cytoplasm to the nucleus. This prevents the transactivation of many inflammatory cytokines including IL-1b, -2, -3, -4, -5, GM-CSF, IFNg, and TNF-a that are thought to contribute to the development of AD [61]. Clinical trials have established the efficacy of these agents both as monotherapy and for their steroid-sparing effects [62, 63]. While they have not been shown to cause the skin atrophy seen with topical steroids, side effects can include transient burning, erythema, and pruritis, which typically improves after the first week of use [52]. In February of 2006, the FDA placed a black box warning in the package insert based on concerns that rare cases of malignancy (e.g. skin cancers and lymphoma) have been reported in patients using these medications although they acknowledge that a causal relationship has not been established [64]. The labeling states that these drugs should be used as second line treatments and their use in children younger than 2 years is not recommended. This action has resulted in considerable frustration within the dermatologic and allergy communities [65–67]. In 2006, a group of AD experts concluded that the potential for adverse systemic effects from TCI is very low, and one should not forestall appropriate use of these agents in AD management [68, 69]. In a recent comprehensive review, Callen et al have summarized both published and FDA meeting reports on the safety of several topical therapies used in AD, and concluded that these medications are safe and well tolerated with only occasional, mild side effects such as burning and stinging upon application [49]. A nested casecontrol study examining the risk of lymphoma in AD patients following exposure to TCIs found no increased risk of malignancy from these agents. In AD patients who did develop lymphoma, the severity of AD was the main factor associated with this risk [70]. Ashcroft et al have performed a meta-analysis of both pimecrolimus and tacrolimus in the treatment of AD [71]. These agents were found to be effective, safe topical agents in the management of AD, but the authors note that additional data will be needed to determine the long term safety gains over the use of topical steroids. Ongoing Phase IV (post-marketing) studies with TCIs in AD patients will likely clarify the safety of these drugs.

266

S.F. Ibrahim et al.

Infection and Antimicrobial Treatments Skin infections caused by a variety of bacterial, fungal, and viral microorganisms frequently modulate the course of AD and complicate the management of these patients. Defective skin barrier, reduced skin lipid content, increased skin surface pH, increased bacterial adhesion, and decreased production of antimicrobial peptides by skin cells, all contribute to an increased propensity for cutaneous colonization and infection in AD [72]. This colonization and infection is thought to stimulate the release of inflammatory cytokines from keratinocytes, further aggravating the disease. Therefore, reduction in the microbial burden often improves overall skin health in these patients. In-depth reviews by Drs. Leung and Wollenberg et al provide a more comprehensive discussion of infections in patients with AD [72, 73].

Bacterial Infections Of the bacteria commonly found on the skin, Staphylococcus aureus has been the best characterized. In certain studies, up to 100% of AD patients are colonized with S. aureus on the skin and/or nasal mucosa as compared to 5–30% of normal controls. Acute AD lesions contain higher numbers of S. aureus than chronic lesions, unaffected atopic skin, or skin from non-atopics [72]. Furthermore, up to 65% of the S. aureus isolates from AD patients are toxin-producing [9]. Many investigators feel that S. aureus colonization aggravates the inflammation and pruritus characteristic of AD. Toxins secreted by S. aureus can act as superantigens, activating T cells and increasing disease activity. Many AD patients also develop IgE antibodies directed against S. aureus toxins, causing greater disease severity [74]. Topical antiseptics (e.g. triclosan, chlorhexidine, bleach [sodium hypochlorite] [234]) have been shown to be effective in reducing skin colonization with S. aureus and/or improving clinical symptoms [75]. Topical antiseptics can be used as a component of emollients or in wet-wrap dressing therapy [9]. Use of topical antibiotics is in part, limited by a higher risk of sensitization against these agents in AD patients. Moreover, there are concerns about the rise of resistant strains of bacteria with continued use of topical and oral antibiotics [76]. Therefore, use of these agents is recommended for short durations (three weeks or less). There is some evidence that topical mupirocin may improve AD activity as well as reduce bacterial counts [77]. Intranasal mupirocin has also been successfully used for intranasal eradication and prophylaxis of S. aureus [78]. The addition of a topical antimicrobial agent to topical corticosteroid preparations has not shown a benefit beyond that of a topical steroid alone [79]. Several clinicians have suggested the use of dilute bleach baths (2 teaspoons of household bleach/gallon of water) to reduce skin colonization while minimizing the emergence of antibiotic resistance [80, 234]. Antibacterial soaps have also been shown to significantly improve skin lesions over placebo soap [81]. Newer antimicrobial approaches include the use of silver-coated textiles and silk fabric, which have anti-friction and antimicrobial action [82, 83].

Update on the Management of Atopic Dermatitis/Eczema

267

Systemic antibiotic therapy should be reserved for more advanced bacterial infections. Short-term therapy with first or second-generation cephalosporins or semisynthetic penicillins, are usually effective, as S. aureus is the most likely causative agent [84]. Unfortunately, reinfection is common after a course of antistaphylococcal therapy. Long term therapy should be avoided to limit the development of bacterial resistance. Community-associated methicillin-resistant S. aureus (CA-MRSA) is now identified in up to 30% of all skin and soft tissue infections [85, 86]. Our own studies have shown up to 14% of AD subjects are colonized with CA-MRSA, based on antibiotic sensitivities [235]. Growing antibiotic resistance will undoubtedly pose a significant threat to the treatment of bacterial infections in general, and will be an increasingly important issue for atopic patients in particular, given their high rates of colonization and frequent use of antimicrobials.

Viral Infections Atopic dermatitis patients have an increased likelihood of developing severe skin infections from viruses that do not typically cause disseminated cutaneous infections in non-atopics [72]. The condition is named after the causative virus: eczema molluscatum from the molluscum contagiosum virus (MCV), eczema vaccinatum from the live vaccinia virus vaccine, and eczema herpeticum from the herpes simplex virus (HSV) type 1 or 2. The latter can cause disseminated infection in patients with several other skin conditions besides AD that are infected with HSV; however the term eczema herpeticum is reserved for disseminated HSV infection specifically in patients with AD. When it occurs in patients with other skin conditions, it is termed Kaposi’s varicelliform eruption [73]. Once again, disturbed skin barrier function, Th2 cell predominance, and lower levels of IFN-a are thought to contribute to the higher incidence of skin infections in AD patients. Eczema vaccinatum has been described in AD patients who have received the smallpox vaccine or more commonly had exposure to a recently vaccinated individual, which can cause a disseminated vaccinia eruption [73]. Therefore, a history of or active AD is a contraindication for smallpox vaccination. New attenuated strains of the virus are being developed, which may reduce the risk of this complication; but their efficacy towards preventing smallpox outbreaks is unknown [87–89]. Eczema herpeticum can be quite serious, often requiring prompt medical attention. The patients at greatest risk for developing eczema herpeticum are those with more severe eczema, higher total IgE, and earlier age of onset [236]. There seems to be a genetic component, based on the fact that there is often a family history of this complication [90, 237] (unpublished data). Skin findings are accompanied by fever, lymphadenopathy, and malaise. Rarely, multi-organ failure may ensue including conjunctivitis, encephalitis, and meningitis [90]. Immediate treatment with systemic anti-virals such as acyclovir is necessary to minimize morbidity and mortality from the disease. Prior to the development of

268

S.F. Ibrahim et al.

modern anti-virals, mortality from eczema herpeticum was reportedly as high as 75% [90]. Topical and systemic immunosuppressive treatments are contraindicated during acute phases of this condition. Suppression of recurrent HSV infection can be achieved with daily oral antiviral treatment [91]. Less severe viral skin infections in AD patients are caused by different strains of the human papilloma virus (HPV), and manifest as warts or verruca. The incidence of warts in AD patients has been estimated to be between 4 and 17% higher than in non-atopics [92]. A large variety of treatment modalities exist and have been reviewed extensively [93, 94]. Lesions of eczema molluscatum can resolve spontaneously; however treatment can accelerate the process and prevent autoinoculation. Treatment typically consists of destructive modalities similar to those suggested for HPV infections. Topical calcineurin inhibitors and topical steroids should be stopped in order to maximize host immune response [92].

Fungal Infections As with bacterial and viral infections, AD patients are also prone to fungal infections of the skin [95]. In particular, Malassezia spp. is known to colonize the skin of both healthy and atopic subjects, especially in seborrheic areas such as the face, and are implicated in exacerbation of AD [96]. Skin lesions of AD in patients with IgE to M. furfur have been shown to improve with antifungal treatment [95]. Additionally, atopic patients are more prone to develop chronic dermatophyte infections, and may show improvement in their AD when treated with antifungals [95].

Antimicrobial Peptides Antimicrobial peptides (AMP) are naturally occurring peptides that have been shown to possess anti-bacterial and anti-viral properties. They have generated considerable interest because of their potential therapeutic use against a variety of pathogens. In the epidermis, AMPs are secreted by keratinocytes and they are considered an integral part of the cutaneous innate immune system [97]. Several groups have noted that AD subjects have diminished AMP production which likely contributes to the susceptibility of AD subjects to skin colonization/infections [98–101]. Manipulation of AMP expression could be a valuable approach to control microbial infections in AD subjects. In recent years, synthetic cationic steroid antibiotics, modeled after the chemical structure of AMP, have been developed for treatment of multi-drug resistant bacteria [102]. Leung et al., have recently shown in an in vitro model that these agents are effective anti-viral compounds capable of limiting Vaccina virus infection [103]. Other studies have shown that the induc-

Update on the Management of Atopic Dermatitis/Eczema

269

tion of AMP is mediated by 1,25-dihydroxyvitamin D3 and the vitamin D receptor [104]. Studying the role of high-dose vitamin D and its effects on AMP production and other aspects of innate immunity in subjects with AD, is an area of active investigation by several groups.

Anti-Itch Treatment Pruritus is the most distressing feature of AD, and the itch-scratch cycle perpetuates the disease. Scratching causes injury to the skin resulting in the release of inflammatory mediators that could themselves fuel the itch, as well as contributing to further barrier impairment and skin infections. The etiology of pruritus in AD is poorly understood, and consequently, highly effective therapy is not available. Current therapies rely on nonspecific approaches to reducing itch such as topical agents, oral antihistamines, and phototherapy. New developments in the study of pruritus may lead to better, targeted therapy and are briefly discussed below. Topical corticosteroids and TIMs have been shown to improve pruritus [105,106]. Anti-pruritic effects are believed to relate to the inhibition of local inflammatory cytokines. In addition, the use of emollients with or without oatmeal baths and wetwraps may reduce the frequency and/or amount of steroid application. Topical doxepin cream (Zonalon™, Bradley Pharmaceuticals, Fairfield NJ) has been used in subjects with AD and other pruritic conditions with variable results [107]. Doxepin is a tricyclic antidepressant drug, with strong anti-H1 and -H2 actions. Several studies have reported a short-term (1 week) improvement in itch, but no improvement in AD severity beyond this period [108]. The addition of topical doxepin to topical corticosteroids has been shown to induce a significantly faster and more substantial reduction in pruritus than corticosteroids alone [109]. Long-term studies on the efficacy of topical doxepin treatment are not available. The sedating effects observed even after fairly limited body surface area applications have limited the usefulness of this treatment. The effectiveness of oral antihistamines for pruritus control in AD patients is often debated [110, 111]. H1 and H2 antagonists have been utilized by many practitioners in the management of the intense pruritis frequently observed in AD. While evidence-based reviews have found insufficient evidence to recommend the use of antihistamines in AD [112], it is our opinion that the soporific effects of the older generation antihistamines are helpful in preventing or minimizing scratching that typically escalates in the evening. Antihistamines may also be useful as, they are effective in treated a variety of comorbid conditions frequently seen in association with AD such as allergic rhinitis, conjunctivitis, and asthma [113, 114]. Beyond the oral and topical treatment modalities discussed above, phototherapy with ultraviolet (UV) radiation has been used successfully to treat AD. Several variations of phototherapy have been described including narrowband UVB (311 nm), broadband UVB, UVA1 (340–400 nm), psoralen plus UVA (PUVA 320–400 nm),

270

S.F. Ibrahim et al.

balneophototherapy, climatotherapy, and extracorporeal photopheresis, although PUVA and UVB are most widely used [115, 116]. Phototherapy is effective when used in conjunction with topical steroids, thereby reducing the total dose of both treatment approaches [117]. There is increasing evidence supporting the efficacy and safety of narrow-band UVB in the management of AD [118–120]. Narrow-band UVB is an effective adjuvant treatment for moderate to severe atopic dermatitis and the treatment is usually well tolerated, although its mechanism of action is still unclear. Several studies suggest that UVB has immunomodulatory effects, such as blocking the function of antigen presenting cells, and inducing the release of TNF-a and IL-10 by keratinocytes [121]. Interestingly, new evidence suggests that UVB rather than UVA may stimulate expression of the antimicrobial peptide LL-37, likely through a Vitamin D-mediated pathway [122]. Furthermore, T-cells within the epidermis seem to be susceptible to UVB-induced apoptosis [123]. Long-term safety of narrowband UVB phototherapy in AD patients will need to be monitored, particularly in its relationship to the development of cutaneous malignancy. As a general rule, phototherapy should be reserved as a second-line treatment in adults and used cautiously in children under 12 years old, as there is little information about long term side-effects in this age group. Advances in cellular and molecular biology have revealed new insight into the biology of itch, particularly in AD patients. Opioid receptors are known to play a central role in the modulation of itch, both centrally and peripherally [124]. Naltrexone, an opiate receptor antagonist has been used in treatment of recalcitrant pruritic diseases. AD patients have been shown to benefit from treatment with both oral and compounded topical preparations [125–127]. Other recent advances in the etiology of itch may provide alternative approaches to treatment. Sonkoly et al demonstrated a significant increase in the expression of IL-31 in atopic skin as compared to psoriatic skin. IL-31 is a T-cell derived cytokine that elicits severe pruritus and dermatitis in a murine model. It was shown that staphylococcal superantigen rapidly induced IL-31 expression in atopic individuals, providing a link between staphylococcal colonization, T-cell activity, and pruritus in patients with AD [128]. This study provides a new target for the development of effective anti-itch therapies, and also supports the notion that antimicrobial agents may have a role in the treatment of pruritus. Sun et al have recently demonstrated that the gastrin-releasing peptide receptor plays an important role in the itch sensation centrally [129]. Thus, perhaps a combination of approaches including the reduction of bacterial burden, central modification, and peripheral blockade of itch mediators may ultimately be the most effective treatment approach for the intense pruritus that defines AD.

Systemic Immunosuppressive Therapy Atopic dermatitis results from an abnormal inflammatory response, therefore many systemic immunosuppressive agents have been used successfully in its management. In general, systemic therapies are reserved for refractory cases in order to minimize

Update on the Management of Atopic Dermatitis/Eczema

271

the risks associated with long-term immunosuppression. Most of the systemic medications currently used for treatment of moderate to severe AD are not FDA approved for this indication. Each requires close follow-up and some degree of clinical and laboratory monitoring to ensure that side effects are detected as early as possible. No single agent has proven superior to others, and therefore agents that are highly effective in one patient may not be suitable for another. Trials of several different systemic agents may be necessary before finding the best therapy for a given patient. Likewise, some patients may only need systemic agents for a limited time as “induction therapy” to reach an acceptable level of symptom control before switching to a maintenance regimen [130]. Patients who are refractory to multiple treatments should undergo skin biopsy and other investigations to ensure that the diagnosis of AD is accurate.

Systemic Steroids Although oral corticosteroids have been used in the treatment of inflammatory skin conditions for over 50 years, few randomized studies have been performed in subjects with AD. The decision to use systemic steroids should not be taken lightly given the numerous systemic side effects including diabetes, hypertension, osteoporosis, cataracts, and avascular necrosis, as well as the risk of relapse upon steroid discontinuation [7]. Short courses of systemic steroids (less than four weeks duration) can be helpful in cases of acute flares of dermatitis; however they should be avoided during periods of rapid adolescent growth to minimize risk of permanent growth retardation [131] and even in the worst cases should be limited to at most 2–3 courses per year. The equivalent of 20–40 mg of prednisone daily for 2 weeks is typically sufficient to relieve severe flares, but the precise dosing and length of treatment is variable, influenced by factors such as bodyweight, disease severity, access to steroid-sparing agents and continued exposure to allergens. Withdrawal of steroids should be gradual to minimize the chances of rebound flares and HPA disruption.

Methotrexate Methotrexate (MTX) is an antimetabolite that competes with folic acid for dihydrofolate reductase, an enzyme that catalyzes folic acid into reduced folate cofactors necessary for DNA synthesis. It has been used for many years to treat cancer as well as autoimmune and inflammatory diseases including psoriasis [132]. By disrupting folate metabolism, MTX inhibits proliferation of rapidly dividing cells such as keratinocytes and T cells. Several studies have indicated that MTX is effective and well-tolerated in AD subjects with moderate-to-severe disease and is comparable in efficacy to other second-line therapies [133–136]. Bateman et al demonstrated a

272

S.F. Ibrahim et al.

dose-dependent reduction in allergen-specific T cells that correlated with clinical response of AD to MTX [137]. The therapeutic approach used for AD is similar to that used for psoriasis. After baseline laboratories are checked (complete blood count, liver function tests) a test dose of 2.5 or 5 mg is administered with repeat laboratory values drawn 5–7 days later. If tolerated, the dose is then increased by 2.5–5 mg weekly until a therapeutic dose that typically falls between 15 and 25 mg/week is reached. The MTX dose for the week is taken in its entirety on one day, with 1 mg of folic acid given on nonMTX days to reduce potential side effects [138]. Nausea, anorexia, fatigue, myelosuppression, pneumonitis, and liver disease are among the potentially toxic effects of MTX. Although patients typically have laboratory monitoring monthly or bimonthly, there have been reports of liver damage occurring in the setting of normal liver function tests. For this reason, the American Academy of Dermatology guidelines recommend a liver biopsy after a cumulative methotrexate dose of 1.5 gm [139]. However recent data has suggested that this figure may be too conservative and patients without preexisting risk factors could potentially receive as high as 4.0 gm before undergoing liver biopsy [140]. MTX has been approved for children older than 2 years with juvenile rheumatoid arthritis, and appears to be well tolerated in the pediatric population [141].

Oral Calcineurin Inhibitors Oral calcineurin inhibitors have been utilized extensively as systemic immunosuppressive agents in solid organ transplant recipients. Their mode of action has been discussed in the TCI section above. Several clinical trials have shown the efficacy of CyA in the treatment of AD in both children and adults at doses of 3–5 mg/kg/ day [142–147]. In one study, relapse of AD after discontinuation of CyA was reported, but the mean scores for disease activity and extent of disease were less than baseline values [148]. Short courses of CyA have also been shown to induce remission in pediatric patients, indicating that treatment plans should be individualized to the patient [144]. Dose-dependent side effects of cyclosporine include – but are not limited to – nephrotoxicity, hypertension and hyperlipidemia, which are why most clinicians limit its use to less than one year. In one study, increases in serum creatinine of over 30% were seen in 7 of 73 (10%) of AD patients treated with CyA and 8% of patients experienced a rebound phenomenon in their dermatitis upon discontinuation of treatment [149]. Although it has been suggested that tolerability of CyA may be better in children [150], other studies have suggested that it may diminish bone mass in the pediatric AD population [151]. Neoral, a microemulsion of CyA with improved pharmacokinetic properties, has been shown to have a faster onset of action and higher initial efficacy in AD [152]. Oral pimecrolimus is a newer generation calcineurin inhibitor that prevents the dephosphorylation of NFAT as described in the topical calcineurin inhibitor section above. A double-blind, placebo-controlled trial with oral pimecrolimus

Update on the Management of Atopic Dermatitis/Eczema

273

(10 mg, 20 mg or 30 mg twice daily for 12 weeks) has recently been completed. This trial has demonstrated significant improvement in the Eczema Area and Severity Index (EASI) scores for the 60 mg per day group compared to placebo. No nephrotoxicity or hypertension was observed during the trial period [152]. A nonhuman primate study with this formulation of pimecrolimus demonstrated an occurrence of lymphoma in monkeys exposed to a dose which represented 30 times the maximum recommended human dose. This finding has lessened the enthusiasm for clinical development of oral pimecrolimus [153]. Tacrolimus (FK506, Prograf) is a macrolide immunosuppressant produced by the soil fungus Streptomyces tsukubaensis with similar mode of action as the other calcineurin antagonists, but 10–100 times more potent than CyA [154, 155]. Like CyA, it is commonly used in solid organ transplant recipients to prevent rejection. Oral tacrolimus has been shown to be effective in inflammatory skin disorders including AD. However its potential side effect profile including infections, hypertension, hyperglcemia, hyperkalemia, nephrotoxicity, neurotoxicity, and increased risk of neoplasia has limited its use in dermatology, although its safety has been shown to be comparable if not superior to that of CyA in the transplant population [154, 156–159]. More controlled trials will be necessary to elucidate its utility in AD and other dermatologic disorders. Sirolimus (rapamycin) is not a calcineurin inhibitor like pimecrolimus, tacrolimus, or CyA, yet acts in a related fashion. Unlike the tacrolimus-FKBP12 complex which inhibits calcineurin, the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) and downstream players. This pathway is known to have a role in cellular growth and proliferation, and study of mTOR inhibitors has received immense scientific interest as potential cancer therapies [160]. Sirolimus is a larger molecule than pimecrolimus or tacrolimus, thereby precluding its use as a topical agent [161]. Unlike the calcineurin inhibitors, sirolimus does not exhibit renal toxicity, and thus can be used in conjunction with these agents. Reitamo et al demonstrated its use in the treatment of psoriasis in conjunction with CyA to reduce the dose and toxicity associated with the latter medication [162]. Side effects associated with sirolimus include lipid abnormalities, elevated liver enzymes, and thrombocytopenia [163]. Its utility and safety in dermatology has yet to be determined beyond preliminary studies that have been published to date [164, 165]. Notably, a new calcineurin inhibitor, ISA247 (Isotechnika, Inc., Scottsdale, AZ) is currently being studied in organ transplantation and psoriasis [166, 167]. It is significantly more potent that CyA, but appears to have less toxicity. Its role in treatment of AD has not been evaluated.

Mycophenolate Mofetil Mycophenolate mofetil (Cellcept) is an inhibitor of inosine monophosphate dehydrogenase (IMP) that preferentially depletes guanine nucleotides in T and B lymphocytes, thereby limiting their proliferation. Several small, open-label studies of

274

S.F. Ibrahim et al.

mycophenolate mofetil have demonstrated good efficacy and safety profiles in children and adults with severe AD [168–172]. Mild headaches, gastrointestinal complaints, and fatigue are the most frequent side-effects associated with its use. Elevated liver enzymes have been reported [173]. Dosing in adults usually starts at 500 mg twice daily and increases to 1–1.5 gm twice daily as needed, based on efficacy and side effects. Maximum benefit can take 8–12 weeks. A new IMP inhibitor, VX-148 (Vertex Pharmaceuticals, Inc., Cambridge, MA) is currently being tested in patients with hepatitis C and psoriasis and appears to be a potent immunosuppressive agent with good pharmacological activity and bioavailability in a murine model [174].

Azathioprine Azathioprine (Imuran, GlaxoSmithKline) is an immunosuppressant drug that is metabolized into 6-mercaptopurine and 6-thioinosinic acid that acts through the inhibition of purine synthesis and cell proliferation. A double-blind, placebocontrolled crossover trial of 37 patients with severe AD showed an improvement in symptoms and reduction in the disruption of work/daytime activities after treatment with azathioprine; however 12 patients discontinued the medication secondary to side effects. Gastrointestinal disturbances and leucopenia were the major side effects. Other side effects associated with its use include fevers, rigors, myalgias, arthralgias, hepatotoxicity, and possibe increased risk of malignancies [175–177]. Meggett et al demonstrated a 37% improvement in AD severity in a double-blind, randomized, control trial with azathioprine [178]. The side effects of azathioprine typically limit the enthusiasm for this therapy in AD. Genetic polymorphisms in the enzyme, thiopurine methyltransferase (TPMT) have been linked to individual differences in azathioprine side effects – particularly bone marrow toxicity – and it is suggested that patients undergo testing prior to initiation of the drug so that dose adjustments can be made [179]. Recommended dose of azathioprine for dermatologic disorders is 1–3 mg/kg/day in persons with normal TPMT activity. Azathioprine has demonstrated equal efficacy and safety profile in children as in adults with AD [180, 181]. An additional study has demonstrated clinical improvement of AD associated with a substantial reduction in serum total IgE in AD patients treated with azathioprine [182]. Regular monitoring of liver function and complete blood count is recommended.

Biologics A new era of highly targeted therapeutic agents has emerged. These agents target specific components of the immune response and this approach holds the promise of reduced side effects as compared with conventional immunosuppressive medications discussed above.

Update on the Management of Atopic Dermatitis/Eczema

275

Many of these drugs are recombinant proteins such as antibodies or soluble receptors, and are truly at the forefront of medical treatment of the disease.

Interferon-g (rIFN-g) Recombinant interferon-g (IFNg) was one of the first immunobiologics studied as a treatment for AD. The rational for IFNg therapy is to restore the balance between Th1 and Th2 cytokines, as IFN-g suppresses the expression and actions of Th2 cytokines such as IL-4 and IL-13, which play a key role in IgE production, eosinophilia, and the initiation of AD. It was somewhat surprising that treatment with IFNg was not shown to lower serum IgE levels in patients with atopic dermatitis treated for 12 weeks. Instead, the clinical improvement noted, correlated with decreases in absolute white blood cell and eosinophil counts [183–185]. The exact mechanism of action of IFNg in the treatment of AD is unclear. A randomized, placebo-controlled trial of 83 severe AD patients demonstrated improvements in symptom scores and physicians’ overall response evaluation [186]. Headaches, myalgias, and chills developed in roughly half of those receiving active treatment. Treated patients were then enrolled in an open label trial and followed for more than 2 years, and no significant adverse events were reported [185]. Although IFNg therapy has not been FDA approved for the treatment of AD, its off-label use by some clinicians is reserved for treatment of acute flares in patients with moderate-to-severe AD [187]. Further studies to determine which AD patients are more likely to respond to IFNg, optimal dosing strategy and long-term safety are needed. For these reasons, as well as for cost reasons, and the flu-like symptoms commonly observed with this therapy, it is not commonly used.

Intravenous Immunoglobulin (IVIg) IVIg is a plasma product pooled from 10,000 to 20,000 donors containing Ig molecules [188]. It has been used successfully in the treatment of primary immunodeficiencies, Kawasaki’s Disease and idiopathic thrombocytopenic purpura. The mechanism of IVIg’s anti-inflammatory action is not fully understood but is thought to involve both the Fc and antigen binding portions of the Ig molecule [188]. Several small case series’ and trials have shown efficacy in the treatment of AD [189–193]. A meta-analysis by Jolles concluded that an improvement was observed in 61% of patients treated with IVIg, that adults were less likely to respond than children (48% vs 90%), and the duration of response was longer in children. It was also shown that IVIg as adjunctive therapy was more effective than monotherapy in adults (59% vs 0%), whereas monotherapy was effective in 90% of children [188]. Dose ranges of IVIg varied from 0.4–2 g/kg for 1–11 cycles.

276

S.F. Ibrahim et al.

IVIg is generally well tolerated, with most side effects occurring within an hour of infusion such as flushing, myalgia, arthralgia, headache, fever, chills, nausea, vomiting, chest tightness, wheezing, changes in blood pressure, tachycardia, and aseptic meningitis. Anaphylaxis is rare, but can occur in the setting of IgA deficient patients [188]. Furthermore, conflicting views have been expressed as to whether or not variability exists between different brands and preparations of IVIg [194, 195]. Certainly, further studies are needed to better characterize the role of IVIG in treatment of severe AD.

Tumor Necrosis Factor (TNF)a inhibitors (Etanercept – Enbrel®, Amgen; Infliximab – Remicade®, Centocor; Adalimumab – Humira®, Abbott) Tumor Necrosis Factor (TNF)-a inhibitors are being used successfully to treat a variety of inflammatory conditions including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. TNFa induces the expression or release of a variety of proteins relevant for the development of AD lesions, including the endothelial adhesion molecule, E-selectin, which facilitates the homing of the cutaneous lymphocyte antigen (CLA) positive memory T cells to the skin [196]. In addition, TNFa induces the production of chemokines important for the attraction of inflammatory cells to lesions of AD including thymus activation regulated chemokine (TARC [CCL17]), macrophage derived chemokine (MDC [CCL22]), and monocyte chemotactic protein (MCP)-4 [CCL13]. Interestingly, studies have failed to demonstrate an increased level of TNF in leukocytes or in serum of atopic dermatitis patients [197, 198], whereas several groups have shown TNF immunoreactivity in lesional skin [199, 200]. Based on these findings, one can theorize that TNF antagonisms may be advantageous in the treatment of AD by decreasing adhesion molecule expression and recruitment of inflammatory cells to dermatitic lesions. Etanercept, a soluble TNF-receptor, and infliximab, a chimeric monoclonal antibody, are currently used to treat the cutaneous and musculoskeletal features of psoriasis. Recent studies have shown that TNF antagonism may be beneficial in some subjects with poorly controlled asthma [201, 202]. Remarkably little is known about how such drugs affect cutaneous allergic inflammation. To address this question, we recently employed the intradermal allergen challenge model to evaluate the clinical and cellular effects of etanercept on the acute and late phase reactions observed in this model [203]. The results from 10 subjects demonstrated that etanercept had no effect on the size of late phase reactions, cellular influx, or endothelial adhesion molecule expression, which is in agreement with the relatively poor clinical efficacy of this class of immunosuppressives in the treatment of atopic dermatitis [204, 205]. Nevertheless, there was an unexpected reduction in the size of the acute phase reactions, suggesting that etanercept can affect mast cell degranulation or its downstream effects, making this a potentially useful drug in the treatment of urticaria. To date, no studies of adalimumab in AD have been conducted.

Update on the Management of Atopic Dermatitis/Eczema

277

Anti-LFA agents (Efalizumab – Raptiva®, Genentech-Xoma) Efalizumab was a recombinant humanized monoclonal antibody that binds to the integrin subunit, CD11a. CD11a is the a subunit of lymphocyte function-associated antigen-1 (LFA-1), a cell surface molecule on T cells that mediates the adhesion to intracellular adhesion molecule (ICAM)-1. ICAM-1 is expressed on antigen presenting cells as well as endothelial cells and keratinocytes. Therefore, by blocking the LFA-1/ICAM-1 interaction, efalizumab inhibited T-cell activation as well as migration into inflammatory sites such as the skin [206]. In acute AD, the CLA+ CD4+ cell predominates, and releases local mediators that drive inflammation and recruitment of other inflammatory cells. Efalizumab was FDA approved for the treatment of moderate to severe chronic plaque psoriasis [196]. Recently, a few case reports and series demonstrated successful treatment of severe and refractory AD with efalizumab [207– 209]. In 2007, an investigator-initiated, prospective, open-label, pilot study conducted on 10 subjects with severe AD, was published [210]. Six out of ten subjects reached at least 50% improvement in EASI score. Overall, efalizumab was well tolerated. There were three significant adverse events during the course of this study, including thrombocytopenia, viral gastroenteritis, and a subject with worsening of disease beyond baseline levels after drug discontinuation. In early 2008 it became clear that patients receiving efalizumab were at increased risk for the development of progressive multifocal leukoencephalopathy (PML) and because of this risk Genentech voluntarily withdrew this drug from the US market in June of 2009.

Anti IgE Agents (Omalizumab – Xolair®, Genentech) Omalizumab is a recombinant humanized IgG monoclonal antibody that binds specifically to the FceRI binding site on soluble human IgE, irrespective of allergen-specificity. It does not bind cell-surface bound IgE, thereby reducing the risk of anaphylaxis [211]. Several important mechanisms of action have been demonstrated, including reduction in free IgE levels, reduction in surface-bound IgE on basophils, mast cells and dendritic cells, and reduction in allergen-triggered response in basophils and mast cells [212, 213]. Omalizumab was FDA approved in June of 2003 for use in patients 12 yrs of age and older, with moderate to severe allergic asthma. Given the clinical benefits seen in trials with antiIgE approaches in allergic diseases such as asthma, allergic rhinitis, and food allergy [211, 214], and levels of serum IgE having been demonstrated to correlate with the severity of atopic dermatitis [215], trials in subjects with atopic dermatitis seem warranted [216]. Two small case series have investigated the use of omalizumab in atopic dermatitis – one demonstrated benefit while the other showed no effect [217–220].

278

S.F. Ibrahim et al.

Notably, the serum IgE varied considerably among treated patients. In the study with the positive clinical response with omalizumab, serum total IgE values were substantially lower than in the study that showed no clinical response. Nevertheless, most of the subjects reported to date have been significantly under dosed based on the fact that they have all had rather elevated total IgE values. Current FDA recommendations for dosing of Xolair in an average-sized adult will only allow for neutralization of serum IgE levels up to 700 IU/ml. Therefore it is not too surprising that clinical improvement was not observed in many of these AD studies where the IgE levels far exceeded this cut off. Unfortunately, the AD patients with severe disease who are in need of new therapeutic options typically have extremely high serum IgE levels that omalizumab – based on current FDA regulations – cannot neutralize. Nevertheless, a randomized, controlled trial of omalizumab in AD patients with serum IgE levels within the appropriate dosing range (< 700 IU/ml) would define the relevance of IgE and its receptors in AD. If IgE pathways prove to be critical for the development of the disease, this and related compounds would provide a viable steroid-sparing treatment option for those moderate to severe AD patients with high serum IgE levels.

Alternative Approaches Probiotics Probiotics are cultures of live microorganisms including Lactobacillus and Bifidobacterium species which, upon ingestion, may provide benefit by improving the balance of the intestinal microflora. They have shown promise in the prevention and perhaps treatment of allergic diseases, including AD [221, 222]. Their mechanism of action is unknown but is thought by some to be related to the fact that intestinal flora of allergic children may be different from that of healthy infants [223, 224]. It has been shown that probiotics improve the mucosal barrier function and thereby reduce leakage of antigens through the mucosa, or have other direct influences on the immune system [225]. In one study, 159 expectant mothers with a personal or family history of atopic disease were randomized to 2 capsules of 109 Lactobacillus species or placebo. Offspring of the active treatment group were 50% less likely to manifest AD symptoms compared to offspring in the placebo-treated group [224]. In another study, 56 infants with moderate to severe AD were randomized to Lactobacillus fermentum or placebo. After 8 weeks of therapy, the group which received the probiotic had significant improvement in tits Severity Scoring of Atopic Dermatitis (SCORAD) index [222]. While some have questioned the findings of these studies, this continues to be an active area of research [226, 227].

Update on the Management of Atopic Dermatitis/Eczema

279

Gamma linoleic Acid (GLA) Gamma linoleic acid (GLA), also known as fatty acid, omega-6 fatty acid, and evening primrose oil, has been studied as an adjuvant in AD treatment. Several studies have shown a defect in essential fatty acids (EFA) metabolism in AD patients’ reduction rate of conversion of dietary EFAin their active metabolites [228]. Polyunsaturated fatty acids are essential components of all cell membranes as well as precursors of eicosanoids, which may play an important role in inflammatory and immunological processes of AD [229]. A recent meta-analysis of clinical trials demonstrated that evening primrose oil had a beneficial effect on pruritis, crusting, edema, and erythema in AD patients, which is apparent between 4 and 8 weeks after treatment [230]. However, the magnitude of this effect was reduced in association with increasing frequency of potent steroid use. Although unlikely to have utility as monotherapy, use of GLA and associated compounds may prove useful in the treatment of AD.

Psychological Interventions Several psychological interventions have been used in management of AD. One of the goals of this approach is to break the itch-scratch cycle that exacerbates the disease and negatively impacts quality of life [231]. These interventions include behavioral management, relaxation therapy, and cognitive behavioral therapy (i.e. mindfulness). Unfortunately few research studies have been conducted to assess the efficacy of such approaches. One controlled trial addressed the effect of hypnotherapy or biofeedback as compared to placebo in AD children, and concluded that there was no difference between the two relaxation techniques. Both however induced a significant reduction from baseline in severity of AD [232]. Given the anecdotal evidence of patients with AD reporting worsening of their disease during times of stress and other preliminary findings, further studies into the contribution of psychological factors to the course of AD will be of interest to the dermatologic community.

Conclusions Atopic dermatitis is a complicated disease that is a challenge to manage. Fortunately, as our understanding of the disease process at the molecular and cellular level increases, so too does our armamentarium of treatment options. By recognizing and avoiding triggers of the disease, maintaining good skin care practice, and deciding upon the best course of treatment that offers maximal relief of symptoms while minimizing side effects, the physician and patient can together determine the appropriate course of treatment.

280

S.F. Ibrahim et al.

References 1. Boguniewicz M, Leung DY. Pathophysiologic mechanisms in atopic dermatitis. Semin Cutan Med Surg 2001;20(4):217–25. 2. Verboom P, Hakkaart-Van L, Sturkenboom M, De Zeeuw R, Menke H, Rutten F (2002) The cost of atopic dermatitis in the Netherlands: an international comparison. Br J Dermatol 147:716–24 3. Emerson RM, Williams HC, Allen BR, Mehta R, Finlay AY (1997) How much. disability does atopic eczema cause compared with other health. problems? Br J Dermatol 137 (S50):19. 4. Beattie PE, Lewis-Jones MS (2006) An audit of the impact of a consultation with a paediatric dermatology team on quality of life in infants with atopic eczema and their families: further validation of the Infants’ Dermatitis Quality of Life Index and Dermatitis Family Impact score. Br J Dermatol 155(6):1249–55 5. Holm EA, Wulf HC, Stegmann H, Jemec GBE. Life quality assessment among patients with atopic eczema. (2006) Br J Dermatol 154:719–725. 6. Paller AS, McAlister RO, Doyle JJ, Jackson A (2002) Perceptions of physicians and pediatric patients about atopic dermatitis, its impact, and its treatment. Clin Pediatr 41(5);323–32 7. Leung DY, Hanifin JM, Charlesworth EN, Li JT, et al. Disease management of atopic dermatitis: a practice parameter. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Work Group on Atopic Dermatitis. Ann Allergy Asthma Immunol. 1997;79(3):197–211. 8. Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation. Br J Dermatol 1994;131(3):406–16. 9. Breuer K, Haussler S, Kapp A, Werfel T (2002) Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 147(1):55–61 10. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113(5):651–7. 11. Sampson HA. The evaluation and management of food allergy in atopic dermatitis. Clin Dermatol 2003;21:183–92. 12. Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics 1987;79(5):683–8. 13. Ramesh S. Food Allergy Overview in Children. Clin Rev Allergy Immunol 2007 Nov 8 (Epup ahead of print) 14. Osterballe M, Hansen TK, Mortz CG, Høst A, Bindslev-Jensen C. The prevalence of food hypersensitivity in an unselected population of children and adults. Pediatr Allergy Immunol 2005;16(7):567–73. 15. Sicherer SH and Sampson HA (2006) 9. Food allergy. J Allergy Clin Immunol 117(2): S470–S47. 16. Sampson HA, Scalon Sm. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr 1989;115:23–27. 17. Lever R, MacDonald C, Waugh P, Aitchison T. Randomised controlled trial of advice on an egg exclusion diet in yourng children with atopic eczema and sensitivity to eggs. Pediatr Allergy immunol 1998;9:13–19 18. von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, et al., German Infant Nutritional Intervention Study Group. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol 2003;111(3):533–40. 19. Muraro A, Dreborg S, Halken S, Host A, Niggemann B, et al. Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed

Update on the Management of Atopic Dermatitis/Eczema

20.

21.

22.

23. 24.

25. 26.

27. 28. 29. 30. 31. 32.

33. 34.

35.

36.

37.

38.

281

observational and interventional studies and final recommendations. Pediatr Allergy Immunol 2004;15(4):291–307. Kagan R, Hayami D, Joseph L, St Pierre Y, Clarke AE. The predictive value of a positive prick skin test to peanut in atopic, peanut-naïve children. Ann Allergy Asthma Immunol 2003;90(6):640–5. Fiocchi A, Assa’ad A, Bahna S; Adverse Reactions to Foods Committee; American College of Allergy, Asthma and Immunology. Food allergy and the introduction of solid foods to infants: a consensus document. Ann Allergy Asthma Immunol 2006;97(1):10–20. Werfel T, Ballmer-Weber B, Eigenmann PA, Niggemann B, Rance F, Turjanmaa K, Worm M. Eczematous reactions to food in atopic eczema: position paper of the EAACI and GA2LEN. Allergy 2007;62(7):723–8. Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 2006;6(10):761–71. Bussmann C, Böckenhoff A, Henke H, Werfel T, Novak N. Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis? J Allergy Clin Immunol 2006;118(6):1292–8. Novak N. Allergen specific immunotherapy for atopic dermatitis. Curr Opin Allergy Clin Immunol 2007;7(6):542–56. Mortz CG, Lauritsen JM, Bindslev-Jensen C, Andersen KE. Prevalence of atopic dermatitis, asthma, allergic rhinitis, and hand and contact dermatitis in adolescents. The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis. Br J Dermatol 2001;144(3):523–32. el Samahy MH, el-Kerdani T. Value of patch testing in atopic dermatitis. Am J Contact Dermat 1997;8(3):154–7. de Groot AC. The frequency of contact allergy in atopic patients with dermatitis. Contact Dermatitis 1990;22(5):273–7. Schöpf E, Baumgårtner A. Patch testing in atopic dermatitis. J Am Acad Dermatol 1989;21(4 Pt 2):860–2. Imokawa G. Lipid abnormalities in atopic dermatitis. J Am Acad Dermatol 2001;45:S29–32. Strid J, Strobel S. Skin barrier dysfunction and systemic sensitization to allergens through the skin. Curr Drug Targets Inflamm Allergy 2005;4(5):531–41. Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 2006;118(1):3–21 Leung DY, Bieber T. Atopic Dermatitis. Lancet 2003;361:151–60. Baranda L, González-Amaro R, Torres-Alvarez B, Alvarez C, Ramírez V. Correlation between pH and irritant effect of cleansers marketed for dry skin. Int J Dermatol 2002;41(8):494–9. Lucky AW, Leach AD, Laskarzewski P, Wenck H. Use of on an emollient as a steroid sparing agent in the treatment of mild to moderate atopic dermatitis in children. Pediatr Dermatol 1997;14:321–4. Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler AJ, Fluhr JW, Williams ML, Elias PM. Ceramide-dominant barrier lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47(2):198–208 Abramovits W, Boguniewicz M; Adult Atopiclair Study Group. A multicenter, randomized, vehicle-controlled clinical study to examine the efficacy and safety of MAS063DP (Atopiclair) in the management of mild to moderate atopic dermatitis in adults. J Drugs Dermatol 2006;5(3):236–44. Belloni G, Pinelli S, Veraldi S. A randomised, double-blind, vehicle-controlled study to evaluate the efficacy and safety of MAS063D (Atopiclair) in the treatment of mild to moderate atopic dermatitis. Eur J Dermatol 2005;15(1):31–6.

282

S.F. Ibrahim et al.

39. Garcia BD, Goldman MP, Gold MH. Comparison of pre- and/or postphotodynamic therapy and intense pulsed light treatment protocols for the reduction of postprocedure-associated symptoms and enhancement of therapeutic efficacy. J Drugs Dermatol 2007;6(9):924–8. 40. Abramovits W, Perlmutter A. MimyX cream. Skinmed 2006;5(1):29–30. 41. Stander S, Reinhardt HW, Luger TA. Topical cannabinoid agonists. An effective new possibility for treating chronic Pruritus. Hautarzt 2006;57(9):801–7. 42. Pulvirenti N, Nasca MR, Micali G. Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: a pilot study. Acta Dermatovenerol Croat 2007;15(2):80–3. 43. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, et al. Common loss-offunction variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38(4):441–6. 44. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007;120(1):150–5. 45. Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler et al. Ceramide-dominant barrier lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47(2):198–208. 46. Williams HC. Clinical Practice. Atopic Dermatitis. New Engl J Med 2005;352(22):2314–24. 47. Boguniewicz M, Leung DY. Atopic dermatitis. J Allergy Clin Immunol 2006;117(2 Suppl Mini-Primer):S475–80. 48. Kiken DA, Silverberg NB. Atopic dermatitis in children, part 2: treatment options. Cutis 2006;78(6):401–6. 49. Callen J, Chamlin S, Eichenfield LF, Ellis C, Girardi M, et al. A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol 2007;156(2):203–21. 50. Atherton DJ. Topical corticosteroids in atopic dermatitis. BMJ 2003;327(7421):942–3. 51. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000;4:1–191 52. Gottlieb AB. Therapeutic options in the treatment of psoriasis and atopic dermatitis. J Am Acad Dermatol 2005;53:S3–16. 53. Ellison JA, Patel L, Ray DW, Clayton PE. Hypothalamic-Pituitary-Adrenal Function and Glucocorticoid Sensitivity in Atopic Dermatitis. Pediatrics 2000;105:794–799. 54. Wamboldt MZ, Laudenslager M, Wambolt FS, Kelsay K, Hewitt J. Adolescents with atopic disorders have an attenuated cortisol response to laboratory stress. J Allergy Clin Immunol 2003;111:509–14. 55. Buske-Kirschbaum A, Geiben A, Höllig H, Morschhäuser E, Hellhammer D. Altered Responsiveness of the Hypothalamus-Pituitary-Adrenal Axis and the Sympathetic Adrenomedullary System to Stress in Patients with Atopic Dermatitis. J Clin Endocrinol Metab 2002;87:4245–4251. 56. Friedlander SF, Hebert AA, Allen DB for the Fluticasone Pediatrics Safety Study Group. Safety of fluticasone propionate cream 0.05% for the treatment of severe and extensive atopic dermatitis in children as young as 3 months. J Am Acad Dermatol 2002;46:387–393. 57. Bleehen SS, Chu AC, Hamann I, Holden C, Hunter JA, Marks R. Fluticasone propionate 0.05% cream in the treatment of atopic eczema: a multicentre study comparing once-daily treatment and once-daily vehicle cream application versus twice-daily treatment. Br J Dermatol 1995;133(4):592–7. 58. Tharp MD. A comparison of twice-daily and once-daily administration of fluticasone propionate cream, 0.05%, in the treatment of eczema. Cutis 1996;57(2 Suppl):19–26. 59. Thomas KS, Armstrong S, Avery A, Po AL, et al. Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema. BMJ 2002;324(7340):768. 60. Stalder JF, Fleury M, Sourisse M, Rostin M, et al. Local steroid therapy and bacterial skin flora in atopic dermatitis. Br J Dermatol 1994;131(4):536–40. 61. Bornhovd E, Burgdorf WH, Wollenberg A. Macrolactam immunomodulators for topical treatment of inflammatory skin diseases. J Am Acad Dermatol 2001;45:736–43

Update on the Management of Atopic Dermatitis/Eczema

283

62. Eichenfeld LF, Lucky AW, Boguniewicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46:495–504 63. Paller A, Eichenfield LF, Leung DY, et al. 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44:S47–57 64. Novartis and Fujisawa FDA Briefing Statements. Pediatric AdvisoryCommittee Meeting of the US Food Drug Adminstration. Washington, DC, 2005. http://www.fda.gov/ohrms/dockets/ ac/05/briefing/2005-4089b2.htm 65. Stern RS. Topical calcineurin inhibitors labeling: putting the “box” in perspective. Arch Dermatol 2006;142(9):1233–5. 66. Fleischer AB Jr. Black box warning for topical calcineurin inhibitors and the death of common sense. Dermatol Online J 2006;12(6):2. 67. Fonacier L, Charlesworth EN, Spergel JM, Leung DY. The black box warning for topical calcineurin inhibitors: looking outside the box. Ann Allergy Asthma Immunol 2006;97(1):117–20. 68. Spergel JM, Leung DY. Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence. Curr Allergy Asthma Rep 2006;6(4):270–4. 69. Qureshi AA, Fischer MA. Topical calcineurin inhibitors for atopic dermatitis: balancing clinical benefit and possible risks. Arch Dermatol 2006;142(5):633–7 70. Arellano FM, Wentworth CE, Arana A, Fernández C, Paul CF. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 2007;127(4):808–16. 71. Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ 2005;330(7490):516. 72. Leung DYM. Infection in atopic dermatitis. Curr opin Ped 2003;15:399–404. 73. Wollenberg A, Wetzel S, Burgdorf WH, Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol 2003;112(4): 667–74. 74. Leung DYM, Harbeck H, Bina P, Reiser RF, Yang E, Norris AD, et al. Presence of IgE antibodies tp Staphylocccal enterotoxins on the skin of patients with Atopic Dermatites: evidence for a new group of allergens. J Clin Invest 1993;92;1374–80. 75. Sporik R, Kemp AS. Topical triclosan treatment of atopic dermatitis. J Allergy Clin Immunol 1997;99:8. 76. Shah M, Mohanraj M. High levels of fusidic acid-resistant Staphylococcus aureus in dermatology patients. Br J Dermatol 2003;148(5):1018–20. 77. Lever R, Hadley K, Downey D, Mackie R. Staphylococcal colonization in atopic dermatitis and the effect of topical mupirocin therapy Br J Dermatol 1988;119(2):189–98. 78. Laupland KB, Conly JM. Treatment of Staphylococcus aureus colonization and prophylaxis for infection with topical intranasal mupirocin: an evidence-based review. Clin Infect Dis 2003;37(7):933–8. 79. Hung SH, Lin YT, Chu CY, Lee CC, et al. Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics. Ann Allergy Asthma Immunol 2007;98(1):51–6. 80. Spagnola C. Atopic Dermatitis. emedicine. http://www.emedicine.com/ped/topic2567.htm 81. Breneman DL, Hanifin JM, Berge CA, Keswick BH, Neumann PB. The effect of antibacterial soap with 1.5% triclocarban on Staphylococcus aureus in patients with atopic dermatitis. Cutis 2000;66(4):296–300. 82. Gauger A, Mempel M, Schekatz A, Schafer T, Ring J, Abeck D. Silver coated textiles reduce Staphylococcus aureus colonization in patients with atopic eczema. Dermatology 2003;207: 15–21. 83. Ricci G, Patrizi A, Bendandi B, Menna G, Varotti E, Masi M. Clinical effectiveness of a silk fabric in the treatment of atopic dermatitis. Br Dermatol 2004;150:127–31. 84. Lubbe J. Secondary infections in patients with atopic dermatitis. Am J Clin Dermatol 2003;4:641–54.

284

S.F. Ibrahim et al.

85. Diekema DJ, Pfaller MA, Schmitz FJ, et al. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 2001;32(Suppl 2): S114–32. 86. Shorr AF. Epidemiology of staphylococcal resistance. Clin Infect Dis 2007;45(Suppl 3): S171–6. 87. Blanchard TJ, Alcami A, Andrea P, Smith GL. Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: implications for use as a human vaccine. J Gen Virol 1998;79 (Pt 5):1159–67. 88. Frey SE, Newman FK, Kennedy JS, Sobek V et al. Clinical and immunologic responses to multiple doses of IMVAMUNE((R)) (Modified Vaccinia Ankara) followed by Dryvax((R)) challenge. Vaccine 2007;[Epub ahead of print]. 89. Parrino J, McCurdy LH, Larkin BD, Gordon IJ et al. Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vacciniaimmune individuals. Vaccine 2007;25(8):1513–25. 90. Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B. Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. J Am Acad Dermatol 2003;49(2):198–205. 91. Zuckerman RA, Lucchetti A, Whittington WL, Sanchez J, Coombs RW, et al. Herpes Simplex Virus (HSV) Suppression with Valacyclovir Reduces Rectal and Blood Plasma HIV-1 Levels in HIV-1/HSV-2-Seropositive Men: A Randomized, Double-Blind, PlaceboControlled Crossover Trial. J Infect Dis 2007;196(10):1500–1508 92. Patrizi A, Neri I, Bianchi F, Passarini B, Ricci G. Facial eruption of viral warts in a child treated with 0.03% tacrolimus ointment for atopic dermatitis. Pediatr Dermatol 2007;24(4): 445–7. 93. Lipke MM. An armamentarium of wart treatments. Clin Med Res 2006;4(4):273–93. 94. Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database Syst Rev 2006;3:CD001781. 95. Faergemann J. Atopic dermatitis and fungi. Clin Microbiol Rev 2002;15(4):545–63. 96. Sugita T, Tajima M, Ito T, Saito M, Tsuboi R, Nishikawa A. Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species. J Clin Microbiol 2005;43(6):2824–9. 97. Gallo RL, Hutterner KM. Antimicrobial peptides: an emerging concept in cutaneous biology. J invest Dermatol 1998;111;739–43. 98. Howell MD, Boguniewicz M, Pastore S, Novak N, Bieber T, et al. Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol 2006;121(3):332–8. 99. Howell MD. The role of human beta defensins and cathelicidins in atopic dermatitis. Curr Opin Allergy Clin Immunol 2007;7(5):413–7. 100. Howell MD, Wollenberg A, Gallo RL, Flaig M, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol 2006;117(4):836–41. 101. Ong PY, Ohtake T, Brandt C, Strickland I, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002;347(15):1151–60. 102. Salmi C, Brunel JM. Therapeutic potential of cationic steroid antibacterials. Expert Opin Investig Drugs 2007;16(8):1143–57. 103. Leung DYM, Streib JE, Savage PB, Howell MD, Cationic steroid antibiotics (CSA) exhibit cytotoxic activity against vaccinia virus (VV). J Allergy Clin Immunol 2005;115(2):1083, S272. 104. Wang TT, Nestel FP, Bourdeau V, Nagai Y, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173(5):2909–12. 105. Heymann WR. Itch. J Am Acad Dermatol 2006;54(4):705–6. 106. Ständer S, Luger TA. Antipruritic effects of pimecrolimus and tacrolimus. Hautarzt 2003;54(5):413–7. 107. Drake LA, Millikan LE. The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis. Doxepin Study Group. Arch Dermatol 1995;131(12):1403–8.

Update on the Management of Atopic Dermatitis/Eczema

285

108. Drake LA, Fallon JD, Sober A. Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream The Doxepin Study Group. J Am Acad Dermatol 1994;31(4):613–6. 109. Berberian BJ, Breneman DL, Drake LA, Gratton D et al. The addition of topical doxepin to corticosteroid therapy: an improved treatment regimen for atopic dermatitis. Int J Dermatol 1999;38(2):145–8. 110. Dimson S, Nanayakkara C. Do oral antihistamines stop the itch of atopic dermatitis? Arch Dis Child 2003;88(9):832–3. 111. Imaizumi A, Kawakami T, Murakami F, Soma Y, Mizoguchi M. Effective treatment of pruritus in atopic dermatitis using H1 antihistamines (second-generation antihistamines): changes in blood histamine and tryptase levels. J Dermatol Sci 2003;33(1):23–9. 112. Klein PA, Clark RA. An evidence-based review of the efficacy of antihistamines in relieving pruritis in atopic dermatitis. Arch Dermatol 1999; 135:1522–1525 113. Fireman P. Therapeutic approaches to allergic rhinitis: treating the child. J Allergy Clin Immunol 2000;105(6 Pt 2):S616–21. 114. Chang AB, Peake J, McElrea MS. Anti-histamines for prolonged non-specific cough in children. Cochrane Database Syst Rev 2006;3:CD005604. 115. Meduri NB, Vandergriff T, Rasmussen H, Jacobe H. Phototherapy in the management of atopic dermatitis: a systematic review. Photodermatol Photoimmunol Photomed 2007;23(4):106–12. 116. Jekler J. Phototherapy of atopic dermatitis with ultraviolet radiation. Acta Derm Venereol Suppl (Stockh) 1992;171:1–37. 117. Valkova S, Velkova A. UVA/UVB phototherapy for atopic dermatitis revisited. J Dermatolog Treat 2004;15(4):239–44. 118. Grundmann-Kollmann M. Phototherapy for atopic eczema with narrow-band UVB. J Am Acad Dermatol 1999;40(6 Pt 1):995–7. 119. George SA, Bilsland DJ, Johnson BE, Ferguson J. Narrow-band (TL-01) UVB air-conditioned phototherapy for chronic severe adult atopic dermatitis. Br J Dermatol 1993; 128:48–56. 120. Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM. Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet 2001;357:201. 121. Schade N, Esser C, Krutmann J. Ultraviolet B radiation-induced immunosuppression: molecular mechanisms and cellular alterations. Photochem Photobiol Sci 2005;4(9): 699–708. 122. Zasloff M. Sunlight, vitamin D, and the innate immune defenses of the human skinJ Invest Dermatol 2005;125(5):xvi–xvii. 123. Krueger JG, Wolfe JT, Nabeya RT, Vallat VP, et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. Exp Med 1999;182:2057. 124. Tominaga M, Ogawa H, Takamori K. Possible roles of epidermal opioid systems in pruritus of atopic dermatitis. J Invest Dermatol 2007;127(9):2228–35. 125. Bigliardi PL, Stammer H, Jost G, Rufli T, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol 2007;56(6):979–88. 126. Heyer G, Groene D, Martus P. Efficacy of naltrexone on acetylcholine-induced alloknesis in atopic eczema. Exp Dermatol 2002;11(5):448–55. 127. Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol 1999;41(4):533–9. 128. Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 2006;117(2):411–7. 129. Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007;448(7154):700–3. 130. Abramovits W. A clinician’s paradigm in the treatment of atopic dermatitis. J Am Acad Dermatol 2005;53(1 Suppl 1):S70–7.

286

S.F. Ibrahim et al.

131. McHenry PM, Williams HC, Bingham EA. Management of atopic eczema. Joint Workshop of the British Association of Dermatologists and the Research Unit of the Royal College of Physicians of London. BMJ 1995;310(6983):843–7. 132. Spuls PI, Witkamp L, Bossuyt PM, et al. A systematic review of five systemic treatments for severe psoriasis. Br J Dermatol 1997;137:943–949 133. Shaffrali FC, Colver GB, Messenger AG, et al. Experience with low-dose methotrexate for the treatment of eczema in the elderly. J Am Acad Dermatol 2003;48:417–9. 134. Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ. An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol 2007;156(2): 346–51. 135. Balasubramaniam P, Ilchyshyn A. Successful treatment of severe atopic dermatitis with methotrexate. Clin Exp Dermatol 2005;30(4):436–7. 136. Goujon C, Bérard F, Dahel K, Guillot I, Hennino A et al. Methotrexate for the treatment of adult atopic dermatitis. Eur J Dermatol 2006;16(2):155–8. 137. Bateman EA, Ardern-Jones M, Ogg GS. Dose-related reduction in allergen-specific T cells associates with clinical response of atopic dermatitis to methotrexate. Br J Dermatol 2007;156(6):1376–7. 138. Morgan SL, Baggott JE, Alarcón GS. Methotrexate in rheumatoid arthritis: folate supplementation should always be given. Bio Drugs 1997;8(3):164–75. 139. Roenigk HH Jr, Auerbach R, Maibach H et al. Methotrexate in psoriasis: Consensus Conference. J Am Acad Dermatol 1998;38:478–85. 140. Henning JS, Gruson LM, Strober BE. Reconsidering liver biopsies during methotrexate therapy. J Am Acad Dermatol 2007;56(5):893–4. 141. Chédeville G, Scuccimarri R, Duffy CM. Survey on the use of methotrexate by pediatric rheumatologists in Canada. J Rheumatol 2007;34(4):818–22. 142. Sowden JM, Berth-Jones J, Ross JS et al. Double-blind, controlled, crossover study of cyclosporine in adults with severe refractory atopic dermatitis. Lancet 1991;338:137–40. 143. Harper JI, Berth-Jones J, Camp RD, Dillon MJ, Finlay AY, Holden CA, O’Sullivan D, Veys PA. Cyclosporin for atopic dermatitis in children. Dermatology 2001;203(1):3–6. 144. Harper JI, Ahmed I, Barclay G, Lacour M, et al. Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 2000;142(1):52–8. 145. Berth-Jones J, Graham-Brown RA, Marks R, Camp RD, et al. Long-term efficacy and safety of cyclosporin in severe adult atopic dermatitis. Br J Dermatol 1997;136(1):76. 146. Berth-Jones J, Finlay AY, Zaki I, Tan B, et al. Cyclosporine in severe childhood atopic dermatitis: a multicenter study. J Am Acad Dermatol 1996;34(6):1016–21. 147. Zaki I, Emerson R, Allen BR. Treatment of severe atopic dermatitis in childhood with cyclosporin. Br J Dermatol 1996;135(Suppl 48):21–4. 148. Salek MS, Finlay AY, Luscombe DK, Allen BR, et al. Cyclosporin greatly improves the quality of life of adults with severe atopic dermatitis A randomized, double-blind, placebocontrolled trial. Br J Dermatol 1993;129(4):422–30. 149. Hijnen DJ, ten Berge O, Timmer-de Mik L, Bruijnzeel-Koomen CA, de Bruin-Weller MS. Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol Venereol 2007;21(1):85–9. 150. Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema - a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007;21(5):606–19. 151. Pedreira CC, King E, Jones G, Moore E, et al. Oral cyclosporin plus topical corticosteroid therapy diminishes bone mass in children with eczema. Pediatr Dermatol 2007;24(6): 613–20. 152. Zurbriggen B, Wüthrich B, Cachelin AB, Wili PB, et al. Comparison of two formulations of cyclosporin A in the treatment of severe atopic dermatitis. Aa double-blind, single-centre, cross-over pilot study. Dermatology 1999;198(1):56–60. 153. Wolff K, Fleming C, Hanifin J et al. Efficacy and tolerability of three different doses of oral pimecrolimus in the treatment of moderate to severe atopic dermatitis: a randomized controlled trial. Br J Dermatol 2005;152:1296–1303. 154. http://www.fda.gov/fdac/departs/2006/206_upd.html#eczema

Update on the Management of Atopic Dermatitis/Eczema

287

155. Skaehill PA. Tacrolimus in dermatologic disorders. Ann Pharmacother 2001;35(5):582–8. 156. Madan V, Griffiths CE. Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther 2007;20(4):239–50. 157. Schroer B, Lockey R. Oral tacrolimus for severe recalcitrant atopic eczema. J Allergy Clin Immunol 2003;111(6):1409–10. 158. Dé Tran QH, Guay E, Chartier S, Tousignant J. Tacrolimus in dermatology. J Cutan Med Surg 2001;5(4):329–35. Epub 2001 May 2. 159. Hachem RR, Yusen RD, Chakinala MM, Meyers BF et al. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant 2007;26(10):1012–8. 160. Hernández D, Miquel R, Porrini E, Fernández A et al. Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression. Transplantation 2007;84(6):706–14. 161. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med 2007;13(10):433–42. 162. Marsland AM, Griffiths CE. The macrolide immunosuppressants in dermatology: mechanisms of action. Eur J Dermatol 2002;12(6):618–22. 163. Reitamo S, Spuls P, Sassolas B, Lahfa M, et al; Sirolimus European Psoriasis Study Group. Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial. Br J Dermatol 2001;145(3):438–45. 164. Thervet E. Sirolimus therapy following early cyclosporine withdrawal in transplant patients: mechanisms of action and clinical results. Int J Nanomedicine 2006;1(3):269–81. 165. Reynolds NJ, Al-Daraji WI. Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clin Exp Dermatol 2002;27(7):555–61. 166. Duncan JI. Differential inhibition of cutaneous T-cell-mediated reactions and epidermal cell proliferation by cyclosporin A, FK-506, and rapamycin. J Invest Dermatol 1994;102(1):84–8. 167. Bissonnette R, Papp K, Poulin Y, Lauzon G, et al; ISA247 Psoriasis Study Group. A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis. J Am Acad Dermatol 2006;54(3) 168. Aspeslet L, Freitag D, Trepanier D, et al. ISA(TX)247; a novel calcineurin inhibitor Transplant Proc 2001;33:1048–51 169. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 2007;157(1):127–32. 170. Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 2007;32(1):23–7. 171. Grundmann-Kollmann M, Kaufmann R, Zollner TM. Treatment of atopic dermatitis with mycophenolate mofetil. Br J Dermatol 2001;145(2):351–2. 172. Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke WH, et al. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 2001;137(7): 870–3. 173. Benez A, Fierlbeck G. Successful long-term treatment of severe atopic dermatitis with mycophenolate mofetil. Br J Dermatol 2001;144(3):638–9 174. Hantash B, Fiorentino D. Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil. Arch Dermatol 2006;142(1):109–10. 175. Jain J, Almquist SJ, Heiser AD et al. Characterization of pharmacological efficacy of VX-148, a new, potent immunosuppressive inosine 5’ – monophosphate dehydrogenase inhibitor. J Pharmacol Exp Ther 2002;302:1272–7. 176. Berth-Jones J, Takwale A, Tan E, Barclay G, et al. Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol 2002;147(2): 324–30. 177. Lear JT, English JS, Jones P, Smith AG. Retrospective review of the use of azathioprine in severe atopic dermatitis. J Am Acad Dermatol 1996;35(4):642–3. 178. Verma KK, Mittal R. Azathioprine as a therapeutic modality for the treatment of severe adult atopic dermatitis. Indian J Dermatol Venereol Leprol 2001;67(4):189–91.

288

S.F. Ibrahim et al.

179. Meggitt SJ, Gray JC, Reynolds NJ. Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet 2006;367(9513):839–46. 180. Evans WE. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 2004;26(2):186–91. 181. Murphy LA, Atherton DJ. Azathioprine as a treatment for severe atopic eczema in children with a partial thiopurine methyl transferase (TPMT) deficiency. Pediatr Dermatol 2003;20(6):531–4. 182. Murphy LA, Atherton DA. retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression. Br J Dermatol 2002;147(2):308–15. 183. Kuanprasert N, Herbert O, Barneston RS. Clinical improvements in and significant reduction of total serum IgE in patients suffering from severe atopic dermatitis treated with oral azathioprine. Australas J Dermatol 2002;43:125–7. 184. Jang IG, Yang JK, Lee HJ, Yi JY, Kim HO, Kim CW, Kim TY. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol 2000;42:1033–40. 185. Chang TT, Stevens SR. Atopic dermatitis: the role of recombinant interferon-gamma therapy. Am J Clin Dermatol 2002;3(3):175–83. 186. Stevens SR, Hanifin JM, Hamilton T, Tofte SJ, Cooper KD. Long-term effectiveness and safety of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged serum IgE levels. Arch Dermatol 1998;134(7):799–804. 187. Hanifin JM, Schneider LC, Leung DY et al. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993;28:189–97. 188. Schneider LC, Baz Z, Zarcone C, Zurakowski D. Long-term therapy with recombinant interferon-gamma (rIFN-gamma) for atopic dermatitis. Ann Allergy Asthma Immunol 1998;80(3):263–8. Chang TT, Stevens SR. Am J Clin Dermatol 2002;3(3):175–83. 189. Jolles S. A review of high-dose intravenous immunoglobulin treatment for atopic dermatitis. Clin Exp Dermatol 2002;27(1):3–7. 190. Bemanian MH, Movahedi M, Farhoudi A, Gharagozlou M, et al. High Doses Intravenous Immunoglobulin versus Oral Cyclosporine in the Treatment of Severe Atopic Dermatitis. Iran J Allergy Asthma Immunol 2005;4(3):139–43. 191. Jolles S, Hughes J. Use of IGIV in the treatment of atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis, and pretibial myxedema. Int Immunopharmacol 2006;6(4):579–91. 192. Jolles S, Sewell C, Webster D, Ryan A, Heelan B, Waite A, Rustin M. Adjunctive high-dose intravenous immunoglobulin treatment for resistant atopic dermatitis: efficacy and effects on intracellular cytokine levels and CD4 counts. Acta Derm Venereol 2003;83(6): 433–7. 193. Paul C, Lahfa M, Bachelez H, Chevret S, Dubertret L. A randomized controlled evaluatorblinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol 2002;147(3):518–22. 194. Lamb SR, Rademaker M. Intravenous immunoglobulin therapy for the treatment of severe atopic dermatitis. Expert Opin Pharmacother 2001;2(1):67–74. 195. Zhang G, Lopez PH, Sheikh KA. Comparison of different brands of IVIg in an in vitro model of immune neuropathy. J Neuroimmunol 2006;173(1-2):200–3. 196. Clark B, Cole JY, Wortley A, Toolan J, et al. Intravenous immunoglobulin-induced panel reactive antibody A reduction: not all preparations are created equal. Transplantation 2003;75(2):242–5. 197. Leung DY, Pober JS, Cotran RS. Expression of endothelial-leukocyte adhesion molecule-1 in elicited late phase allergic reactionset. J Clin Invest 1991;87:1805–1809. 198. Laan MP, Koning H, Baert MR, Oranje AP, et al. Levels of soluble intercellular adhesion molecule-1, soluble E-selectin, tumor necrosis factor-alpha, and soluble tumor necrosis factor receptor p55 and p75 in atopic children. Allergy 1998;53(1):51–8.

Update on the Management of Atopic Dermatitis/Eczema

289

199. Takahashi T, Sasaki Y, Hama K, Furue M, Ishibashi Y. Production of IL-4, IL-2, IFN-gamma, and TNF-alpha by peripheral blood mononuclear cells of patients with atopic dermatitis. J Dermatol Sci 1992;3(3):172–80. 200. de Vries IJ, Langeveld-Wildschut EG, van Reijsen FC, Dubois GR. Adhesion molecule expression on skin endothelia in atopic dermatitis: effects of TNF-alpha and IL-4. J Allergy Clin Immunol 1998;102(3):461–8. 201. Ackermann L, Harvima IT. Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-alpha and their degranulation is associated with expression of ICAM-1 in the epidermis. Arch Dermatol Res 1998;290(7):353–9. 202. Howarth PH, Babu KS, Arshad HS, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependant asthma. Thorax 2005;60(12):1012–8. 203. Berry MA, Hargadon D, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006;354:697–708. 204. Conner E, Bochner BS, Brummet M, Beck LA. The Effect of Etanercept on the Human Cutaneous Allergic Response. J Allergy Clin Immunol 2007, in press. 205. Buka RL, Resh B, Roberts B, et al. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol 2005;53(2):358–359. 206. Jacobi A, Antoni C, Manger B, Schuler G, Hertl M. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2005;52(3 Pt 1):522–6. 207. Leonardi CL. Efalizumab; an overview. J Am Acad Dermatol 2003;49:S98–104. 208. Farshidi A, Sadeghi P. Successful treatment of severe refractory atopic dermatitis with efalizumab. J Drugs Dermatol 2006;5(10):994–8. 209. Hassan AS, Kaelin U, Braathen LR, Yawalkar N. Clinical and immunopathologic findings during treatment of recalcitrant atopic eczema with efalizumab. J Am Acad Dermatol 2007;56(2):217–21. 210. Weinberg JM, Siegfried EC. Successful treatment of severe atopic dermatitis in a child and an adult with the T-cell modulator efalizumab. Arch Dermatol 2006;142(5):555–8. 211. Takiguchi R, Tofte S, Simpson B, Harper E. Efalizumab for severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 2007;56(2):222–7. 212. Babu KS, Arshad SH, Holgate ST. Anti-IgE treatment: an update and review of omalizumab and FceRI receptor. Allergy 2001;56:1121–1128. 213. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell Fcepsilon RI expression and function. J Allergy Clin Immunol 2004;114(3):527–30. 214. Soresi S, Togias A. Mechanisms of action of anti-immunoglobulin E therapy. Allergy Asthma Proc 2006;27(2 Suppl 1):S15–23. 215. Chang TW, Wu PC, Hsu CL, Hung AF. Anti-IgE antibodies for the treatment of IgEmediated allergic diseases. Adv Immunol 2007;93:63–119. 216. Wuthrich B, Benz A, Skvaril F. IgE and IgG4 levels in children with atopic dermatitis. Dermatologica 1983;166(5):229–35. 217. Beck LA, Saini S. Wanted: A study with omalizumab to determine the role of IgE-mediated pathways in atopic dermatitis. J Am Acad Dermatol 2006;55(3):540–1. 218. Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J, Hussain I. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol 2006;55(1):168–70. 219. Lane JE, Cheyney JM, Lane TN, Kent DE, Cohen DJ. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol 2006;54(1):68–72. 220. Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 2005;53(2):338–40. 221. Forman SB, Garrett AB. Success of omalizumab as monotherapy in adult atopic dermatitis: case report and discussion of the high-affinity immunoglobulin E receptor, FcepsilonRI. Cutis 2007;80(1):38–40. 222. Prescott SL, Dunstan JA, Hale J, Breckler L, et al. Clinical effects of probiotics are associated with increased interferon-gamma responses in very young children with atopic dermatitis. Clin Exp Allergy 2005;35(12):1557–64.

290

S.F. Ibrahim et al.

223. Weston S, Halbert A, Richmond P, Prescott SL. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child 2005;90(9):892–7. 224. Kalliomäki M, Kirjavainen P, Eerola E, Kero P, et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001;107(1):129–34. 225. Kalliomaki M, Salminen S, Arvilommi H et al. Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial. Lancet 2001;357(9262):1076–9 226. Madsen K. Probiotics and the immune response. J Clin Gastroenterol 2006;40(3):232–4. 227. Williams HC. Two “positive” studies of probiotics for atopic dermatitis: or are they? Arch Dermatol 2006;142(9):1201–3. 228. Williams HC. Prevention of atopic eczema: a dream not so far away? Arch Dermatol 2002;138(3):391–2. 229. Horrobin DF. Essential fatty acid metabolism and its modification in atopic eczema. Am J Clin Nutr 2000;71(1 Suppl):367S–72S. 230. Ziboh VA, Miller CC. Essential fatty acids and polyunsaturated fatty. acids: significance in cutaneous biology. Annu Rev Nutr 1990;10:433–10. 231. Morse NL, Clough PM. A meta-analysis of randomized, placebo-controlled clinical trials of Efamol evening primrose oil in atopic eczema Where do we go from here in light of more recent discoveries. Curr Pharm Biotechnol 2006;7(6):503–24. 232. Horne DJ, White AE, Varigos GA. A preliminary study of psychological therapy in the management of atopic eczema. Br J Med Psychol 1989;62(Pt 3):241–8. 233. Sokel B, Kent CA, Lansdown R, Atherton D, Glover M, Knibbs J. A comparison of hypnotherapy and biofeedback in the treatment of childhood atopic eczema. Contemp Hypnosis 1993;10(3). 234. Huang JT, Abrams M, Tlougan B et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics. 2009;123(5):e808–14. 235. Warner J, McGirt LY, Beck LA. Biomarkers of Th2 Polarity and Disease Severity are Predictive of Staphylococcal Colonization in Atopic Dermatitis Subjects. Br J Dermatol 2008;160(1):183–5. 236. Beck LA, Boguniewicz M, Hata T, Schneider LC, Hanifin J, Gallo R, Paller AS, Lieff S, Reese J, Zaccaro D, Milgrom H, Barnes KC, Leung DY. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol 2009; 25. [Epub]. 237. Gao P-S, Rafaels NM, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Barnes KC, Leung DY. Filaggrin Mutations that Confer Risk of Atopic Dermatitis Confer Greater Risk for Eczema Herpeticum. J Allergy Clin Immunol 2009 (accepted).

Immunosuppressants as Treatment for Atopic Dermatitis Bartlomiej Kwiek and Natalija Novak

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting about 20% of children and up to 3% of adults worldwide. The clinical manifestation of AD is based on the interaction of specific genetic predispositions with a large number of environmental factors. Treatment of AD depends on the course and severity of the disease as well as the most important trigger factors such as aero- or foodallergens, microbial pathogens or other exogenous and endogenous influences [1]. Here we provide an overview of the mode of action of different immunosuppressants, which are frequently used as treatment for AD.

Glucocorticosteroids Nearly 60 years ago, the Nobel Prize for Physiology and Medicine was awarded for isolation and synthesis of cortisol, the physiological prototype of all synthetic glucocorticosteroids (GCS) and its introduction as an anti-inflammatory drug. The use of local and systemic GCS in dermatology and in particular as a treatment for AD started some years later [2, 3]. Nowadays, topical GCS are still the first line therapy for AD in cases in which anti-inflammatory treatment is required [4]. Both efficacy and safety of local and systemic GCS are connected with a wide spectrum of effects and include anti-inflammatory actions, which are related to their physiological role as modulators of the natural response of our immune system to stress and infectious stimuli. A large number of synthetic derivatives of GCS with a wide spectrum of anti-inflammatory properties and differences in their capacity to penetrate skin B. Kwiek Department of Dermatology, Medical University of Warsaw, Warsaw, Poland N. Novak () Department of Dermatology and Allergy, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_17, © Springer 2010

291

292

B. Kwiek and N. Novak

have been developed until now. This diversity in the character of GCS has to be taken into account when interpreting in vivo and in vitro studies on the mechanisms of GCS.This diversity might provide quite different results or data which might seem to be conflicting at first sight.

GCS Signaling Cortisol and GCS are small lipophylic agents, which easily penetrate cell membranes and invade the cytoplasm, where they can bind to the glucocorticosteroid receptor (GR). Ligation of GCS to GR is followed by the nuclear translocation of the GCS–GR complex. This process is regulated by chaperones from the heat shock protein (hsp) family and immunophilins [5, 6]. Among several variants of GR, which are a product of alternative splicing and translation, GR-a targets the GCS regulated genes, while GR-b exerts regulatory functions and is responsible for GCS resistance [7, 8]. Once the activated GCS–GR complex enters the nucleus, it forms a homodimer and interacts with the glucocorticosteroid responsive element (GRE) on DNA-specific sequences in the promoter region of GCS regulated genes It either activates transcription at the positive GRE site or suppresses transcription via the negative GRE site. The process of activation of anti-inflammatory genes is called “transactivation” and induces the expression of annexins (including annexin/lipocortin-1), secretory leuko-protease inhibitor (SLPI), inhibitor of nuclear factor-kB (NF-kB) (IkB-a), mitogen-activated kinase phosphatase-1 (MKP-1), glucocorticoid-induced leucine zipper protein (GILZ), and interleukin (IL)-10 [9]. Additionally, direct contact of DNA-activated GR influences other transcription factors or coactivator molecules by protein-protein interactions, which results in gene suppression called “transrepression.” This process includes the inhibition of NF-kB, activating protein-1 (AP-1) and signal transducers, and activators of transcription (STAT) family proteins. GR protein undergoes several posttranscriptional modifications including phosphorylation, which is important for the GCS response [10]. GCS action is related to chromatin remodeling by regulation of histone acylation or deacylation, which results in gene transcription or repression [9]. Further on, GCS influence the mRNA stability of inflammatory proteins, thus modulating post transcriptional steps of inflammatory responses [11]. However, some of the clinical responses (in particular the rapid responses) observed with GCS are most likely not based on transcription-related mechanisms but rather a result of nongenomic mechanisms such as the modulation of GR expression itself or cell membrane fluidity [12, 13]

GCS and the Th1/Th2 Balance GCS influence both the level of cytokines and the response to cytokines, and favor immune responses of the Th2 type, while blocking immune responses of the Th1 type [14–20]. It is supposed that GCS block interleukin (IL)-12 related STAT-4

Immunosuppressants

293

phosphorylation of T cells in vitro, [17] which in addition to the inhibition of interferon (IFN)-g production in GCS treated skin, favor Th2 immune responses [21]. GCS suppress interferon regulatory factor (IRF) -1, -3 and -7 gene expression in peripheral blood mononuclear cells (PBMC) [22] and increase granulocytemacrophage colony stimulating factor (GM-CSF) receptor expression on monocytes in vitro [23]. In accordance with findings concerning a Th2 shift upon GCS treatment, increased IgE synthesis by B cells in response to GCS treatment has been described [20]. Despite these results, the efficacy of GCS in the early Th2 dominated phase of AD could be explained mostly by their inhibitory effect on the production of so-called initial phase cytokines such as tumor necrosis-a and interleukin-1b, as well as the Th2 cytokines IL-3, IL-4, IL-5, GM-CSF and reduction of the expression the high affinity receptor for IgE (FceRI) on mononuclear cells [11, 24]. GCS do not only exert immunosilencing functions on the cytokine network [14]. In addition they promote the expression of regulatory/anti-inflammatory mediators including IL-10 and the respective IL-10 receptor (IL-10R), transforming growth factor (TGF)-b receptors I, II, III [22] and thymosin-b4 [25] by a variety of immunocompetent cells. GCS have been shown further to promote the development and function of regulatory CD4+CD25+FOXP3+ T cells (Treg) in asthma patients [26]. This is of particular importance considering the latest findings on the role of Treg in the pathogenesis of autoimmune and allergic diseases [27]. Evidence of a deregulation of Treg in AD skin has been provided very recently [28], supporting the idea of a GCS related induction of Treg functions as a potential mode of action of GCS in AD. However, mild GCS such as hydrocortisone did not influence the number of FOXP3+ T cells in AD skin [29].

GCS and Antigen Presentation One of the most striking effects of systemic and topical GCS is a random depletion of all CD1a+ epidermal dendritic cells (DC) [30], including Langerhans Cells (LC) and inflammatory dendritic epidermal cells (IDEC) [31, 32]. Monocytes are direct precursors of LC and IDEC [33, 34]. Therefore induction of monocytopenia [35], apoptosis of monocytes as early DC precursor’s [36, 37] and inhibition of the recruitment of DC precursors in AD could be of importance for GCS related depletion of DC from the epidermis. Downregulation of monocyte chemoattractants, such as macrophage derived chemokine (MDC), IL-16 and the chemokine regulated upon activation, normal T cells expressed and secreted (RANTES) [38–40] contribute to this process. Lately, a nonmyeloid subtype of DC, called plasmacytoid DC (PDC), was described and characterized by a CD1a-CD123+BDCA2+ phenotype. PDC are believed to play an important role in innate immune responses to viral infections by secreting high amounts of type I interferons, and coordinating innate and acquired immune processes. Deregulated distribution of PDC in blood, dermal and epidermal compartment of AD subjects compared to healthy individuals or individuals

294

B. Kwiek and N. Novak

with other chronic inflammatory skin diseases has been shown [41–43]. Further on, modified expression of FceRI and altered IFN-a and IFN-b production by PDC of AD patients could be of importance to impaired responses to viral infections observable in subgroups of AD patients. Besides the influence of GCS on myeloid DC, topically applied GCS deplete PDC from the dermis of lesional AD skin. Clinical significance of this finding for both efficacy and potential side effects of GCS in AD, such as increased susceptibility to viral skin infections, remains to be evaluated [44].

GCS and Leucocyte Migration The atopy patch test (APT) is a model for the cutaneous allergic response in AD. It was shown that leucocytes influx into the skin after epicutaneous application of aeroallergens during the APT can be inhibited by GCS [21, 45]. Migration of immuncompetent cells to the skin is a multistep process orchestrated by several chemokines, and chemokine receptors and associated with the presence and activity of adhesion molecules. GCS are strong suppressor of adhesion molecule expression in vitro and in vivo, including the suppression of ICAM, VCAM and E-selectin on endothelial cells [21, 46]. This phenomenon seems to be limited to GCS with moderate to strong potency, while mild GCS applied topically does not exert these effects [47]. Some GCS affect additionally adhesion molecule expression on circulating leukocytes. Together, this might result in the inhibition of leukocytes adhesion to endothelial cells and thereby recruitment of leukocytes to the site of inflammation [48]. The production of chemokines by PBMC and epidermal cells has been shown to be affected by GCS in several studies [38, 49, 50]. Topical treatment with GCS leads to decreased serum levels of TARC/CCL17(Thymus and activation regulated chemokine), macrophage derived chemokine (MDC)/CCL22, IL-16 and eotaxins for instance [40, 51, 52]. GCS reduce leukocyte infiltration in the epidermis and dermis [21] and the likelihoodof re-triggering eczema after GCS application is directly dependent on the intensity of leukocyte infiltration. Consequently, the rationale behind this mode of treatment could be to keep the number of infiltrating leukocytes low and prevent relapses of AD by repetitive application of GCS.

GSC and Cell Viability/Skin Barrier Besides the influence on leucocytes migration, induction of apoptosis of several inflammatory cells in the skin and the circulation is of importance for the reduction of inflammatory cell recruitment which goes along with GCS treatment. GCS have been shown to induce apoptosis of monocytes, macrophages, myeloid DC, PDC and T cells [31, 32, 37, 53].

Immunosuppressants

295

In addition to the induction of apoptosis of leucocytes, GCS are also capable of protecting cells from programmed cell death [54]. It is assumed that this bivalent function of GCS is related to their physiological role in both immunosupression and protection of inflamed tissue from inflammation induced destruction, and is believed to be mediated by Bcl-2 family proteins. T cell mediated keratinocyte apoptosis plays a major role in the pathogenesis of AD [55]. Activated T cells have been shown to release IFN-g, which upregulates the expression of Fas on the surface of keratinocytes. In the next step, keratinocyte apoptosis is induced by the interaction of Fas ligand expressed by activated T cells with its respective receptor (Fas/CD95) on the surface of keratinocytes. GCS can inhibit this process mainly by reducing T cell activation; but given in high doses, GCS affect T cell mediated apoptosis and in addition induce directly the cell death of keratinocyte [56]. Topical GCS were shown to decrease enhanced transepidermal water loss in AD skin and improve disease related disruption of skin barrier [57]. This is most likely related to their influence on the viability of keratinocytes [56] and the reduction of inflammatory cytokines in the skin, which indirectly impair the skin barrier function [58]. The lesional and nonlesional skin of AD patients is highly colonized with microbes such as Staphylococcus aureus bacteria. Upon treatment of AD with GCS, the level of S. aureus colonization drops significantly [59]. This might be a consequence of a GCS-restored skin barrier followed by hiding of extracellular matrix molecules known to act as adhesins to S. aureus (e.g., fibronectin, collagens, fibrinogen, elastin, or laminin) [60, 61]. S. aureus produced superantigens are able to activate T cells, bridging T cell receptor (TCR) and major histocompatibility class (MHC) II molecules directly regardless their clonality. In contrast to regular antigen related TCR activation, which can be blocked by GCS, superantigen induced TCR related PBMC proliferation was shown to be resistant to GCS blockade in vitro [62, 63]. Additionally, S. aureus superantigens are able to induce the inactive variant GRb, which leads to GCS resistance.

GSC and Mast Cells/Eosinophils Increased numbers of skin infiltrating mast cells is a typical feature of AD and is associated with increased serum levels of soluble stem cell factor (sSCF), which promotes migration, differentiation and maturation of mast cells [64]. GCS deplete mast cells from the skin after 3 weeks of topical treatment [65]. Simultaneously the levels of sSCF and the soluble form of its receptor (tyrosine kinase transmembrane receptor – KIT) decrease [64]. Eosinophilia and elevated levels of eosinophil granule proteins are typical features of active AD, especially the allergic/extrinsic subtype which goes along with a high number of sensitizations and elevated serum IgE levels. GCS decrease the level of serum IL-5, the main and selective growth, differentiation, activation and

296

B. Kwiek and N. Novak

chemotactic factor for human eosinophils. GCS also decrease the level of IL-5 secreted by stimulated human T cells in vitro [66]. Lower levels of IL-5 in response to GCS treatment shorten the survival of skin eosinophils and reduce eosinophil infiltration of the skin [67]. Depletion of eosinophils upon GCS treatment also results from decreased chemotactic signals other than IL-5, such as eotaxin-3 (CCL26), IL-16 [68] and reduction of the expression of the adhesion molecules ICAM-1(CD54) and ICAM-3 (CD50), important for eosinophil activation and recruitment [69] mediated by GCS.

Cyclosporine The immunosuppressive drug Cyclosporine A (CsA) was introduced in 1978 in transplantation medicine, to prevent organ rejection [70]. CsA binds to cyclophillin and blocks the activation of T cells by preventing the production of cytokines which support the proliferation of T cells such as IL-2 [71]. Nowadays, CsA is also used as a treatment for severe cases of AD, and its safety and efficacy has been proven in several studies [72, 73]. One of the most prominent features of AD is the strong infiltration of the skin lesions with activated CD4+ T cells. Immunhistological investigations have shown that the dermal infiltrate is mainly composed of CD4+ and CD8+ cells with a CD4/CD8 ratio similar to that found in the peripheral blood [74]. It is well known that the human immune system harbours a powerful army of cutaneous T cells bearing the cutaneous lymphocyte antigen (CLA) on their surface, which enables them to be immediately recruited into the skin on invasion of foreign antigens. Cyclosporine treatment significantly reduces the number of CD4+/ CLA+ and CD3+/CLA+ T cells in the peripheral blood of treated AD patients, while the number of CD3+, CD4+ and CD8+ cells as well as CD8+/CLA+ T cells remains unchanged. Reduced numbers of CD14+, CD25+, CD36+ and IL-8 producing inflammatory cells are detectable in the skin of AD patients after therapy with CsA, indicating a decreased infiltration of activated cell types in response to the CsA treatment [75]. Reduced production of the proinflammatory cytokines IL-6 and IL-8 by PBMC isolated from the peripheral blood of children treated with CsA has been shown, indicating a reduced activation of different cell subtypes not only in the skin but also in the blood in response to CsA treatment [76].

CsA and Keratinocytes Fas ligand mediated keratinocyte apoptosis has been supposed to play a major role in the pathogenesis of AD [55]. Interestingly, this process has been shown to be partially prevented by CsA treatment, which is mainly a result of the CsA related reduction of the activation state of T cells [56].

Immunosuppressants

297

CSA and Leukocyte Migration Chemokines expressed by endothelial cells act on leukocytes rolling on the endothelium and increase the affinity of leukocyte integrins to their ligands. Integrin activation is critical for the adherence of leukocytes to the endothelium and migration towards a chemical gradient into extravascular tissue. In acute AD, enhanced serum levels of several chemokines such as CCL2/MCP-1 (monocyte chemoattractant protein-1), CCL4/MIP-1b (macrophage inflammatory protein), CCL5/RANTES (regulated on activation, normal T cell expressed and secreted), CCL11/Eotaxin, CCL17/TARC, CCL22/MDC, CCL26/eotaxin-3, CCL27/CTACK (cutaneous T cell attracting chemokine) and CX3CL1 /Fractalkine and other chemotactic factors like IL-16 and soluble CD30 (sCD30) have been observed [74]. These chemokines are supposed to contribute to the chemotaxis of eosinophils and Th2 cells as well as being precursors of skin DC from the blood into the peripheral tissue. Evidence of a counteraction of CsA on the recruitment of inflammatory cells arises from studies showing a reduced amount of the chemokines CCL22 and CCL17 produced by monocyte-derived DC, derived from monocytes of AD patients after treatment with CsA, and by PBMC stimulated with house dust mite allergens and coincubated with CsA in vitro [49]. Both chemotactic factors have been shown further to correlate with the disease activity of AD [77]. CCL17 as ligand of the CC-chemokine receptor (CCR)-4, induces cutaneous lymphocyte trafficking in AD [78], while CCL22 is mainly produced by DC and macrophages, and induces migration of DC and CD4+ T cells [79]. As a correlate of these findings, serum levels of CCL17 and CTACK profoundly decrease during systemic treatment with CsA [80]. The amounts of sCD30 [81, 82], eosinophilic cationic protein as an indicator for eosinophil activation [83] and soluble E-selectin are reduced in the blood of AD patients treated with CsA [84]. Another characteristic feature of most AD patients is the Th2 overbalance, mirrored by elevated serum levels of Th2 cytokines and Th2 prone micromilieu in the skin in the acute phase of the disease as well as increased serum levels of total and allergenspecific IgE. The Th2 dominated cytokine pattern of T cells in the peripheral blood of patients treated with CsA changes, showing reduced production of the Th2 cytokines interleukin IL-4, IL-5 and IL-13, indicating that a partial restorage of the Th2 overbalance in AD is achievable by CsA [85].

CsA and IgE Autoreactivity There is some evidence that an important subgroup of patients with AD, which benefits from treatment with CsA might belong to the group of AD patients who have developed IgE autoreactivity. Immunoglobulin E autoreactivity has been implicated as an important immunopathogenetic factor in AD in the last few years. Molecular analysis of allergens has revealed striking similarities between environmental allergens and human proteins, leading to the hypothesis that autoimmune reactions

298

B. Kwiek and N. Novak

might play a role [86]. IgE-reactive autoantigens directed against human proteins have been cloned from human epithelial copy DNA (cDNA) expression libraries and have been found to primarily represent intracellular proteins [87]. Autoantigens characterized for AD are Hom s 1-5 and DSF70 [88]. These autoantigens seem to act as adjuvants to the immunological mechanisms in AD patients with elevated IgE levels, as they have been detected in IgE-immune complexes of AD sera. The release of autoallergens from the damaged tissue, putatively triggered by mechanical factors such as scratching, could trigger responses mediated by mast cells, T cells, and IgE. Since IgE autoreactivity is already detectable in a subgroup of children with severe sensitizations against food- or aeroallergens, the manifestation of IgE autoreactivity and the decision, whether an individual may have a chronic persistent course until adulthood or clearance of the disease during childhood seem to take part already in infancy [89]. IgE autoallergen levels decrease as a consequence of successful treatment with CsA [90]. This finding indicates that CsA might suppress the activity of T cells which support the production of IgE autoantibodies and reduce the contact of autoreactive B cells with autoantibodies leading to reduced IgE autoreactivity [90]. However, which of the CsA induced effects described here represent rather primary mechanisms of CsA acting directly on target cells or rather secondary phenomena that might go along with a general decrease of the disease activity induced by CsA, remains to be clarified.

Calcineurine Inhibitors CsA, tacrolimus, and pimecrolimus share common molecular targets. They inhibit the function of calcineurine, the enzyme that dephosorylates NFAT [91]. CsA binds calcineurine indirectly by interaction with cyclophilin, a member of the immunophilin family, while another immunophilin – FKBP-12 is a binding molecule for both tacrolimus and pimecrolimus [92]. Although the role of immunophilins associated with their enzymatic peptidyl prolyl cis/trans isomerases (PPI) activity is multidirectional, their influence on Ca++/Calmoduline/Calcineurine/NFAT is why they have been named as calcineurine inhibitors (CNI). Binding calcineurine by the immunophilin-calcineurine inhibitor complex prevents dephosphorylation and nuclear translocation of NFAT. This leads to inhibition of the transcription of proinflammatory cytokines in T cells. NFAT and NFAT family members as well as calcineurine and immunophilins are integral parts of a high number of immunocompetent cells.

CNI and T cells NFAT signaling in T cells is involved in both Th1 and Th2 differentiation and proliferation of T cells. Thus, inhibition of NFAT results in the blockade of these processes. It was shown that tacrolimus blocks IL-2 synthesis and proliferation of

Immunosuppressants

299

T cells in AD [93]. Both topical tacrolimus and pimecrolimus were shown to inhibit Th1 and Th2 cytokine production (IL-5, IL-13, IL-10 and IFN-g) by CD4+ and CD8+ T cells in AD skin and strongly reduce the T cell infiltration [94, 95]. Whether CNI induce T cell apoptosis directly or indirectly remains to be clarified [96]. In contrast to systemic use of CNI, topical application of these compounds has only minimal effects on circulating lymphocyte numbers [94, 95]. The reduction of lymphocyte infiltrates after CNI treatment are partially the effect of decreased expression of adhesion molecules on endothelial cells [47] together with decreased production of chemotactic factors, such as IL-16 in tacrolimus treated skin and ccl!/ in PBMC from AD patients [49, 97]. In contrast to GCS, tacrolimus is capable of blocking superantigen stimulated T cell proliferation thus representing an alternative therapy in the case of GCS resistance [98]. Interestingly tacrolimus does not only exert inhibitory functions on cytokine production, but has shown to act synergistically on Treg from AD patients to inhibit T cell proliferation. Additionally topical application of tacrolimus leads to increased numbers of TGF-b producing Treg, which can be of importance to the immunoregulatory and anti-inflammatory effects of this compound [29].

CNI and Antigen Presentation The clinical picture of eczematous skin in AD implicates the role of allergic reactions of the delayed type. Understanding the central role of IgE bearing DC on one hand and introduction of APT as a model for AD on other hand, have provided important background information for therapeutic strategies which target the process of antigen uptake and presentation in AD. Recent findings have proved that different subtypes of DC are affected in their phenotype and functions by CNI. In contrast to GCS, topical CNI do not deplete epidermal CD1a+ DC [31, 32, 94, 95, 99]. Interestingly, while the total number of myeloid DC in the skin remains unchanged after treatment with CNI, IDEC are rapidly depleted from the epidermis simultaneously with the improvement of the skin lesions. Considering the role of IDEC in perpetuating and amplifying the FceRI related allergic response [100] this phenomenon could be one of the central events responsible for topical CNI efficacy. Both tacrolimus and pimecrolimus do not profoundly change the number of LC in the epidermis, which might be of importance for preservation of the postulated role of LC in the maintenance of local tolerance. In contrast to the different influence of GCS and CNI on myeloid DC, GCS and pimecrolimus were shown to homogenously deplete PDC from the dermis [44]. Despite impact of CNI on DC balance, they profoundly modulate the function of DC. CNI reduce MHC II and costimulatory molecule expression of DC, impair the stimulatory properties of DC toward T cells and inhibit DC maturation. This is the case of in vitro generated DC treated with CsA and tacrolimus [101, 102] as well as ex vivo isolated LC from the skin of AD patients treated with tacrolimus, [103] while the functional inhibition of human DC induced by pimecrolimus was minimal [104]. However, it was shown that pimecrolimus modulates DC in the

300

B. Kwiek and N. Novak

murine system [105]. While IL-12 production by human monocyte derived DC was not affected by pimecrolimus treatment [36], tacrolimus inhibited IL-12 secretion by DC in both mouse [101] and human models [106]. Antigen presentation by epidermal DC in AD is related to the presence of FceRI on the DC surface and so called antigen focusing results in the amplification of the allergic response to antigens. In this context, tacrolimus was shown to reduce the expression of FceRI on LC and IDEC in the lesional skin of AD, and might therefore be responsible for the reduction of the antigen-uptake and presentation process in AD [99].

CNI and Eosinophils IL-5 synthesis was found to be downregulated by tacrolimus and CsA in PBMC and T cells [66, 107]. During AD treatment with systemic CsA, the blood count of CD4+IL-5+ and CD8+IL-5+ cells decreases together with a reduction of the eosinophilia [85]. In skin treated topically with CNI, IL-5 is downregulated in both CD4+ and CD8+ cells together with a lowered level of eotaxin, CCR3, RANTES and IL-16, which could be of importance for the reduction of eosinophil recruitment to AD skin [94, 95, 97, 108]. Decrease of IL-5 in the skin is accompanied by a decrease of the serum level of this cytokine and can be important for a reduced generation of eosinophils from the bone marrow.

CNI and Effector Cells The function, survival, and proliferation of mast cells are heavily impaired by CNI [109]. Topical CNI inhibits FceRI-mediated production of histamine, eicosanoids, and cytokines (including IL-4 and TNF-a) by mast cells and basophils [110, 111] while the total number of mast cells in the skin remains unaffected [94, 95].

CNI and Keratinocytes Keratinocytes are involved in the pathophysiology of AD by secreting enhanced amounts of GM-CSF, IL-1, TNF-a, and inducible nitric oxide synthase (iNOS). CNI was shown to inhibit GM-CSF and iNOS production by human AD keratinocytes [56, 112]. Additionally topical tacrolimus was shown to induce the release of anti-inflammatory mediators such as TGF-b from keratinocytes and upregulates IL-10R [112, 113]. CNI inhibit T cell mediated apoptosis of keratinocytes [56], which might be responsible for a reduced spongiosis observable after topical application of CNI [94, 95].

Immunosuppressants

301

While tacrolimus and pimecrolimus do not influence the viability of keratinocytes directly [112, 114], tacrolimus reduces keratinocytes proliferation [112, 114, 115].

Mycophenolate Mofetil Mycophenolate mofetil (MMF) is a 2-morpholinoethyl ester of mycophenolic acid, which selectively and reversibly inhibits inosine monophosphate dehydrogenase and suppresses de novo synthesis of purine in T and B cells. Mycophenolic acid inhibits leukocyte recruitment and their adhesion to endothelial cells [116]. Successful treatment of adults - and in a few studies also of children with AD -with MMF has been reported [116–118]. Therefore, MMF has been suggested as alternative therapy for moderate to severe AD mainly for recalcitrant forms of AD in single cases. However, sufficient data from double-blind placebo controlled studies including a high number of AD patientsis necessary to confirm these results. Side effects of MMF treatment include dose-dependent nausea, vomiting, diarrhoea, abdominal pain, and bone marrow suppression with increased risk of infection. Further on, case reports of liver enzyme abnormalities in treated patients exist [119]. Concerns about the use of MMF in AD have been raised due to the high bacterial colonization in AD patients on one hand and the enhanced risk of infections as a side effect of the drug on the other hand [120]. Therefore careful risk benefit analysis resulting from controlled studies with MMF in AD and detailed knowledge about the mode of action of MMF in ADare indispensable, to assess the value of MMF as a treatment for AD.

Methotrexate Methotrexate (MTX) has been used for the treatment of T cell mediated skin disorders such as psoriasis or rheumatoid arthritis for a long time. In some small studies, a putative effect of MTX as treatment for adult patients with moderate to severe AD has been provided with clinical improvement in 70% of the patients after 3 months [121]. Significant improvement of disease activity in 52% of the cases from baseline and quality of life of the patients has been shown in another, open-label doseranging study using MTX in adult patients with moderate to severe AD [122, 123]. MTX is an antimetabolite, which has profound anti-inflammatory activities. MTX increases the concentration of adenosine and binds to anti-inflammatory adenosine receptors. Adenosine acts as endogenous mediator of anti-inflammatory mechanisms and mediates cytokine expression as well as upregulation of adhesion molecule expression. Therefore, the anti-inflammatory effects of MTX might lead to improvement of AD in a subgroup of patients. As a consequence, the exact mode of action of this treatment in AD has to be studied in more detail in the future.

302

B. Kwiek and N. Novak

Intravenous Immunoglobulines Intravenous immunoglobulines (IVIG) was administered for the first time over 50 years ago to patients with antibody deficiencies. Since then a high number of inflammatory and autoimmune disorders have been treated with IVIG. A few studies in which IVIG have been used as a monotherapy for children with AD [124] or as adjunctive therapy in adults with AD [125] have shown a positive clinical effect derived by IVIG on the severity of AD. The positive effect of IVIG on AD is not completely surprising, looking at the main cells and structures targeted by IVIG, which play a central role in the pathogenesis of AD. Primary target cells of IVIG are antigen presenting cells (APC) such as dendrite cells (DC). IVIG attenuate DC differentiation and maturation, and downregulate the expression of costimulatory molecules essential for T cell stimulation [126, 127]. Further, IVIG functionally block Fc receptors but increase the functions of inhibitory Fc gamma RIIB [128]. Dose dependent effects of IVIG on induction and prevention of apoptosis of peripheral blood cells by the death receptor Fas (CD95) has been shown and might represent another mode of action of IVIG of relevance in AD [129]. Comparable to GCS and CNI, IVIG are able to reduce T cell mediated keratinocyte apoptosis [56]. One major point of relevance for AD might be the enhanced steroid sensitivity induced by IVIG and achievable GCS sparing effects [131]. However, the relatively high price and the consideration of the cost-benefit ratio as well as the relatively low experience and studies in a broad number of patients with AD preclude IVIG from their use as standard therapy in the clinical practice for a high number of AD patients so far.

Biologicals Biologic agents are proteins which can be extracted from animal tissue or synthesized in large quantities with the help of recombinant DNA techniques. Several drugs have been designed to treat inflammatory skin disorders by targeting specific cells, cytokines, or interactions between ligands and receptors [132]. Efalizumab is a humanized monoclonal antibody to the alpha-1 integrin CD11a, which is a component of LFA1 on the surface of T cells. The interaction between LFA1 on T cells and ICAM-1 on APC represents an important costimulatory signal which induces T cell activation. ICAM-1 on endothelial cells also interacts with LFA-1 on circulating T cells. This interaction is necessary for the migration of T cells into inflamed skin. The effect of efalizumab bases not only on the inhibition of the interaction of APC and T cells, but also on the inhibition of the migration of T cells to the skin and the binding of T cells to endothelial cells [133]. Due to its potential to inhibit T cell activation, Efalizumab is being now used in open-label pilot studies for the treatment of AD with relatively good clinical results in comparison to other biologicals in a majority of treated patients [134, 135]. However, double blind placebo controlled studies including a high number of AD patients are required to decide

Immunosuppressants

303

whether Efalizumab or other biologics might represent alternative treatments for specific subgroups of AD patients.

Conclusion Research of the last years has profoundly improved our knowledge regarding the mode of action of immunosuppressants in AD. Together with the increasing knowledge gained on the subject of the complex pathophysiology of AD, novel therapeutic strategies taking different AD subtypes into consideration need to be developed to supplement our current repertoire of immunmodulators and optimize the treatment of AD.

References 1. Leung DY, Bieber T (2003) Atopic dermatitis. Lancet 361:151–160 2. Sternberg TH, Newcomer VD, Linden IH (1952) Treatment of atopic dermatitis with cortisone. J Am Med Assoc 148:904–907 3. Sulzberger MB, Witten VH (1952) The effect of topically applied compound F in selected dermatoses. J Invest Dermatol 19:101–102 4. Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P, Hamid Q, Kapp A, Leung DY, Lipozencic J, Luger TA, Muraro A, Novak N, Platts-Mills TA, Rosenwasser L, Scheynius A, Simons FE, Spergel J, Turjanmaa K, Wahn U, Weidinger S, Werfel T, Zuberbier T (2006) Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy 61:969–987 5. Pratt WB, Galigniana MD, Morishima Y, Murphy PJ (2004) Role of molecular chaperones in steroid receptor action. Essays Biochem 40:41–58 6. Wu B, Li P, Liu Y, Lou Z, Ding Y, Shu C, Ye S, Bartlam M, Shen B, Rao Z (2004) 3D structure of human FK506-binding protein 52: implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex. Proc Natl Acad Sci USA 101:8348–8353 7. Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, Chrousos GP, Klemm DJ (1997) Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med 186:1567–1574 8. Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids-new mechanisms for old drugs. N Engl J Med 353:1711–1723 9. Barnes PJ (2006) How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148:245–254 10. Ismaili N, Garabedian MJ (2004) Modulation of glucocorticoid receptor function via phosphorylation. Ann N Y Acad Sci 1024:86–101 11. Mozo L, Suarez A, Gutierrez C (2004) Glucocorticoids up-regulate constitutive interleukin-10 production by human monocytes. Clin Exp Allergy 34:406–412 12. Falkenstein E, Norman AW, Wehling M (2000) Mannheim classification of nongenomically initiated (rapid) steroid action(s). J Clin Endocrinol Metab 85:2072–2075 13. Long F, Wang YX, Liu L, Zhou J, Cui RY, Jiang CL (2005) Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids 70:55–61 14. Almawi WY, Melemedjian OK, Rieder MJ (1999) An alternate mechanism of glucocorticoid antiproliferative effect: promotion of a Th2 cytokine-secreting profile. Clin Transplant 13:365–374

304

B. Kwiek and N. Novak

15. Blotta MH, DeKruyff RH, Umetsu DT (1997) Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes. J Immunol 158:5589–5595 16. Dozmorov IM, Miller RA (1998) Generation of antigen-specific Th2 cells from unprimed mice in vitro: effects of dexamethasone and anti-IL-10 antibody. J Immunol 160:2700–2705 17. Franchimont D, Galon J, Gadina M, Visconti R, Zhou Y, Aringer M, Frucht DM, Chrousos GP, O’Shea JJ (2000) Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes. J Immunol 164:1768–1774 18. Liberman AC, Refojo D, Druker J, Toscano M, Rein T, Holsboer F, Arzt E (2007) The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB J 21:1177–1188 19. Miyaura H, Iwata M (2002) Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168:1087–1094 20. Zieg G, Lack G, Harbeck RJ, Gelfand EW, Leung DY (1994) In vivo effects of glucocorticoids on IgE production. J Allergy Clin Immunol 94:222–230 21. Langeveld-Wildschut EG, Riedl H, Thepen T, Bihari IC, Bruijnzeel PL, Bruijnzeel-Koomen CA (2000) Modulation of the atopy patch test reaction by topical corticosteroids and tar. J Allergy Clin Immunol 106:737–743 22. Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O’Shea JJ, Chrousos GP, Bornstein SR (2002) Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 16:61–71 23. Hawrylowicz CM, Guida L, Paleolog E (1994) Dexamethasone up-regulates granulocytemacrophage colony-stimulating factor receptor expression on human monocytes. Immunology 83:274–280 24. Gosset P, Lamblin-Degros C, Tillie-Leblond I, Charbonnier AS, Joseph M, Wallaert B, Kochan JP, Tonnel AB (2001) Modulation of high-affinity IgE receptor expression in blood monocytes: opposite effect of IL-4 and glucocorticoids. J Allergy Clin Immunol 107:114–122 25. Young JD, Lawrence AJ, MacLean AG, Leung BP, McInnes IB, Canas B, Pappin DJ, Stevenson RD (1999) Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat Med 5:1424–1427 26. Karagiannidis C, Akdis M, Holopainen P, Woolley NJ, Hense G, Ruckert B, Mantel PY, Menz G, Akdis CA, Blaser K, Schmidt-Weber CB (2004) Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114:1425–1433 27. Akdis M, Blaser K, Akdis CA (2006) T regulatory cells in allergy. Chem Immunol Allergy 91:159–173 28. Verhagen J, Akdis M, Traidl-Hoffmann C, Schmid-Grendelmeier P, Hijnen D, Knol EF, Behrendt H, Blaser K, Akdis CA (2006) Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol 117:176–183 29. Caproni M, Torchia D, Antiga E, Volpi W, del BE, Fabbri P (2006) The effects of tacrolimus ointment on regulatory T lymphocytes in atopic dermatitis. J Clin Immunol 26:370–375 30. Belsito DV, Flotte TJ, Lim HW, Baer RL, Thorbecke GJ, Gigli I (1982) Effect of glucocorticosteroids on epidermal Langerhans cells. J Exp Med 155:291–302 31. Hoetzenecker W, Ecker R, Kopp T, Stuetz A, Stingl G, Elbe-Burger A (2005) Pimecrolimus leads to an apoptosis-induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis. J Allergy Clin Immunol 115:1276–1283 32. Schuller E, Oppel T, Bornhovd E, Wetzel S, Wollenberg A (2004) Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis. J Allergy Clin Immunol 114:137–143 33. Novak N, Kraft S, Haberstok J, Geiger E, Allam P, Bieber T (2002) A reducing microenvironment leads to the generation of FcepsilonRIhigh inflammatory dendritic epidermal cells (IDEC). J Invest Dermatol 119:842–849 34. Palucka AK, Banchereau J (2006) Langerhans cells: daughters of monocytes. Nat Immunol 7:223–224

Immunosuppressants

305

35. Fauci AS, Dale DC, Balow JE (1976) Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med 84:304–315 36. Kalthoff FS, Chung J, Musser P, Stuetz A (2003) Pimecrolimus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroids. Clin Exp Immunol 133:350–359 37. Schmidt M, Pauels HG, Lugering N, Lugering A, Domschke W, Kucharzik T (1999) Glucocorticoids induce apoptosis in human monocytes: potential role of IL-1 beta. J Immunol 163:3484–3490 38. Baumer W, Seegers U, Braun M, Tschernig T, Kietzmann M (2004) TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines. Br J Dermatol 151:823–830 39. Kakinuma T, Nakamura K, Wakugawa M, Yano S, Saeki H, Torii H, Komine M, Asahina A, Tamaki K (2002) IL-4, but not IL-13, modulates TARC (thymus and activation-regulated chemokine)/CCL17 and IP-10 (interferon-induced protein of 10kDA)/CXCL10 release by TNF-alpha and IFN-gamma in HaCaT cell line. Cytokine 20:1–6 40. Masuda K, Katoh N, Okuda F, Kishimoto S (2003) Increased levels of serum interleukin-16 in adult type atopic dermatitis. Acta Derm Venereol 83:249–253 41. Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma E, Moderer M, Rothenfusser S, Wetzel S, Endres S, Hartmann G (2002) Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119:1096–1102 42. Novak N, Allam JP, Hagemann T, Jenneck C, Laffer S, Valenta R, Kochan J, Bieber T (2004) Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J Allergy Clin Immunol 114:364–370 43. Stary G, Bangert C, Stingl G, Kopp T (2005) Dendritic cells in atopic dermatitis: expression of FcepsilonRI on two distinct inflammation-associated subsets. Int Arch Allergy Immunol 138:278–290 44. Hoetzenecker W, Meindl S, Stuetz A, Stingl G, Elbe-Burger A (2006) Both pimecrolimus and corticosteroids deplete plasmacytoid dendritic cells in patients with atopic dermatitis. J Invest Dermatol 126:2141–2144 45. Oldhoff JM, Knol EF, Laaper-Ertmann M, Bruijnzeel-Koomen CA, de Bruin-Weller MS (2006) Modulation of the atopy patch test: tacrolimus 0.1% compared with triamcinolone acetonide 0.1%. Allergy 61:622–628 46. Aziz KE, Wakefield D (1996) Modulation of endothelial cell expression of ICAM-1, E-selectin, and VCAM-1 by beta-estradiol, progesterone, and dexamethasone. Cell Immunol 167:79–85 47. Caproni M, Torchia D, Antiga E, Volpi W, Fabbri P (2006) Expression of adhesion molecules in atopic dermatitis is reduced by tacrolimus, but not by hydrocortisone butyrate: a randomized immunohistochemical study. Clin Exp Dermatol 31:813–817 48. Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G (1992) A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA 89:9991–9995 49. Furukawa H, Nakamura K, Zheng X, Tojo M, Oyama N, Akiba H, Nishibu A, Kaneko F, Tsunemi Y, Saeki H, Tamaki K (2004) Enhanced TARC production by dust-mite allergens and its modulation by immunosuppressive drugs in PBMCs from patients with atopic dermatitis. J Dermatol Sci 35:35–42 50. Vestergaard C, Yoneyama H, Murai M, Nakamura K, Tamaki K, Terashima Y, Imai T, Yoshie O, Irimura T, Mizutani H, Matsushima K (1999) Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions. J Clin Invest 104:1097–1105 51. Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, Torii H, Komine M, Asahina A, Tamaki K (2002) Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin Exp Immunol 127: 270–273

306

B. Kwiek and N. Novak

52. Fujisawa T, Fujisawa R, Kato Y, Nakayama T, Morita A, Katsumata H, Nishimori H, Iguchi K, Kamiya H, Gray PW, Chantry D, Suzuki R, Yoshie O (2002) Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis. J Allergy Clin Immunol 110:139–146 53. Abe M, Thomson AW (2006) Dexamethasone preferentially suppresses plasmacytoid dendritic cell differentiation and enhances their apoptotic death. Clin Immunol 118:300–306 54. Amsterdam A, Tajima K, Sasson R (2002) Cell-specific regulation of apoptosis by glucocorticoids: implication to their anti-inflammatory action. Biochem Pharmacol 64:843–850 55. Trautmann A, Altznauer F, Akdis M, Simon HU, Disch R, Brocker EB, Blaser K, Akdis CA (2001) The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol 117:927–934 56. Trautmann A, Akdis M, Schmid-Grendelmeier P, Disch R, Brocker EB, Blaser K, Akdis CA (2001) Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis. J Allergy Clin Immunol 108:839–846 57. Xhauflaire-Uhoda E, Thirion L, Pierard-Franchimont C, Pierard GE (2007) Comparative effect of tacrolimus and betamethasone valerate on the passive sustainable hydration of the stratum corneum in atopic dermatitis. Dermatology 214:328–332 58. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY (2007) J Allergy Clin Immunol 120:150–155 59. Gong JQ, Lin L, Lin T, Hao F, Zeng FQ, Bi ZG, Yi D, Zhao B (2006) Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 155:680–687 60. Cho SH, Strickland I, Boguniewicz M, Leung DY (2001) Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 108:269–274 61. Remitz A, Kyllonen H, Granlund H, Reitamo S (2001) Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions. J Allergy Clin Immunol 107:196–197 62. Hauk PJ, Hamid QA, Chrousos GP, Leung DY (2000) Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol 105:782–787 63. Li LB, Goleva E, Hall CF, Ou LS, Leung DY (2004) Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol 114:1059–1069 64. Kanbe T, Soma Y, Kawa Y, Kashima M, Mizoguchi M (2001) Serum levels of soluble stem cell factor and soluble KIT are elevated in patients with atopic dermatitis and correlate with the disease severity. Br J Dermatol 144:1148–1153 65. Lavker RM, Schechter NM (1985) Cutaneous mast cell depletion results from topical corticosteroid usage. J Immunol 135:2368–2373 66. Mori A, Kaminuma O, Suko M, Mikami T, Nishizaki Y, Ohmura T, Hoshino A, Asakura Y, Miyazawa K, Ando T, Okumura Y, Yamamoto K, Okudaira H (1997) Cellular and molecular mechanisms of IL-5 synthesis in atopic diseases: a study with allergen-specific human helper T cells. J Allergy Clin Immunol 100:S56–S64 67. Wedi B, Raap U, Lewrick H, Kapp A (1997) Delayed eosinophil programmed cell death in vitro: a common feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis. J Allergy Clin Immunol 100:536–543 68. Kagami S, Saeki H, Komine M, Kakinuma T, Tsunemi Y, Nakamura K, Sasaki K, Asahina A, Tamaki K (2005) Interleukin-4 and interleukin-13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cells. Clin Exp Immunol 141:459–466 69. Juan M, Mullol J, Roca-Ferrer J, Fuentes M, Perez M, Vilardell C, Yague J, Picado C (1999) Regulation of ICAM-3 and other adhesion molecule expressions on eosinophils in vitro. Effects of dexamethasone. Allergy 54:1293–1298 70. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Pentlow BD, Rolles K (1978) Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2:1323–1327

Immunosuppressants

307

71. Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR (1989) Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 246:1617–1620 72. Harper JI, Ahmed I, Barclay G, Lacour M, Hoeger P, Cork MJ, Finlay AY, Wilson NJ, GrahamBrown RA, Sowden JM, Beard AL, Sumner MJ, Berth-Jones J (2000) Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 142:52–58 73. Hijnen DJ, ten BO, Timmer-de ML, Bruijnzeel-Koomen CA, de Bruin-Weller MS (2007) Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol Venereol 21:85–89 74. Maintz L, Novak N (2007) Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol 17:267–283 75. van JT, Kozel MM, Tank B, Troost R, Prens EP (1992) Cyclosporine in atopic dermatitis. Modulation in the expression of immunologic markers in lesional skin. J Am Acad Dermatol 27:922–928 76. Bunikowski R, Gerhold K, Brautigam M, Hamelmann E, Renz H, Wahn U (2001) Effect of low-dose cyclosporin a microemulsion on disease severity, interleukin-6, interleukin-8 and tumor necrosis factor alpha production in severe pediatric atopic dermatitis. Int Arch Allergy Immunol 125:344–348 77. Jahnz-Rozyk K, Targowski T, Paluchowska E, Owczarek W, Kucharczyk A (2005) Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis. Allergy 60:685–688 78. Campbell JJ, O’Connell DJ, Wurbel MA (2007) Cutting Edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions. J Immunol 178:3358–3362 79. Yamashita U, Kuroda E (2002) Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol 22:105–114 80. Hijnen D, De Bruin-Weller M, Oosting B, Lebre C, De JE, Bruijnzeel-Koomen C, Knol E (2004) Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cellattracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are diseasespecific markers for atopic dermatitis. J Allergy Clin Immunol 113:334–340 81. Caproni M, Salvatore E, Cardinali C, Brazzini B, Fabbri P (2000) Soluble CD30 and cyclosporine in severe atopic dermatitis. Int Arch Allergy Immunol 121:324–328 82. Bottari V, Frezzolini A, Ruffelli M, Puddu P, Fontana L, De PO (1999) Cyclosporin A (CyA) reduces sCD30 serum levels in atopic dermatitis: a possible new immune intervention. Allergy 54:507–510 83. Yamada H, Kurashimo S, Chihara J, Matsukura M, Yudate T, Tezuka T (1999) Overexpression of CD11b on eosinophils in atopic dermatitis: downregulation by cyclosporin A and upregulation by interleukin 5. Int Arch Allergy Immunol 120 Suppl 1:100–103 84. Kagi MK, Joller-Jemelka H, Wuthrich B (1999) Soluble E-selectin correlates with disease activity in cyclosporin A-treated patients with atopic dermatitis. Allergy 54:57–63 85. Farrell AM, Antrobus P, Simpson D, Powell S, Chapel HM, Ferry BL (2001) A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy. Br J Dermatol 144:24–33 86. Valenta R, Natter S, Seiberler S, Roschanak M, Mothes N, Mahler V, Eibensteiner P (1999) Autoallergy: a pathogenetic factor in atopic dermatitis? Curr Probl Dermatol 28:45–50 87. Seiberler S, Bugajska-Schretter A, Hufnagl P, Binder BR, Stockl J, Spitzauer S, Valent P, Valenta R (1999) Characterization of IgE-reactive autoantigens in atopic dermatitis. 1. Subcellular distribution and tissue-specific expression. Int Arch Allergy Immunol 120:108–116 88. Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM (2000) Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions. J Allergy Clin Immunol 105:1211–1220 89. Mothes N, Niggemann B, Jenneck C, Hagemann T, Weidinger S, Bieber T, Valenta R, Novak N (2005) The cradle of IgE autoreactivity in atopic eczema lies in early infancy. J Allergy Clin Immunol 116:706–709

308

B. Kwiek and N. Novak

90. Kinaciyan T, Natter S, Kraft D, Stingl G, Valenta R (2002) IgE autoantibodies monitored in a patient with atopic dermatitis under cyclosporin A treatment reflect tissue damage. J Allergy Clin Immunol 109:717–719 91. Rusnak F, Mertz P (2000) Calcineurin: form and function. Physiol Rev 80:1483–1521 92. Schiene-Fischer C, Yu C (2001) Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS Lett 495:1–6 93. Dumont FJ (2000) FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 7:731–748 94. Simon D, Vassina E, Yousefi S, Kozlowski E, Braathen LR, Simon HU (2004) Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after shortterm topical tacrolimus treatment. J Allergy Clin Immunol 114:887–895 95. Simon D, Vassina E, Yousefi S, Braathen LR, Simon HU (2005) Inflammatory cell numbers and cytokine expression in atopic dermatitis after topical pimecrolimus treatment. Allergy 60:944–951 96. Migita K, Eguchi K (2001) FK 506-mediated T-cell apoptosis induction. Transplant Proc 33:2292–2293 97. Reich K, Hugo S, Middel P, Blaschke V, Heine A, Gutgesell C, Williams R, Neumann C (2002) Evidence for a role of Langerhans cell-derived IL-16 in atopic dermatitis. J Allergy Clin Immunol 109:681–687 98. Hauk PJ, Leung DY (2001) Tacrolimus (FK506): new treatment approach in superantigenassociated diseases like atopic dermatitis? J Allergy Clin Immunol 107:391–392 99. Wollenberg A, Sharma S, von BD, Geiger E, Haberstok J, Bieber T (2001) Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigenpresenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 107:519–525 100. Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft S, Bieber T (2004) FcepsilonRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol 113:949–957 101. Matsue H, Yang C, Matsue K, Edelbaum D, Mummert M, Takashima A (2002) Contrasting impacts of immunosuppressive agents (rapamycin, FK506, cyclosporin A, and dexamethasone) on bidirectional dendritic cell-T cell interaction during antigen presentation. J Immunol 169:3555–3564 102. Duperrier K, Velten FW, Bohlender J, Demory A, Metharom P, Goerdt S (2005) Immunosuppressive agents mediate reduced allostimulatory properties of myeloid-derived dendritic cells despite induction of divergent molecular phenotypes. Mol Immunol 42:1531–1540 103. Panhans-Gross A, Novak N, Kraft S, Bieber T (2001) Human epidermal Langerhans’ cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 107:345–352 104. Stuetz A, Baumann K, Grassberger M, Wolff K, Meingassner JG (2006) Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus. Int Arch Allergy Immunol 141:199–212 105. Krummen MB, Varga G, Steinert M, Stuetz A, Luger TA, Grabbe S (2006) Effect of pimecrolimus vs. corticosteroids on murine bone marrow-derived dendritic cell differentiation, maturation and function. Exp Dermatol 15:43–50 106. Szabo G, Gavala C, Mandrekar P (2001) Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells. J Investig Med 49:442–449 107. Wada K, Kaminuma O, Mori A, Nakata A, Ogawa K, Kikkawa H, Ikezawa K, Suko M, Okudaira H (1998) IL-5-producing T cells that induce airway eosinophilia and hyperresponsiveness are suppressed by dexamethasone and cyclosporin A in mice. Int Arch Allergy Immunol 117 Suppl 1:24–27 108. Park CW, Lee BH, Han HJ, Lee CH, Ahn HK (2005) Tacrolimus decreases the expression of eotaxin, CCR3, RANTES and interleukin-5 in atopic dermatitis. Br J Dermatol 152:1173–1181

Immunosuppressants

309

109. Ito F, Toyota N, Sakai H, Takahashi H, Iizuka H (1999) FK506 and cyclosporin A inhibit stem cell factor-dependent cell proliferation/survival, while inducing upregulation of c-kit expression in cells of the mast cell line MC/9. Arch Dermatol Res 291:275–283 110. Sengoku T, Kishi S, Sakuma S, Ohkubo Y, Goto T (2000) FK506 inhibition of histamine release and cytokine production by mast cells and basophils. Int J Immunopharmacol 22:189–201 111. Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, Henz BM (2001) The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 108:275–280 112. Lan CC, Kao YH, Huang SM, Yu HS, Chen GS (2004) FK506 independently upregulates transforming growth factor beta and downregulates inducible nitric oxide synthase in cultured human keratinocytes: possible mechanisms of how tacrolimus ointment interacts with atopic skin. Br J Dermatol 151:679–684 113. Muschen A, Mirmohammadsadegh A, Jarzebska-Deussen B, Abts HF, Ruzicka T, Michel G (1999) Differential IL-10 receptor gene expression in acute versus chronic atopic eczema. Modulation by immunosuppressive drugs and cytokines in normal cultured keratinocytes. Inflamm Res 48:539–543 114. Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, Schuler W, Schulz M, Werner FJ, Winiski A, Wolff B, Zenke G (1999) A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 141:264–273 115. Karashima T, Hachisuka H, Sasai Y (1996) FK506 and cyclosporin A inhibit growth factorstimulated human keratinocyte proliferation by blocking cells in the G0/G1 phases of the cell cycle. J Dermatol Sci 12:246–254 116. Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke WE, Kaufmann R, Zollner TM (2001) Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 137:870–873 117. Heller M, Shin HR, Orlow SJ, Schaffer JV (2007) Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 157:127–132 118. Murray ML, Cohen JB (2007) Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 32:23–27 119. Hantash B, Fiorentino D (2006) Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil. Arch Dermatol 142:109–110 120. Hansen ER, Buus S, Deleuran M, Andersen KE (2000) Treatment of atopic dermatitis with mycophenolate mofetil. Br J Dermatol 143:1324–1326 121. Goujon C, Berard F, Dahel K, Guillot I, Hennino A, Nosbaum A, Saad N, Nicolas JF (2006) Methotrexate for treatment of adult atopic dermatitis. Eur J Dermatol 16:155–158 122. Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ (2007) An open-label, dose ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol 156:346–351 123. Balasubramaniam P, Ilchyshyn A (2005) Successful treatment of severe atopic dermatitis with methotrexate. Clin Exp Dermatol 30:436–437 124. Paul C, Lahfa M, Bachelez H, Chevret S, Dubertret L (2002) A randomized controlled evaluator-blinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol 147:518–522 125. Jolles S, Sewell C, Webster D, Ryan A, Heelan B, Waite A, Rustin M (2003) Adjunctive high-dose intravenous immunoglobulin treatment for resistant atopic dermatitis: efficacy and effects on intracellular cytokine levels and CD4 counts. Acta Derm Venerol 83:433–437 126. Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, Chevailler A, Mouthon L, Weill B, Bruneval P, Kazatchkine MD, Kaveri SV (2003) Inhitibion of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101:758–765 127. Bayry L, Lacroix-Desmazes S, Delignat S, Mouthon L, Weill B, Kazatchkine MD, Kaveri SV (2003) Intravenous immunoglobulin abrogates dendritic cell differentiation induced by

310

128. 129.

130.

131.

132. 133. 134.

135.

B. Kwiek and N. Novak interferon-alpha present in serum from patients with systemic lupus erythematosus. Arthritis Rheum 48:3497–4502 Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486 Altznauer F, von Gunten S, Spath P, Simon HU (2003) Concurrent presence of agonistic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations. J Allergy Clin Immunol 112:1185–1190 Andersson J, Skansen-Saphir U, Sparrelid E, Andersson U (1996) Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol 104:10–20 Spahnn JD, Leung DY, Chan MT, Szefler SJ, Gelfand EW (1999) Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunoglobulin. J Allergy Clin Immunol 103:421–426 Wilsmann-Theis D, Martin S, Reber M, Kwiek B, Bieber T, Novak N (2006) Biologicals dramatic advances in the treatment of psoriasis. Curr Pharm Des 12:989–999 Leonardi CL (2003) Efalizumab: an overview. J Am Acad Dermatol 49:S98–S104 Takiguchi R, Tofte S, Simpson B, Harper E, Blauvelt A, Hanifin J, Simpson E (2007) Efalizumab for severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 56:222–227 Weinberg JM, Siegfried EC (2006) Successful treatment of severe atopic dermatitis in a child and an adult with the T-cell modulator efalizumab. Arch Dermatol 142:555–558

Management of Anaphylaxis Phillip Lieberman

The Prevention of Anaphylactic Episodes General Preventive Measures Obviously, anaphylaxis is an unavoidable aspect of the practice of medicine. With the growing use of polypharmacy and the present epidemic of allergic disease, its incidence is increasing [1]. Although it is not possible to prevent all such episodes, some general preventive measures can reduce the frequency and severity of these events (Table 1). Prior to the administration of any drug, a thorough drug allergy history should be obtained. Interpretation of this history requires knowledge of the biochemical and immunologic cross-reactivity amongst drugs. When a history of an allergic reaction to a drug is present, a substitute, non-cross reactive medication should be administered when possible. Because parenteral administration of medication usually produces more severe reactions than oral administration, the oral route should be used whenever possible. When parenteral administration is required, the patient should be observed for 20–30 min after the injection is given. Although anaphylactic reactions due to drug mislabeling are rare, such instances have been recorded. In our mobile society where patients remove drugs from their original containers and repackage them, especially when traveling, such instances can occur more often. Therefore proper labeling of drugs is essential, and whenever a drug is suspected as the cause of an episode, the contents of the container from which it was taken should be checked against the label.

P. Lieberman () Division of Allergy and Immunology, Departments of Medicine and Pediatrics, University of Tennessee, Memphis, 7205 Wolf River Boulevard, Suite 200, Germantown, TN 38138 USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_18, © Springer 2010

311

312

P. Lieberman

Table 1 Measures to reduce the incidence of anaphylaxis and anaphylactic deaths General Obtain thorough history for drug allergy. Avoid drugs that have immunologic or biochemical cross-reactivity with any agents to which the patient is sensitive. Administer drugs orally rather than parenterally when possible. Check all drugs for proper labeling. Keep patients in the office 30 min after injections. For Patients at Risk Make sure all medical charts are clearly labeled for drug allergies. Have patient wear and carry warning identification such as jewelry and/or wallet cards. Teach self-injection of epinephrine and caution patients to keep an epinephrine kit with them. Discontinue beta-adrenergic blocking agents, angiotensin-converting enzyme (ACE) inhibitors, ACE blockers, monoamine oxidase inhibitors, and certain tricyclic antidepressants when possible. Use preventive techniques when patients are required to undergo a procedure or take an agent that places them at risk. Such techniques include pretreatment, provocative challenge, and desensitization.

Preventive Measures for Patients at Risk Medical charts should be clearly labeled, denoting a patient’s drug allergies. All patients at risk should carry identifying information such as a wallet card and/or identifying jewelry. Jewelry can be obtained from Medic Alert (2323 Colorado Road, Turlock, California 95382, www.medicalert.org). All patients at risk for anaphylaxis should be supplied with automatic epinephrine injector kits. It should be emphasized that they must keep the kit with them at all times. It is well known that patients fail to keep such kits with them, and even when they have them available, are reluctant to use them [2]. It has also been documented that diligent efforts to educate patients on the importance of keeping epinephrine available can improve adherence rates regarding maintaining the availability of epinephrine and its appropriate utilization [3]. Patients at risk for anaphylaxis should avoid, if possible, taking certain classes of medication (Table 2). These include beta-blockers [4], ACE inhibitors [5], monoamine oxidase inhibitors, and tricyclic anti-depressants [6, 7]. In addition, there is at least a theoretical admonition against such patients taking angiotensin blocking agents. Beta-blockers are contraindicated because they prevent and/or alter the effects of epinephrine administered for therapy or produced by the body during the natural compensatory response to hypotension. ACE inhibitors prevent the degradation of kinins, which play a role in the production of anaphylactic events and also interfere with the natural compensatory response to hypotension by preventing the production of angiotensin II [5]. Angiotensin blocking agents also interfere with the action of angiotensin II, thus blocking a natural response to hypotension. Monoamine

Treatment of Anaphylaxis

313

Table 2 Drugs which should be avoided in patients who are at risk of anaphylactic events (e.g., insect sting hypersensitive patients, patients with recurrent idiopathic anaphylaxis, etc.) Drug Potential adverse effect Beta-adrenergic Diminishes the effect of exogenously administered blockers epinephrine and endogenously manufactured epinephrine that occurs as a response to hypotension. ACE inhibitors Blocks the destruction of kinins which can play a role in the production of anaphylactic events as well as prevents the production of angiotensin II which occurs as a compensatory response to hypotension. Angiotensin receptor May block the effect of angiotensin II, synthesized as a response blockers to hypotension, at its receptor site. Monoamine oxidase Prevent the degradation of epinephrine, thus complicating the inhibitors choice of dose. Tricyclic antidepressants Prevent the reuptake of catecholamines at neuronal endings, thus again complicating the choice of dose of epinephrine

oxidase inhibitors and tricyclics complicate the dosing of epinephrine. The former does so by preventing its degradation, and the latter by preventing re-uptake of catecholamines at neuronal endings, thus exaggerating the effect of exogenously administered sympathomimetic amines [6, 7]. Of course in some instances it is necessary to administer a drug or a diagnostic agent to a patient who has had a previous reaction to administration of this drug or agent. In these instances published protocols employing desensitization, provocative challenges, or pretreatment regimens should be employed.

Management of the Acute Event Treatment Administered in a Medical Facility It is believed that prompt initiation of therapy prevents fatalities. Therefore rapid recognition with immediate onset of treatment is essential. The steps of therapy may be divided into those which should be “reflexive” in nature and therefore performed immediately, and those which may be initiated after further evaluation (Table 3). It is important to stress that the steps noted in Table 3 are subject to the discretion of the physician managing the care of the patient. Variations in their sequence and performance would depend on clinical judgment. To initiate therapy, the medications and apparatus for treatment must be available. There have been a number of position statements listing drugs and equipment which should be on hand for the management of anaphylaxis [5]. Table 4 is a summation of these suggestions with revisions. Table 5 is a list of drugs and other agents used in the treatment of anaphylaxis with suggested dosages.

314

P. Lieberman

Table 3 Treatment of anaphylaxis Requires immediate action Place lying flat on back with legs elevated Assess airway and secure if needed Ventilate if required Initiate High flow oxygen Rapid assessment of level of consciousness Vital signs Administer epinephrine 0.01 mg/kg to a maximum of 0.5 mg in anterolateral thigh Obtain intravenous access with large bore needle if hypotension present Treatment that can be instituted later after further evaluation For continued hypotension consider: Intravenous fluids Vasopressors other than epinephrine If wheezing present: Administer albuterol ventilation If patient is unresponsive and receiving beta-adrenergic blocker, consider: Atropine for bradycardia Glucagon for hypotension Ipratropium inhalation for wheezing not responsive to albuterol For cutaneous symptoms as well as possibly hypotension, consider: H1/H2 blockers Corticosteroids

Table 4 Equipment and medication needed for treatment of anaphylaxis in the office Primary Tourniquet 1- and 5-ml disposable syringes Oxygen tank and mask/nasal prongs Epinephrine solution (aqueous) 1:1,000 (1-ml ampules and multidose vials) Epinephrine solution (aqueous) 1:10,000 (commercially available preloaded in a syringe) Diphenhydramine injectable Ranitidine or cimetidine injectable Injectable corticosteroids Ambu-bag, oral airway, laryngoscope, endotracheal tube, No. 12 needle Intravenous setup with large bore catheter IV fluids: 2,000 ml crystalloid, 1,000 ml hydroxyethyl starch Aerosol beta 2 bronchodilator and compressor nebulizer Glucagon Normal saline 10-ml vial for epinephrine dilution Electrocardiogram Supporting Suction apparatus Dopamine Sodium bicarbonate (continued)

Treatment of Anaphylaxis

315

Table 4 (continued) Primary Aminophylline Atropine IV “setup” with needles, tape, and tubing Non-latex gloves Optional Defibrillator Calcium gluconate Lidocaine Neuroleptics for seizures

Table 5 Drugs and other agents used in the treatment of anaphylaxis Drug Dose and route of administration Comment Epinephrine IMa: 1:1,000 0.3–0.5 ml IM Initial drug of choice for all lateral thigh (adult); 1:1,000 episodes; should be given 0.01 mg/kg or 0.1–0.3 ml IM immediately; may repeat q lateral thigh (child) 5–15 min If no response to IM IVb: 0.1–1.00 ml of 1:1,000 aqueous epinephrine diluted in administration and patient 10 ml normal saline IV (see text in shock with cardiovascular for details) collapse consider intravenous administration Alternatively, an epinephrine infusion can be prepared by adding 1 mg (1 ml) of 1:1,000 dilution of epinephrine to 250 ml of D5W to yield a concentration of 4.0 mcg/ml. This solution is infused at a rate of 1–4 mcg/min (15–60 drops per minute with a microdrop apparatus) [60 drops per minute = 1 ml = 60 ml/h] ), increasing to a maximum of 10 mcg/min. Antihistamines Diphenhydramine 25–50 mg IM or IV (adult); 12.5– Route of administration depends 25 mg PO, IM, or IV (child) on severity of episode Ranitidine 1 mg/kg IV ranitidine Cimetidine 4 mg/kg IV cimetidine Cimetidine should be administered slowly because rapid administration has been associated with hypotension; doses shown are for adults; dose in children less well established (continued)

316

P. Lieberman

Table 5 (continued) Drug Dose and route of administration Corticosteroids Hydrocortisone

100 mg−1 g IV or IM (adult), 10–100 mg IV (child)

Drugs for resistant bronchospasm Aerosolized Dose as for asthma beta- agonist (albuterol, levalbuterol) Aminophylline Dose as for asthma

Volume expanders Crystalloids (normal saline or Ringer’s lactate) Colloids (hydroxyethyl starch) Vasopressors Dopamine

Norepinephrine Phenylephrine Vasopressin

1,000–2,000 ml rapidly in adults; 30 ml/kg in first hour in children. 500 ml rapidly followed by slow infusion in adults

400 mg in 500 ml dextrose 5% in water as IV infusion; 2–20 mcg/kg/min 0.5–20 mcg/min 20–200 mcg/min 0.04 units/min or 2.4 units/h

Drugs employed in patients who are beta-blocked Atropine sulfate 0.3–0.5 mg IV; may repeat every 10 min to a maximum of 2 mg in adults Glucagon

Ipratropium

Initial dose of 1–5 mg IV followed by infusion of 5–15 mcg/min titrated against blood pressure Inhaled

Comment Exact dose not established; other preparations such as methylprednisolone can be used as well; for milder episodes, prednisone 30–60 mg may be given (see text) Useful for bronchospasm not responding to epinephrine

Rarely indicated for recalcitrant asthma bronchospasm; betaagonist is drug of choice Rate of administration titrated against blood pressure response for IV volume expander; after initial infusion, further administration requires tertiary care monitoring; in patients who are beta-blocked larger amounts may be needed Dopamine probably the drug of choice, but other agents have been successfully employed (see text). The rate of infusion should be titered against the blood pressure response; continued infusion requires intensive care monitoring Glucagon is probably the drug of choice with atropine useful only for treatment of bradycardia. Ipratropium might be considered as an alternative or added to inhaled beta-adrenergics for wheezing.

a

IM = intramuscular IV = intravenous

b

Immediate Measures As noted, the initial step in the management of anaphylaxis is a rapid assessment of the patient’s status with emphasis on evaluation of the airway and state of consciousness. If the airway is compromised it should be secured immediately and ventilation should be initiated if necessary. The patient should be placed in the

Treatment of Anaphylaxis

317

supine position with legs elevated, and vital signs should be obtained. Variations in the Trendelenburg position may be necessary if the patient is wheezing severely and dyspneic. When the antigen has been injected in the arm, a tourniquet proximal to the injection site should be considered. However, there is no proven efficacy of this procedure. If such a tourniquet is utilized, care should be taken to release it every five minutes (for a minimum of three minutes) during therapy. It should be left in place no longer than 30 min. Oxygen should be started at a high flow rate. In children, an estimate of the patient’s weight should be made to help guide dosage decisions. Epinephrine is the drug of choice and should be administered simultaneously while the patient is being assessed. The route of administration depends on the severity of the reaction. In most instances the intramuscular route can be utilized. The site of administration should be the anterolateral thigh (vastus lateralis muscle). The adult dose is 0.3–0.5 ml (0.3–0.5 mg) of a 1:1,000 solution. In children, the dose is 0.01 mg/kg. These dosages can be repeated two to three times as needed at 5 to 15-min intervals.

Measures Initiated After Further Evaluation When severe hypotension is present, especially if there is cardiac collapse, and no response to intramuscular administration, epinephrine should be administered intravenously. Numerous intravenous regimens have been suggested [5]. Regardless of the dose and regimen employed, care should be taken and the patient should be monitored for arrhythmias. The dose administered depends on the severity of the episode and should be titrated against the response. There is evidence in animal models [8] and humans [9,10] that a continuous infusion is superior to bolus administration. However, simple bolus administration has been utilized successfully. The intravenous bolus preparation can be prepared by diluting 0.1 ml (0.1 mg) of a 1:1,000 aqueous epinephrine solution in 10 ml of normal saline. This 10 ml dose can be infused over 5–10 min. There are a number of suggestions for constant intravenous infusion. Epinephrine can be prepared for constant infusion by adding 1 ml (1 mg) of a 1:1,000 dilution of epinephrine to 250 ml of D5W to yield a concentration of 4.0 mcg/ml. This solution is infused at a rate of 1–4 mcg/min (15–60 drops per minute with a microdrop apparatus [60 drops per minute equals 1 ml equals 60 ml/h]), increasing to a maximum of 10.0 mcg/min for adults and adolescents. For children, a dosage of 0.01 mg/kg may be infused (up to a maximum dose of 0.3 mg) [11]. An alternative method of infusion, which can be used when an infusion pump is available, has been recommended by Brown, et al., who conducted a prospective study of the treatment of human anaphylaxis induced by insect sting [12]. This is the only dose response study, known to the author, that compares the dose administered with the improvement in blood pressure . Brown, et al. recommended 1 mg (1 cc) of epinephrine 1:1,000 diluted in 100 ml administered intravenously by infusion pump.

318

P. Lieberman

The initial rate was 30–100 ml/h. Subsequent administration was titrated up or down depending upon the patient’s response and the side effects. The infusion was stopped 30 min after resolution of symptoms and signs. It should be emphasized that if intravenous epinephrine is given, cardiovascular monitoring is indicated. In the absence of the ability to gain intravenous access, sublingual injection (rather than subcutaneous or intramuscular) has been suggested as an alternative route because of the rich vascularity of this area [5]. The same dose utilized for intramuscular injection could be given in the posterior third of the sublingual area. A number of reports have presented evidence that other vasopressors may be helpful if there is a lack of response to epinephrine. These agents include dopamine [5] and vasopressin [13]. The use of vasopressin was given further credence by a study comparing vasopressin and epinephrine for cardiopulmonary resuscitation. In this study, the effects of vasopressin were similar to those of epinephrine in the management of ventricular fibrillation and pulseless electrical activity, but superior in patients with asystole. Vasopressin, in this setting, followed by epinephrine, was postulated to be more effective than epinephrine alone in the treatment of refractory cardiac arrest [14]. However, another trial failed to find vasopressin improved survival in cardiac arrest [15]. Unfortunately, hypotension does not always respond to vasopressor treatment, regardless of the agent used. Hypotension can persist even in the face of maximal vasoconstriction. In this instance, it is believed to be caused by a shift of fluid from the intravascular to the extravascular space. In such cases, the mainstay of treatment should be the restoration of intravascular volume. This is best accomplished by the rapid administration of large volumes of fluid. It has been debated whether colloids or crystalloids should be used, and there are arguments to support both forms of therapy [5]. However, the most important component of fluid therapy is not the composition of the fluid itself, but rather the rate of administration. Large volumes of crystalloid are often required. For example, 1,000–2,000 ml of lactated ringers or normal saline should be given rapidly. In an adult, depending on the blood pressure, a rate of 5–10 ml/kg in the first five minutes has been suggested. Children can receive up to 30 ml/kg of crystalloid solution in the first hour. The alternative to crystalloid therapy is the colloid, hydroxyethyl starch. Adults can receive rapid infusion of 500 ml followed by a slow infusion thereafter. In patients taking betablocking agents, the necessary volume of fluid and rate of infusion may be much greater. For example, 5–7 L may be needed before stabilization occurs. Of course, patients requiring a large volume of fluid should be monitored closely and should be in a tertiary medical facility. An interesting observation regarding the potential benefit of methylene blue for refractory hypotension occurring during an anaphylactic event was recently reported [16]. In a case of refractory hypotension occurring during an anaphylactic event due to the administration of protamine and not responding to standard therapy, the intravenous administration of 100 mg of methylene blue reversed hypotension and restored normal pulmonary artery pressure within minutes. In addition to the significance of this observation regarding the potential of methylene blue as a treatment for refractory hypotension, it also supports the contention that nitric

Treatment of Anaphylaxis

319

oxide is an important mediator of hypotension in some patients with anaphylaxis because methylene blue acts by inhibiting the production of nitric oxide. Patients receiving beta-adrenergic blocking agents may present other problems. They are often resistant to standard therapeutic regimens. They can experience refractory hypotension, bradycardia, and relapsing manifestations. In such patients, both inotropic and chronotropic functions of the heart are suppressed, resulting in bradycardia with marked hypotension. They can be resistant to epinephrine and other vasodepressors. Atropine and glucagon have been recommended for therapy in patients with beta-adrenergic blockade. Atropine is useful only for bradycardia; it exerts no beneficial effect on the inotropic function of the heart. Atropine sulfate can be administered intramuscularly or subcutaneously in a dose of 0.3–0.5 mg every 10 min to a maximum of 2 mg. Glucagon, a polypeptide hormone produced by the alpha cells of the pancreas, has both inotropic and chronotropic effects on the heart. The inotropic effect does not depend upon catecholamines or their receptors and is therefore unaltered by beta-adrenergic blockade. For this reason, glucagon may be the drug of choice in patients who are beta-blocked. The dose of glucagon is 1–5 mg intravenously as a bolus, followed by an infusion of 5–15 mcg/ min titrated against the clinical response. The administration does not produce myocardial irritability. Its cardiotonic effects can be seen within the first 5 min, and become maximal between 5 and 15 min after a single 5 mg bolus. The most common side effects of glucagon administration are nausea and vomiting. Resistant bronchospasm can be treated with inhaled ipratropium bromide and/or aminophylline. Antihistamine therapy can be useful as adjunctive treatment given with epinephrine [17]. Although antihistamine therapy is not life-saving, it can be effective in the treatment of cutaneous manifestations as well as hypotension. A combination of H1 and H2 antagonists may be superior to an H1 antagonist alone [17]. Both intramuscular and intravenous routes can be used depending on the severity of the event. The role of corticosteroids in the management of anaphylaxis has not been clearly elucidated. Based on an extrapolation of their effect on other allergic diseases, however, there is a rationale for their use. It has been suggested that they may be effective in preventing recurrences, especially the biphasic response [18]. Nonetheless other studies have not substantiated the beneficial effect of corticosteroids in this regard [19]. There is no established dose or drug of choice. Suggested intravenous doses for severe episodes are seen in Table 5. In addition, it is probably wise to give oral prednisone (30–60 mg) to patients who have experienced milder episodes of anaphylaxis and have been discharged from therapy.

Treatment in the Field by the Patient Treatment in the field is of course initiated by the patient. It consists of the immediate administration of epinephrine by automatic epinephrine injector. Intuitively it would seem that such therapy would be administered routinely and appropriately.

320

P. Lieberman

However, such is not the case. Over the past several years a number of investigations have uncovered problems regarding the prescription of epinephrine by physicians and the use of this drug by patients. In many instances physicians fail to prescribe automatic epinephrine injectors for individuals who have experienced a previous event [5], and when prescriptions are given, incorrect instructions regarding the use of the injector are not uncommon [5]. Patients themselves, as noted, fail to keep epinephrine with them and even when they do have it often do not administer it appropriately [20]. These problems mandate attention to the education of patients at risk regarding the use of epinephrine and emphasis regarding the necessity to keep injectors with them at all times. The route of choice of administration of epinephrine in the outpatient setting is the anterolateral thigh (vastus lateralis muscle). Such administration produces a more rapid rise to peak plasma levels than administration via the deltoid or by subcutaneous injection in the arm [21]. Another problem with field administration of epinephrine is that patients fail to refill their prescriptions and therefore their injectors become out of date. Simons and associates have shown that out of date EpiPens still function in spite of the fact that their plastic sheaths may show sign of wear. In most instances they found that the epinephrine, even though out of date, was not discolored and no precipitants were visible. Nonetheless there was some decrease in bioavailability, which depended on several factors, including the length of time the epinephrine had been out of date. However, because such injectors still show potency it is suggested that patients administer the drug in spite of the fact that the injector may not be in date [22]. Episodes that occur in the field may require more than one injection of epinephrine. This may be related to the severity of the episode or to a recurrence after an asymptomatic phase (biphasic reaction). Two injections may be required anywhere from 16% to approximately 33% of cases [23]. Thus it is wise in most instances to prescribe at least two automatic epinephrine injectors. The patient should be told that if epinephrine is required, he/she should immediately go to the nearest medical facility (preferably someone else should drive the patient) and should take the second injection if he/she has not improved after 5–10 min and has not yet reached the medical facility. In cases where hypotension has occurred during previous episodes, the patient should also lie flat with feet elevated if possible. In such instances, patients should be told to always keep a cellular telephone with them in case they are not able to travel to an emergency facility. In this instance, they should contact an emergency medical management team to transport them to such a facility.

The Observation Period After Resolution of Symptoms Although there are no controlled trials establishing the ideal observation period after successful treatment of an event, recognition that biphasic reactions can occur has resulted in recommendations for more prolonged observation in certain cases [19,24].

Treatment of Anaphylaxis

321

Table 6 Indications for prolonged observation (8–24 h after resolution of symptoms) in episodes of anaphylaxis • • • •

Moderate to severe reaction Episode in an asthmatic with wheezing Ingested antigen (possibility of continued absorption) Previous history of a biphasic response

Resuscitation guidelines [24] have been established to guide physicians regarding the observation period. These are noted in Table 6.

Fatalities First of all, it is important to realize that the level of severity of a previous reaction is not necessarily predictive of the severity of a future event. That is, repeat reactions can be more severe than initial reactions, and fatalities have occurred in patients who have experienced an initial mild event [25]. Death can be due to several causes. The majority are either respiratory or cardiovascular in nature. However, death can be due to disseminated intravascular coagulation [25]. It is important to note that death can occur in the field setting in spite of appropriate therapy with epinephrine. Pumphrey and Gowland [26] studied 48 deaths between 1999 and 2006. Nine of the patients who died used epinephrine correctly. One of these used three injections. Two of the patients who did use epinephrine correctly had outdated injectors. As noted previously, death could occur in patients with previous mild reactions. Over one-half of the deaths in this series occurred in patients where the previous reaction had been classified as mild. In a previous study by Pumphrey [27], he noted that four deaths were associated with the patient assuming an upright or sitting posture after having been recumbent. He attributed these deaths to the “empty heart syndrome” with the heart contracting in the absence of blood in the ventricles because of decreased venous return occurring when the patient sat up or stood up. Another factor in Pumphrey’s series was the food related to anaphylactic events. He found that tree nuts and peanuts were the most common foods involved. Asthma was also a risk factor. In a series evaluated by Rotskoff, et al. [28], it was concluded that elderly patients with comorbid diseases are at risk, and that a rapid onset of symptoms after exposure might also be a risk factor. As in Pumphrey’s series, of note is the fact that there was a death in spite of the fact that epinephrine was administered appropriately and in time. In an ongoing series of fatalities, Bock, et al. [29] reported a group of 32 individuals who died with food-induced anaphylaxis. They also found nuts and peanuts to be the most common foods associated with anaphylactic deaths. However, deaths also occurred because of other foods including shellfish in their series. All of the subjects who had data evaluated had asthma. Four of their 32 reported cases had epinephrine administered in a timely and appropriate manner. From a review of these data, several risk factors for death emerge. These are summarized in Table 7.

322

P. Lieberman

Table 7 Risk factors for fatal reactions • Asthma • Elderly with comorbid conditions • Teenagers (perhaps because they have a decreased adherence rate in regard to carrying automatic epinephrine injectors with them) • Food allergy to tree nuts and peanuts • Rapid onset of symptoms after exposure to responsible agent • Injected antigen • Assuming the sitting or standing posture prior to complete cardiovascular stabilization

References 1. Warner JO (1997) Anaphylaxis; the latest allergy epidemic. Pediatr Allergy Immunol 18:1–2 2. Lieberman P (2003) Use of epinephrine in treatment of anaphylaxis. Curr Opin Allergy Clin Immunol 3:313–318 3. Webb L, Lieberman P (2006) Anaphylaxis: a review of 601 cases. Ann Allergy Immunol 97:39–43 4. Lieberman P, Kemp SF, Oppenheimer J, Lang DM, Bernstein IL, Nicklas RA (2005) Letter reply. J Allergy Clin Immunol 116:933–936 5. Lieberman P (2003) Anaphylaxis and anaphylactoid reactions. In: Allergy: Principles and Practice, edition 6, Adkinson F, Yunginger J, Busse W, Bochner B, Holgate S, Simons FER (eds) (Mosby, an affiliate of Elsevier, US) pp 1497–1522 6. Physicians Desk Reference (PDR) (2005) Thomson, page 1186 7. Physicians Desk Reference (PDR) (2005) Thomson, page 732 8. Mink SN, Simons FER, Simons KJ, et al. (2004) Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs. Clin Exp Allergy 34(11):1776-1783 9. Gei A, Pachecho L, Van Hook J (2003) The use of continuous infusion of epinephrine for anaphylactic shock during labor. Obstet Gynecol 102:1332–1335 10. Brown SGA (2005) Cardiovascular aspects of anaphylaxis: implications for treatment and diagnosis. Curr Opin Allergy Clin Immunol 5:369–364 11. Lieberman P, Kemp S, Oppenheimer J, Lang D, Bernstein I, Nicklas R (2005) The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol 115:S483–S523 (supplement) 12. Brown SGA, Blackman KE, Stenlake V, Heddle RJ (2004) Insect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 21:149–154 13. Schummer W, Schummer C, Wippermann J (2004) Anaphylactic shock: is vasopressin the drug of choice? Anaest 101:1025–1027 14. Wenzel V, Krismer AC, Arantz HR(2004) A comparison of vasopressin and epinephrine for out of hospital cardiopulmonary resuscitation. N Engl J Med 350:105–113 15. Stiell IG, Herbert PC, Wells GA (2001) Vasopressin versus epinephrine for in hospital cardiac arrest: a randomized controlled trial. Lancet 358:105–109 16. Sheth SS, Del Duca D, Ergina P, Clarke AE (2007) Methylene blue as a treatment for refractory anaphylaxis. J Allergy Clin Immunol 17. Lin RY, Curry A, Pesola G (2000) Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med 36:462–468 18. Ellis AK, Day JH (2007) Incidence and characteristics of biphasic anaphylaxis: a perspective evaluation of 103 patients. Ann Allergy Asthma Immunol 98:64–69

Treatment of Anaphylaxis

323

19. Lieberman P (2005) Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 95:217–226 20. Sicherer S, Simons EFR (2005) Quandaries in prescribing emergency action plans and selfinjectable epinephrine for first-aid management of anaphylaxis in the community. J Allergy Clin Immunol 115:575–583 21. Simons FE, Gu X, Simons KJ (2001) Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 108:871–873 22. Simons FER, Gu X, Simons KJ (2000) Outdated EpiPen and EpiPen Junior autoinjectors: past their prime? J Allergy Clin Immunol 105:1025–1030 23. Kelso JM (2006) A second dose of epinephrine for anaphylaxis: how often needed and how to carry? J Allergy Clin Immunol 117(2):464–465 24. Soar J, Deakin C, Nolen J (2005) European Resuscitation Council guidelines for resuscitation 2005, Section 7. Cardiac arrest in special circumstances. Resuscitation 6751:S135–S170 (supplement). 25. Pumphrey RSH (2004) Fatal anaphylaxis in the UK, 1992-2001. In: Anaphylaxis (publication of The Novartis Foundation, John Wiley & Sons Ltd, summary of Novartis Foundation Symposium 257, 2004. John Wiley & Sons Ltd, the Atrium, Southern Gate, Chichester, UK), pp 116–132 26. Pumphrey RSH, Gowland M (2007) Further fatal allergic reactions to food in the United Kingdom, 1999-2006. J Allergy Clin Immunol 19:1018 27. Pumphrey RSH (2003) Fatal posture in anaphylactic shock. J Allergy Clin Immunol 112:451– 452 (Letter to Editor) 28. Rotskoff BD, Greenberger PA, Lifschultz B (2003) Fatal anaphylaxis: postmortem findings and associated comorbid disease. J Allergy Clin Immunol 111:S101 (abstract) 29. Bock SA, Munoz-Furlong A, Sampson HH (2007) Further fatalities caused by anaphylactic reactions to food, 2001–2006. J Allergy Clin Immunol 119:1016–1018

Anaphylaxis: Are Regulatory T Cells the Target of Venom Immunotherapy? Marek Jutel, Mübeccel Akdis, Kurt Blaser, and Cezmi A. Akdis

Abbreviations SIT VIT PIT TReg Tr1

Specific immunotherapy Venom immunotherapy Peptide immunotherapy T regulatory Type-1 T regulatory

Introduction The immunological mechanism of venom immunotherapy (VIT) was unclear for a long time. VIT has been demonstrated to influence the deviated immune response in allergic individuals in a specific manner and eventually redirect the immune system towards normal immunity. A rise in allergen-blocking IgG antibodies, particularly of the IgG4 class, which supposedly block allergen and IgE-facilitated antigen presentation [1], the generation of IgE-modulating CD8+ T cells [2] and a reduction in the numbers of mast cells and eosinophils, including the release of mediators [3, 4] were shown to be associated with successful allergen-specific immunotherapy (SIT). Later on, SIT was found to be associated with a decrease in IL-4 and IL-5 production by CD4+ T helper (Th) 2 cells [5, 6], and in some experimental conditions with a

M. Akdis, K. Blaser, and C.A. Akdis Swiss Institute of Allergy and Asthma Research (SIAF), Obere Street 22, CH-7270, Davos, Switzerland M. Jutel () Swiss Institute of Allergy and Asthma Research (SIAF), Obere Street 22, CH-7270, Davos, Switzerland; Department of Clinical Immunology, Wroclaw Medical University, Traugutta 57, PL-50-419, Wroclaw, Poland e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_19, © Springer 2010

325

326

M. Jutel et al.

shift towards increased IFN-g production [7–9]. Distinct Th1 and Th2 subpopulations of T cells counter-regulate each other and play a role in distinct diseases [10]. The mechanism of repolarization of specific T cell activity from dominating Th2type towards Th1-type, as observed during VIT had been a matter of controversy. A new light was shed when a further subtype of T cells, with immunosuppressive function and cytokine profiles distinct from either Th1 and Th2 cells, termed regulatory/ suppressor T cells (TReg) has been described [11, 12]. The evidence for their existence in humans has been demonstrated [13, 14]. In addition to Th1 cells, TReg cells are able to inhibit the development of allergic Th2 responses and play a major role in allergen-SIT [13, 15] (Fig. 1). Recent studies have also demonstrated that peripheral T-cell tolerance is crucial for a healthy immune response and successful treatment of allergic disorders [13–15]. The crucial role of TReg cells in the induction of allergen-specific peripheral tolerance during VIT has been well documented. Thus, the basis for new developments in SIT has been created.

Fig. 1 Induction of Immune deviation towards TReg cell response leads to peripheral tolerance in allergen-specific immunotherapy and healthy immune response. TReg cells utilize multiple suppressor factors to regulate undesired activity of effector cells. IL-10 and TGF-b suppress IgE production and induce non-inflammatory Ig isotypes IgG4 (more relevant in venom SIT) and IgA, respectively. Furthermore, these two cytokines directly suppress allergic inflammation induced by effector cells such as mast cells, basophils, and eosinophils. In addition, TReg cells inhibit Th2 cells, which can no longer provide cytokines such as IL-3, IL-4, IL-5, and IL-13. These cytokines are required for the differentiation, survival, and activity of mast cells, basophils, and eosinophils (red line: suppression, black line: stimulation)

TReg Cells and Venom Immunotherapy

327

Types of TReg Cells and Allergic Responses to Insect Venoms Generation of allergen-specific CD4+ T helper cells is responsible for the development of allergic diseases. Under the influence of interleukin (IL)-4 (IL-4), naive T cells activated by APC differentiate into Th2 cells [10,16]. Once generated, effector Th2 cells produce IL-4, IL-5, and IL-13 and mediate several regulatory and effector functions. These cytokines induce the production of allergen-specific IgE by B cells, development and recruitment of eosinophils, production of mucus, and contraction of smooth muscles [10]. The degranulation of basophils and mast cells by IgE-mediated cross-linking of receptors is the key event in type 1 hypersensitivity, which may lead to chronic allergic inflammation. Importantly, although Th2 cells are responsible for the development of allergic diseases, Th1 cells may contribute to chronicity and effector phase in allergic diseases [17–19]. The cardinal difference between venom allergy and true atopic diseases like allergic rhinitis, asthma, and atopic dermatitis is the lack of many chronic events of allergic inflammation leading to tissue injury and remodeling [20]. Peripheral T-cell tolerance to allergens, which is characterized by functional inactivation of the cell to antigen encounter, can overcome both acute and chronic events in allergic reactions. It is well established that TReg cells suppress immune responses via cellto-cell interactions and/or the production of suppressor cytokines [12, 13, 21]. Peripheral T-cell tolerance is characterized mainly by generation of allergenspecific TReg cells, suppressed proliferative and cytokine responses against the major allergen [14, 22, 23]. Type-1 T regulatory (Tr1) cells are defined by their ability to produce high levels of IL-10 and TGF-b [12, 24] and suppress naive and memory T helper type 1 or 2 responses. There is now clear evidence that IL-10- and/or TGF-bproducing Tr1 cells are generated in vivo in humans during the early course of allergen-SIT, suggesting that high and increasing doses of allergens induce Tr1 cells in humans [13, 15, 25]. Regulatory/suppressor Th3 cells, which produce high levels of TGF-b, and variable amounts of IL-4 and IL-10 upon activation with appropriate antigen or anti-CD3 antibody are indicated in mucosal tolerance [26]. CD4+CD25+ TReg cells constitute 5–10% of peripheral CD4+ T cells and express the IL-2 receptor a chain (CD25) [27]. They can prevent the development of autoimmunity and transplantation rejection indicating that the normal immune system contains a population of professional TReg cells involved in active mechanism of immune suppression [21, 28]. There are other TReg cells including CD8+ TReg cells, which may play a role in oral tolerance [29], double negative (CD4−CD8−) TCRab+ TReg cells that mediate tolerance in several experimental autoimmune diseases [30] and gd TReg cells which can play a role in the inhibition of immune responses to tumors [31]. In addition, a regulatory role for IL-10-secreting B cells and dendritic cells has been recently suggested [32]. Some other cells may also show possible regulatory function. It has been demonstrated that natural killer cells, epithelial cells, macrophages, and glial cells express suppressor cytokines such as IL-10 and TGF-b. Although their role has not been coined as professional regulatory cells, these cells may efficiently contribute to the generation and maintenance of a regulatory/ suppressor-type immune response [33].

328

M. Jutel et al.

Role of TReg Cells During Natural Tolerance and Venom SIT Changes in immune response to bee venom (BV) has been intensively investigated during VIT, PLA-peptide immunotherapy (PLA-PIT) [6, 34–36]. Successfully treated patients develop specific T cell unresponsiveness against the entire PLA allergen as well as the T cell epitope-containing peptides. The decreased proliferative responses did not result from deletion as they were restored by addition of IL-2 and IL-15. The same anergic state of specific T cells has been observed in protected hyperimmune individuals such as bee keepers [13]. Since, stimulation of anergized cells in the presence of IL-4 induce recovery of a Th2 cytokine pattern typical for an allergy, the microenvironmental conditions regulate T cell phenotypes in VIT. Thus, successful SIT may be more difficult to achieve in an established polyspecific allergy and atopy. The unresponsive state of specific cells results from increased IL-10 secretion [13]. The cellular origin of IL-10 was demonstrated as the antigenspecific T cell population and activated CD4+CD25+ T cells, Tr1 lymphocytes as well as monocytes, and B cells [13]. The allergic status of the patients might affect the efficacy of TReg-mediated T cell unresponsiveness. Mamessier and colleagues have shown that in less severe subjects (grade I and II – according to Mueller scale) increase in frequency of CD4+CD25+ T cells appeared early but was delayed in more severe subjects (grade III–IV). Also IL-10-producing T cells increased gradually in both groups but were in a lower frequency in more severe patients. Accordingly, in the study of Bellinghausen et al. it has been shown that function of TReg in wasp venom allergic subjects is dependent on allergen concentration with different thresholds for individual patients and much lower threshold for non-allergic individuals [34]. It has been shown that tolerance to aeroallergens is associated with activation of TGF-b-secreting TReg [15]. This, however, has not been shown during VIT. Discrepancies in the mechanisms of control of immune response to venoms and to aeroallergens might be different routes of natural allergen exposure, with the involvement of mucosal immune system in the latter case. IL-10 also plays an inhibitory role on IgE and effector cells of allergic inflammation (Fig. 1). However, VIT does not abolish the capacity by B cells to produce specific IgE and IgG4 antibodies; the ratio of specific IgE to IgG4 decreases up to 100-fold. VIT-induced IL-10 counter-regulates antigen-specific IgE and IgG4 antibody syntheses. It is a potent suppressor of both total and allergen-specific IgE, while simultaneously IgG4 formation is increased [13]. Thus, IL-10 regulates specific isotype formation and skews the specific response from an IgE to an IgG4 dominated phenotype. Similar findings suggesting induction of IgG4 by TReg cells have been observed in other allergies [23, 37]. Most patients are protected against bee stings already at an early stage of VIT which is not paralleled by changes in antibody formation. It has been shown that lower amounts of mediators of anaphylaxis (e.g., histamine or sulphidoleukotrienes) are released during VIT [7]. These effects may be attributed to direct suppressive effect of IL-10 on effector cells (mast cells, basophils). Thus, the role of

TReg Cells and Venom Immunotherapy

329

TReg cells is not limited to suppression of TH2 cells. Peripheral tolerance uses multiple mechanisms to suppress allergic inflammation. Apparently, TReg cells contribute to the control of allergen-specific immune responses by suppression of antigenpresenting cells that support the generation of effector TH2 and TH1 cells; suppression of TH2 and TH1 cells; suppression of allergen-specific IgE and induction of IgG4 and/or IgA; suppression of mast cells, basophils, and eosinophils; and interaction with resident tissue cells [38]. Peptide immunotherapy (PIT) is another attractive approach for investigation of peripheral T-cell tolerance in humans. In the clinical study using PIT in BV allergy with a mixture of short peptides that directly represented the T cell epitopes (17, 12, and 11 amino acids) of the BV major allergen, phospholipase A2 were administered [39]. The study showed modulation of the immune response against the whole allergen inducing specific T cell tolerance and a decrease in the specific IgE:IgG4 ratio [39]. Several ongoing studies suggest the role of TReg cells and their cytokines in PIT [40, 41]. One recent study has shown that VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction. A significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25bright and/or Foxp3+ CD4+ T cells was demonstrated [42]. Moreover, after multiple bee stings, venom antigen-specific Th1 and Th2 cells show a switch towards IL-10-secreting Tr1 cells [43]. Recently, an important role of antihistamine pretreatment in enhancement of clinical efficacy of VIT has been indicated [44]. Considerable evidence has emerged to suggest that histamine participates in the immune regulation of the inflammatory response in several diseases. As a small molecular weight monoamine that binds to four different G-protein-coupled receptors, histamine has recently been demonstrated to regulate several essential events in the immune response [45–47]. Histamine receptor (HR) 2 is coupled to adenylate cyclase and studies in different species and several human cells demonstrated that inhibition of characteristic features of the cells primarily by cAMP formation dominates in HR2dependent effects of histamine [48]. Histamine released from mast cells and basophils by high allergen doses during SIT interferes with the peripheral tolerance induced during SIT in several pathways. Histamine enhances Th1-type responses by triggering the HR1, whereas both Th1- and Th2-type responses are negatively regulated by HR2. Human CD4+Th1 cells predominantly express HR1 and CD4+Th2 cells express HR2, which results in their differential regulation by histamine [45, 46]. Histamine induces the production of IL-10 by DC 18. In addition, histamine induces IL-10 production by Th2 cells [49], and enhances the suppressive activity of TGF-b on T cells [50]. All three of these effects are mediated via HR2, which is relatively highly expressed on Th2 cells and suppresses IL-4 and IL-13 production and T cell proliferation [45, 46] (Fig. 2). Apparently, these recent findings suggest that HR2 may represent an essential receptor that participates in peripheral tolerance or active suppression of inflammatory/immune responses. Histamine also regulates antibody isotypes including IgE14. High amount of

330

M. Jutel et al.

HR2 induction of IL-10 suppression of IL-12 Th2 or tolerance inducing DC

prdominant HR2 low HR1 suppressed Th2 cytokines tolerance

HR2: induction of humoral immunity and suppression of cellular immunity. suppressed specific IgE HR1-deleted mice show increased specific IgE

Th2 H monocytes and dendritic cells are suppressed via HR2

histamine

modulation of B cell antibody production

Fig. 2 Histamine released during allergen-SIT plays a suppressive role on monocytes and monocyte-derived dendritic cells via HR2 (DC). Th2 cells express predominant HR2, which acts as the negative regulator of proliferation, and suppression of IL-4 and IL-13 production, suggesting a role for HR2 on T cells for peripheral tolerance. Histamine also modulates antibody production by directly effecting B cell antibody production as a co-stimulatory receptor on B cells and enhances humoral immune responses via HR2. Allergen-specific IgE production is differentially regulated in HR1- and HR2-deficient mice. HR1-deleted mice show increased allergen-specific IgE production, whereas HR2-deleted mice show suppressed IgE production

allergen-specific IgE is induced in HR1-deleted mice. In contrast, deletion of HR2 leads to a significantly less amounts of allergen-specific IgE production, probably due to direct effect on B cells and indirect effect via T cells. After multiple stings HR2 was up-regulated on specific Th2 cells. HR2 displays a dual effect by directly suppressing allergen-stimulated Th2 cells and increasing IL-10 production [43]. The long-term protection from honeybee stings by terfenadine pretreatment during rush immunotherapy with honeybee venom in a double-blind, placebo-controlled (DBPC) trial was analyzed [51]. After an average of 3 years, 41 patients were re-exposed to honeybee stings. Surprisingly, none of the 20 patients who had been given HR1-antihistamine pretreatment, but 6 of the 21 given placebo, had a systemic allergic reaction to the re-exposure by either a field sting or a sting challenge. This highly significant difference suggests that antihistamine pretreatment during the initial dose-increase phase may have enhanced the long-term efficacy of immunotherapy. In a prospective DBPC study using levocetirizine pretreatment during VIT, it has been shown that in allergen-specific T cells HR1/HR2 ratio was decreased after 21 days of treatment. However, this was prevented by levocetirizine. In addition, IL-10 levels were higher in the levocetirizine group [52]. Expression of HR1 on T lymphocytes is strongly reduced during ultra-rush immunotherapy, which may lead to a dominant expression, and function of tolerance-inducing HR2 administration of antihistamines decreases the HR1/HR2 expression ratio, which may enhance the suppressive effect of histamine on T cells. In a mice model it has

TReg Cells and Venom Immunotherapy

331

been shown that Clemastine increased IgE production while decreasing IgG2a production against BV [53]. This Th2 shift of the humoral response appeared to be caused by reduced IFN-g and enhanced IL-4 secretion from allergen-specific T cells. However, the doses of antihistamines used were 103-fold the regular doses used in humans. Further studies are required to substantiate these promising findings supporting the role of histamine signaling in the modulation of the immune response. These findings account for possible recommendation of antihistamine pretreatment in the induction phase of all VIT patients.

Conclusion There is growing evidence supporting the role for TReg cells and/or immunosuppressive cytokine – IL-10 as a mechanism, by which venom-SIT and healthy immune response to venoms is mediated leading to both suppression of Th2 responses, ensuring a well-balanced immune response, and a switch from IgE to IgG4 antibody production (Fig. 1). These mechanisms can be better used by improvement of vaccines including recombinant allergens, immunogenic peptides, or immune reactive adjuvants along with elaboration of more efficacious, rapid desensitization protocols as well as antihistamine pretreatment. Acknowledgments The authors’ laboratories are supported by the Swiss National Foundation Grants: 32-112306, 32-65436, 32-105865 and Polish National Science Committee Grant No. 1387/PO5/2000/19.

References 1. van Neerven RJ, Wikborg T, Lund G, Jacobsen B, Brinch-Nielsen A, Arnved J, Ipsen H: Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. J. Immunol. 1999;163:2944–2952 2. Rocklin RE, Sheffer A, Greineder DK, Melmon KL: Generation of antigen-specific suppressor cells during allergy desensitization. N. Engl. J. Med. 1980;302:1213–1219 3. Creticos PS, Adkinson NF, Jr., Kagey-Sobotka A, Proud D, Meier HL, Naclerio RM, Lichtenstein LM, Norman PS: Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. J. Clin. Invest. 1985;76:2247–2253 4. Rak S, Lowhagen O, Venge P: The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J. Allergy Clin. Immunol. 1988;82:470–480 5. Secrist H, Chelen CJ, Wen Y, Marshall JD, Umetsu DT: Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J. Exp. Med. 1993;178:2123–2130 6. Akdis CA, Akdis M, Blesken T, Wymann D, Alkan SS, Muller U, Blaser K: Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. J. Clin. Invest. 1996;98:1676–1683

332

M. Jutel et al.

7. Jutel M, Muller UR, Fricker M, Rihs S, Pichler WJ, Dahinden C: Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils. Clin. Exp. Allergy 1996;26:1112–1118 8. Durham SR, Till SJ: Immunologic changes associated with allergen immunotherapy. J. Allergy Clin. Immunol. 1998;102:157–164 9. Bellinghausen I, Metz G, Enk AH, Christmann S, Knop J, Saloga J: Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur. J. Immunol. 1997;27:1131–1139 10. Romagnani S: Immunologic influences on allergy and the TH1/TH2 balance. J. Allergy Clin. Immunol. 2004;113:395–400 11. Powrie F, Correa-Oliveira R, Mauze S, Coffman RL: Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J. Exp. Med. 1994;179:589–600 12. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742 13. Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K: Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 1998;102:98–106 14. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, Kegel C, Disch R, Schmidt-Weber CB, Blaser K, Akdis CA: Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J. Exp. Med. 2004;199:1567–1575 15. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis AC: IL-10 and TGF-b cooperate in regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur. J. Immunol. 2003;33:1205–1214 16. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA: Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004;117:515–526 17. Trautmann A, Akdis M, Kleemann D, Altznauer F, Simon HU, Graeve T, Noll M, Brocker EB, Blaser K, Akdis CA: T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J. Clin. Invest. 2000;106:25–35 18. Klunker S, Trautmann A, Akdis M, Verhagen J, Schmid-Grendelmeier P, Blaser K, Akdis AC: A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IP-10, Mig and iTac for T cell chemotaxis towards epidermis in atopic dermatitis. J. Immunol. 2003;171:1078–1084 19. Akdis M, Trautmann A, Klunker S, Daigle I, Kücüksezer UC, Deglmann W, Disch R, Blaser K, Akdis CA: T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells. FASEB J. 2003;17:1026–1035 20. Akdis CA, Blaser K, Akdis M: Apoptosis in tissue inflammation and allergic disease. Curr. Opin. Immunol. 2004;16:717–723 21. Wood KJ, Sakaguchi S: Regulatory T cells in transplantation tolerance. Nat. Rev. Immunol. 2003;3:199–210 22. Akdis CA, Blesken T, Akdis M, Wüthrich B, Blaser K: Role of IL-10 in specific immunotherapy. J. Clin. Invest. 1998;102:98–106 23. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis C: IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur. J. Immunol. 2003;33:1205–1214 24. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG: IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 2001;166:5530–5539 25. Nasser SM, Ying S, Meng O, Kay AB, Ewan PW: Interleukin-10 levels increase in cutaneous biopsies of patients undergoing wasp venom immunotherapy. Eur. J. Immunol. 2001;31:3704–3713 26. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994;265:1237–1240

TReg Cells and Venom Immunotherapy

333

27. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995;155:1151–1164 28. Shevach EM: CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2002;2:389–400 29. Weiner HL: Oral tolerance for the treatment of autoimmune diseases. Annu. Rev. Med. 1997;48:341–351 30. Strober S, Cheng L, Zeng D, Palathumpat R, Dejbakhsh-Jones S, Huie P, Sibley R: Double negative (CD4-CD8- alpha beta+) T cells which promote tolerance induction and regulate autoimmunity. Immunol. Rev. 1996;149:217–230 31. Seo N, Tokura Y, Takigawa M, Egawa K: Depletion of IL-10- and TGF-beta-producing regulatory gamma delta T cells by administering a daunomycin-conjugated specific monoclonal antibody in early tumor lesions augments the activity of CTLs and NK cells. J. Immunol. 1999;163:242–249 32. Mauri C, Gray D, Mushtaq N, Londei M: Prevention of athritis by interleukin 10-producing B cells. J. Exp. Med. 2003;197:489–501 33. Akdis CA, Blaser K, Akdis M: Genes of tolerance. Allergy 2004;59:897–913 34. Bellinghausen I, König B, Böttcher I, Knop J, Saloga J: Regulatory activity of human CD4+ CD25+ T cells depends on allergen concentration, type of allergen and atopy status of the donor. Immunology 2005;116:103–111 35. Akdis CA, Blaser K: Bypassing IgE and targeting T cells for specific immunotherapy of allergy. Trends Immunol. 2001;22:175–178 36. Muller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, Blaser K: Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J. Allergy Clin. Immunol. 1998;101:747–754 37. Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK, Staple SQ, Aalberse RC, Till SJ, Durham SR: Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J. Immunol. 2004;172:3252–3259 38. Akdis M, Blaser K, Akdis CA: T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J. Allergy Clin. Immunol. 2005;116:961–968 39. Müller UR, Akdis CA, Fricker M, Akdis M, Bettens F, Blesken T, Blaser K: Successful immunotherapy with T cell epitope peptides of bee venom phospholipase A2 induces specific T cell anergy in bee sting allergic patients. J. Allergy Clin.Immunol. 1998;101:747–754 40. Oldfield WL, Larche M, Kay AB: Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial. Lancet 2002;360:47–53 41. Larche M: Peptide-based immunotherapy: new developments. Arb. Paul Ehrlich Inst. Bundesamt Sera Impfstoffe Frankf. A. M. 2003;(94):133–139; discussion 139–140 42. Pereira-Santos MC, Baptista AP, Melo A, Alves RR, Soares RS, Pedro E, Pereira-Barbosa M, Victorino RM, Sousa AE. Expansion of circulating Foxp3+CD25bright CD4+ T cells during specific venom immunotherapy. Clin. Exp. Allergy 2008, 38:291–297 43. Meiler , Zumkehr J, Klunker S, Rückert B, Akdis CA, Akdis M. In vivo switch to IL-10secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 2008;205: 2887–2898 44. Muller U, Hari Y, Berchtold E: Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy. J. Allergy Clin. Immunol. 2001;107:81–86 45. Jutel M, Watanabe T, Akdis M, Blaser K, Akdis CA: Immune regulation by histamine. Curr. Opin. Immunol. 2002;14:735–740 46. Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OAR, Malolepszy J, Zak-Nejmarrk T, Koga R, Kobayashi T, Blaser K, Akdis AC: Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 2001;413:420–425 47. Akdis CA, Blaser K: Histamine in the immune regulation of allergic inflammation. J. Allergy Clin. Immunol. 2003;112:15–22

334

M. Jutel et al.

48. Del Valle J, Gantz I: Novel insights into histamine H2 receptor biology. Am. J. Physiol. 1997;273:G987–996 49. Osna N, Elliott K, Khan MM: Regulation of interleukin-10 secretion by histamine in TH2 cells and splenocytes. Int. Immunopharmacol. 2001;1:85–96 50. Kunzmann S, Mantel P-Y, Wohlfahrt JG, Akdis M, Blaser K, Schmidt-Weber CB: Histamine enhances TGF-beta1-mediated suppression of Th2 responses. FASEB J. 2003;17:1089–1095 51. Müller U, Hari Y, Berchtold E: Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy. J. Allergy Clin. Immunol. 2001;107:81–86 52. Müller UR, Jutel M, Reimers A, Zumkehr J, Huber C, Kriegel C, Steiner U, Haeberli G, Akdis M, Helbling A, Schnyder B, Blaser K, Akdis C. Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy. J. Allergy Clin. Immunol. 2008;122:1001–1007 53. Johansen P, Senti G, Maria Martínez Gómez J, Kündig TM. Medication with antihistamines impairs allergen-specific immunotherapy in mice. Clin. Exp. Allergy 2008;38:512–519

Food Allergy: Opportunities and Challenges in the Clinical Practice of Allergy and Immunology Julie Wang and Hugh A. Sampson

Introduction Food allergy affects up to 6% of children and 3–4% of adults in the United States (1), and remains the leading cause of outpatient anaphylaxis in most surveys (2). The prevalence of food allergy is greatest in the first 2 years of life and decreases with age. The most common food allergens causing reactions in children include milk, egg, wheat, soy, peanuts, tree nuts, fish, and shellfish. While the majority of children outgrow their allergy to milk, egg, wheat and soy, allergies to peanut, tree nuts, fish and shellfish are often life-long. Although any food can cause anaphylaxis, the most commonly implicated foods for severe allergic reactions are peanuts, tree nuts, fish, and shellfish (3). Currently, there are no treatments that can cure or provide long-term remission from food allergy. The mainstay of management consists of avoidance and education as well as providing emergency medications for the treatment of allergic reactions. This approach is generally effective; however, avoidance can be quite difficult as several of these food allergens are ubiquitous in our diets; thus, patients and their families experience a significant negative impact on their quality of life. Therefore, there are several new strategies currently being investigated with the aim of long-term treatment and possible cure.

J. Wang and H.A. Sampson () Division of Allergy and Immunology, Department of Pediatrics, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, NY, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_20, © Springer 2010

335

336

J. Wang and H.A. Sampson

Allergen-Specific Immunotherapy Allergen Immunotherapy Subcutaneous Immunotherapy (SCIT) Subcutaneous immunotherapy (SCIT) that has been used since 1911, is standardized and is highly efficacious for allergic rhinitis, asthma, and insect sting allergy (4). Moreover, its efficacy persists after discontinuation of immunotherapy. Thus, SCIT is an attractive treatment option for food allergy given its efficacy and safety in other allergic disorders. The first successful use of SCIT for food allergy was reported by Freeman in 1930 in a fish-allergic patient (5). Subsequently, no new reports emerged until the 1990s when a few groups reported their experience with SCIT for peanut allergy (6). In a double-blind, placebo-controlled trial of rush immunotherapy in peanut allergic patients, three patients were able to complete the study. There was a 67–100% decrease in symptoms induced by double-blind, placebo-controlled food challenge (DBPCFC) and 2–5-log reduction in end-point skin prick tests to peanut extract in these patients. Only one placebo patient completed the study; there was no change in DBPCFC symptom score or skin test sensitivity for this individual. However, the study had to be terminated prematurely because of a severe adverse reaction and the rate of systemic reaction with the rush immunotherapy protocol was 13.3%. Another study of SCIT for peanut allergy was published by Nelson et al. (7), in 1997. This group treated six peanut allergic patients with a rush protocol and patients were on maintenance immunotherapy for 1 year. For comparison, six untreated controls were used. All patients treated with immunotherapy had improved tolerance as demonstrated by DBPCFC and decreased sensitivity on skin test as compared to controls who showed no change. However, only three patients were able to reach the maintenance dose during this trial. The remaining three patients required dose reductions because of systemic side effects. This resulted in either partial or complete loss of protection. Overall, systemic reactions were common both during the initial rush protocol and with maintenance injections (39%). Bullock et al. (8) reported a case of successful desensitization for peanut allergy. They also examined immunologic parameters in their patient and found increased peanut-specific IgG4 levels. Specific IgE levels declined from pretreatment levels, but still remained significantly elevated. Overall, these studies demonstrate that SCIT can lead to increased tolerance; however, unacceptably high rates of adverse systemic reactions is a significant disadvantage to this method. In addition, there are no long-term studies investigating whether the increased tolerance persists after discontinuation of treatment, as it does for aeroallergen immunotherapy. Since the pollen-fruit syndrome (PFS) is, in many cases, due to cross-reactivity with pollens, SCIT would seem to be a logical treatment for PFS as well. A study of birch immunotherapy for apple allergy in 49 birch pollen sensitive adults with

Food Allergy: Opportunities and Challenges

337

apple-induced PFS found a reduction of oral symptoms in 84% and decreased skin test sizes in 88%, but an increase in apple-specific IgE was observed in 38% (9). None of the control subjects reported a reduction in PFS symptoms or showed a decrease in skin test reactivity at follow-up. This study was limited by the selfreported symptoms and lack of placebo controls. Another study of birch SCIT found decreased symptoms (based on DBPCFC) and skin test sizes in the treated group, but there was no placebo SCIT group for comparison (10). Instead, the comparison was made with a group of patients who used medication for symptomatic treatment. A case report of a patient with improved oral symptoms to fennel, cucumber, and melon after 3.5 years of SCIT with grass, mugwort, and ragweed was also reported (11). In contrast, several studies have not shown similar efficacy of immunotherapy for PFS. Bucher et al. (12) placed 15 adults on SCIT for birch to treat PFS to apple and hazelnut. Open challenges were performed before and after SCIT. The authors found limited benefit of immunotherapy with birch for PFS. Similarly, another study found no benefit of subcutaneous and sublingual immunotherapy to birch for PFS to apple (13). A pediatric study from Sweden indicated no beneficial effect of birch SCIT or oral immunotherapy for food allergic symptoms (14). In addition to difficulties in objective evaluations for improvement in symptoms, there is no consensus for target doses; thus, SCIT remains an unproven therapeutic approach for PFS.

Oral Immunotherapy (Specific Oral Tolerance Induction, SOTI) Since there is a high incidence of adverse reactions with SCIT, alternative routes of immunotherapy administration are being explored to improve the risk–benefit ratio. There is an expanding body of literature that reports a high rate of efficacy with oral immunotherapy (75–86%) (15–17). Several studies have been published for trials with various food allergens. A trial of egg oral immunotherapy in non-anaphylactic patients was published. Buchanan et al. (18) treated seven patients with a modified rush immunotherapy with build-up to a daily maintenance dose of 300 mg. The patients were kept on maintenance dose for the duration of the study. Four patients who passed a DBPCFC at the end of the 24-month trial underwent a second DBPCFC after 3–4 months without immunotherapy; two patients passed this second DBPCFC. The authors found a significant increase in egg-specific IgG, but no change in eggspecific IgE post-treatment. All tolerated significantly more egg than at the study onset, with two patients demonstrating oral tolerance. Of note, this study did not include control patients, was not blinded, and only included children without a history of anaphylaxis to egg. Patriarca et al. (19) reported on a larger group of patients who received immunotherapy to a variety of food allergens. In this study, 42 patients with food allergy underwent sublingual–oral desensitization to milk, egg, fish, wheat, apple, and/or beans. Ten patients who refused to participate in the desensitization protocol and remained on elimination diets served as the control group. Six patients in the treatment

338

J. Wang and H.A. Sampson

group dropped out of the study due to poor compliance. Another four patients stopped the protocol because of continued symptoms not controlled by oral antihistamines or cromolyn sodium. All of the remaining patients (85.7%) had negative DBPCFCs, which were performed at the completion of the desensitization protocol. Prophylactic oral antihistamines or cromolyn sodium was administered to 11 patients (30.6%) who experienced mild side effects. Patients were maintained on therapy, so it is unclear whether any of these patients achieved tolerance or whether they reached a desensitized state. One of the main criticisms of these studies has been the non-randomized nature of the trials. Two studies incorporated randomization into their trial design, but neither were blinded or placebo-controlled. Morisset et al. (20) studied 57 children with cow’s milk allergy and 84 children with egg allergy. For the milk-allergic group, 27 children were randomized to oral immunotherapy and 30 children continued avoidance diets. Post-treatment, there was significant improvement in clinical tolerance and decrease skin test reactivity in the group treated with oral immunotherapy. For those with egg allergy, 49 underwent egg oral immunotherapy and 35 children continued avoidance diets. There was an improvement in clinical tolerance; however, this did not reach statistical significance. The egg immunotherapy group did demonstrate decreased skin test size and specific IgE after treatment. Staden et al. (21) performed a randomized study of oral immunotherapy in 45 children with food allergy to egg or milk. The children were randomly assigned to one of two groups, 25 to specific oral tolerance induction (SOTI) and 20 to continue the elimination diet. At the end of 18–24 months, the children underwent DBPCFC and then a repeat challenge 2 months later (off SOTI). There was a similar rate of complete tolerance between the two groups (36% for those on SOTI, 35% for those adhering to an elimination diet). However, another seven patients in the SOTI group developed partial tolerance and could include some egg or milk as part of their regular diets. The authors suggested that this partial tolerance provides a larger margin of safety for these children from accidental ingestions. Also, these children have improved quality of life since additional food products are included in their diets. Overall, 64% of the SOTI group achieved improved tolerance after treatment. All patients in the SOTI arm did experience side effects; however, all were considered mild to moderate. Four children had systemic reactions; these were treated with oral antihistamines and corticosteroids. No severe systemic reactions occurred. The authors cautioned that SOTI requires close continuous supervision of the children by an allergist. They also identified certain factors that reduced the threshold for SOTI-induced allergic reactions, which included exercise, respiratory tract infections, and the pollen season if the patient is pollen-allergic, during the doseescalation and maintenance phases of therapy. Skripak et al. [42] performed the first double-blind, placebo-controlled oral immunotherapy study for milk allergy in children. Twenty children were randomized and 12 completed 3–4 months of active immunotherapy. After treatment, the threshold for reactions to milk was increased for all children on active OIT. Although no significant changes in specific IgE levels or skin prick test results were observed, there was

Food Allergy: Opportunities and Challenges

339

a significant increase in milk-specific IgG and IgG4 in the active group. The majority of participants experienced reactions during the post-OIT food challenge, demonstrating that complete protection from allergic reactions due to milk was not achieved. All participants continued daily intake of milk, therefore, it is unclear whether any OIT participants achieved tolerance rather than desensitization to milk. Longo et al. [43] demonstrated that OIT can be safe and effective for highly milk allergic children in their OIT trial. After 1 year, 36% of the OIT group had unrestricted diets, and more than half (54%) were able to tolerate limited amounts of milk (ranging from 5–150mL). Adverse reactions were common and occurred in all children on OIT. This study demonstrated that OIT can be effective even for those with the most severe allergies. The authors noted that although adverse events were common, in cases of persistent milk allergy and a high risk of accidental exposures and reactions, the risks of treatment may be acceptable. Recently, Jones et al. [44] reported an open-label peanut (OIT) study in which desensitization was successful in 93% of patients. Declines in skin prick tests and peanut-specific IgE levels and increases in peanut-specific IgG4 were observed. A significant decrease in basophil activation was detected, as well as increases in several cytokines, including IL-10 and IL-5, suggesting that OIT does not cause the typical downregulation of Th2 and upregulation of Th1 profiles. Furthermore, T-cell microarrays demonstrated downregulation of apoptotic genes, indicating a potential role for apoptosis in OIT. These studies show that oral immunotherapy is a promising treatment option for food allergy. However, evidence to date do not demonstrate that apparent improvements in tolerance are due to true induction of oral tolerance and not the natural history of food allergy. Further trials using placebo-controls and mechanistic studies should provide insight.

Sublingual Immunotherapy (SLIT) Sublingual immunotherapy, which has been demonstrated to be safe and effective treatment for allergic rhinitis and asthma, is another attractive option for the treatment of food allergy. The first case of successful SLIT for the treatment of food allergy was reported by Mempel et al. (22) for a patient with kiwi anaphylaxis. Enrique et al. (23) published a randomized double-blind, placebo-controlled study investigating SLIT for hazelnut allergy. Twelve patients were treated with SLIT for 5 months using the sublingual-discharge technique. Six patients had symptoms consistent with pollen-fruit syndrome (PFS) to hazelnut and five patients had a history of anaphylaxis to hazelnut (one participant withdrew consent on the first day of SLIT). The SLIT extract contained Cor a 1 (Bet v 1 homologue) and Cor a 8 (lipid transfer protein). Eleven patients received placebo. Significant increases in threshold of sensitivity to hazelnut allergen were observed following treatment with hazelnut SLIT. There was also an increase in hazelnut-specific IgG4 and IL-10 after treatment in the active group. The systemic reaction rate was low (0.2%) and only occurred during the build-up phase. Treatment with antihistamine was sufficient.

340

J. Wang and H.A. Sampson

Local reactions occurred in 7.4% and consisted mostly of oral pruritus. As for the other routes for immunotherapy, further studies are needed to assess the long-term efficacy of this technique, optimal treatment doses and duration, as well as its applicability to other allergenic foods. A recent randomized, double-blind, placebo-controlled clinical trial of SLIT for peach allergy also reported promising results of improved allergen tolerance that was associated with decreases in skin test reactivity and significant increases in IgE and IgG4 to Pru p 3. [45] A multicenter study investigated the effects of birch pollen SLIT for PFS. [46] Twenty patients with pollen-associated apple allergy received SLIT for 1 year. Although improvement in nasal provocation scores to birch pollen was seen in 9 patients, there was no significant improvement in their apple-induced oral symptoms. Furthermore, there was no change in specific IgE or IgG4 to the major apple allergen, Mal d 1 after treatment, suggesting that SLIT with birch pollen may have no clinical effect on associated apple allergy. Overall, immunotherapy still appears to be a viable option for the treatment of food allergy, especially as safer routes of administration are being explored. Certainly, additional randomized, placebo-controlled studies are necessary to determine the true efficacy of this method and to standardize extracts, protocols, and durations of treatment. In addition, studies to elucidate the mechanisms of this treatment will provide insight into whether treatment is inducing true oral tolerance.

Modified Recombinant Vaccines Since significant adverse effects occurred with conventional immunotherapy for peanut, modified recombinant food proteins are being investigated for use in allergen-specific treatment of food-induced anaphylaxis. Modified peanut allergens, in which the primary sequences of IgE-binding epitopes of the major peanut proteins (Ara h 1, 2, 3) are altered using site-directed mutagenesis to decrease IgE binding capacity, have been engineered. These recombinant proteins stimulate T cells from peanut allergic individuals to proliferate, but have greatly reduced IgE-binding capacity as compared to wild-type peanut protein (24,25). Heat-killed Escherichia coli (HKE) producing recombinant peanut proteins have been shown to have protective effects in a murine model of peanut anaphylaxis (26). Peanut-sensitized mice were treated with HKE containing modified Ara h 1–3 (HKE-MP123; low, medium, and high doses), HKE-containing vector alone, or placebo. Mice treated with HKE-MP123 demonstrated reduced symptom scores during peanut challenge as compared to the placebo-treated group. The medium and high dose HKE-MP123 treated groups were protected for up to 10 weeks post-treatment. The high-dose treated group demonstrated the most significant decrease in IgE levels and decreased production of IL-4, IL-5, IL-13, and IL-10, and increased IFN-g and TGF-b production by splenocytes. The proposed mechanisms involve Th1 cytokines and/or T regulatory cells suppressing Th2 cell activation and mast cell/basophil mediator release on re-exposure to antigen (27, 28). The HKE-mAra h 1–3 has been manufactured in

Food Allergy: Opportunities and Challenges

341

a GMP facility clinical trials have been initiated for use in man and is undergoing final toxicology studies prior to submitting an IND application to the FDA.

Peptide Immunotherapy The use of food allergen peptide immunotherapy has also shown potential. These peptide fragments contain T cell epitopes, but are not of sufficient length to crosslink IgE and, therefore, cannot trigger mast cell or basophil activation. A preliminary study using pepsin-digested peanut peptides showed the ability to induce IFN-g (Th1 cytokine) in a concentration-dependent manner (29). In a murine model of peanut allergy, Li et al. (30) were able to demonstrate that mice receiving immunotherapy with peptides containing IgE epitopes to Ara h 2, a major peanut protein, prior to allergen challenge experienced only mild allergic reactions as compared to sham-treated mice, which exhibited severe anaphylactic reactions. In addition, the treated mice had smaller drops in rectal temperatures and lower plasma histamine levels than the sham-treated mice. Although these preliminary studies demonstrate this technique to be a promising approach to the treatment of food allergy, validating the stability and uniformity of peptide mixtures for use in human poses a significant challenge.

Immunostimulatory Sequence-Conjugated Protein Immunotherapy Immunostimulatory sequences (ISS), such as CpG oligodeoxynucleotides, bound to proteins can act as adjuvants to promote switching to a Th1 response (31). ISS conjugated to allergenic proteins may be more immunogenic and less allergenic. Initial studies with ragweed allergen showed that immunotherapy with ISS in combination with Amb a 1, the major ragweed allergen, promoted Th1 responses and reduced allergenicity in mice, rabbits, and primates (32). Horner et al. (33) immunized C3H/HeJ mice with either a plasmid encoding beta-galactosidase (beta-gal) or beta-gal protein plus an immunostimulatory sequence oligodeoxynucleotide (ISS-ODN). The mice then underwent a sensitization protocol to beta-gal. Mice immunized with beta-gal plus ISS-ODN were protected from developing fatal anaphylaxis and had lower plasma histamine levels after allergen challenge compared to the group treated with beta-gal protein alone. A similar approach is being investigated in a murine model of peanut-induced anaphylaxis (34). Mice were immunized with either ISS-linked Ara h 2 (a major peanut protein) or ISS-linked Amb a 1 prior to sensitization with peanut. The mice were then challenged with Ara h 2 five weeks after initial sensitization. Mice treated with ISS-linked Ara h 2 had lower symptom scores and lower plasma histamine levels following challenge with Ara h 2 compared to the mice treated with ISS-linked Amb a 1. The investigators also noted a significantly higher Ara h 2-spe-

342

J. Wang and H.A. Sampson

cific IgG2a level in the ISS-linked Ara h 2 treated mice, but there was no significant difference in specific-IgE or IgG1 levels between the two groups. These findings suggest that immunostimulatory sequence-conjugated protein immunotherapy may be an effective method of preventing the development of food allergy.

Plasmid DNA Immunotherapy Another approach to immunomodulate allergen-induced anaphylaxis utilizes allergen gene immunization. Roy et al. (35) synthesized DNA nanoparticles containing the gene for Ara h 2, a major peanut allergen, by complexing plasmid DNA with chitosan and orally administered these nanoparticles to mice. Immunized mice demonstrated less severe and delayed anaphylactic responses following challenge compared to mice treated with “naked” DNA or those that were unimmunized. These mice also had decreased IgE levels, lower plasma histamine, and lesser vascular leakage. This approach may also be effective in preventing the development of peanut allergy, but concerns regarding the use in humans is a potential disadvantage of this technique.

Allergen Non-Specific Immunotherapy Anti-IgE Treatment with anti-IgE antibodies has been investigated in a double-blind, randomized, dose-ranging trial in 84 patients with a history of peanut allergy (36). Patients were randomized to receive either TNX-901 (150, 300, or 450 mg of anti-IgE antibodies) or placebo. Patients who received the highest dose (450 mg) of anti-IgE, monthly for 4 months, had a significant decrease in symptoms with peanut challenge as compared to the placebo group. The median threshold of sensitivity to peanut increased from less than 1 peanut (178 mg) to almost 9 peanuts (2.8 gms). Therapy was well-tolerated. However, while 25% of patients were able to tolerate over 20 peanuts following therapy, another 25% failed to develop any change in tolerance to peanut following treatment. Recently, investigation of another anti-IgE preparation, omalizumab (Xolair®, Genentech), has been at least temporarily discontinued (37).

Herbal Medicine Alternative approaches have also been shown to have beneficial effects on food allergy in murine models. The Traditional Chinese Herbal Medicine formula, FAHF-2, has protective effects on peanut-sensitized mice. Peanut-allergic mice

Food Allergy: Opportunities and Challenges

343

treated with FAHF-2 had no signs of anaphylaxis after peanut challenge, but all sham-treated mice had severe symptoms of anaphylaxis, decreased rectal temperatures, elevated plasma histamine, and marked vascular leakage (38). The clinical effects were associated with decreased peanut-specific IgE levels and Th2 cytokine production (IL-4, IL-5, IL-13). The protective effects of FAHF-2 were demonstrated to last up to 6 months post-therapy, which represents about 25% of the life-span of the mouse (39). These results were initially based on mice given the FAHF-2 during peanut sensitization, but recent studies have demonstrated that FAHF-2 can induce tolerance to peanut in mice with established peanut allergy. This protection persisted for 4 weeks post-treatment and was associated with decreased production of IL-4 and IL-5, but increased IFNgamma (40). Studies with human T cells have also been performed to investigate the effect of FAHF-2. Purified human PBMCs were obtained from peanut-allergic individuals and stimulated with crude peanut extract in the presence and absence of FAHF-2. The cells stimulated in the presence of FAHF-2 had a decrease in antigen-dependent T-cell proliferation. There was also a dose-dependent decrease in Th2 cytokine production (IL-5 and IL-13) and increase in IFN-g production, indicating that FAHF-2 specifically inhibits the Th2 response (41). Recently, the U.S. FDA approved a botanical drug IND for FAHF-2 and a Phase I trial is currently underway.

Summary and Conclusions The current accepted treatment strategy for food allergy is strict avoidance of the offending allergens and education regarding the use of epinephrine and an emergency plan in cases of accidental ingestions or exposures. While this method is generally effective, these pose a significant negative impact on the quality of life of both patients and their families. Therefore, the development of new therapies for food allergy that are safer and more effective are essential. We have described several promising approaches being investigated, which will hopefully provide long-term treatment options and potentially a cure for food allergy.

References 1. Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol, 2006; 117 (2 Suppl):S470–S475 2. Yocum MW, Butterfield JH, Klein JS, Volcheck GW, Schroeder DR, Silverstein MD. Epidemiology of anaphylaxis in Olmsted County: A population-based study. J Allergy Clin Immunol, 1999; 104 (2 Pt 1):452–456 3. Burks W, Bannon GA, Sicherer S, Sampson HA. Peanut-induced anaphylactic reactions. Int Arch Allergy Immunol, 1999; 119 (3):165–172

344

J. Wang and H.A. Sampson

4. Joint Task Force on Practice Parameters, American Academy of Alllergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 2003;90:1–40 5. Freeman J. “Rush” inoculation. Lancet, 1930; 1:744 6. Oppenheimer JJ, Nelson HS, Bock SA, Christensen F, Leung DYM. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol, 1992; 90:256–262 7. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol, 1997; 99 (6 Pt 1):744–751 8. Bullock RJ, Barnett D, Howden ME. Immunologic and clinical responses to parenteral immunotherapy in peanut anaphylaxis – a study using IgE and IgG4 immunoblot monitoring. Allergol Immunopathol (Madr), 2005; 33 (5):250–256 9. Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in birch pollenhypersensitive patients. Clin Exp Allergy, 1998; 28 (11):1368–1373 10. Bolhaar ST, Tiemessen MM, Zuidmeer L, van Leeuwen A, Hoffmann-Sommergruber K, BruijnzeelKoomen CA, et al. Efficacy of birch pollen immunotherapy on cross-reactive food allergy confirmed by skin tests and double-blind food challenges. Clin Exp Allergy, 2004; 34 (5):761–769 11. Asero R. Fennel, cucumber, and melon allergy successfully treated with pollen-specific injection immunotherapy. Ann Allergy Asthma Immunol, 2000; 84 (4):460–462 12. Bucher X, Pichler WJ, Dahinden CA, Helbling A. Effect of tree pollen-specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy, 2004; 59 (12):1272–1276 13. Skamstrup Hansen K, Sondergaard KM, Stahl SP, et al. Food allergy to apple and specific immunotherapy with birch pollen. Mol Nutr Food Res, 2004; 48:441–448 14. Moller C. Effect of pollen immunotherapy on food hypersensitivity in children with birch pollinosis. Ann Allergy, 1989; 62 (4):343–345 15. Patriarca G, Nucera E, Pollastrini E, Roncallo C, De Pasquale T, Lombardo C, Pedone C, Gasbarrini G, Buonomo A, Schiavino D. Oral specific desensitization in food-allergic children. Dig Dis Sci, 2007; 52(7):1662–1672 16. Patriarca G, Nucera E, Roncallo C, Pollastrini E, Bartolozzi F, De Pasquale T et al. Oral desensitizing treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther, 2003; 17(3):459–465 17. Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG. A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy. Allergy, 2004; 59 (9):980–987 18. Buchanan AD, Green TD, Jones SM, Scurlock AM, Christie L, Althage KA, Steele PH, Pons L, Helm RM, Lee LA, Burks AW. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol, 2007; 119 (1):199–205 19. Patriarca G, Nucera E, Pollastrini E, Roncallo C, De Pasquale T, Lombardo C, Pedone C, Gasbarrini G, Buonomo A, Schiavino D. Oral specific desensitization in food-allergic children. Dig Dis Sci, 2007; 52:1662–1672 20. Morisset M, Moneret-Vautrin DA, Guenard L, Cuny JM, Frentz P, Hatahet R, Hanss Ch, Beaudouin E, Petit N, Kanny G. Oral desensitization in children with milk and egg allergies obtains recovery in a significant proportion of cases. A randomized study in 60 children with cow’s milk allergy and 90 children with egg allergy. Allerg Immunol (Paris), 2007; 39 (1):12–19 21. Staden U, Rolnick-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy, 2007; 62(11):1261–1269 22. Mempel M, Rakoski J, Ring J, Ollert M. Severe anaphylaxis to kivi fruit: immunologic changes related to successful sublingual allergen immunotherapy. J Allergy Clin Immunol, 2003; 111 (6):1406–1409 23. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol, 2005; 116 (5):1073–1079

Food Allergy: Opportunities and Challenges

345

24. King N, Helm R, Stanley JS, et al. Allergenic characteristics of a modified peanut allergen. Mol Nutr Food Res, 2005; 49 (10):963–971 25. Bannon GA, Cockrell G, Connaughton C, et al. Engineering, characterization and in vitro efficacy of the major peanut allergens for use in immunotherapy. Int Arch Allergy Immunol, 2001; 124 (1–3):70–72 26. Li XM, Srivastava K, Grishin A, et al. Persistent protective effect of heat-killed Escherichia coli producing “engineered,” recombinant peanut proteins in a murine model of peanut allergy. J Allergy Clin Immunol, 2003; 112 (1):159–167 27. Bissonnette EY, Befus AD. Inhibition of mast cell-mediated cytotoxicity by IFN-alpha/beta and -gamma. J Immunol, 1990; 145 (10):3385–3390 28. Pierkes M, Bellinghausen I, Hultsch T, Metz G, Knop J, Saloga J. Decreased release of histamine and sulfidoleukotrienes by human peripheral blood leukocytes after wasp venom immunotherapy is partially due to induction of IL-10 and IFN-gamma production of T cells. J Allergy Clin Immunol, 1999; 103 (2 Pt 1):326–332 29. Hong SJ, Michael JG, Fehringer A, Leung DY. Pepsin-digested peanut contains T-cell epitopes but no IgE epitopes. J Allergy Clin Immunol, 1999; 104 (2 Pt 1):473–478 30. Li S, Li XM, Burks AW, Bannon GA, Sampson HA. Modulation of peanut allergy by peptidebased immunotherapy. J Allergy Clin Immunol, 2001; 107 (2):S233 31. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med, 1997; 186 (10):1623–1631 32. Tighe H, Takabayashi K, Schwartz D, et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol, 2000; 106 (1 Pt 1):124–134 33. Horner AA, Nguyen MD, Ronaghy A, Cinman N, Verbeek S, Raz E. DNA-based vaccination reduces the risk of lethal anaphylactic hypersensitivity in mice. J Allergy Clin Immunol, 2000; 106 (2):349–356 34. Srivastava K, Li XM, Bannon GA, Burks AW, Eiden J, Vannest G, Tuck R, Rodriguez R, Sampson HA. Investigation of the use of Iss-linked Ara h2 for the treatment of peanut-induced allergy. J Allergy Clin Immunol, 2001; 107 (2):S233 35. Roy K, Mao HQ, Huang SK, Leong KW. Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy [see comments]. Nat Med, 1999; 5 (4):387–391 36. Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med, 2003; 348 (11):986–993 37. Sampson HA, Leung DYM, Burks AW, Lack G, Bahna SL, Jones SM, et al. A phase II, randomized, double-blind, parallel group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immun, 2007; 119 (1): S117 38. Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol, 2005; 115 (1):171–178 39. Srivastava KD, Zhang T, Qu C, Sampson HA, Li XM. Silencing peanut allergy: A Chinese Herbal Formula, Fahf-2, completely blocks peanut-induced anaphylaxis for up to 6 months following therapy in a murine model of peanut allergy. J Allergy Clin Immunol, 2006; 117 (2):S328 40. Qu C, Srivastava K, Ko J, Zhang TF, Sampson HA, Li XM. Induction of tolerance after establishment of peanut allergy by the food allergy herbal formula-2 is associated with up-regulation of interferon-gamma. Clin Exp Allergy, 2007; 37 (6):846–855 41. Ko J, Busse PJ, Shek L, Noone SA, Sampson HA, Li XM. J Allergy Clin Immunol, 2005; 115 (2), S34 42. Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG, et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol 2008; 122(6):1154–1160 43. Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L, Ventura A. Specific oral tolerance induction in children with very severe cow’s milk-induced reactions. J Allergy Clin Immunol 2008; 121(2):343–347

346

J. Wang and H.A. Sampson

44. Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, Francis JM, Durham S, Vickery BP, Zhong X, Burks AW. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009; 124(2):292–300 45. Fernández-Rivas M, Garrido Fernández S, Nadal JA, Díaz de Durana MD, García BE, González-Mancebo E, Martín S, Barber D, Rico P, Tabar AI. Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. Allergy. 2009; 64(6):876–883 46. Kinaciyan T, Jahn-Schmid B, Radakovics A, Zwolfer B, Schreiber C, Francis JN, et al. Successful sublingual immunotherapy with birch pollen has limited effects on concomitant food allergy to apple and the immune response to the Bet v 1 homolog Mal d 1. J Allergy Clin Immunol 2007; 119(4):937–943

Early Immunological Influences on Asthma Development: Opportunities for Early Intervention Patrick G. Holt

Introduction The prevalence of atopic disease, in particular atopic asthma, has increased markedly in developed countries over the last 20 years. The rate of this increase has slowed significantly over the last few years and may be approaching a plateau, suggesting that the bulk of subjects with susceptible genotypes in current birth cohorts may already be responding maximally to the environmental factors which are responsible for driving the disease process. The resulting impact of these environmentally induced changes in asthma prevalence on health care systems in the developed countries is extremely high. An increasingly wide body of epidemiological evidence suggests that the countries of the developing world are no longer immune to this epidemic, as lifestyle changes associated with economic expansion recreate the patterns of environmental risk factors which drive disease in the developed world. The long term solution to this problem clearly does not lie in the development of more and better symptomatic treatments, but instead requires a more radical series of approaches aimed at reduction of the overall burden of disease [1]. This chapter reviews developments in the recent literature on asthma etiology, which collectively suggest a range of testable strategies for primary and secondary prevention of atopic asthma. The recent key findings are those emerging from cross-sectional and prospective cohort studies on atopic disease pathogenesis in pediatric populations.These indicate that the major gene x environment interactions responsible for disease inception occur during early childhood, when the immune functions underlying the inflammatory effector mechanisms which ultimately drive

P.G. Holt () Telethon Institute for Child Health Research, Centre for Child Health Research, the University of Western Australia, Perth, WA, Australia e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_21, © Springer 2010

347

348

P.G. Holt

disease pathogenesis are undergoing final maturation. It is clear that the kinetics of this immune maturation process varies markedly within human populations, and these variations represent important determinants of susceptibility to development of atopic diseases. This chapter briefly summarizes the evidence supporting this general concept, and discusses intervention strategies aimed at prophylaxis of atopy, which arise from these findings.

Postnatal Development of Immune Competence It is well established that infancy is a period of attenuated immune competence, resulting from a broad range of maturational deficiencies in immune regulatory and effector mechanisms [2–4]. Recent research indicates that these deficiencies are not evenly distributed throughout the immune system. In particular, it is evident that the most profound immune maturational defect in fetal, and neonatal life is within the T-helper (Th)-1 arm of the adaptive immune system, skewing overall immune function towards the Th2 phenotype [5]. This represents an evolutionary adaptation to protect the fetoplacental unit from the toxic effect of Th1 cytokines such as IFNg, which potentially may be produced locally in cellular immune responses triggered as a result of histoincompatibility between mother and fetus, and/or arising from responses to infections. Th1 responses in this milieu are recognized as a major cause of fetal loss [5, 6]. A broad range of immunoregulatory mechanisms operate at the fetomaternal interface to prevent such T-cell-mediated responses reaching significant levels. These include constitutive production within the placenta by cells such as trophoblasts of Th1 inhibitory and Th2 trophic molecules including IL-4, IL-10 [7], progesterone [8] and PGE2 [7]. These mechanisms are further bolstered by local production of regulatory molecules which inhibit T-cell activation such as tryptophan metabolites [9] and IL-10 [10], together with expression on local tissues of FasL [11] which is a potent trigger of apoptosis in preactivated T-cells. After birth, the confrontation of the newborn by a microbially hostile environment dictates the necessity for selective upregulation of Th1-associated effector mechanisms, as these are central to host antimicrobial defence and hence survival.This is necessitated because levels of protective maternal antibody progressively wane in the infant. The initial signals of postnatal upregulation of Th1 functions are provided by normal microbial exposure, particularly involving commensal organisms that colonize the gastrointestinal tract GIT during early infancy [12, 13]. Specific molecular signature molecules including lipopolysaccharide (LPS) and microbial nucleic acids are recognized via the TOLL family of receptors expressed on cells of the innate immune system [14], and these interactions trigger production of a range of Th1-inducing maturation factors including IL-12 and IL-23 by cell populations such as monocytes and (in particular) dendritic cells (DC). This series of microbial-driven interactions leading

Potential Strategies for Asthma Prevention

349

to production of immune maturation-enhancing molecules provides a plausible set of mechanisms for the Hygiene Hypothesis which has been invoked as a contributing factor in changing patterns of disease expression over recent time [15]. However it is also becoming clear that microbial exposure is also of central importance in driving maturation of T-regulatory cell (Treg) function, which is also attenuated at birth (reviewed in [16]), and moreover may be further reduced in infants at high risk of atopy [17]. The capacity to produce both Th1 and Th2 cytokines increases in normal subjects during infancy, but this maturation process typically appears to be initiated earlier and initially progresses faster for the Th2 cytokines, maintaining the fetal-like Th2-skewed pattern of immune function [18, 19]. The basis for persistence of this response phenotype during infancy appears to be multifactorial and involves the functions of several cell types. However the ratelimiting cells may be within the DC population, which at birth are dominated by DC2 cells which selectively drive Th2 differentiation, maintaining the pattern established during fetal life [20]. DC are present in only relatively low numbers in the infant circulation, in particular the plasmacytoid DC population [21]. Moreover, the antigen presentation (APC) functions of circulating DC remain markedly attenuated throughout infancy, and continue to skew T-cell activation responses towards the Th2 profile [22]. It is also important to note the results of animal model studies demonstrating that maturation of DC populations in mucosal tissues in the lung and airways progresses slowly during the preweaning period [23, 24], and the overall kinetics of this process is determined by intensity of exposure to environmental (including infectious) irritants [24]. Postmortem studies on tissues from infant airways suggest a comparable pattern of microbial-driven maturation of this important regulatory population in humans [25]. Given the central importance of airway mucosal DC in both the initiation of sensitization to aeroallergens and in reactivation of Th2-memory cells responsible for driving the asthma late phase response [26, 27], it is feasible that infection-driven maturation of this DC population may have long term consequences in relation to pathogenesis of atopic asthma. It is also evident that the functional competence of the CD4+ T-cell system matures relatively slowly in most normal infants. In particular, the capacity of infant CD4+ Th-cells to develop stable clones is low relative to adults, and their ability to secrete both Th1 and Th2 cytokines is comparably diminished, though the degree of attenuation is greatest for Th1 cytokines, notably IFNg [28]. The principal mechanism(s) underlying this developmental attenuation is/are intrinsic to the T-cells themselves and are independent of APC function [28]. In particular, hypermethylation of CpG motifs in the proximal promoter of the IFNg gene is a defining feature of neonatal naive CD4+ T-cells and limits capacity for rapid upregulation of IFNg gene expression in these cells [29]. It is notable that CPG methylation in the IFNg promoter is less marked in CD8+ T-cells and NK cells during infancy,and IFNg responses of these cell types are less attenuated than in their CD4+ T-cell counterparts [29–31].

350

P.G. Holt

Recent Thymic Emigrants (RTE) and the Conundrum of Intrauterine Sensitisation to Allergens Findings from many laboratories including the author’s (reviewed in [32]) suggesting the presence of allergen responsive T-cells in cord blood have stimulated debate on the potential for transplacental priming against dietary and inhalant allergens (e.g., see [33]). However, recent studies which have addressed in more detail the issue of the precise identification of allergen responsive cells in cord blood (e.g., [34]) seriously question earlier conclusions. In particular, it has been known for some time that the bulk of T-cells in the blood of human neonates express a range of unique markers not found in adult T-cells, in particular intracellular T-cell receptor (TcR) excision circles [35, 36]. These cells are RTE, and they slowly decline proportionately within the circulating T-cell population over infancy and early childhood as they are replaced by conventional (“mature”) naive T-cells from the thymus, and/or via slow homeostatic turnover. Recent studies from our group have demonstrated an unexpected contribution from these immunologically naive RTE to early postnatal T-cell responses in vitro. Notably, we have demonstrated that the CD4+ T-cells in cord blood which respond in vitro to environmental allergens via proliferation and cytokine production appear to be exclusively CD45RA- immunologically, immunologically naive RTE [16]. The basis for this apparent nonspecific reactivity to allergens appears to be structural alterations in the TcR of RTE which enable “promiscuous” low affinity interactions with a broad range of antigens, as opposed to the high specificity and high affinity of such reactions by genuine T-memory cells. These low affinity interactions trigger initial rapid proliferation and initial cytokine production by the RTE, which is then terminated via apoptotic death unless cytokines such as IL-4 or IL-7 are present at high concentrations to “rescue” the cells [16]. A comparable response pattern has been observed in neonatal CD8+ T-cells in mice [37]. A potentially important byproduct of these responses is activation of Treg cells which are present in the neonatal circulation, but are initially functionally inert until activated [37].

Immune Maturation and Genetic Risk for Atopic Disease Earlier studies in our laboratory established that the kinetics of postnatal maturation of CD4+ Th-cell cytokine response capacity in children at high genetic risk (HR) of atopy (i.e., positive family history) was slower than in low risk (LR) children with negative family history [28]. This was independent of APC activity, and was most marked for Th1 cytokines, resulting in exaggeration in the HR children of the developmentally normal pattern of Th2 skewing [28]. These observations have been confirmed in many independent labs [32]. This attenuation appears to be due at least in part to polymorphisms in genes encoding microbial pattern recognition receptors such as CD14 and TLR2, which are more frequent in HR children [38, 39].

Potential Strategies for Asthma Prevention

351

However, the key to the role of this attenuation in relation to atopy pathogenesis is timing. Notably, the life period during which Th2 function is differentially low in HR children coincides with the time at which initial “priming” of allergen-specific CD4+ T-cell memory responses is most commonly initiated [34, 40–42]. Attenuated crossregulation from Th1 cytokines in this period may accordingly favor development of Th2 polarized memory. It is important to note that the maturational Th1 defect in HR children is restricted to CD4+ Th-cells, and we have reported that the activity of cytokine secreting CD8+ T-cells in infants who develop early atopy is enhanced relative to those who remain free of sensitization [30].This is reflected by changing patterns of IFNg gene promoter methylation in CD8+ T-cells [31]. The exaggerated attenuation of Th1 function in HR infants may have consequences not directly related to atopic sensitisation. For example, a number of studies have shown that vaccine responses in HR children are less than in the population at large. In particular, antibody responses to pneumococcal vaccine are reduced [43] and T-cell memory to BCG vaccination in these children is short-lived relative to nonatopics [44]. T-cell responses to antigens in the DTaP vaccine during infancy are relatively Th2polarized [18]. Moreover, in addition, reduced capacity to secrete Th1 cytokines in these children is associated with increased risk of respiratory viral infections during infancy, in particular RSV [18, 45]. Recent studies from our group and others have emphasized the importance of the temporal “window” in relation to these mechanisms. It is noteworthy that in many HR children who initially express attenuated Th1 function, the underlying maturation process rapidly accelerates beyond 12 months of age to the extent that a major subset of these children eventually become hyperproducers of both Th1 and Th2 cytokines [18]. By 6 years of age this is evident in the responses of atopic children to both vaccine antigens and allergens [2], and this pattern is even more marked by 12 years of age [46]. This finding may have implications for asthma pathogenesis in the light of evidence suggesting a positive link between bronchial hyperresponsiveness and excessive Th1 cytokine production in atopic children [47].

Pathways Leading to Development of Wheeze in Childhood: Towards a Rational Basis for Development of Effective Prevention Strategies Findings from prospective studies on children exemplified by two large birth cohorts in Perth [48, 49] and the Tucson cohort [50] provide the basis for the schema shown in Fig. 1 The control focus of this schema is the conundrum of why progression to development of significant persistent wheezing disease amongst children who become sensitized to inhalants is restricted to a subset of only around 25–30% of this population [51]. The distinguishing feature of these children appears to be early development of sensitization [52, 53] accompanied by the development of wheezing lower respiratory infections (wLRI) during infancy [49, 50]. These two causes of airway inflammation appear to interact synergistically to drive asthma development, as the highest risk of development of persistent asthma is seen in

+

5

rapid clearance

LRT

Th2 memory

3

repeated infection

exposure

4

intercurrent moderate-severe airway inflammation

persistent low-moderate airway inflammation

9.0-13.0

PERSISTENT ASTHMA

Odds Ratios for asthma at age 6 years

2.0-4.0

intermittent wheeze

pertubation of lung growth/differentiation

~2.0 intermittent wheeze

4

Fig. 1 Risk for asthma development during early childhood Prospective birth cohort studies indicate that early sensitization to inhalants and severe lower respiratory tract (LRT) infections can independently increase risk for asthma development, and these two factors can interact synergistically to maximize ensuing disease risk. Odds Ratios derived from [34, 49]

Potential asthma prevention strategies 1. Stimulation of postnatal maturation of immune functions (e.g. prebiotics, probiotics, immunostimulatoty vaccines) 2. Immunoprophylaxis (prevention of initial atopic sensitisation by stimulating tolerance induction) 3. Early immunotherapy (SIT or SLIT to prevent consolidation of allergen specific Th2 memory) 4. Protection of growing airways against viral- or allergy-induced inflammation (anti-inflammatory drugs) 5. Protection against severe LRT infections (specific anti-virals; non-specific stimulation of mucosal immune functions)

URT viral infection

+

exposure

consolidation and spread

Th2 priming

tolerance

maturational defect(s) in immune function

1

allergen

2

infancy

Legend : Prospective birth cohort studies indicate that early sensitisation to inhalants and severe lower respiratory tract (LRT) infections can independently increase risk for asthma development, and these two factors can interact synergistically to maximise ensuing disease risk. Odds Ratios derived from Refs 34,49

352 P.G. Holt

Potential Strategies for Asthma Prevention

353

children who experience both atopic sensitization and multiple severe infections during infancy [49, 54]. Our most recent findings [34, 48] have narrowed this “window” period of maximum risk to sensitisation to below 2 years of age. It is hypothesized that the occurrence of these inflammatory events during infancy in the period of rapid postnatal lung growth perturbs underlying cellular differentiation programs, thus disturbing the development of key structure: function relationships in lung and airway tissues which are central to development of normal respiratory function. The resulting abnormal functional phenotype “tracks” into later life and may eventually manifest as persistent asthma [54].

Strategies for Primary and Secondary Prevention of Persistent Atopic Asthma: Current and Future Options The central feature of the model in Fig. 1 is the requirement of synergism between the atopy and infection pathways in order to generate maximal risk of persistent asthma development. Accordingly, attenuation of either pathway has the theoretical potential to prevent progression to persistent disease. In principle, a broad range of approaches directed toward this aim are testable with the information and resources currently available, and these are discussed below.

Rational for Early Intervention Strategies for Asthma Prevention Previous indications [52, 53] that the severity of the asthma-associated sequelae of atopy is inversely related to age of initial sensitization have been further supported by more recent findings by our group. Notably, we have recently shown that synergism between early viral infections and atopic sensitization in relation to subsequent asthma risk is only seen if sensitization occurs below 2 years of age [55]. Furthermore, the earlier children are sensitized, the more intense are their allergen-specific Th2 cytokine responses later in childhood [56]. Additionally, recent prospective birth cohort studies tracking into the teen years have clearly demonstrated that persistent wheeze at 6 years of age tracks stably into the late teen years [57]. These observations argue strongly that the key period for protection of HR children against the asthmapromoting effects of airway inflammation is during early childhood. In this context, one of the key potential targets for early intervention is the process of primary allergic sensitisation. Relevant to this strategy, there is a continuing debate concerning precisely when relevant T-cell priming against allergens actually commences. In particular, earlier studies including our own (reviewed in [33]) have demonstrated putative allergen-responsive T-cells in cord blood, suggesting that T-cell priming may occur transplacentally. However we have since demonstrated

354

P.G. Holt

[16] that T-cells apparently responding to allergens in cord blood were not Th-memory cells but instead immature thymic emigrants which interact nonspecifically with protein antigens. More recently, we have shown in a prospective cohort study tracking allergen-specific T-cell memory in children, that stable Th-memory to mite allergen does not develop until beyond 6 months of age [34]. This argues that allergen-specific interventions should only be initiated postnatally. However, this may not necessarily apply to interventions targeted at innate immunity, given the recent report suggesting that maternal exposure to microbial stimuli during pregnancy may contribute towards lowering risk of atopy in their offspring via effects on postnatal development of TLR functions [58].

Targeting Postnatal Maturation of Immune Competence The range of immune functions shown to be attenuated in children in the period of infancy during which allergen specific T-cell sensitization most commonly occurs, has expanded progressively over the last decade. Of particular interest are findings showing that one of the key factors limiting early T-cell competence is innate immune function [4]. A recent example is the report from our group demonstrating that the principal factor limiting the expression of Th-memory responses to vaccine antigens in vitro was attenuated antigen presentation activity by DC [22]. Numerous studies have reported that these developmental deficiencies are more pronounced in HR infants, and these include observations related to monocytes, DC, Th-cells, and most recently T-reg cell populations [17]. With regard to testable treatments aimed at promoting maturation of immune functions during infancy (intervention point #1 in Fig. 1), there is continuing interest in modulation of gastrointestinal tract (GIT) colonization with the commensals that normally drive this postnatal process. Earlier claims of positive findings with probiotics in infants [59] have stimulated numerous follow-up trials which have met with mixed success, but at the time of writing this chapter the most recently published studies do not show consistent protection against AD or atopy [60–62]. There is also increasing interest in the potential of “prebiotic” oligosaccharides, the feeding of which is suggested to promote colonization of commensals with probiotic activity such as bifidobacteria [63], and one study has reported reduced AD in infants treated with prebiotic for 6 months [64]. It is also pertinent to note recent claims from a trial involving prebiotic administration to women during pregnancy followed by subsequent combined prebiotic/probiotic treatment of their infants, which reportedly showed protection against eczema at 2 yrs of age [65]. An alternative approach also being studied in some centres involves attempts to boost immune competence in older HR children with more potent microbial stimuli derived from killed microorganisms, including the use of mycobacterial vaccines. Recent attempts to replicate findings of clinical efficacy from the use of M. Vaccae vaccine have yielded at best only very modest positive effects [66] or equivalence to placebo [67]. It is possible that such stimuli may be of more benefit in younger

Potential Strategies for Asthma Prevention

355

age groups, but this remains to be tested. There are also increasingly widespread attempts to utilize orally delivered microbial extracts in this context, particularly in relation to protection against early infections.This approach is discussed in greater detail below in relation to protection against infections.

Protection against the Induction and Persistence of Allergic Sensitization Immunotherapy targeted at increasingly younger age groups, aimed either at desensitization per se or at prevention of progression from mild to severe atopic disease, is being widely practised. Much of the impetus for expansion of activity in this area is being provided via recent promising findings in children as young as 3 years with sublingual immunotherapy (SLIT; [68]) which obviates compliance-related problems associated with use of subcutaneous immunotherapy (SIT). A more radical approach is currently being tested by our group, under the auspices of the NIH Immune Tolerance Network (ITN; www.immunetolerance.org) in conjunction with collaborators in Melbourne and New York, with extensions planned to European sites. This approach derives from the concept developed here [69] that aeroallergen sensitization during infancy was the result of a failure of immunological mechanisms operative in the oropharyngeal and upper respiratory mucosae which normally promote development of protective tolerance to inhaled allergens. A comparable process operates in the GIT and protects against sensitization to dietary allergens. The concept being tested is that enhancing the intensity of allergen exposure of the oropharyngeal mucosa in nonsensitized HR infants employing allergens given repeatedly as sublingual drops will enhance this tolerance process, thus reducing both sensitization and subsequent asthma (intervention #2 in Fig. 1). The overall active treatment period is 1 year, with a 3 year follow-up. The results of this trial on prevention of sensitization of immunologically naive infants will not be known for at least 4 years. However, in the interim, results are becoming available from a variety of alternative trial approaches focusing on later stages of the atopic march i.e., attempts to attenuate or reverse the allergic phenotype in children who are already sensitized (intervention #3 in Fig. 1). The principal rationale for this approach is provided via the clear connection (reviewed [70]) between early allergic rhinitis and subsequent development of bronchial asthma in children. Direct support for this concept comes from the 5 year follow-up of a recent large trial in 6–12 year old children demonstrating significant SIT-mediated protection of pollen allergic rhinitic children from progression to asthma [71]. It has been claimed earlier that SIT can also protect children against sensitization to “bystander” allergens which were not part of the SIT treatment [72] .This claim has also gained further recent independent support [73]. As noted above, a major focus of current interest in this area is the use of SLIT, and a range of reviews are available which summarize recent (largely positive) findings ([68, 74, 75]; see also individual studies [76–78]).

356

P.G. Holt

Early Treatment with Anti-Inflammatory Drugs to Blunt the Asthma-Promoting Effects of Airway Inflammation in Children As noted in Fig. 1, the highest level of risk for development of persistent asthma stems from interactions between viral and inhalant allergy-induced inflammation on early postnatal lung growth and differentiation. It seems likely that this would be a cumulative process, and hence any measures which successfully reduce the overall burden of inflammatory damage during this period should potentially be of benefit to the prevention of asthma development (intervention #4 in Fig. 1). However the selection of effective drugs for use in the relevant young age groups involved, represents a major unresolved issue. In this regard it is highly pertinent to note the conclusions from a recent large trial on 2 year treatment of HR children aged 2–3 years with inhaled corticosteroid (ICS), which did not change later development of asthma symptoms after cessation of treatment [79]. Earlier studies on the long term use of ICS in childhood had reached similar conclusions [80, 81]. The precise reasons for the failure of steroids in this context remain to be explained, particularly in view of their known potency as anti-inflammatory agents. One possible explanation involves potential ICS-mediated side effects on DC functions. Notably, we have demonstrated previously that postnatal development of the airway mucosal DC networks which control immunological homeostasis in the lung and airways is inhibited by ICS [24, 82]. These cells regulate host responses to pathogens including viruses, and also the balance between tolerance and immunity to inhaled nonpathogenic antigens including aeroallergens. It is accordingly feasible that the negative effects of ICS in this regard may outweigh the benefits accruing from their anti-inflammatory activity. The leukotriene receptor antagonist Montelukast has also been used in young children, but while providing short term symptomatic relief in viral bronchiolitis [83, 84], it did not prevent development of persistent disease. We have previously argued that drugs selectively targeting individual components of the Th2-associated inflammatory cascade also merit trial in these younger age groups [1], but the paucity of safety data in the relevant age groups again remains an issue.

Protection Against Early Respiratory Viral Infections: The Ultimate Challenge As noted in the schema in Fig. 1, airways inflammation arising from early lower respiratory tract viral infections is a major contributor to risk for early development of persistent asthma, and the key viruses in this context appear to be RSV and Rhinovirus [48]. The relative contributions of each virus at the population level cannot currently be precisely quantified, but both are clearly significant in disease

Potential Strategies for Asthma Prevention

357

pathogenesis [55]. Protection of HR infants against these infections during infancy thus represents a prime target for asthma prophylaxis (intervention #5 in Fig. 1), Based on animal studies, in the case of RSV it is claimed that specific properties of the virus-associated F protein endows it with unique capabilities to stimulate bystander Th2 immunity and hence to interact directly with atopic processes [85]. Recent human-based evidence, including the demonstration of increased hospitalization risk for bronchiolitis in infants with AD following RSV infection [86] and increased Th2 reactivity in infants in the wake of RSV infection [87], is consistent with this postulate. No vaccines are currently available for either virus, but a humanized monoclonal antibody against RSV is available which has been shown to be effective in prevention of RSV bronchiolitis in HR infants [88–90]. A higher affinity version of the antibody (known as Numax®; [91]) has recently undergone successful multicentre trials and merits evaluation in the context of the viral pathway in Fig. 1. There is clearly a need for development of other types of antiviral drugs for use in this context in these young age groups, but at present the available options are somewhat limited. However one class of preparations is being employed with some success in related contexts, and may merit investigation for protection against early asthma development. Notably, several competing bacterial-derived immunostimulants are in current use in a range of clinical settings including pediatrics. The two best known are OM-85 [92] and Ribomunyl [93], both of which are given orally. Their precise mechanism(s) of action remain to be defined, but it appears feasible that they may function via stimulation of recirculating effector cells (such as Th-cells and B-memory cells) which are part of the common mucosal immune system. OM-85 has undergone successful trials for reduction of risk for infection-induced exacerbations in adult COPD patients [94], and has been used extensively for prevention of acute respiratory infections in young children [95, 96]. Ribomunyl has been reportedly used in children with comparable success [84], particularly in the prevention of recurrent respiratory infections, including during infancy [97].

Conclusions The current paradigm for asthma treatment, notably aggressive treatment of clinically relevant established disease with selective and nonselective anti-inflammatory drugs, does not represent the ideal long term solution to the increasingly expensive public health problems posed by the asthma epidemic. Instead, early identification of children at HR of asthma development, and intervention in advance of the establishment of persistent disease, has potential to markedly reduce the overall burden of disease in the community. A range of potential early intervention options are undergoing testing internationally, and it appears likely that the overall approach will eventually enter the ranks of “standard” treatments for HR children.

358

P.G. Holt

References 1. P.G. Holt, P.D. Sly, F.D. Martinez, S.T. Weiss, B. Björkstén, E. von Mutius, and U. Wahn (2004) Drug development strategies for asthma: in search of a new paradigm. Nat Immunol 5:695–698 2. B. Adkins (1999) T-cell function in newborn mice and humans. Immunol Today 20:330–335 3. P.G. Holt (1995) Postnatal maturation of immune competence during infancy and early childhood. Pediatr Allergy Immunol 6:59–70 4. Levy, O. (2007) Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7:379–390 5. T.G. Wegmann, H. Lin, L. Guilbert, and T.R. Mosmann (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 14:353–356 6. L. Krishnan, L.J. Guilbert, T.G. Wegmann, M. Belosevic, and T.R. Mosmann (1996) T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resportions. J Immunol 156:653–662 7. I. Roth, D.B. Corry, R.M. Locksley, J.S. Abrams, M.J. Litton, and S.J. Fisher (1996) Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10. J Exp Med 184:539–548 8. C.M. Hilkens, P. Kalinski, M. de Boer, and M.L. Kapsenberg (1997) Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype. Blood 90:1920–1926 9. D.H. Munn, M. Zhou, J.T. Attwood, I. Bondarev, S.J. Conway, B. Marshall, C. Brown, and A.L. Mellor (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193 10. J. Szekeres-Bartho, Z. Faust, P. Varga, L. Szereday, and K. Kelemen (1996) The immunological pregnancy protective effect of progesterone is manifested via controlling cytokine production. Am J Reprod Immunol 35:348–351 11. S. Guller and L. LaChapelle (1999) The role of placental Fas ligand in maintaining immune privilege at maternal-fetal interface. Seminars in Reproductive Endocrinology 17:39–44 12. M. Böttcher, A. Sandin, E. Norin, T. Midtvedt, and B. Björkstén (2000) Microflora associated characteristics in faeces from allergic and non-allergic children. Clin Exp Allergy 30:590–596 13. P.G. Holt (1995) Environmental factors and primary T-cell sensitisation to inhalant allergens in infancy: reappraisal of the role of infections and air pollution. Pediatr Allergy Immunol 6:1–10 14. R.J. Ulevitch (1999) Endotoxin opens the Tollgates to innate immunity. Nat Med 5:144–145 15. D.P. Strachan (2000) Family size, infection and atopy: the first decade of the hygiene hypothesis. Thorax 55(Suppl.1):S2–S10 16. C.A. Thornton, J.W. Upham, M.E. Wikström, B.J. Holt, G.P. White, M.J. Sharp, P.D. Sly, and P.G. Holt (2004) Functional maturation of CD4+ CD25+ CTLA4+ CD45RA+ T regulatory cells in human neonatal T cell responses to environmental allergens. J Immunol 173:3084–3092 17. U. Haddeland, A.B. Karstensen, L. Farkas, K.O. Bo, J. Pirhonen, M. Karlsson, W. Kvavik, P. Brandtzaeg, and B. Nakstad (2005) Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatr Allergy Immunol 16:104–112 18. J. Rowe, C. Macaubas, T. Monger, B.J. Holt, J. Harvey, J.T. Poolman, R. Loh, P.D. Sly, and P.G. Holt (2001) Heterogeneity in diphtheria-tetanus-acellular pertussis vaccine-specific cellular immunity during infancy: relationship to variations in the kinetics of postnatal maturation of systemic Th1 function. J Infect Dis 184:80–88 19. J. Rowe, C. Macaubas, T. Monger, B.J. Holt, J. Harvey, J.T. Poolman, P.D. Sly, and P.G. Holt (2000) Antigen-specific responses to Diphtheria-Tetanus-Acellular Pertussis vaccine in human infants are initially Th2 polarized. Infect Immun 68:3873–3877

Potential Strategies for Asthma Prevention

359

20. S. Miyazaki, H. Tsuda, M. Sakai, S. Hori, Y. Sasaki, T. Futatani, T. Miyawaki, and S. Saito (2003) Predominance of Th2-promoting dendritic cells in early human pregnancy decidua. J Leuko Biol 74:514–522 21. N. Teig, D. Moses, S. Gieseler, and U. Schauer (2002) Age-related changes in human blood dendritic cell subpopulations. Scand J Immunol 55:453–457 22. J.W. Upham, A. Rate, J. Rowe, M. Kusel, P. Sly, and P. Holt (2006) Dendritic Cell immaturity during infancy restricts the capacity to express vaccine-specific T-cell memory. Infect Immun 74:1106–1112 23. D.J. Nelson, and P.G. Holt (1995) Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local Dendritic Cells to activation signals. J Immunol 155:3517–3524 24. D.J. Nelson, C. McMenamin, A.S. McWilliam, M. Brenan, and P.G. Holt (1994) Development of the airway intraepithelial Dendritic Cell network in the rat from class II MHC (Ia) negative precursors: differential regulation of Ia expression at different levels of the respiratory tract. J Exp Med 179:203–212 25. T. Tschernig, A.S. Debertin, F. Paulsen, W.J. Kleemann, and R. Pabst (2001) Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life. Thorax 56:427–431 26. P.G. Holt, P.A. Stumbles, J.A. Thomas, C.L. Pimm, and S.F. Proksch (2000) Regulation of T-cell responses to inhaled allergen: the central role of the airway mucosal dendritic cell carpet. ACI International Suppl. 1:62–63 27. J.C. Huh, D.H. Strickland, F.L. Jahnsen, D.J. Turner, J.A. Thomas, S. Napoli, I. Tobagus, P.A. Stumbles, P.D. Sly, and P.G. Holt (2003) Bidirectional interactions between antigen-bearing Respiratory Tract Dendritic Cells (DCs) and T-cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J Exp Med 198:19–30 28. P.G. Holt, J.B. Clough, B.J. Holt, M.J. Baron-Hay, A.H. Rose, B.W.S. Robinson, and W.R. Thomas (1992) Genetic ‘risk’ for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy 22:1093–1099 29. G.P. White, P.M. Watt, B.J. Holt, and P.G. Holt (2002) Differential patterns of methylation of the IFNg promoter at CpG and non-CpG sites underlie differences in IFNg gene expression between human neonatal and adult CD45RO- T-cells. J Immunol 168:2820–2827 30. J. Rowe, T. Heaton, M. Kusel, D. Suriyaarachchi, M. Serralha, B.J. Holt, N. de Klerk, P.D. Sly, and P.G. Holt (2004) High IFN-g production by CD8+ T cells and early sensitization among infants at high risk of atopy. J Allergy Clin Immunol 113:710–716 31. G.P. White, E.M. Hollams, S. Yerkovich, A. Bosco, B.J. Holt, M.R. Bassami, M. Kusel, P.D. Sly, and P.G. Holt (2006) CpG methylation patterns in the IFNg promoter in naive T-cells: variations during Th1 and Th2 differentiation and between atopics and nonatopics. Pediatr Allergy Immunol 17:557–564 32. P.G. Holt (1996) Primary allergic sensitisation to environmental antigens: perinatal T-cell priming as a determinant of responder phenotype in adulthood. J Exp Med 183:1297–1301 33. S.L. Prescott, C. Macaubas, B.J. Holt, T. Smallacombe, R. Loh, P.D. Sly, and P.G. Holt (1998) Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T-cell responses towards the Th-2 cytokine profile. J Immunol 160:4730–4737 34. J. Rowe, M. Kusel, B.J. Holt, D. Suriyaarachchi, M. Serralha, E. Hollams, S.T. Yerkovich, L.S. Subrata, C. Ladyman, A. Sadowska, J. Gillett, E. Fisher, R. Loh, L. Soderstrom, S. Ahlstedt, P.D. Sly, and P.G. Holt (2007) Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohort. J Allergy Clin Immunol 119:1164–1173 35. J. Hassan and D.J. Reen (2001) Human recent thymic emigrants-identification, expansion and survival characteristics. J Immunol 167:1970–1976 36. D.J. Reen (1998) Activation and functional capacity of human neonatal CD4 T cells. Vaccine 16:1401–1408

360

P.G. Holt

37. M.A. Gavin and M.J. Bevan (1995) Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity 3:793–800 38. M. Baldini, I.C. Lohman, M. Halonen, R.P. Erickson, P.G. Holt, and F.D. Martinez (1999) A polymorphism in the 5’ - flanking region of the CD14 gene is associated with circulating soluble CD14 levels with total serum IgE. Am J Resp Cell Mol Biol 20:976–983 39. R.P. Lauener, T. Birchler, J. Adamski, C. Braun-Fahrlander, A. Bufe, U. Herz, E. von Mutius, D. Nowak, J. Riedler, M. Waser, and F.H. Sennhauser (2002) Expression of CD14 and Tolllike receptor 2 in farmers’ and non-farmers’ children. Lancet 360:465–466 40. C. Macaubas, P.D. Sly, P. Burton, K. Tiller, A. Yabuhara, B.J. Holt, T.B. Smallacombe, G. Kendall, M.C. Jenmalm, and P.G. Holt (1999) Regulation of T-helper cell responses to inhalant allergen during early childhood. Clin Exp Allergy 29:1223–1231 41. S.L. Prescott, C. Macaubas, T. Smallacombe, B.J. Holt, P.D. Sly, and P.G. Holt (1999) Development of allergen-specific T-cell memory in atopic and normal children. Lancet 353:196–200 42. A. Yabuhara, C. Macaubas, S.L. Prescott, T. Venaille, B.J. Holt, W. Habre, P.D. Sly, and P.G. Holt (1997) Th-2-polarised immunological memory to inhalant allergens in atopics is established during infancy and early childhood. Clin Exp Allergy 27:1261–1269 43. P.D. Arkwright, L. Patel, A. Moran, M.R. Haeney, C.I. Ewing, and T.J. David (2000) Atopic eczema is associated with delayed maturation of the antibody response to Pneumococcal vaccine. Clin Exp Immunol 122:16–19 44. T. Shirakawa, T. Enomoto, S. Shimazu, and J.M. Hopkin (1997) Inverse association between tuberculin responses and atopic disorder. Science 275:77–79 45. C.C. Copenhaver, J.E. Gern, Z. Li, P.A. Shult, L.A. Rosenthal, L.D. Mikus, C.J. Kirk, K.A. Roberg, E.L. Anderson, C.J. Tisler, D.F. DaSilva, H.J. Hiemke, K. Gentile, R.E. Gangnon, and R.F. Lemanske (2004) Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life. Am J Respir Crit Care Med 170:175–180 46. J.M. Smart and A.S. Kemp (2002) Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease. Clin Exp Allergy 32:796–802 47. T. Heaton, J. Rowe, S. Turner, R.C. Aalberse, N. de Klerk, D. Suriyaarachchi, M. Serralha, B.J. Holt, E. Hollams, S. Yerkovich, K. Holt, P.D. Sly, J. Goldblatt, P.N. Le Souef, and P.G. Holt (2005) An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 365:142–149 48. M.M.H. Kusel, N.H. de Klerk, P.G. Holt, T. Kebadze, S.L. Johnston, and P.D. Sly (2006) Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study. Pediatr Infect Dis J 25:680–686 49. W.H. Oddy, N.H. de Klerk, P.D. Sly, and P.G. Holt (2002) The effects of respiratory infections, atopy, and breastfeeding on childhood asthma. Eur Respir J 19:899–905 50. F.D. Martinez, A.L. Wright, L.M. Taussig, C.J. Holberg, M. Halonen, W.J. Morgan, and T.G.H.M. Associates (1995) Asthma and wheezing in the first six years of life. N Engl J Med 332:133–138 51. A.J. Woolcock, J.K. Peat, and L.M. Trevillion (1995) Is the increase in asthma prevalence linked to increase in allergen load? Allergy 50:935–940 52. J.K. Peat, C.M. Salome, and A.J. Woolcock (1990) Longitudinal changes in atopy during a 4-year period: Relation to bronchial hyperresponsiveness and respiratory symptoms in a population sample of Australian schoolchildren. J Allergy Clin Immunol 85:65–74 53. D. Sherrill, R. Stein, M. Kurzius-Spencer, and F. Martinez (1999) Early senstization to allergens and development of respiratory symptoms. Clin Exp Allergy 29:905–911 54. P.G. Holt and P.D. Sly (2002) Interactions between respiratory tract infections and atopy in the aetiology of asthma. Eur Respir J 19:538–545 55. M.M.H. Kusel, N.H. de Klerk, T. Kebadze, V. Vohma, P.G. Holt, S.L. Johnston, and P.D. Sly (2007) Early-life respiratory viral infections, atopic sensitization and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 119:1105–1110 56. S.W. Turner, T. Heaton, J. Rowe, D. Suryiaarachchi, M. Serralha, B.J. Holt, P.J. Franklin, S.M. Stick, J. Goldblatt, P.D. Sly, P.N. le Souëf, and P.G. Holt (2007) Early-onset atopy is associated

Potential Strategies for Asthma Prevention

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68. 69. 70. 71.

72.

361

with enhanced lymphocyte cytokine responses in 11-year-old children. Clin Exp Allergy 37:371–380 W.J. Morgan, D.A. Stern, D.L. Sherrill, S. Guerra, C.J. Holberg, T.W. Guilbert, L.M. Taussig, A.L. Wright, and F.D. Martinez (2005) Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 172:1253–1258 M.J. Ege, C. Bieli, R. Frei, R.T. van Strien, J. Riedler, E. Ublagger, D. Schram-Bijkerk, B. Brunekreef, M. van Hage, A. Scheynius, G. Pershagen, M.R. Benz, R. Lauener, E. von Mutius, and C. Braun-Fahrlander (2006) Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allergy Clin Immunol 117:817–823 M. Kalliomäki, S. Salminen, H. Arvilommi, P. Kero, P. Koskinen, and E. Isolauri (2001) Probiotics in primary prevention of atopic disease: a randomised placebo controlled trial. Lancet 357:1076–1079 M.L. Brouwer, S.A. Wolt-Plompen, A.E. Dubois, S. van der Heide, D.F. Jansen, M.A. Hoijer, H.F. Kauffman, and E.J. Duiverman (2006) No effects of probiotics on atopic dermatitis in infancy: a randomized placebo-controlled trial. Clin Exp Allergy 36:899–906 R. Folster-Holst, F. Muller, N. Schnopp, D. Abeck, I. Kreiselmaier, T. Lenz, U. von Ruden, J. Schrezenmeir, E. Christophers, and M. Weichenthal (2006) Prospective, randomized controlled trial on Lactobacillus rhamnosus in infants with moderate to severe atopic dermatitis. Br J Dermatol 155:1256–1261 A.L. Taylor, J.A. Dunstan, and S.L. Prescott (2007) Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 119:184–191 A. Kapiki, C. Costalos, C. Oikonomidou, A. Triantafyllidou, E. Loukatou, and V. Pertrohilou (2007) The effect of a fructo-oligosaccharide supplemented formula on gut flora of preterm infants. Early Hum Dev 83:335–339 G. Moro, S. Arslanoglu, B. Stahl, J. Jelinek, U. Wahn, and G. Boehm (2006) A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 91:814–819 K. Kukkonen, E. Savilahti, T. Haahtela, K. Juntunen-Backman, R. Korpela, T. Poussa, T. Tuure, and M. Kuitunen (2007) Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 119:192–198 M.G. Davies, C. Symons, S. Shaw, and E.R. Kaminski (2006) An open study to assess the efficacy clinically and immunologically of M. vaccae vaccine in patients with atopic dermatitis. J Dermatol Treat 17:74–77 J. Berth-Jones, P.D. Arkwright, D. Marasovic, N. Savani, C.R. Aldridge, S.N. Leech, C. Morgan, S.M. Clark, S. Ogilvie, S. Chopra, J.I. Harper, C.H. Smith, G.A. Rook, and P.S. Friedmann (2006) Killed Mycobacterium vaccae suspension in children with moderate-tosevere atopic dermatitis: a randomized, double-blind, placebo-controlled trial. Clin Exp Allergy 36:1115–1121 G. Passalacqua and S.R. Durham (2007) Allergic rhinitis and its impact on asthma update: allergen immunotherapy. J Allergy Clin Immunol 119:881–891 P.G. Holt (1994) A potential vaccine strategy for asthma and allied atopic diseases in early childhood. Lancet 344:456–458 J. Corren (2007) The connection between allergic rhinitis and bronchial asthma. Curr Opin Pulm Med 13:13–18 B. Niggemann, L. Jacobsen, S. Dreborg, H.A. Ferdousi, S. Halken, A. Host, A. Koivikko, D. Koller, L.A. Norberg, R. Urbanek, E. Valovirta, U. Wahn, and C. Moller (2006) Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 61:855–859 A. Des Roches, L. Paradis, J.-L. Menardo, S. Bouges, J.-P. Daurés, and J. Bousquet (1997) Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific

362

73.

74.

75.

76.

77.

78.

79.

80. 81.

82.

83. 84.

85. 86.

87.

88. 89.

P.G. Holt immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 99:450–453 A. Inal, D.U. Altintas, M. Yilmaz, G.B. Karakoc, S.G. Kendirli, and Y. Sertdemir (2007) Prevention of new sensitizations by specific immunotherapy in children with rhinitis and/or asthma monosensitized to house dust mite. J Investig Allergol Clin Immunol 17:85–91 C.E. Baena-Cagnani, G. Passalacqua, M. Gomez, M.E. Zernotti, and G.W. Canonica (2007) New perspectives in the treatment of allergic rhinitis and asthma in children. Curr Opin Allergy Clin Immunol 7:201–206 M. Penagos, E. Compalati, F. Tarantini, R. Baena-Cagnani, J. Huerta, G. Passalacqua, and G.W. Canonica (2006) Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebocontrolled, double-blind trials. Ann Allergy Asthma Immunol 97:141–148 K.H. Lue, Y.H. Lin, H.L. Sun, K.H. Lu, J.C. Hsieh, and M.C. Chou (2006) Clinical and immunologic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, randomized, placebo-controlled study. Pediatr Allergy Immunol 17:408–415 C.K. Niu, W.Y. Chen, J.L. Huang, K.H. Lue, and J.Y. Wang (2006) Efficacy of sublingual immunotherapy with high-dose mite extracts in asthma: a multi-center, double-blind, randomized, and placebo-controlled study in Taiwan. Respir Med 100:1374–1383 E. Valovirta, L. Jacobsen, C. Ljorring, A. Koivikko, and J. Savolainen (2006) Clinical efficacy and safety of sublingual immunotherapy with tree pollen extract in children. Allergy 61:1177–1183 T.W. Guilbert, W.J. Morgan, R.S. Zeiger, D.T. Mauger, S.J. Boehmer, S.J. Szefler, L.B. Bacharier, R.F. Lemanske, Jr., R.C. Strunk, D.B. Allen, G.R. Bloomberg, G. Heldt, M. Krawiec, G. Larsen, A.H. Liu, V.M. Chinchilli, C.A. Sorkness, L.M. Taussig, and F.D. Martinez (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354:1985–1997 H. Bisgaard, M.N. Hermansen, L. Loland, L.B. Halkjaer, and F. Buchvald (2006) Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 354:1998–2005 C.S. Murray, A. Woodcock, S.J. Langley, J. Morris, and A. Custovic (2006) Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet 368:754–762 D.J. Nelson, A.S. McWilliam, S. Haining, and P.G. Holt (1995) Modulation of airway intraepithelial Dendritic Cells following exposure to steroids. Am J Respir Crit Care Med 151:475–481 H. Bisgaard (2003) A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 167:379–383 C.F. Robertson, D. Price, R. Henry, C. Mellis, N. Glasgow, D. Fitzgerald, A.J. Lee, J. Turner, and M. Sant (2007) Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 175:323–329 P.J. Openshaw and J.S. Tregoning (2005) Immune responses and disease enhancement during respiratory syncytial virus infection. Clin Microbiol Rev 18:541–555 L.G. Stensballe, K. Kristensen, E.A. Simoes, H. Jensen, J. Nielsen, C.S. Benn, and P. Aaby (2006) Atopic disposition, wheezing, and subsequent respiratory syncytial virus hospitalization in Danish children younger than 18 months: a nested case-control study. Pediatrics 118:e1360–e1368 S. Kristjansson, S.P. Bjarnarson, G. Wennergren, A.H. Palsdottir, T. Arnadottir, A. Haraldsson, and I. Jonsdottir (2005) Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response. J Allergy Clin Immunol 116:805–811 D. Bonnet, A.A. Schmaltz, and T.F. Feltes (2005) Infection by the respiratory syncytial virus in infants and young children at high risk. Cardiol Young 15:256–265 J.R. Groothuis, E.A. Simoes, M.J. Levin, C.B. Hall, C.E. Long, W.J. Rodriguez, J. Arrobio, H.C. Meissner, D.R. Fulton, R.C. Welliver, D.A. Tristram, G.R. Siber, G.A. Prince, M. Van Raden, V.G. Hemming, and The Respiratory Syncytial Virus Immune Globulin Study Group

Potential Strategies for Asthma Prevention

90.

91.

92. 93.

94.

95.

96.

97.

363

(1993) Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. New Eng J Med 329:1524–1530 S.E. Wenzel, R.L. Gibbs, M.V. Lehr, and E.A. Simoes (2002) Respiratory outcomes in highrisk children 7 to 10 years after prophylaxis with respiratory syncytial virus immune globulin. Am J Med 112:627–633 A. Mejias, S. Chavez-Bueno, A.M. Rios, M.F. Aten, B. Raynor, E. Peromingo, P. Soni, K.D. Olsen, P.A. Kiener, A.M. Gomez, H.S. Jafri, and O. Ramilo (2005) Comparative effects of two neutralizing anti-respiratory syncytial virus (RSV) monoclonal antibodies in the RSV murine model: time versus potency. Antimicrob Agents Chemother 49:4700–4707 M. Soler, R. Mutterlein, and G. Cozma (2007) Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease. Respiration 74:26–32 J. Bousquet and A. Fiocchi (2006) Prevention of recurrent respiratory tract infections in children using a ribosomal immunotherapeutic agent: a clinical review. Paediatr Drugs 8:235–243 J.P. Collet, P. Shapiro, P. Ernst, T. Renzi, T. Ducruet, and A. Robinson (1997) Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering Committee and Research Group. Prevention of Acute Respiratory Infection by an Immunostimulant. Am J Respir Crit Care Med 156:1719–1724 J.V. Jara-Perez and A. Berber (2000) Primary prevention of acute respiratory tract infections in children using a bacterial immunostimulant: a double-masked, placebo-controlled clinical trial. Clin Ther 22:748–759 U.B. Schaad, R. Mutterlein, and H. Goffin (2002) Immunostimulation with OM-85 in children with recurrent infections of the upper respiratory tract: a double-blind, placebo-controlled multicenter study. Chest 122:2042–2049 J.M. Vautel, J. Cauquil, and A.M. Perruchet (1993) Prevention of recurrent ear, nose and throat infections in young children with Ribomunyl: double-blind, placebo-controlled study. Curr Ther Res 53:722–729

Asthma and Allergy in Childhood: Prediction and Early Diagnosis Karin C. Lødrup Carlsen and Göran Wennergren

Why Should We Predict Disease? Clinicians would be at a great advantage if they at an early stage could identify the children who would develop asthma or other allergic disease in the future and who would remain or become healthy in later childhood and adult life. Then, resources could be focused more towards those with likely persistent disease to ensure optimal relevant management. For the scientists, identifying children who will go on to develop a disease, could provide a strong basis for understanding disease development as well as for giving appropriate advice to the community on how to prevent or diminish the potential harmful influences whenever possible. Parents need to know at the earliest possible stage whether or not their coughing or wheezing child is starting a life long career in allergic diseases, or if the symptoms are passing with a healthy outcome. Thus, appropriate early management, primary or secondary prevention, and prognosis estimates, all point to the necessity or value of trying to predict any disease. However, this has proven difficult. A PubMed search (October 2007) with the four index words: predict, asthma (or allergy), birth, child gave 17 hits (for both outcomes), of which none attempted to use factors known at birth for predicting asthma or allergy in children. On the other hand, evaluation of early life factors (infancy and early childhood) for predicting the same outcomes have been more widely reported, although relatively rarely with significant predictive capacities

K.C.L. Carlsen () Department of Paediatrics, Division of Woman and Child, Oslo University Hospital, Ullevål University Hospital, NO-0407, Oslo, Norway; The Faculty of Medicine, University of Oslo, Oslo, Norway e-mail: [email protected] G. Wennergren Department of Paediatrics, Queen Silvia Children’s Hospital, Göteborg University, SE-416 85, Göteborg, Sweden e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_22, © Springer 2010

365

366

K.C.L. Carlsen and G. Wennergren

(see below). Thus, there is a need to discuss what prediction entails: from a statistical and conceptual point of view, as well as from a clinical and scientific point of view, in relation to allergic disease development. Furthermore, early diagnosis of allergic disease is closely connected to prediction. Optimal management will depend upon an earliest possible diagnosis, and early appropriate diagnosis improves the likelihood of prognosis estimates. The present chapter will therefore concentrate upon factors that increase or decrease the likelihood of allergic disease at present or in the future, as well as discussing possible models for predicting prognosis in established diseases. However, the discussion will be limited to prediction within childhood up towards early adulthood.

Some Definitions and Considerations Table 1 outlines some of the statistical terms central to diagnostic tests or prediction. The term “predictors” are commonly used in statistical models for analysing associations between one outcome and several factors, such as in regression models.

Table 1 Definitions of the central terms used for consideration of prediction Sensitivity: The probability of the test finding disease among those who have the disease or the proportion of people with disease who have a positive test result. Sensitivity = true positives/(true positives + false negatives) Specificity: The probability of the test finding NO disease among those who do NOT have the disease or the proportion of people free of a disease who have a negative test. Specificity = true negatives/(true negatives + false positives) Positive Predictive Value (PPV): The percentage of people with a positive test result who actually have the disease. Positive predictive value = true positives/(true positives + false positives) Negative Predictive Value (NPV): The percentage of people with a negative test who do NOT have the disease. Negative predictive value = true negatives / (true negatives + false negatives) Likelihood Ratio: The likelihood that a given test result would be expected in a patient with a disease compared to the likelihood that the same result would be expected in a patient without that disease. Likelihood Ratio Positive (LR+): The odds that a positive test result would be found in a patient with, versus without, a disease. Likelihood Ratio Positive (LR+) = Sensitivity / (1 - Specificity). The probability of a test result being positive in a person with the disease divided by the probability of a test result being positive in a person without the disease. Likelihood Ratio Negative (LR-): The odds that a negative test result would be found in a patient without, versus with, a disease. Likelihood Ratio Negative (LR-) = (1- Sensitivity) / Specificity. The probability of a test result being negative in a person who has the disease, divided by the probability of a negative test result in a person who doesn’t have the disease

Prediction and Early Diagnosis

367

However, only rarely do authors state how much of the explained variability of the outcome is identified by all the factors included in the models. Thus, a “predictor” in such cases is more likely to reflect the potential effect upon the outcome by the risk factor in question, rather than the ability of the factor to predict the outcome. Thus, a consideration of prediction models may be necessary to understand the difference. With statistical approaches to assess whether or not a factor may increase or decrease the risk of disease, we often use the term odds ratio, or relative risk. Prediction models are generally used to assess the likelihood of a certain outcome in an individual if they fulfil the criteria (factors) listed in the model. The odds ratio or relative risk estimates how much the presence of a factor increases or decreases the risk, as compared to the absence of the factor. To predict the dichotomous event of asthma (or allergy), the appropriate statistical analysis is a logistic regression analysis [1]. The logit model (logistic regression analysis) has several appealing properties, including that the coefficients determined for each independent variable in the model have a simple interpretation in terms of odds ratios, being a type of risk measure that under certain assumptions can be compared to relative risk. Furthermore, the probability of a subject having asthma or not at a certain time point is easily estimated. However, the generalised measure of predictive power, also known as Nagelkerke’s R2 (R squared, that may be interpreted as the proportion of variance explained by the independent variables) is rarely reported. Some of the disadvantages of such models include the fact that estimations of odds ratios involve successive approximations, and in complex diseases there is usually not one single “correct” solution. Secondly, if the standard error of the estimate is more than three times the value of the estimate, the results should be interpreted with caution. If the dispersion differs among groups of subjects, the estimated coefficients tend to shrink towards 0. This unobserved heterogeneity and the magnitude of the estimated coefficients will be conservative, and all relevant covariates should preferentially be included. Finally, all complex models should always be assessed for the model fit, and statistical advice [1] is recommended.

Prediction Versus Risk Factors In order to employ a risk assessment for prediction, it must be noted that a risk factor has to be extremely strongly associated with a disease within a population if it should be of any screening value [2]. It has been stated that even a relative odds of 200 between highest and lowest fifths yields a detection rate of no more than 56% for a 5% false positive rate, provided, distribution of the screening variable is approximately Gaussian with similar SD in affected and unaffected people [2]. Thus, it is reasonable to ask if any of the currently known risk factors for asthma or allergy has any potential for predicting disease in an individual. As an example, family allergic history, a traditional “predictor” or at least highly significant risk factor for allergic diseases [3], is losing ground in relation to asthma with the current

368

K.C.L. Carlsen and G. Wennergren

asthma epidemic [4, 5]. Although children born into families with allergies or asthma are at increased risk of the diseases, the majority of children with disease appears to come from families without parental allergic diseases [5]. Other risk factors that have been relatively consistently associated with asthma, such as exposure to tobacco smoke products and to house dust mites [6] or indoor dampness [7] are not very accurate for predicting asthma in any individual child, although the risk of asthma is increased. Predicting capacity may depend not only on the strength of association between the factor and the outcome, but also at what stage of life prediction is attempted in relation to the age by which the outcome is defined. Or put in another way: when do we have the “true” answer of an outcome? This is particularly relevant for allergic diseases, which may appear at any age, although the majority of asthma has been symptomatic in the first few years of life [8], whereas allergy to some foods like egg and milk are common in the first 1 or 2 years of life, decreasing thereafter [9] in most children. The precision of prediction is likely to be inversely related to the time between prediction point and outcome. For instance, estimated prediction by a clinical score of obstructive airways disease during early childhood, for asthma in school age [10] may be more successful than for asthma in adulthood. Likewise, recurrent wheezing during pre-school years is more likely to predict current asthma during school age than post puberty, after which the gender shift in asthma incidence is well recognised [11]. Thus, not only is the time at which prediction is attempted important per se, but the older the child, the more relevant information is likely to be available to create prediction models. And likewise, the older the individual, the more likely an outcome is to represent the “truth”, particularly in diseases such as asthma, which is greatly heterogeneous during early childhood [12]. On the other hand, an objective factor such as cord blood immunoglobulin E (IgE) appeared to better predict atopy at 7 years than did serum IgE during infancy [13]. It could therefore be useful to consider time of prediction in relation to birth, at debut of disease, in school age, during puberty and early adulthood, with outcomes during pre-school age, school age, early and late adulthood. Prediction of outcomes demands a high degree of specification of phenotypes, since risk factors may differ for non-allergic vs allergic asthma and asthma vs allergic sensitisation or for lung function decline. In the following, we will describe some of the tools (Table 2) that have been used for prediction or to identify predictors (risk factors), and subsequently discuss the current status of predictive models for asthma and allergic diseases.

Table 2 Tools used for predicting allergic diseases 1. 2. 3. 4. 5. 6. 7.

Questionnaires Blood analyses (Cord blood IgE, early specific IgE, sCD14, IFN-g, IL-4 etc) Skin prick tests Clinical diseases expression Lung function Family history Constructed prediction models

Prediction and Early Diagnosis

369

Tools for Prediction Questionnaires are widely used due to the simplicity of distribution, but have the major drawback that specified phenotypes may be difficult to verify without objective test measures. Prediction may subsequently have less ascertained outcomes, and recall bias (in retrospective studies) may clearly influence the accuracy of prediction. For example, in some instances, such as in the Tasmanian birth cohort follow-up study, the outcomes in adulthood were established by questionnaires and analysed in relation to investigations in the subjects at age 7 years [14]. In this study, asthma as well as atopic eczema identified by age 7 years, female gender, maternal asthma and early or frequent asthma attacks at 7 years were predictors for adult asthma, with mean OR of about 1.4–1.7 [14]. However, the predictive capacity of each factor was not discussed, although a child with none of the risk factors had a 7% chance of having current asthma as an adult, whereas each risk factor was associated with about a 50% increase in risk, resulting in a chance of current asthma in adulthood of 11% with one risk factor, 16% with two risk factors present and so on. The predicted chance was greater than 50% in only 0.5% of all the children and in 5% of the children with parent reported asthma, with similar risk assessments for current atopic asthma [14]. Blood analyses have commonly been used for predicting asthma, allergic rhinitis, atopic eczema and combined allergic disease as well as lung function. Most common among blood tests are the use of cord blood IgE or serum total or specific IgE to predict asthma and allergy [3, 13, 15–22], with variable results. However, although total IgE has been assessed as a predictor on its own [15, 23], the results have demonstrated limited or little value for identification of later atopic disease expression [13]. Specific IgE antibodies (s-IgE) used to detect allergic sensitisation has been reported from many studies to precede atopic disease [13, 17, 18, 24, 25], or to predict obstructive airways disease at the time of s-IgE measurement [13, 26, 27]. Furthermore, the use of s-IgE measurements at 6 months of age in high risk infants with a specifically designed paediatric allergy panel test was reported to precede atopic diseases by 5 years with a very high positive predictive value, but the usefulness of the test was limited by a low sensitivity (approximately 24%) [28]. The usefulness of measuring s-IgE in the first or second year of life for predicting allergic rhinitis or food allergy in school age or early adulthood is less well elucidated, but is likely to be hampered by low sensitivity of identifying s-IgE at least as inhalant allergens at this particular age. Eosinophils and their secretory proteins such as eosinophils cationic protein (ECP) have also been used to predict development and persistence of asthma and other atopic diseases [13, 18, 21, 29–39]. The predictive role of the eosinophils in asthma and other allergic diseases has been debated, and in the mid-1990s serum ECP was extensively studied. However, although serum ECP appeared useful to predict persistence of wheeze after 2 years [21], Øymar demonstrated that neither

370

K.C.L. Carlsen and G. Wennergren

eosinophils count, nor ECP could be used to predict asthma among infants admitted to hospital with their first bronchiolitis [29]. Some early studies suggested that high interleukin 4 (IL-4) in cord blood [40], and low interferon-g (IFN-g) [41,42] during infancy was associated with increased risk of asthma in later childhood, although the Swedish study by Borres et al [40] found no association between IFN-g and atopic disease by 18 months. Skin prick tests (SPT) have been used in most birth cohort studies of asthma and allergy [43, 44], as well as in many other prospective studies with similar focus [45, 46], to assess the risk of atopic diseases in children demonstrating early allergic sensitisation. In line with this, a positive SPT to egg at 1 year (in a high risk population) had a high predictive capacity for atopic eczema and moderate predictive capacities for allergic rhinitis, asthma and any atopic disorder at 7 years [13]. However, since the number of children sensitised to aeroallergens in this age is low [47] during the first 2 years of life, positive SPT as a predictor is likely to be flawed by low sensitivity. For prediction of food allergy tolerance development, one study found that the size of wheal was associated with the prognosis of peanut allergy tolerance in one retrospective study in young children [48], whereas others found that SPT responses could not predict loss of symptomatic food allergy [46]. Clinical disease expression is probably more a marker of disease than a predictor, although scores have been made to try to predict persistence of disease [10, 22]. However, in high risk infants, a truly predictive assessment was reported in 1995 by Zeiger et al in a prospective randomised study of maternal and infant food allergy avoidance among 165 children followed from birth to 7 years of age [13]. Food allergy demonstrated at 4 years doubled the risk of asthma or allergic rhinitis at 7 years, whereas food sensitisation (assessed with skin prick tests) at age 4 and 12 months presented a high predictive capacity for atopic dermatitis, and moderate predictive capacities for allergic rhinitis, asthma or any atopic disorder at 7 years [13], much in line with the findings from another birth cohort study (the German MAS study) [49]. In the latter study, Bergmann et al [50] identified that atopic dermatitis in the first 3 months was a risk factor for aeroallergen sensitization at 5 years, modified by a positive family history for atopic diseases which increased the risk. Although these risk factors were also significantly associated with the manifestation of allergic airway disease, the positive predictive value for this outcome at age 5 years was only 50%. Early symptoms of obstructive airways disease are, quite expectedly, a risk for later asthma. It seems that infants and young children with wheezing severe enough to need hospital treatment are at particular risk for asthma later during childhood and early adulthood [51–54]. Thus, recent follow-up studies from Finland and Sweden show that infants and young children who react with wheezing during viral infections, have a clearly increased risk of asthma not only at school age but also in early adulthood [53, 54]. In these subjects, who were hospitalised before the age of 2 years due to wheezing, asthma prevalence at age 17–20 years was 30–43%, depending on the asthma definition used, compared with 11–15% in the control groups [53, 54]. The strongest risk factors for presence of asthma in early adulthood in these children with early wheezy bronchitis/bronchiolitis, were current allergy,

Prediction and Early Diagnosis

371

bronchial hyper-responsiveness and female gender [54]. Independent infantile risk factors were female gender and passive smoking [54]. The connexion between prenatal smoke exposure and asthma appeared to be mediated via the development of bronchial hyper-responsiveness [55]. Smoke exposure in infancy on the other hand, was associated with an increased risk of active smoking in early adult age, which is in turn linked to asthma [55]. Lung function measurements have been assessed for predictive capacity of asthma or asthma like phenotypes for several decades, whereas the associations between lung function at, or shortly after birth and obstructive airways disease in later childhood and early adulthood have been studied in a limited number of studies only [56–58]. Equipment to measure infant lung function has been available from the 1980s, and the first infants who had such measurements are subsequently currently in their early adulthood. The most common measure, often regarded as the “gold standard” for infant lung function measures is the partially forced flowvolume measurements, often referred to as the “squeeze-jacket technique” giving the resultant parameter flow at (estimated) functional residual capacity (VmaxFRC) [59–61]. However, other techniques such as measurements of tidal flow-volume loops giving the tPTEF/tE (time to reach peak expiratory flow to total expiratory time) that are simpler to use and which do not require sedation have been used for neonatal measures of lung function [62–64], with recent predictive results reported during school age [58]. In a prospective birth cohort study, assessing a history of asthma and current asthma at 10 years from lung function measured at 2 days of age, demonstrated that in children with low tPTEF/tE (<0.20) and reduced compliance of the respiratory system (Crs) (below median), almost 45% had asthma by 10 years, and 28% had current asthma at 10 years of age, respectively [58]. On the other hand, this means that among these children starting life with reduced lung function, 55% never had asthma and approximately 70% of children did not have current asthma at 10 years of age. Looking at each lung function measure separately, tPTEF/tE <0.20 had the best positive and negative predictive value (PPV and NPV) of 31.3 and 85.1, respectively, with an OR of 1.90 (1.06–3.42) for a history of asthma by 10 years [58]. Among other studies that assessed the value of early lung function for later asthma, the Tucson study described persistently reduced lung function from 3 months to 6 years of life among children with transient early wheezing, compared to children with never wheeze, persistent wheezing and late onset wheezing [60]. However, the predictive capacity of early lung function was not discussed. Several, but not all [65] studies reported that reduced lung function in the first few months of life (prior to clinical disease) increased the risk of bronchiolitis [66] or asthma in pre-school age [64, 67, 68]. Furthermore, not all studies have shown associations between early life lung function measures and assessments in later childhood. Reduced VmaxFRC at a few months of life was not significantly associated with wheezing after 3 years in the Tucson study [60], and flow limitation in infancy was a predictor of increased wheeze [57], but not asthma at 6 and 11 years [57] in the Perth study. Others described the association between infant and later lung function through childhood [69] and into adulthood [56] demonstrating a great degree of tracking of

372

K.C.L. Carlsen and G. Wennergren

lung function (i.e. later lung function is largely dependent upon pre-morbid lung function), and with little change after adjusting to clinical wheezy phenotypes [56, 69]. It is not clear whether using lung function in sub-groups, i.e. with a positive family history of atopy will improve the predictive capacity on an individual level, since data are currently lacking. Family history. Parental history of asthma seems to have better predictive value for future asthma in the child [22, 70, 71], than family history of atopy [54]. Prediction models or indices have been developed and reported in a few studies. Clough et al [72] developed models to predict 12 months persistent wheezing in infant wheezers, with maximal predictive value (78%) when they included personal atopy, parental atopy, age and cytokine studies. On the other hand, in the Tucson Children’s Respiratory Study, Castro-Rodriguez et al [22] developed two clinical indices at 3 years of age to define risk of asthma in school age, finding active asthma on at least one time-point between 6 and 13 years in 76% and 59% of children with their positive stringent and loose index models, respectively. Their indices included characteristics of wheezing 0–3 years, doctor’s diagnosed parental asthma or eczema, wheezing unrelated to colds, eosinophilia, or allergic rhinitis. Later, the criteria in this Asthma Predictive Index have been slightly modified [70]. To the major criteria, i.e. parental history of asthma and physician diagnosed atopic dermatitis, allergic sensitization to ³1 aeroallergen have also been added. Among the minor criteria, allergic sensitization to milk, egg, or peanuts have replaced physician-diagnosed allergic rhinitis [70]. So far, only one study [10] (to the authors’ knowledge) has included severity of (frequency and/or persistence) and/or hospital admissions for obstructive airways disease (OAD) within the first 2 years of life in the predictive model, giving PPV and NPV of 55% and 92%, respectively for a history of asthma or current asthma with a severity score of 6–12 compared to zero. Noticeably, the score applied at 1 year of age (OAD by 1 year) did not significantly predict 10-year outcomes [10], suggesting that not only the first, but also the second year of life is an important determinant of later airways disease. The use of the Castro-Rodriguez score (slightly modified) in the latter birth cohort study resulted in a maximum PPV of 48% and NPV of 86%in the Oslo study, including blood tests and parental atopy [10]. Thus, clinical atopic disease expression appears good predictors of later atopic disease, particularly early OAD for later asthma (during childhood), whereas other atopic phenotypes, such as atopic dermatitis appear less valuable as predictor for asthma. Thus, the few risk models that have been used for early prediction of asthma outcomes in school age mainly [10, 22, 72] vary greatly in their predicting capacity, and it is not known how appropriate these models may be for outcomes in early adulthood. To summarise the discussion on whether or not we can predict asthma or allergy, it is clear that most of the known risk factors for atopic diseases are of little value to predict future asthma or allergy in healthy, young individuals. On the other hand, early manifestation of atopic diseases, most noticeably early wheeze, early food or inhalant allergy and atopic eczema are phenotypes that increase the risk of later asthma, allergic rhinitis or allergic sensitisation, but with varying predictive capacity.

Prediction and Early Diagnosis

373

To date, the best predictive capacity for asthma appears to be obtained for an eightyear follow-up time after determining a severity score of OAD based upon frequency and severity of asthma episodes by 2 years of age. For the future, prediction models should include discussions related to gender, particularly for outcomes pre or post puberty. Furthermore, in the near future, it is likely that including genetic predisposition will improve predictability of the models, since this is likely to modify the effects of risk factors upon asthma, allergic rhinitis, atopic eczema or food allergies.

Early Diagnosis Why is early diagnosis important? First of all, careful diagnosis is likely to lead to optimalised management, and, in view of the discussion above, give an indication of prognosis. By early and thorough diagnostic considerations, it is likely that research into disease development improves, particularly in relation to uncovering risk as well as protective factors for each of the atopic or allergic phenotype expressions. When known, accurate diagnosis at an early age may prompt appropriate environmental advice (particularly in secondary and tertiary prevention), and facilitate a discussion on what the benefits and costs are of different management strategies. The allergy march has been much discussed, and indicates a progression from one phenotype to the next. However, as is well recognised, any of the phenotypes maybe present without co-existing phenotypes, or they may appear in duet or in multiplex within a very short time period. Furthermore, the expression of disease may be undulating, such as atopic eczema and food allergy, but which is also seen with asthma. Thus, it would be necessary to consider the following phenotypes: early wheeze versus asthma, atopic eczema, allergic rhinitis, food allergies, allergic sensitisation versus allergic diseases and combined allergic diseases. The natural course of allergic diseases has been widely described, and include several or all of these phenotypes [24, 46, 49, 73–78]. Commonly, atopic eczema and/or food allergy appears within the first year of life, often with concurrent wheezy lower respiratory tract infections. Thereafter follows asthma and/or allergic rhinitis whilst the atopic eczema and food allergy often go into remission during the pre-school years. Since each of these manifestations may appear on its own, or be part of complex disease, it is important to consider the extent to which one disease may be a marker of one of the other diseases or not. For instance, recurrent wheezing in a one-year-old child with atopic eczema is more likely to be the debut of persistent asthma than if the child had no other atopic manifestation. A very interesting question is whether early diagnosis and early treatment alters the natural course of the disease, in addition to giving symptom control? A Danish study in the beginning of the 1990s indicated that early treatment with inhaled corticosteroids improved lung function development in children with asthma [79]. More recent studies have not found effects on the natural course of the asthma disease or development of lung function [80–83]. However, even if early treatment

374

K.C.L. Carlsen and G. Wennergren

does not alter the natural course of the disease, the benefits with early treatment in terms of symptom control are motivation enough for stressing the importance of early diagnosis. Acknowlegement The authors wish to thank Petter Mowinckel for his contribution to the discussion of statistical considerations of prediction.

References 1. Hosmer DW, Lemeshow S. Applied logistic regression. 2nd ed. John Wiley and Sons, New York, 2000. 2. Wald NJ, Hackshaw AK, Frost CD. When can a risk factor be used as a worthwhile screening test? BMJ 1999; 319: 1562–1565. 3. Croner S. Prediction and detection of allergy development: influence of genetic and environmental factors. J Pediatr 1992; 121: S58–S63. 4. Christie GL, McDougall CM, Helms PJ. Is the increase in asthma prevalence occurring in children without a family history of atopy? Scott Med J 1998; 43: 180–182. 5. Burke W, Fesinmeyer M, Reed K, Hampson L, Carlsten C. Family history as a predictor of asthma risk. Am J Prev Med 2003; 24: 160–169. 6. Gold DR. Environmental tobacco smoke, indoor allergens, and childhood asthma. Environ Health Perspect 2000; 108 Suppl 4: 643–651. 7. Bornehag CG, Sundell J, Sigsgaard T. Dampness in buildings and health (DBH): Report from an ongoing epidemiological investigation on the association between indoor environmental factors and health effects among children in Sweden. Indoor Air 2004; 14 Suppl 7: 59–66. 8. Loftus BG, Price JF. Clinical and immunological characteristics of pre-school asthma. Clin Allergy 1986; 16: 251–257. 9. Høst A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol 2002; 89 Suppl 1: 33–37. 10. Devulapalli CS, Carlsen KC, Håland G, Munthe-Kaas MC, Pettersen M, Mowinckel P, et al. Severity of obstructive airways disease by two years predicts asthma at 10 years of age. Thorax 2008; 63: 8–13. 11. Almqvist C, Worm M, Leynaert B. Impact of gender on asthma in childhood and adolescence: a GA(2)LEN review. Allergy 2008; 63: 47–57. 12. Aas K. Heterogeneity of childhood asthma. Allergy 1981; 36: 3–14. 13. Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol 1995; 95: 1179–1190. 14. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles GG. Factors in childhood as predictors of asthma in adult life. BMJ 1994; 309: 90–93. 15. Kjellman NI. IgE in neonates is not suitable for general allergy risk screening. Pediatr Allergy Immunol 1994; 5: 1–4. 16. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001; 107: 891–896. 17. Kulig M, Bergmann R, Niggemann B, Burow G, Wahn U. Prediction of sensitization to inhalant allergens in childhood: evaluating family history, atopic dermatitis and sensitization to food allergens. The MAS Study Group. Multicentre Allergy Study. Clin Exp Allergy 1998; 28: 1397–1403. 18. Kotaniemi-Syrjänen A, Reijonen TM, Romppanen J, Korhonen K, Savolainen K, Korppi M. Allergen-specific immunoglobulin E antibodies in wheezing infants: the risk for asthma in later childhood. Pediatrics 2003; 111: e255-e261.

Prediction and Early Diagnosis

375

19. Perkin MR, Strachan DP, Hc W, Lack G, Golding J. The predictive value of early life total immunoglobulin E measurement in identifying atopic children in a population-based birth cohort study. Pediatr Allergy Immunol 2006; 17: 118–124. 20. Odelram H, Björkstén B, Leander E, Kjellman NI. Predictors of atopy in newborn babies. Allergy 1995; 50: 585–592. 21. Villa JR, Garcia G, Rueda S, Nogales A. Serum eosinophilic cationic protein may predict clinical course of wheezing in young children. Arch Dis Child 1998; 78: 448–452. 22. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000; 162: 1403–1406. 23. Hjalte K, Croner S, Kjellman NI. Cost-effectiveness of neonatal IgE-screening for atopic allergy before 7 years of age. Allergy 1987; 42: 97–103. 24. Cantani A, Micera M. Natural history of cow’s milk allergy. An eight-year follow-up study in 115 atopic children. Eur Rev Med Pharmacol Sci 2004; 8: 153–164. 25. Eysink PE, ter Riet G, Aalberse RC, van Aalderen WM, Roos CM, Van Der Zee JS, et al. Accuracy of specific IgE in the prediction of asthma: development of a scoring formula for general practice. Br J Gen Pract 2005; 55: 125–131. 26. Meyers DA, Freidhoff LR, Marsh DG. Predicting skin test sensitivity and total serum IgE levels in family members. J Allergy Clin Immunol 1986; 77: 608–615. 27. Wickman M, Ahlstedt S, Lilja G, van Hage HM. Quantification of IgE antibodies simplifies the classification of allergic diseases in 4-year-old children. A report from the prospective birth cohort study--BAMSE. Pediatr Allergy Immunol 2003; 14: 441–447. 28. Lilja G, Öman H, Johansson SG. Development of atopic disease during childhood and its prediction by Phadiatop Paediatric. Clin Exp Allergy 1996; 26: 1073–1079. 29. Øymar K, Bjerknes R. Is serum eosinophil cationic protein in bronchiolitis a predictor of asthma? Pediatr Allergy Immunol 1998; 9: 204–207. 30. Okano M, Nishizaki K, Nakada M, Kawarai Y, Goto S, Satoskar AR, et al. Prevalence and prediction of allergic rhinitis using questionnaire and nasal smear examination in schoolchildren. Acta Otolaryngol Suppl 1999; 540:58–63. 31. Øymar K. High levels of urinary eosinophil protein X in young asthmatic children predict persistent atopic asthma. Pediatr Allergy Immunol 2001; 12: 312–317. 32. Pohunek P, Kucera P, Sukova B, Votava F, Zikan J. Serum ECP taken in the acute episode of bronchial obstruction can predict the development of bronchial asthma in young children. Allergy Asthma Proc 2001; 22: 75–79. 33. Bahceciler NN, Barlan IB, Nuhoglu Y, Basaran MM. Which factors predict success after discontinuation of inhaled budesonide therapy in children with asthma? J Asthma 2002; 39: 37–46. 34. Kim CK, Kim JT, Kang H, Yoo Y, Koh YY. Sputum eosinophilia in cough-variant asthma as a predictor of the subsequent development of classic asthma. Clin Exp Allergy 2003; 33: 1409–1414. 35. Lex C, Ferreira F, Zacharasiewicz A, Nicholson AG, Haslam PL, Wilson NM, et al. Airway eosinophilia in children with severe asthma: predictive values of noninvasive tests. Am J Respir Crit Care Med 2006; 174: 1286–1291. 36. Sekerel BE, Civelek E, Karabulut E, Yildirim S, Tuncer A, Adalioglu G. Are risk factors of childhood asthma predicting disease persistence in early adulthood different in the developing world? Allergy 2006; 61: 869–877. 37. Piippo-Savolainen E, Remes S, Korppi M. Does blood eosinophilia in wheezing infants predict later asthma? A prospective 18–20-year follow-up. Allergy Asthma Proc 2007; 28: 163–169. 38. Lex C, Jenkins G, Wilson NM, Zacharasiewicz A, Erin E, Hansel TT, et al. Does sputum eosinophilia predict the response to systemic corticosteroids in children with difficult asthma? Pediatr Pulmonol 2007; 42: 298–303. 39. Martinez FD, Stern DA, Wright AL, Taussig LM, Halonen M. Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Thorax 1995; 50: 1067–1072.

376

K.C.L. Carlsen and G. Wennergren

40. Borres MP, Einarsson R, Björkstén B. Serum levels of interleukin-4, soluble CD23 and IFN gamma in relation to the development of allergic disease during the first 18 months of life. Clin Exp Allergy 1995; 25: 543–548. 41. Kondo N, Kobayashi Y, Shinoda S, Takenaka R, Teramoto T, Kaneko H, et al. Reduced interferon gamma production by antigen-stimulated cord blood mononuclear cells is a risk factor of allergic disorders--6-year follow-up study. Clin Exp Allergy 1998; 28: 1340–1344. 42. Guerra S, Lohman IC, Halonen M, Martinez FD, Wright AL. Reduced interferon gamma production and soluble CD14 levels in early life predict recurrent wheezing by 1 year of age. Am J Respir Crit Care Med 2004; 169: 70–76. 43. Keil T, Kulig M, Simpson A, Custovic A, Wickman M, Kull I, et al. European birth cohort studies on asthma and atopic diseases: II. Comparison of outcomes and exposures--a GA2LEN initiative. Allergy 2006; 61: 1104–1111. 44. Keil T, Kulig M, Simpson A, Custovic A, Wickman M, Kull I, et al. European birth cohort studies on asthma and atopic diseases: I. Comparison of study designs -- a GALEN initiative. Allergy 2006; 61: 221–228. 45. Kagamimori S, Naruse Y, Kakiuchi H, Yamagami T, Sokejima S, Matsubara I, et al. Does an allergy skin test on school-children predict respiratory symptoms in adulthood? Clin Exp Allergy 1996; 26: 262–269. 46. Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr 1989; 115: 23–27. 47. Lødrup Carlsen KC, Granum B. Soluble CD14: role in atopic disease and recurrent infections, including otitis media. Curr Allergy Asthma Rep 2007; 7: 436–443. 48. Spergel JM, Beausoleil JL, Pawlowski NA. Resolution of childhood peanut allergy. Ann Allergy Asthma Immunol 2000; 85: 473–476. 49. Illi S, von Mutius E, Lau S, Nickel R, Gruber C, Niggemann B, et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004; 113: 925–931. 50. Bergmann RL, Edenharter G, Bergmann KE, Forster J, Bauer CP, Wahn V, et al. Atopic dermatitis in early infancy predicts allergic airway disease at 5 years. Clin Exp Allergy 1998; 28: 965–970. 51. Wennergren G, Åmark M, Åmark K, Óskarsdóttir S, Sten G, Redfors S. Wheezing bronchitis reinvestigated at the age of 10 years. Acta Paediatr 1997; 86: 351–355. 52. Hyvärinen MK, Kotaniemi-Syrjänen A, Reijonen TM, Korhonen K, Korppi MO. Teenage asthma after severe early childhood wheezing: an 11 year prospective follow-up. Pediatr Pulmonol 2005; 40: 316–323. 53. Piippo-Savolainen E, Remes S, Kannisto S, Korhonen K, Korppi M. Asthma and lung function 20 years after wheezing in infancy: results from a prospective follow-up study. Arch Pediatr Adolesc Med 2004; 158: 1070–1076. 54. Goksör E, Åmark M, Alm B, Gustafsson PM, Wennergren G. Asthma symptoms in early childhood – what happens then? Acta Paediatr 2006; 95: 471–478. 55. Goksör E, Åmark M, Alm B, Gustafsson PM, Wennergren G. The impact of pre- and postnatal smoke exposure on future asthma and bronchial hyper-responsiveness. Acta Paediatr 2007; 96: 1030–1035. 56. Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 2007; 370: 758–764. 57. Turner SW, Palmer LJ, Rye PJ, Gibson NA, Judge PK, Young S, et al. Infants with flow limitation at 4 weeks: outcome at 6 and 11 years. Am J Respir Crit Care Med 2002; 165: 1294–1298. 58. Håland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC, Pettersen M, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006; 355: 1682–1689. 59. Young S, Arnott J, Le Souef PN, Landau LI. Flow limitation during tidal expiration in symptom-free infants and the subsequent development of asthma. J Pediatr 1994; 124: 681–688.

Prediction and Early Diagnosis

377

60. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. N Engl J Med 1995; 332: 133–138. 61. Wildhaber JH, Dore ND, Devadason SG, Hall GL, Hamacher J, Arheden L, et al. Comparison of subjective and objective measures in recurrently wheezy infants. Respiration 2002; 69: 397–405. 62. Lødrup Carlsen KC, Magnus P, Carlsen KH. Lung function by tidal breathing in awake healthy newborn infants. Eur Respir J 1994; 7: 1660–1668. 63. Dezateux C, Fletcher ME, Dundas I, Stocks J. Infant respiratory function after RSV-proven bronchiolitis. Am J Respir Crit Care Med 1997; 155: 1349–1355. 64. Lødrup Carlsen KC, Carlsen KH, Nafstad P, Bakketeig L. Perinatal risk factors for recurrent wheeze in early life. Pediatr Allergy Immunol 1999; 10: 89–95. 65. Clarke JR, Salmon B, Silverman M. Bronchial responsiveness in the neonatal period as a risk factor for wheezing in infancy. Am J Respir Crit Care Med 1995; 15: 1434–1440. 66. Young S, O’Keeffe PT, Arnott J, Landau LI. Lung function, airway responsiveness, and respiratory symptoms before and after bronchiolitis. Arch Dis Child 1995; 72: 16–24. 67. Young S, Arnott J, O’Keeffe PT, Le Souef PN, Landau LI. The association between early life lung function and wheezing during the first 2 years of life. Eur Respir J 2000; 15: 151–157. 68. Murray CS, Pipis SD, McArdle EC, Lowe LA, Custovic A, Woodcock A. Lung function at one month of age as a risk factor for infant respiratory symptoms in a high risk population. Thorax 2002; 57: 388–392. 69. Håland G, Carlsen KH, Devulapalli CS, Pettersen M, Mowinckel P, Lødrup Carlsen KC. Lung function development in the first 2 years of life is independent of allergic diseases by 2 years. Pediatr Allergy Immunol 2007; 18: 528–534. 70. Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol 2004; 114: 1282–1287. 71. Piippo-Savolainen E, Remes S, Kannisto S, Korhonen K, Korppi M. Early predictors for adult asthma and lung function abnormalities in infants hospitalized for bronchiolitis: a prospective 18- to 20-year follow-up. Allergy Asthma Proc 2006; 27: 341–349. 72. Clough JB, Keeping KA, Edwards LC, Freeman WM, Warner JA, Warner JO. Can we predict which wheezy infants will continue to wheeze? Am J Respir Crit Care Med 1999; 160: 1473–1480. 73. Guillet G, Guillet MH. Natural history of sensitizations in atopic dermatitis. A 3-year followup in 250 children: food allergy and high risk of respiratory symptoms. Arch Dermatol 1992; 128: 187–192. 74. Kjellman NI. Natural course of asthma and allergy in childhood. Pediatr Allergy Immunol 1994; 5 (6 Suppl): 13–18. 75. Amdekar YK. Natural history of asthma in children. Indian J Pediatr 2001; 68 Suppl 4: S3-S6. 76. Landau LI. Definitions and early natural history. Med J Aust 2002; 177 Suppl: S38-S39. 77. Wood RA. The natural history of food allergy. Pediatrics 2003; 111: 1631–1637. 78. Koh MS, Irving LB. The natural history of asthma from childhood to adulthood. Int J Clin Pract 2007; 61: 1371–1374. 79. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88:373–378. 80. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054–1063. 81. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354: 1985–1997. 82. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN study team. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet 2006; 368: 83. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354: 1998–2005.

Early Interventions in Allergic Diseases L. Karla Arruda, Dirceu Solé, and Charles K. Naspitz

Introduction Atopy has been defined as the genetic predisposition to develop IgE antibody responses to a variety of common environmental allergens. Clinically, atopy is expressed by asthma, allergic rhinoconjunctivitis and atopic dermatitis. It has been recognized that the “atopic march” evolves from food allergy and atopic dermatitis in the first 2 years of life, followed by asthma and allergic rhinitis. Over the past 30 years, the prevalence of allergies and asthma has increased significantly in developed countries, and asthma is one of the most common chronic diseases in children. Evidence indicates that environmental factors acting early in life, including respiratory viral infections, exposure to pets and microbial products, day-care attendance, breast feeding, and exposure to allergens, tobacco smoke and other pollutants, are key events for establishment of sensitization and development of chronic, persistent symptoms of allergic diseases [1]. It is thought that gene–environment interactions play a crucial role in these processes. Therefore, attempts to successfully prevent development of allergic diseases should be a priority. At present, there are no genetic markers for atopy or asthma which could be used routinely in clinical practice and family history of atopy has been used to identify children genetically at-risk of developing allergic diseases. These children from high-risk families have been the focus of most of the intervention studies. In this chapter, we discuss risk factors for development of sensitization and allergic disease, focussing on preventive strategies for allergies and asthma at an early age.

L.K. Arruda () Division of Clinical Immunology, Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP 14049-900, Brazil e-mail: [email protected] D. Solé and C.K. Naspitz Division of Allergy, Clinical Immunology and Rheumatology, Federal University of São Paulo, São Paulo, Brazil

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_23, © Springer 2010

379

380

L.K. Arruda et al.

Risk Factors for Allergies and Asthma Respiratory Viruses, Wheezing, Allergen Sensitization and Asthma Infections with respiratory viruses, particularly human rhinovirus (HRV) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract (LTR) illnesses associated with wheezing in children. Although acute wheezing episodes may be severe enough to require hospitalization, majority of children presenting wheezing illnesses early in life will no longer wheeze by the age of 6 [2]. However, in a proportion of these children, early-life-wheezing is a clinical manifestation of asthma. Respiratory viral infections have been implicated in the pathogenesis of asthma in several ways: during infancy, certain viruses have been linked to inception of the asthma phenotype; in children with established asthma, viral respiratory infections play a significant role in triggering acute exacerbations that might lead to hospitalizations and frequent outpatient visits; in children with repeated infections due to day-care attendance or contact with older siblings, respiratory viruses may have a paradoxical effect of reducing long-term risk of allergy and asthma, through alterations of cytokine response profiles. In the first 3 years of life, most LRT illnesses with wheezing are associated with infection by RSV. In the northern hemisphere, RSV accounts for 60–80% of wheezing episodes in children younger than 2 years of age [3]. It has been shown that children who wheeze with RSV infection in early life have lower level of lung function prior to infection [2]. Most children have serum RSV antibody by the age of 2, yet reinfections are common. Although risk of subsequent wheezing after RSV may decrease significantly with age, recurrent episodes of wheezing due to active RSV infections may occur throughout childhood. Transmission requires close contact, and occurs either by large-particle aerosols or by contamination of hands and inoculation into the eye or nose, with an average incubation period of 2–8 days [4]. More recently, the role of HRVs in causing acute wheezing has been appreciated. HRVs are small, nonenveloped, positive-strand RNA viruses in the family Picornaviridae, with over 100 identified serotypes with minimal cross-antigenicity [5]. HRV infects only higher primates, and causes illness only in humans, with replication restricted to the respiratory epithelium [6]. In temperate climates, HRV has been estimated to cause up to 80% of autumn colds [5, 7]. In tropical countries, available evidence indicates that HRV is frequently associated with acute respiratory illnesses (ARI). HRV transmission requires close exposure and occurs mainly by hand-to-hand contact, followed by self-inoculation into the eye or nose. It can also be transmitted by airborne spread. Once HRV reaches the nasal cavity, infection occurs in virtually 100% of susceptible subjects; and approximately 75% of those infected develop illness after 1–2 days incubation [5]. Sensitive PCR-based assays have established the importance of HRV as the cause of LRT illnesses, in addition to upper respiratory tract symptoms. A recent study with in situ hybridization applied to lower airway biopsy specimens has demonstrated presence of HRV in the LTR of 45% of a group of children 3–26 months of age with recurrent respiratory symptoms [8].

Early Interventions in Allergic Diseases

381

Other viruses have also been associated with wheezing LRT illnesses in children at lower frequencies, including influenza, human parainfluenza viruses, human coronavirus, adenovirus, human metapneumovirus, and the recently identified human bocaviruses (HBoV) – however at a lower frequency [9]. In keeping with observations made in temperate climates, it has been shown that infection with respiratory viruses and family history of allergy, were independently associated with wheezing among infants [10]. Results of this case-control study carried out in Ribeirão Preto, a city in southeast Brazil, revealed that, in the group of children under 2 years of age, respiratory viruses were detected in 60.8% of wheezing infants versus 13.3% of controls, and RSV was detected in 39% wheezing children and none of the controls. Rhinovirus RNA was found in 20.2 and 10% of the wheezing and control children, respectively, though this difference was not significant (p = 0.21). The frequency of RSV was lower than that reported in temperate regions (39% versus 60–80%). However, considering the subgroup of infants 0–6 months-old, 61% tested positive for RSV antigen. RSV infections were predominantly found in the months of February to May, corresponding to late summer and early to midfall, indicating that the virus occurs in a different seasonal pattern as compared to that of the northern hemisphere. In the group of children 2–12 years of age, respiratory viruses were not significantly associated with wheezing [10]. In the United States, Heymann et al have shown that viral infections, especially HRV, were the dominant risk factor for wheezing among children hospitalized before the age of 3 [11]. In their study, 84% of wheezing children p = 3 years-old were positive for virus, compared to 54% of controls (p < 0.001); RSV was the dominant pathogen in the winter months among children 2 years-old or younger; however, rhinovirus was detected more often among wheezing children hospitalized in the other months of the year (58%) as compared to controls (26%, p < 0.04) [11]. One important issue would be whether infections with respiratory viruses particularly RSV and HRV occurring early in life could function as triggers or “adjuvants” for subsequent development of sensitization and persistent symptoms of allergic diseases. The rational for this hypothesis would be the potential of these infections to induce significant damage to the airways which might facilitate penetration of allergen(s) and/or trigger events related to airway remodeling. RSV enters the cell by fusion of the viral envelope with the cell membrane, and causes syncytia formation as a result of fusion of the infected cells to adjacent ones. Replication in the bronchiolar epithelium causes necrosis of ciliated cells, peribronchiolar inflammation with abundant lymphocytes and macrophages, and impairment of secretion clearance, resulting in small airway obstruction and the hyperinflation characteristic of bronchiolitis. Clinically, involvement of the LRT is characterized by tachypnea, dyspnea, cough, expiratory wheezing, air trapping, hyperaeration of the lungs on chest X-rays, and intercostal muscle retractions and cyanosis [4].The pathogenesis of HRV infection is based on the release of cytokines, chemokines, and inflammatory mediators triggered by productive viral replication in a limited number of cells. A number of chemokines, particularly CXCL8 (IL-8), CCL3 (macrophage inflammatory protein 1a) and CCL5 (RANTES) are major mediators released during respiratory viral infections, which could recruit virus-specific T-cells as well as allergen-specific T-cells that in turn could augment

382

L.K. Arruda et al.

any ongoing allergic response in the lung [12, 13]. It has been speculated that the contemporaneous occurrence of cycles of viral-induced and allergen-induced inflammation in the airways during the period of rapid lung growth and remodeling in infancy interacts synergistically to disrupt underlying tissue differentiation programs. This interaction could result in deleterious changes in ensuing respiratory functions, which may then manifest as persistent wheeze and/or asthma [14]. Studies have shown association of RSV bronchiolitis and other early respiratory tract infections with recurrent wheezing or symptomatic asthma during the first 4–7 years of life [15,16]. A long-term study carried out in Tucson, Arizona, revealed an association of LTR infection caused by RSV early in life with persistent wheezing at 3 and 6 years of age; however, this effect was lost at age 13 [17, 18]. Besides RSV, HRV [19] may be potentially implicated in the subsequent development of childhood asthma. Lemanske et al. have shown that, in a group of 285 children at high risk of asthma, studied during the first 3 years of life, infection with HRV in the first year was the greatest risk factor for persistent wheezing in the third year [20]. The authors showed that 63% of children who wheezed during rhinovirus season continued to wheeze in the third year, as compared to only 20% of all other infants (OR = 6.6). A study in Finland revealed that infants hospitalized for rhinovirus-induced wheezing presented a fourfold higher risk of asthma in school age, as compared to wheezing infants from whom no rhinovirus was identified. Children with atopic dermatitis were especially likely to develop wheezing during HRV infections [21]. These studies highlight the previously unrecognized potential role of rhinovirus infection occurring in early life in the onset of asthma. Follow-up of children 0–2 years of age who participated in the emergency room study in Brazil [22] revealed that, after 2 years, 52% presented persistent wheezing. In contrast to studies carried out in temperate regions, viral infections were not a risk factor for persistent wheezing. On the other hand, early sensitization particularly to mites and cockroach, at 2–4 years of age, and exposure to high levels of cockroach allergen in the home in the first 2 years of life were both strong and independent risk factors for persistence of wheezing. It has been consistently shown that early allergen sensitization becomes a major risk factor for wheezing exacerbations and hospitalizations for wheezing after age 3 [17, 22–25]. It is thought that IgE-mediated inflammation found in most children with persistent symptoms of asthma is a key factor in causing lung function impairment and airway remodeling. Previous studies in Brazil have shown that day-care centers and schools, in addition to homes, are sources of significant exposure to mite and cockroach allergens, which might contribute to sensitization [26, 27]. Heymann et al have demonstrated that sensitization to house dust mites and other aeroallergens was an important risk factor for hospital admissions for wheezing and adverse responses to viral infections, particularly those caused by rhinovirus, in 3–18 years old children [11], highlighting the synergistic effect of sensitization, allergen exposure, and concomitant viral infection in augmenting inflammatory responses in the airways [28]. The possibility that viral and atopy-associated inflammation may interact synergistically to drive asthma pathogenesis has been raised recently by Kusel et al. [14]. Results of this community-based cohort, involving 198 children followed from

Early Interventions in Allergic Diseases

383

birth to 5 years, revealed that acute LTR infection caused by rhinovirus or RSV in the first year of life interacted with atopy in infancy (sensitization £ 2 years-old) to promote later asthma [14]. It is well recognized that exacerbations of asthma, in patients with established disease, are often triggered by respiratory viral infections, particularly those caused by rhinovirus. In asthmatic patients, persistence of HRV up to 6 weeks following infection or exacerbation of asthma, has been reported [29, 30], suggesting that an aberrant immune response to HRV may be involved in the development of acute exacerbations in atopic individuals with asthma. Also, coexistence of atopy enhances the clinical effect of HRV infection, increasing intensity and duration of bronchial hyperreactivity [31]. Finally, it has been suggested that repetitive viral infections might confer protection to development of asthma, based on their ability to skew the immune system away from the Th2-type response [13, 15]. Day-care attendance and/or siblings significantly increased the likelihood of occurrence of RSV or rhinovirus infections, and increased the risk of rhinovirus-induced wheezing at an early age. Neonatal interferon (IFN)-g responses were lower in infants with high frequency of respiratory infections; conversely, frequent infections were associated with a smaller decline of IFN-g responses during the first year of life, indicating that preexisting immunologic factors may influence the expression of viral infections in infancy [15].

Breast Feeding Exclusive breast feeding for at least 4 months has been associated with protection against development of asthma or atopic diseases [32, 33], but other studies have failed to demonstrate protection by breast milk [34]. Bottcher et al. [35] found no relationship in levels of cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-16, IFN-g, TGF-b1, TGF-b2), chemokines (RANTES, eotaxin) or secretory IgA in breast milk, and development of sensitization or allergic symptoms, or levels of salivary IgA during the first 2 years of life.

Endotoxin Endotoxin is a constituent of the outer membrane of gram-negative bacteria, found ubiquitously in nature, being present in most indoor environments as a component of house dust. Endotoxin stimulates the release of potent proinflammatory cytokines. Exposure to high levels of endotoxin in dust is associated with induction of asthma in sensitive patients [36, 37]. It has been demonstrated that bacterial endotoxin is capable of producing Th1associated cytokines, IFN-g, and IL-12 and therefore, has the potential to decrease

384

L.K. Arruda et al.

allergen sensitization. Chronic endotoxin exposure, before polarized T-cell responses are established, might be expected to protect against allergen sensitization by continuously enhancing Th1-type lymphocyte development [38]. This assumption has been partially confirmed by studies in humans showing that exposure to high levels of endotoxin in early life was associated with protection against allergic sensitization [39, 40]. An experimental study with pregnant BALB/c mice has shown that combined exposure to endotoxin during prenatal and postnatal phases suppressed allergenspecific sensitization (IgE production), eosinophilic airway inflammation (reduced numbers of eosinophils in bronchoalveolar lavage fluids), and in vivo airway reactivity in response to methacholine. The suppression of allergen-mediated inflammatory responses was associated with increased Toll-like receptor and T-bet expression by lung tissues and a shift toward predominantly Th1 immune responses [41]. Similar results were observed by Wang and McCusker [42]. The relationship of exposure to microbial agents (endotoxin, fungal agents, and other microbial contaminants) early in life (3 months of age) and the development of atopic sensitization and physician-diagnosed asthma and wheeze in the first 4 years of life, in children of atopic mothers, was investigated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study. A significant reduction in the development of asthma was associated with early exposure to these substances [43]. Children who were born and raised in a farm environment and exposed to poultry and livestock were reported to have lower prevalence of asthma and/or allergic diseases in comparison to those living in urban area [44, 45]. Until recently, exposure to high levels of endotoxin was associated with exposure to farm animals, presence of pets in home, number of people living in the house, and cleaning habits [46]. However, results of a study carried out on children from rural areas in Europe, evaluating farm-related exposures and health outcomes, revealed that levels of endotoxin and extracellular polysaccharides were associated with health outcomes independent of farm exposures [47]. It has recently been shown by Simpson et al. that the impact of endotoxin may be genetically determined [48]. In the setting of a birth cohort study, increasing endotoxin exposure was associated with reduced risk of allergic sensitization and eczema, and increased risk of nonatopic wheeze, only in children with the CC genotype at −159 of the CD14 gene [48].

Pet Ownership Several prospective birth cohort studies have raised the issue of whether keeping of pets , particularly keeping of dogs or cats, might decrease the risk of developing sensitization to those allergens and have confirm these results in part [49–51]. A systematic review of the scientific literature concerning keeping of pets within the first 2 years of life and prevalence of asthma has shown that exposure to pets

Early Interventions in Allergic Diseases

385

was associated with increased risk of asthma and wheezing in children older than 6 years of age and a tendency for protection in those aged below 6 years [52]. In a recent study, a protective effect of early exposure to cat was documented [53]; however it hasn’t happened unanimously and some bias of selection may have accounted for the results. So, the protective effect observed might be attributable to allergen or other exposures associated with pet ownership (eg. Endotoxin), but may in part be due to the prior removal of pets in families where children are sensitized or symptomatic or in families with a positive history for atopy at the time the child was born [49]. Platts-Mills and colleagues [54] while evaluating the immune response among 226 children, 47 of whom had asthma and airway hyperresponsiveness, have demonstrated that increasing the exposure to house dust mites was associated with an increase in frequency of sensitization to dust mite allergen. The highest category of exposure to cat allergen though was associated with decreased frequency of sensitization and higher prevalence of IgG antibody to Fel d 1. However, the occurrence of sensitization to dust mite or cat allergens was the strongest independent risk factor for asthma (mite OR = 4.2; cat OR = 6.1).

Tobacco Smoke Maternal tobacco smoking during gestation is an important avoidable risk factor associated with elevated levels of IgE in cord blood, subsequent asthma and allergic diseases in childhood [55–57], and reduction of pulmonary function in children [58]. Increased production of IL-13 by cord blood cells has been found in newborns whose mothers had smoked during gestation as compared with those who never smoked [56]. Macaubas et al. [59] reported a direct relationship of maternal tobacco smoking with both low concentrations of IL-4 and IFN-g in cord blood and increased risk of wheezing by age 6 years. A recent experimental study on BALB/c mice has shown that daily in utero exposure to maternal tobacco smoking was associated with exacerbation of subsequent adult responses to initial allergen exposure [60]. There is a strong body of evidence to support the role of exposure of children to environmental tobacco smoke (ETS) in increasing the incidence of asthma, wheeze, cough, bronchitis, bronchiolitis, pneumonia, and impaired pulmonary function. ETS increases both the prevalence and severity of asthma, as judged by increases in the frequency of attacks, the number of emergency room visits, and the risk of intubation [55, 57]. The risk associated with parental smoking seems to be greater at younger ages. Although a dose–response relationship between ETS exposure and respiratory outcomes has been demonstrated, at present there is no threshold dose of ETS exposure below which an effect will not occur, and therefore active intervention measures and policies to reduce or eliminate children’s exposure to ETS should be strongly encouraged [55]. Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-a (TNF) and lymphotoxin-a (LTA) have been associated with asthma and atopy in some

386

L.K. Arruda et al.

studies. Secondhand smoke and ozone both stimulate TNF production. In a recent study, Wu et al. genotyping six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA have observed that genetic variation in TNF may contribute to childhood asthma and that association may be modified by parental smoking [61]. A home-based, individualized, intervention study [62] carried out among inner city children with atopic asthma which included education and remediation for exposure to both allergens and ETS, resulted in reduction of asthma associated morbidity.

Therapeutic and Preventive Strategies Perspectives of Treatment and Prevention of Respiratory Viral Infections Few specific interventions are available to reduce the impact of respiratory viruses. No vaccine is currently available for RSV prophylaxis. The disease enhancement caused by formalin-inactivated vaccine in the 1960s plus results of more recent unsuccessful trials of live-attenuated vaccines, have significantly slowed progress toward an RSV vaccine. Passive immunization/immunoprophylaxis with monthly infusions of RSV immunoglobulin or monthly intramuscular injections of humanized monoclonal antibody, during the RSV season, reduced the incidence and severity of RSV infections in high-risk children including those preterm babies less than 6 months-old, children with congenital heart disease, and children less than 2 years with bronchopulmonary dysplasia [4]. The large number of HRV serotypes with minimal cross-antigenicity has hampered the development of an HRV vaccine. It may be possible to reduce exposure to HRV by washing of hands after contact with a cold sufferer or after handling objects that may have been contaminated with respiratory secretions [5]. Immunization with formalin-inactivated or live-attenuated multivalent influenza virus vaccines and chemoprophylaxis for influenza virus A are the methods available for preventing influenza. Influenza vaccine is used prior to the influenza season. The inactivated vaccine has an approximate 70–90% efficacy in preventing illness in healthy children and adults. In summary, there are virtually no effective strategies targeted at the respiratory viruses for treatment or prevention of viral-induced wheezing illnesses in children. However, evidence indicates that treatment of lung inflammation with inhaled corticosteroids or blocking viral-induced overproduction of leukotrienes with leukotriene-receptor antagonist Montelukast may be effective in decreasing severity and frequency of viral-induced wheezing in young children with recurrent or persistent symptoms [63, 64]. A double-blind, controlled trial (PREVIA study) investigated the effect of treatment with Montelukast for 12 months in 2–5 years-old children with intermittent asthma. Approximately half of these children were positive for at least one respiratory virus, including HRV, coronavirus, and RSV in their nasal

Early Interventions in Allergic Diseases

387

aspirates during exacerbations of symptoms. The results showed that Montelukast had a beneficial effect, decreasing frequency of exacerbations, increasing time between acute wheezing episodes, and reducing the need for inhaled corticosteroids during exacerbations [64].

Environmental Interventions in Genetically Predisposed Infants Preventive strategies have focused on manipulating the environment of high-risk individuals as an attempt to reduce the prevalence of allergies and asthma in children. At present, six primary prevention controlled studies are in progress [65]. The longest follow-up reported has been from the Isle of Wight study [66]. In this randomized, controlled study, a group of 120 high-risk infants was recruited prenatally, and development of allergic diseases and sensitization to common allergens was assessed at ages 1, 2, 4 and 8 years. Intervention included strict elimination of common food allergens (dairy products, egg, wheat, nuts, fish, and soy) to the age of 12 months. Lactating mothers followed the same restriction diet (except wheat) for the duration of breast feeding. Extensively hydrolyzed formula was given as a supplement to the child from birth, or when breast feeding was discontinued before 9 months. Stringent allergen avoidance measures were also instituted at birth, aimed at reducing exposure to house dust mites. Repeated measurement analysis showed a sustained preventive effect of allergen avoidance on asthma, atopic dermatitis, and sensitization to allergens over the period of the first 8 years of life, and on allergic rhinitis at age 8 [67]. Therefore, the conclusion was that stringent avoidance of mite and food allergens applied to high-risk children in infancy were beneficial and resulted in reduction of allergic sensitization and clinical manifestations of allergy, beyond the period of avoidance [67]. Likewise, outcome of the Canadian Primary Prevention Study on high risk infants has been reported at age 7 years, showing that intervention during the first year of life, comprising avoidance of mite, pet allergens and ETS, as well as dietary regimen, resulted in reduction of asthma symptoms and asthma diagnosed by a pediatric allergist in the intervention group. In the Canadian study, no significant effect of intervention was observed for bronchial hyperreactivity, allergic sensitization, allergic rhinitis, or atopic dermatitis at age 7 years [68]. Initial results from other cohorts look promising; however further follow-up will be necessary before any recommendations can be made [65]. Results of the Manchester Asthma and Allergy Study (MAAS) have been reported up to the age of 3, and showed that stringent mite and pet allergen avoidance measures starting during gestation, resulted in decrease in severe wheezing and exercise induced wheezing at age 1, and improved pulmonary function in the intervention group at age 3. However sensitization to mites was increased at 3 years of age [69]. In the Study of Prevention of Allergy in Children in Europe (SPACE), environmental control measures aimed at reducing exposure to dust mite allergens at birth and education failed to prevent sensitization at age 2 [70]. Another study looking at the effects of mite avoidance measures during gestation and education. The PIAMA study, showed a modest benefit

388

L.K. Arruda et al.

of reduction of cough apart from colds at 2 years of age [71]. The results of the Childhood Asthma Prevention Study (CAPS), carried out in Australia, revealed that house dust mite allergen avoidance in conjunction with supplementation of diet with omega-3 fatty acids (abundant in fish and canola-based oils), applied to children with high risk of asthma, resulted in decrease in cough and sensitization to mites at 3 years of age , with no significant differences in wheeze [72]. The conclusion of these prospective studies so far is that environmental measures taken to decrease exposure to dust mite allergens, even if started during gestation, appear to have limited beneficial effects. However, dust mite avoidance in conjunction with stringent dietary avoidance measures applied to high-risk infants of highly motivated families, may result in prevention of sensitization and clinical manifestations of allergy up to 8 years. Follow-up of some of the studies is still too short to allow more definitive recommendations.

Pharmacological Treatment The prophylactic treatment with an antihistamine, ketotifen, in atopic dermatitis patients was followed by a fourfold reduction in incidence of asthma related symptoms, mainly in those with high levels of serum total IgE [73]. Similar results were observed among children with high risk of developing asthma. The incidence of asthma in preasthmatic patients treated with ketotifen was 9% versus 31% in the placebo group [74]. Warner et al. have evaluated long-term treatment with cetirizine as a preventive tool for the onset of asthma in children aged less than 2 years with atopic dermatitis and without asthma, in a double-blind, randomized, placebo-controlled trial (the Early Treatment of the Atopic Child, ETAC study). At the end of 18 months of active treatment, they observed a significant reduction in the onset of asthma among grass pollen-sensitized infants and dust mite-sensitized infants. These differences were sustained only for the grass pollen-sensitized infants after 18 months of treatment interruption. They concluded that cetirizine truly delays or, in some cases, prevents the development of asthma in a subgroup of infants with atopic dermatitis sensitized to grass pollen and, to a lesser extent, to house dust mite [75]. More recently, preliminary results of the Early Prevention of Asthma in Atopic Children (EPAAC) study, shows that the use of levocetirizine daily for 18 months was safe among atopic children 12–24 months of age [76]. On the whole, these studies indicate that the antihistamines ketotifen, cetirizine, and levocetirizine are safe for use in very young atopic children, and that they may have a role in preventing development of asthma in some of these children, particularly those with atopic dermatitis, and those allergic to house dust mite and grass pollen at an early age [76]. The hypothesis that early introduction of inhaled corticosteroids in young children at high risk of developing asthma could change the natural history of the disease has been investigated. A recent study in preschool children at high risk of asthma revealed that 2 years of treatment with inhaled corticosteroid was highly effective in reducing symptoms and asthma exacerbations, though the benefit was

Early Interventions in Allergic Diseases

389

no longer present during a third treatment-free year, indicating that corticosteroids may not have disease modifying effects [63]. In this trial, the Prevention of Early Asthma in Kids (PEAK), 285 children aged 2–3 years were randomized to receive either 88 mcg Fluticasone twice daily for 2 years or placebo, and at the end of the second year, treatments were interrupted. Clinical and functional differences favoring the children treated with inhaled Fluticasone disappeared a few weeks after discontinuation of regular treatment. Recently, two other studies carried out in the United Kingdom and Denmark [77, 78] reached similar conclusions as the PEAK trial: very early treatment of asthma with inhaled corticosteroids, even before the persistent form of the disease has become evident, does not change the natural clinical course of the disease, and does not seem to affect the level of lung function attained at the end of follow-up, despite the fact that this form of treatment is very effective in controlling asthma symptoms while in use [79].

Allergen-Specific Immunotherapy Specific immunotherapy (SIT) administered by the subcutaneous route is an efficient treatment for IgE-mediated disease to defined allergens [80]. Beneficial effects of SIT in children have been demonstrated in preventing new sensitizations in children monosensitized to mites [81, 82] and in slowing the progression to asthma in those with seasonal allergic rhinitis, sensitized to pollen allergens (the PAT study) [83]. Follow-up of children with allergic rhinitis sensitized to birch or grass pollens, who underwent SIT for 3 years [83] showed that the effect of SIT in preventing development of asthma was still evident 2 years after SIT was discontinued [84]. Concerns regarding the use of SIT in asthma include the possibility of severe anaphylaxis; however guidelines have been developed to minimize risks of reaction [80]. Sublingual immunotherapy (SLIT) is increasingly being regarded as an efficient tool for the treatment of patients with asthma and/or rhinitis, as indicated by results of meta-analysis of studies carried out in children and adults [85]. The increased safety and ease of administration of SLIT makes this strategy very attractive as a form of early intervention in young children with IgE-mediated disorders, which could modify the natural course of allergic diseases. Studies addressing the use of SLIT in young children however have not been reported. Issues including standardization of the vaccines, establishment of effective doses and schedules for administration, compliance, and better understanding of mechanisms of action and magnitude of efficacy need further research [85].

Conclusions Evidence suggests that events taking place between 2 and 3 years of age might be crucial determinants in the development of allergies and asthma [86]. Strategies to prevent development of sensitization and progression to disease or to elicit long

390

L.K. Arruda et al.

Table 1 Recommendations based on the World Allergy Organization Project Report and Guidelines on Prevention of Allergy and Allergic Asthma – primary prevention Infants without a special risk for allergic diseases Exclusive breast feeding for 6 months is recommended by the WHO: if a supplement is needed, a conventional cow-milk-based formula is recommended (B) No special maternal diet during pregnancy or lactation (A) Avoidance of solid foods until 6 [4] months of age (B) Avoidance of exposure to tobacco smoke (also during pregnancy) (B) Infants with a high risk for allergic diseases Exclusive breast feeding for at least 6 months: if a supplement is needed, a documented hypoallergenic formula is recommended for the first 4 months of life; after the age of 4 months, high-risk children can receive the same nutrition as nonhigh-risk children (A) No special maternal diet during pregnancy or lactation (A) Avoidance of solid foods until 6 [4] months of age (B) Environmental measures Avoidance of tobacco smoke (also during pregnancy) (B) Reduction of allergen exposure early in life (house dust mites, furred pets, cockroaches) (B) Avoidance of damp housing conditions (C) Avoidance of pollutants (C)

Table 2 Recommendations based on the World Allergy Organization Project Report and Guidelines on Prevention of Allergy and Allergic Asthma – secondary prevention Avoidance of tobacco smoke (B) Patients who have perennial asthma, rhinitis, or eczema and who are allergic to house dust mites or animal dander should try to reduce their exposure to the relevant allergens (A, B). Recommended measures include: Removal of relevant pets Reduction of indoor relative humidity below 50% if possible Encasing of mattresses with documented protective coverings Washing of pillows in hot water (>55°C) regularly or encasing of pillows with documented protective coverings Washing of bedding in hot water (>55%) regularly (every 1–2 weeks) Removal of carpets in bedroom

lasting remission of symptoms are strongly desirable. However, current environmental interventions and treatment modalities with pharmacotherapy do not meet these expectations. According to the recent published World Allergy Organization Project Report and Guidelines on Prevention of Allergy and Allergic Asthma document [87], some evidence-based recommendations can be highlighted (Tables 1 and 2). Acknowledgments Dr. L. Karla Arruda’s research on risk factors for asthma in children in Brazil is supported by FAPESP and CNPq, Instituto de Investigação em Imunologia, L.K.A. and D.S. are recipients of CNPq scholarships.

Early Interventions in Allergic Diseases

391

References 1. Von Mutius E. Influences in allergy: epidemiology and the environment. J Allergy Clin Immunol 2004;113:373-9 2. Martinez FD. Development of wheezing disorders and asthma in preschool children. Pediatrics 2002;109:362–7 3. Gern J, Busse WW. The role of viral infections in the natural history of asthma. J Allergy Clin Immunol 2000;106:201–12 4. Piedra PA, Englund JA, Glezen WP. Respiratory syncytial virus and parainfluenza viruses. In: Richman DD, Whitley RJ, Hayden FG (eds) Clinical Virology. ASM Press, Washington, 2002, p763 5. Gwaltney JM Jr, Heinz BA. Rhinovirus. In: Richman DD, Whitley RJ, Hayden FG (eds) Clinical Virology. ASM Press, Washington, 2002, p 995. 6. Arruda E, Boyle TR, Winther B, Pevear DC, Gwaltney JM, Hayden FG. Localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization. J Infect Dis 1995;171:1329–33 7. Arruda E, Pitkaranta A, Witek TJ Jr, Doyle CA, Hayden FG. Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol 1997;35:2864–8 8. Malmström K, Pitkäranta A, Carpen P, Pelkonen A, Malmberg LP, Turpeinen M, Kajosaari M, Sarna S, Lindahl H, Haahtela T, Mäkelä MJ. Human rhinovirus in bronchial epithelium of infants with recurrent respiratory symptoms. J Allergy Clin Immunol 2006;118:591–6 9. Chung JY, Han TH, Kim SW, Kim CK, Hwang ES. Detection of viruses identified recently in children with acute wheezing. J Med Virol 2007;79:1238–43 10. Camara AA, Silva JM, Ferriani VPL, Tobias KR, Macedo IS, Padovani MA, Harsi CM, Cardoso MR, Chapman MD, Arruda E, Platts-Mills TA, Arruda LK. Risk factors for acute wheezing among children in a subtropical environment: role of respiratory viruses, IgE antibodies and allergen exposure. J Allergy Clin Immunol 2004;113:551–7 11. Heymann PW, Carper HT, Murphy DD, Platts-Mills TAE, Patrie J, McLaughlin AP, Shaker MS, Hellems M, Peerzada J, Hayden FG, Hatley TK, Chamberlain R. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol 2004;114: 239–47 12. Schaller M, Hogaboam CM, Lukacx N, Kunkel SL. Respiratory viral infections drive chemokine expression and exacerbate the asthmatic response. J Allergy Clin Immunol 2006;118:295–302 13. Copenhaver CC, Gern JE, Li Z, Shult PA, Rosenthal LA, Mikus LD, Kirk CJ, Roberg KA, Anderson EL, Tisler CJ, DaSilva DF, Hiemke HJ, Gentile K, Gangnon RE, Lemanske RF. Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life. Am J Respir Crit Care Med 2004;1170:175–80 14. Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL, Sly PD. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007;119:1105–10 15. Lemanske RF Jr. Viral infections and asthma inception. J Allergy Clin Immunol 2004;114:1023–26 16. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000;161:1501–7 17. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, Wright AL, Martinez FD. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354:541–5 18. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD. Tucson Children´s Respiratory Study: 1980 to present. J Allergy Clin Immunol 2003;111:661–75

392

L.K. Arruda et al.

19. Kotaniemi-Syrjanen A, Vainionpaa R, Reijonen TM, Waris M, Korhonen K, Korppi M. Rhinovirus-induced wheezing in infancy – the first sign of childhood asthma? J Allergy Clin Immunol 2003;111:66–71 20. Lemanske RF Jr, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, Kirk CJ, Reisdorf E, Roberg KA, Anderson EL, Carlson-Dakes KT, Adler KJ, Gilbertson-White S, Pappas TE, Dasilva DF, Tisler CJ, Gern JE. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 2005;116:571–7 21. Korppi M, Kotaniemi-Syrjanen A, Waris M, Vainionpää R, Reijonen TM. Rhinovirusassociated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis 2004;23:995–9 22. Silva JM, Camara AA, Tobias KR, Macedo IS, Cardoso MR, Arruda E, Chapman MD, PlattsMills TA, Arruda LK, Ferriani VP. A prospective study of wheezing in young children: the independent effects of cockroach exposure, breast-feeding and allergic sensitization. Pediatr Allergy Immunol 2005;16:393–401 23. Platts-Mills TAE, Rakes GP, Heymann PW. The relevance of allergen exposure to the development of asthma in childhood. J Allergy Clin Immunol 2000;105:S503–8 24. Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323:502–7 25. Eggleston PA, Rosenstreich D, Lynn H, Gergen P, Baker D, Kattan M, Mortimer KM, Mitchell H, Ownby D, Slavin R, Malveaux F. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102:563–70 26. Tobias KR, Ferriani VP, Chapman MD, Arruda LK. Exposure to indoor allergens in homes of patients with asthma and/or rhinitis in southeast Brazil: effect of mattress and pillow covers on mite allergen levels. Int Arch Allergy Immunol 2004; 33:365–70 27. Rullo VE, Rizzo MC, Arruda LK, Sole D, Naspitz CK. Daycare centers and schools as sources of exposure to mites, cockroach, and endotoxin in the city of São Paulo, Brazil. J Allergy Clin Immunol 2002;110:582–8 28. Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ 2002;324:1–5 29. Jartti T, Lehtinen P, Vuorinen T, Koskenvuo M, Ruuskanen O. Persistence of rhinovirus and enterovirus RNA after acute respiratory illness in children. J Med Virol 2004;72:695–9 30. Kling S, Dinninger H, Williams Z, Vermeulen J, Weinberg E, Latiff K, Ghildyal R, Bardin P. Persistence of rhinovirus RNA after asthma exacerbations in children. Clin Exp Allergy 2005; 35:672–8 31. Holgate S. Rhinoviruses in the pathogenesis of asthma: the bronchial epithelium as a major disease target. J Allergy Clin Immunol 2006;118:587–90 32. Hanson LA, Korotkova M, Telemo E. Breast-feeding, infant formulas, and the immune system. Ann Allergy Asthma Immunol 2003;90:59–63 33. Oddy WH. A review of the effects of breastfeeding on respiratory infections, atopy and childhood asthma. J Asthma 2004; 41:605–21 34. Sears MR, Greene JM, Willan AR, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Poulton R. Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study. Lancet 2002; 360:901–7 35. Bottcher MF, Jenmalm MC, Bjorksten B. Cytokine, chemokine and secretory IgA levels in human milk in relation to atopic disease and IgA production in infants. Pediatr Allergy Immunol 2003;14:35–41 36. Michel O, Ginanni R, Duchteau J, Vertongen F, Le Bom B, Sergysels R. Domestic endotoxin exposure and clinical severity of asthma. Clin Exp Allergy 1991;21:441–8 37. Michel O, Kips J, Duchateau J, Vertongen F, Robert L, Collet H, Pauwels R, Sergysels R. Severity of asthma is related to endotoxin in house dust. Am J Respir Crit Care Med 1996;154:1641–6

Early Interventions in Allergic Diseases

393

38. Asher I, Dagli E. Environmental influences on asthma and allergy. In: Johansson SGO, Haahtela T (eds) Prevention of Allergy and Allergic Asthma – World Allergy Organization Project Report and Guidelines. Karger, Basel, 2004, pp36–101 39. Gereda JE, Leung DYM, Thatayatikom A, Streib JE, Price MR, Klinnert MD, Liu AH. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitization in infants at high risk of asthma. Lancet 2000;355:1680–3 40. Gereda JE, Klinnert MD, Price MR, Leung DY, Liu AH. Metropolitan home living conditions associated with indoor endotoxin levels. J Allergy Clin Immunol 2001;107:790–6 41. Gerhold K, Avagyan A, Seib C, Frei R, Steinle J, Ahrens B, Dittrich AM, Blumchen K, Lauener R, Hamelmann E. Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J Allergy Clin Immunol 2006;118:666–73 42. Wang Y, McCusker C. Neonatal exposure with LPS and/or allergen prevents experimental allergic airway disease: development of tolerance using environmental antigens. J Allergy Clin Immunol 2006;118:143–51 43. Douwes J, van Strien R, Doekes G, Smit J, Kerkhof M, Gerritsen J, Postma D, de Jongste J, Travier N, Brunekreef B. Does early indoor microbial exposure reduce the risk of asthma? The Prevention and Incidence of Asthma and Mite Allergy birth cohort study. J Allergy Clin Immunol 2006;117:1067–73 44. Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grise L, Maisch S, Carr D, Gerlach F, Bufe A, Lauener RP, Schierl R, Renz P, Nowak D, von Mutius E. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002; 347: 869–77 45. Waser M, Schierl R, von Mutius E, Maisch S, Carr D, Riedler J, Eder W, Schreuer M, Nowak D, Braun-Fahrländer C; ALEX Study Team. Determinants of endotoxin levels in living environments of farmers’ children and their peers from rural areas. Clin Exp Allergy 2004;34:389–97 46. Thorne PS, Metwali N, Avol E, McConnel RS. Surface sampling for endotoxin assessment using eletrostatic wiping cloths. Ann Occup Hyg 2005;49:401–6 47. Ege MJ, Frei R, Bieli C, Schram-Bijkerk D, Waser M, Benz MR, Weiss G, Nyberg F, van Hage M, Pershagen G, Brunekreef B, Riedler J, Lauener R, Braun-Fahrländer C, von Mutius E; PARSIFAL Study team. Not all farming environments protect against the development of asthma and wheeze in children. J Allergy Clin Immunol 2007;119:1140–7 48. Simpson A, John SL, Jury F, Niven R, Woodcock A, Ollier WE, Custovic A. Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am J Respir Crit Care Med 2006;174:386–92 49. von Mutius E, Schmid S; PASTURE Study Group. The PASTURE project: EU support for the improvement of knowledge about risk factors and preventive factors for atopy in Europe. Allergy 2006;61:407–13 50. Svanes C, Jarvis D, Chinn S, Burney P. Childhood environmental and adult atopy: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol 1999;103:415–20 51. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA 2002;288:963–72 52. Apelberg BJ, Aoki Y, Jaakkola JJ. Systematic review: exposure to pets and risk of asthma-like symptoms. J Allergy Clin Immunol 2001;107:455–60 53. Fasce L, Tosca MA, Silvestri M, Olcese R, Pistorio A, Rossi GA. “Early” cat ownership and the risk of sensitization and allergic rhinitis in Ligurian children with respiratory symptoms. Ann Allergy Asthma Immunol 2005;94:561–5 54. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001;357:752–6 55. DiFranza JR, Aligne CA, Weitzman M. Prenatal and postnatal environmental tobacco exposure and children’s health. Pediatrics 2004;113:1007–15

394

L.K. Arruda et al.

56. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003;58:1053–8 57. Lannerö E, Wickman M, Pershagen G, Nordvall L. Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 2006;7:3 58. Gilliland FD, Berhane K, Li YF, Rappaport EB, Peters JM. Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med 2003;167:917–24 59. Macaubas C, Klerk NH, Holt BJ, Wee C, Kendall G, Firth M, Sly PD, Holt PG. Association between antenatal cytokine production and the development of atopy and asthma at age 6 years. Lancet 2003;362:1192–7 60. Penn AL, Rouse RL, Horohov DW, Kearney MT, Paulsen DB, Lomax L. In utero exposure to environmental tobacco smoke potentiates adult responses to allergen in BALB/c mice. Environ Health Perspect 2007;115:548–55 61. Wu H, Romieu I, Sienra-Monge JJ, Rio-Navarro BE, Anderson DM, Dunn EW, Steiner LL, Lara-Sanchez IC, London SJ. Parental smoking modifies the relation between genetic variation in tumor necrosis factor-a (TNF) and childhood asthma. Environ Health Perspect 2007;115:616–22 62. Morgan WJ, Crain EF, Gruchalla RS, O’Connor GT, Kattan M, Evans R, Stout J, Malindzak G, Smartt E, Plaut M, Walter M, Vaughn B, Mitchell H; Inner-City Asthma Study Group. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004;351:1068–80 63. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF, Strunk RC, Allen DB, Bloomberg GR, Heldt G, Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985–97 64. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005;171:315–22 65. Simpson A, Custovic A. Allergen avoidance in the primary prevention of asthma. Curr Opin Allergy Clin Immunol 2004;4:45–51 66. Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomised controlled study. Thorax 2003;58:489–93 67. Arshad SH, Bateman B, Sadeghnejad A, Gant C, Matthews SM. Prevention of allergic disease during childhood by allergen avoidance: the Isle of Wight prevention study. J Allergy Clin Immunol 2007;119:307–13 68. Chan-Yeung M, Ferguson A, Watson W, Dimich-Ward H, Rousseau R, Lilley M, Dybuncio A, Becker A. The Canadian Childhood Asthma Primary Prevention Study: outcomes at 7 years of age. J Allergy Clin Immunol 2005;116:49–55 69. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, Simpson A, Custovic A; NAC Manchester Asthma and Allergy Study Group. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 2004;170:433–9 70. Horak F, Matthews S, Ihorst G, Arshad SH, Frischer T, Kuehr J, Schwieger A, Forster J; The SPACE study group. Effect of mite-impermeable mattress encasings and an educational package on the development of allergies in a multinational randomized, controlled birth-cohort study – 24 months results of the Study of Prevention of Allergy in Children in Europe. Clin Exp Allergy 2004;34:1220–5 71. Koopman LP, van Strien RT, Kerkhof M, Wijga A, Smit HA, de Jongste JC, Gerritsen J, Aalberse RC, Brunekreef B, Neijens HJ; Prevention and Incidence of Asthma and Mite Allergy (PIAMA) Study. Placebo-controlled trial of house dust mite-impermeable mattress covers: effect on symptoms in early childhood. Am J Respir Crit Care Med 2002;166:307–13

Early Interventions in Allergic Diseases

395

72. Peat JK, Mihrshahi S, Kemp AS, Marks GB, Tovey ER, Webb K, Mellis CM, Leeder SR. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. J Allergy Clin Immunol 2004;114:807–13 73. Iikura Y, Naspitz CK, Mikawa H, Talaricoficho S, Baba M, Sole D, Nishima S. Prevention of asthma by ketotifen in infants with atopic dermatitis. Ann Allergy 1992;68:233–6 74. Bustos GJ, Bustos D, Bustos GJ, Romero O. Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 1995;25:568–73 75. Warner JO; ETAC Study Group. Early Treatment of the Atopic Child. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up. J Allergy Clin Immunol 2001;108:929–37 76. Simons FE; Early Prevention of Asthma in Atopic Children (EPAAC) Study Group. Safety of levocetirizine treatment in young atopic children: An 18-month study. Pediatr Allergy Immunol 2007;18:535–42. Epub 2007 Jun 11 77. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN study team. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomized, controlled study. Lancet 2006;368:754–62 78. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998–2005 79. Martinez FD. Asthma treatment and asthma prevention: a tale of 2 parallel pathways. J Allergy Clin Immunol 2007;119:30–3 80. Bousquet J, Lockey R, Malling HJ, Alvarez-Cuesta E, Canonica GW, Chapman MD, Creticos PJ, Dayer JM, Durham SR, Demoly P, Goldstein RJ, Ishikawa T, Ito K, Kraft D, Lambert PH, Lowenstein H, Muller U, Norman PS, Reisman RE, Valenta R, Valovirta E, Yssel H. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American academy of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998;81:401–5 81. Des Roches A, Paradis L, Menardo J-L, Bouges S, Daurés J-P, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extrat. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997;99:450–3 82. Pajno GB, Barbeiro G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitization in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six year follow-up study. Clin Exp Allergy 2001;31:1392–7 83. Möller C, Dreborg S, Ferdousi HA, Halken S, Høst A, Jacobsen L, Koivikko A, Koller DY, Niggemann B, Norberg LA, Urbanek R, Valovirta E, Wahn U. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-Study). J Allergy Clin Immunol 2002;l09:251–6 84. Niggeman B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S, Høst A, Koivikko A, Koller D, Norberg LA, Urbanek R, Valovirta E, Wahn U, Möller C; PAT Investigator Group. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 2006;61:855–9 85. Pajno GB. Sublingual immunotherapy: the optimism and the issues. J Allergy Clin Immunol 2007;119:796–801 86. Kurukulaaratchy RJ, Matthews S, Arshad SH. Does environment mediate earlier onset of the persistent childhood asthma phenotype? Pediatrics 2004;113:345–50 87. Host A, Boner A, Odhiambo J, Custovic A, Lockey R. Preventive measures: early interventions In: Joahansson SGO, Haahtela T (eds) Prevention of Allergy and Allergic Asthma – World Allergy Organization Project Report and Guidelines. Karger, Basel, 2004, pp135–151

Birth Cohort Studies for the Prevention of Allergy: New Perspectives—Where Do We Go from Now? Mascha Rochat and Erika von Mutius

Introduction There has been an increase in the prevalence of asthma and other allergic diseases in both industrialized and developing countries over the past decades [1]. In population based studies, prevalence estimates of asthma, atopic dermatitis, and allergic rhinitis vary from 7–10%, 15–20%, and 15–20%, respectively [2, 3], and different increase rates of each of these diseases have been reported in countries around the world [1, 4]. The reasons for this increase are still largely unknown, but interactions between various types of environmental exposures in populations with distinct genetic backgrounds have been proposed [1]. Allergic diseases have therefore become a major public health problem as well as a burden to health care resources, and they not only adversely affect the quality of life of millions of children and adults, but most importantly can be life-threatening in their most severe form. An urgent need to formulate strategies, leading to a reduction of their morbidity and mortality is thus required. This reduction could be achieved through primary or secondary prevention, and much research in both areas has been undertaken.

Study Design A necessary prerequisite for effective primary prevention measures is to know the different determinants of allergic diseases. Many determinants have been studied, discovered and defined through different study types during the last decades; but as described below, each of these study designs has distinct advantages and disadvantages, and should be adopted after due consideration.

M. Rochat and E. von Mutius () University Children’s Hospital, Lindwurmstr. 4, 80337, Munich, Germany e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_24, © Springer 2010

397

398

M. Rochat and E. von Mutius

Cross-Sectional Studies Most of the risk and protective factors such as housing conditions (dampness), allergen exposure, active and passive smoking, pet keeping, breastfeeding or viral infections were primarily identified through cross-sectional or retrospective studies. The term cross sectional study is used to describe a study design that measures the prevalence of exposures and diseases in a given population simultaneously. The potential of cross-sectional studies is to generate hypotheses and, in case of consistent findings across numerous studies, suggest causal relations, particularly, if doseresponse patterns can be observed. They are, however, limited in their capacity to describe a time sequence between potential risk factors and health effects. The fact that they can be done in a relatively short period of time and are less expensive than cohort studies confers advantages.

Cohort Studies To assess whether a time sequence, meaning the necessity for the cause to precede the outcome, is present, the study design should be prospective and include accepted welldefined diagnostic criteria and outcome measures, a sufficient duration of follow-up, and a proper sample size for adequate statistical evaluation [5]. In Ancient Rome, a cohort was one of ten divisions of a Roman military legion and was constituted with young men of similar age coming from one region. Members were often injured or killed in service but were not replaced. The cohort was then disbanded when the term of enlistment was over [6]. Historically, the term “cohort” was introduced into epidemiological studies in 1935 by Dr. Wade Frost, the leading US-American epidemiologist of the time [7]. He used the term to describe what would now be called generation studies. Over the years, its current meaning slowly emerged and a cohort study is now a well defined study design. A cohort study tracks outcome(s) forward in time. At the beginning of the observation period, the probands can be divided into two or more groups based on exposure, treatment, and/or risk factors. The groups are then followed for a period of time and the incidence of the outcome(s) is documented. The cohort can be drawn from the general population or a population at high risk for developing the respective disease. A birth cohort is a cohort of individuals born within a given period of time. It is often used to define a cohort of children followed since birth (or since pregnancy). Unfortunately cohort studies are very expensive and time consuming, and absence of follow-up may cause major problems.

Observational Birth Cohort Studies Observational cohort studies are considered “natural” experiments where the natural course is observed. Several observational birth cohort studies investigating allergies were initiated during the last decades. The aims were to identify risk factors that

Birth Cohort Studies for the Prevention of Allergy

399

could be modified to prevent or limit the development of allergic diseases; and predictors to target potential prevention strategies in the susceptible population.

Interventional Birth Cohort Studies For conclusive proof of evidence for causal relationships, well-designed, doubleblind randomised controlled trials or interventional cohort studies including a control for confounders, as well as proper registration of compliance and follow-up of dropouts are required [5]. In interventional studies, two or more groups are recruited at the beginning of the trial and one or more interventions are initiated. At least one group is left to its natural course and is used as a control. All groups are then followed for a given period of time. Unfortunately, interventional studies with proper randomisation and double blinding are not always possible. The effect of breastfeeding or maternal smoking, for example, cannot be tested by means of randomised controlled trials for obvious ethical reasons. Even though interventional studies can address either the general population or children at high risk of developing allergic diseases, most of them have been performed on high risk children to maximize the benefits, reduce the expense of recruiting a large population, and obtain maximum co-operation from the parents. The definition of high risk is, however, very heterogeneous. Some studies used a questionnaire based approach asking about allergy or asthma in first degree relatives (mother, biological father, siblings). Others confirmed the diagnosis with laboratory tests (specific IgE, skin-prick test or elevated cord blood IgE). Similarly, hereditary was defined either as single or multiple. In general, interventions aiming at the prevention of allergies can be categorized into two aspects: “avoidance” and “immune deviation”. The “avoidance” concept is based on the expectation that by avoiding allergens during the critical period of sensitization, the immune system will not react to these allergens later on and allergic diseases will not occur. The “immune deviation” concept postulates that the immune system can be “educated” to develop tolerance to environmental allergens. During the last decades, there have been an increasing number of prospective interventional birth cohorts, testing either one or multiple of the known risk or protective factors. Most of them have been based on the avoidance concept.

Defining Allergies As mentioned above, the determinants of allergic diseases are a prerequisite for preventive measures, but a precise definition of the disease is equally mandatory. Even though such a statement seems obvious, it is in fact a challenge to define an allergic “outcome”, as the term allergy describes various diseases among which asthma, allergic rhinitis and atopic dermatitis are the most common. But other diseases such as urticaria or food allergy can also be found under this umbrella term.

400

M. Rochat and E. von Mutius

Therefore, different research groups reporting on allergies may actually be reporting on very different disease entities. Atopic diseases were originally grouped under one term because they are associated with an elevation of either total or specific immunoglobulin E (IgE) (also termed “atopy”). This association is, however, loose and many patients with “atopic” illnesses have normal IgE levels and lack specific IgE antibodies in their serum. The relevance of allergic sensitization as an outcome is furthermore to be debated since not many children with a positive allergy test either as prick or RAST test are asymptomatic [8]. Given this ambiguity, the EAACI recently revised the nomenclature and proposed standard definitions in 2001 and subsequently in 2004 [9]. But, as these have not always been used, comparisons between the different studies are often difficult, if not impossible. This may partly explain why controversial results emerge from different studies. To complicate matters even further, some diseases have been divided into different phenotypes. Asthma, for example, which is a chronic inflammatory disorder of the airways that can cause recurrent episodes of wheezing, breathlessness, chest tightness, and cough in susceptible individuals has been shown to begin in early life with wheezing symptoms. Based on the time of onset, the natural course and the different risk factors and determinants, wheezing children can be grouped into at least three different phenotypes: transient wheezers (present only in the first 3 years of life); persistent wheezers (beginning in the first 3 years and persisting beyond 3 years of age); and late-onset wheezers (beginning between 3 and 6 years of age) [10]. Taking into account these different phenotypes, it can be postulated that asthma may not be one disease but rather a syndrome and that distinct mechanisms underlie the apparently equivalent clinical manifestations.

Natural Course of Allergic Illnesses It is very important to take into consideration the natural course of the disease when evaluating potential preventive measures. Even though no clinical symptoms are detectable at birth, recent studies show evidence that food and inhalant allergens can reach the fetal circulation [11]. However, the role of this exposure in determining subsequent patterns of immunologic memory and disease is conflicting [12, 13]. In infancy, the main allergic outcomes are atopic dermatitis, gastrointestinal symptoms and recurrent wheezing, whereas asthma and allergic rhinoconjunctivitis are the main diseases later in childhood [14]. Adverse reactions to foods, mainly cow’s milk, hen’s egg, peanut, wheat and soy protein are most common in the first years of life, whereas allergy to inhalant allergens such as house dust mites, animal dander and pollen mostly occurs later [15]. Recent findings from the German Multicentre Allergy Study (MAS) birth cohort suggest that in most cases asthma does not follow a first manifestation of atopic dermatitis claimed as “atopic march”. Rather, in most cases both conditions are either manifest in an individual child or the infant is only affected by one illness. The combination of conditions results in more severe asthma as well as more severe eczema, and lung function parameters are significantly reduced in these children at school age [16].

Birth Cohort Studies for the Prevention of Allergy

401

Risk Factors and Protective Exposures Prospective birth cohorts have helped us greatly to understand the natural history of allergic diseases by following a cohort of either high risk children or children representative of the general population for various periods of time. Additionally, most of them have studied, and reported specific risk or protective factors. These factors are briefly detailed below, with an emphasis on the ones that have been studied in interventional studies.

Nutrition Maternal Diet There is strong evidence that maternal dietary allergens can cross the placental barrier and pass into the breast milk [17, 18]. The hypothesis, that reduced maternal allergen intake may reduce fetal allergen exposure and thus avoid early sensitization was therefore tested in a number of studies. Mothers were asked to refrain from consuming a varying number of allergenic products (cow’s milk, eggs, peanuts, fish, citrus fruits) [19–21] either during pregnancy, lactation or both [19–22] for a period of time ranging from four weeks to a few months. Despite the variety of study approaches, no conclusive evidence of a preventive effect of maternal dietary restrictions during pregnancy or lactation on the development of allergic diseases was observed [19–23]. On the contrary, potential adverse effects on maternal nutritional status and on gestational weight gain, fetal growth and preterm birth have been observed [23]. As maternal dietary interventions did not have an effect on the development of allergic diseases, other dietary habits were investigated. The substantial shift in dietary fatty acid intake in many populations around the world favouring n-6 polyunsaturated fatty acid (PUFA) (margarine, vegetable oil) over n-3 PUFA (oily fish) resulted in the hypothesis that the intake of certain fatty acids may increase the risk of developing allergies. Observational studies assessing maternal dietary intake during the last 4 weeks of pregnancy [24] or the PUFA content of breast milk [25] concluded that low levels of n-3 PUFA intake correlated with the development of allergic diseases or atopic eczema during the first two years of life. These findings were, however, not confirmed when using skin test reactivity as an outcome [26]. Interventional studies are needed before any firm recommendation can be issued.

Breastfeeding A recent review of the literature [27] reported a protective effect of exclusive breastfeeding on the development of allergic diseases especially among high risk children. Even though one long-term prospective birth cohort confirmed these findings [28],

402

M. Rochat and E. von Mutius

several recent long-term observational birth cohort studies not included in the previously published meta-analyses have shown breastfeeding to be a risk factor for the development of allergic diseases mainly in high risk children [29]. Matheson et al [30] followed a cohort from childhood to middle-age and concluded that “in high risk children, breast-feeding, although important for the protection of the infant against early wheezing illness (asthma), eczema, and food allergies, does not appear to protect against the development of asthma, allergic rhinitis, or food and inhalant allergies in the long term”. Truly randomised interventional birth cohorts on exclusive breastfeeding cannot be performed for ethical reasons, but Kramer et al [31] used a similar approach and performed a cluster randomised trial by selecting at random study areas in Bellarussia where breastfeeding was promoted. The investigators followed 13,889 children up to the age of 6 years. Children in the interventional sites were significantly more likely to be breastfed and by the age of 6 years no protective effect of prolonged and exclusive breastfeeding on asthma or allergy was found.

Hypoallergenic Infant Formula If breastfeeding is not possible, products with highly reduced allergenicity based on hydrolysed protein or amino acid mixtures can be used as a substitute. A number of interventional cohort studies on different formulas have been undertaken. Most of the studies were performed in high risk populations, only a few were in the general population. The study designs and formulas under investigation differed considerably between the studies, which rendered comparisons difficult [32]. Cow’s milk was compared to hydrolyzed or extensively hydrolyzed casein formula or to partially hydrolyzed or extensively hydrolyzed whey formula in different combinations. Taken together, the results indicate that a hydrolysed formula is not superior to exclusive breastfeeding for the prevention of allergy. Among high risk infants who cannot be exclusively breastfed, there is some evidence to suggest that prolonged feeding with a hydrolysed formula as compared to a cow’s milk formula reduces transiently the incidence of infant and childhood atopic dermatitis, but not asthma in the first years of life [33]. Longitudinal studies following children up to school age are needed to see whether there is any prolonged benefit from such interventions.

Infantile Diet The evidence that introduction of solid foods to infants before 4 months of age increases the risk of allergic diseases is conflicting. In general, there is insufficient evidence to suggest that on its own, the early introduction of solids to infants is associated with an increased incidence of asthma, food allergy and allergic rhinitis. Unfortunately, many studies lack a rigorous design and are thus susceptible to multiple biases. No evidence was found to support a delayed introduction

Birth Cohort Studies for the Prevention of Allergy

403

of solid foods beyond the sixth month of life for the prevention of atopic dermatitis or atopic sensitization [34]. However, there is a consistent association between the persistence of eczema and the introduction of solid foods before age 4 months that is supported by long term follow-up studies and the dose-dependent nature of the association. Furthermore, it is also noteworthy that the preventive effect of breastfeeding and hydrolyzed formulas was only observed in studies including avoidance of complementary foods during at least the first 4 months of life [35]. Clearly, additional evidence from well designed randomised longitudinal studies is needed to endorse recommendations on delayed solid food introduction in infancy. Prospective studies investigating the potential effects of other dietary factors such as fish oil, omega-3 fatty acids, antioxidants (vitamin C, vitamin E and selenium), magnesium or sodium which have been found to be either protective or risk factors in cross-sectional studies are still awaited.

Probiotics Observational studies have found a correlation between the colonization of the gastrointestinal tract with lactobacillus as well as eubacteria and a decrease in allergic diseases [34]. During the last years, interventional birth cohorts have therefore examined the effect of different doses of probiotics (live microbial food ingredients) on the development of allergic diseases. All studies were conducted on high risk infants and each studied a different probiotic bacterial strain. After administering either the probiotics Lactobacillus GG, Lactobacillus reuteri or a mixture of four probiotics and one prebiotic to pregnant women and subsequently to their offspring for the first 6 [36, 37] and 12 [38] months, three studies saw a protective effect on the incidence of eczema [36] and atopic eczema [37, 38] up to the age of 2 [37, 38] and 7 years [36]. One survey administered Lactobacillus acidophilus to infants during the first 6 months, but not to their mothers during pregnancy [39]. The authors found an increase in atopic eczema, but did not see an effect on the cumulative incidence of eczema at the age of 12 months. Whether these contrasting results are attributable to different bacterial strains or to the postnatal administration remains unclear. Moro et al. showed a beneficial effect of a mixture of prebiotic oligosaccharides (GOS/FOS) added to bottle fed infants in reducing the incidence of atopic eczema during the first six months of age [40]. Taken together, the current evidence suggests that probiotics might have a preventive effect on the development of eczema. However, in our opinion, a number of issues remain unanswered which preclude firm recommendations on the use of probiotics for the prevention of allergies: which is the best probiotic strain? What is the optimal dose? Is there any effect among children from the general population without a family history of atopic diseases in first degree relatives? Is this preventive effect prolonged into childhood years? Are other allergic illnesses such as asthma and hay fever also amenable to prevention by the administration of probiotics?

404

M. Rochat and E. von Mutius

Environmental Factors As mentioned above, two concepts prevail with respect to potential preventive strategies. One concept is based on the rationale of risk factor avoidance, particularly of allergen avoidance. The other complementing concept is based on the identification of protective factors, in particular the hygiene hypothesis postulating that “allergies may be the result of a misdirected immune response in the absence of infection” [41]. Many, mostly cross-sectional studies aiming at the identification of harmful and protective environmental exposures for the development of allergies have been performed. In the following sections we will focus on cohort studies investigating either avoidance or immune modulation pathways.

Environmental Tobacco Smoke Environmental tobacco smoke (ETS) exposure either during pregnancy or early life is one of the most consistent risk factors for the development of respiratory symptoms, wheezing and asthma [1]. Active smoking has been associated with the onset of asthma in adolescents and adults in a number of studies [1]. Exposure to ETS is therefore the most important preventable inducer and trigger of asthma. Because of the consistence of findings across numerous populations worldwide, the avoidance of ETS is warranted for the prevention of asthma and other respiratory diseases. There is less evidence, however, to suggest that ETS exposure also affects the incidence of atopic sensitisation.

Traffic Related Pollution While it is well accepted that air pollution in general can trigger symptoms in children with established asthma [42], its influence on the development of allergies is not clear. Cross sectional studies have shown strong evidence to support an association between air pollutants associated with traffic exposure and respiratory health, however, the evidence is conflicting regarding the development of allergic diseases and atopic sensitization. To our knowledge there are only two observational cohort studies among children investigating traffic pollution and health outcome at the ages of two and four years, respectively. As acknowledged by the authors, the short duration of follow-up, limits the interpretation of the results, and the positive relation with wheezing, asthma, and sensitization to food allergens must therefore be interpreted with caution [43, 44].

Inhaled Allergens The level of aeroallergen exposure varies according to the geo-economic situation. House dust mite (HDM) is the most important allergen in humid climates; pet allergens might be more relevant in colder countries; Alternaria species prevail in dry

Birth Cohort Studies for the Prevention of Allergy

405

climates and cockroach is one of the dominant allergens in inner-city areas in the US. These allergens have been investigated in numerous studies over the past decades, because their exposure affects a persons risk of developing IgE antibodies against them [45]. Without allergens in the environment, specific sensitization towards that allergen cannot occur. In a German birth cohort, the levels of HDM and cat allergen concentrations in domestic carpet dust were strongly related to the development of atopic sensitization towards these allergens in the first 3–7 years of life [46]. A clear dose-response relationship was found as well as a strong effect modification by the familial background, for atopic diseases. In the group of children with a positive family history of atopy, mite allergen concentration below 750 ng/gm dust resulted in a 3% sensitization rate, whereas in the group of children without a positive family exposure up to 25,000 ng/mg dust was associated with a sensitization rate of 3%. These findings indicate that no general exposure threshold for allergic sensitization can be proposed. As might be expected HDM exposure was not related to the propensity of mounting IgE responses towards other environmental antigens. Likewise, the propensity to develop asthma may not be affected by levels of environmental allergen exposure. This notion is supported by findings from prospective cohort studies where no relation between the level of exposure to HDM and the incidence of asthma and persistent wheeze was found [45]. However, the interaction of higher indoor allergen exposure and the development of atopic sensitization towards these allergens in the first 3 years of life resulted in more severe asthma [47]. Recent findings from a number of interventional studies have further corroborated these notions. In the interventional studies, HDM reduction measures were initiated either during pregnancy or at birth, and the children were followed until the ages of 7–8 years old. Although a reduction of HDM could be documented after radical allergen reduction measures were undertaken, the results of one study showed an increased risk in mite sensitization at the age of 3 years, an increase in atopic dermatitis and no significant differences in respiratory symptoms between the interventional and the control groups by the age of 8 [48]. Other studies, using more practical interventional measures such as mattress covers, showed no protective effect on the prevalence of asthma and atopic sensitization up to the age of 2 years [49, 50]. In inner-city areas in the US comprehensive environmental interventions to decrease indoor allergen levels, including cockroach and dust-mite allergens, resulted in reduced asthma-associated morbidity among 5 to 11 year old children [51].

Pets As with other allergens, exposure to pet allergen increases the risk of subsequent specific sensitization and thus potentially increases the incidence of allergic diseases. This notion was challenged in 1999 by studies showing that early life exposure to pets was associated with a lower prevalence of allergic rhinitis and asthma at school age and reduced cat sensitization as well as atopy in adulthood. A review of the associations between pet exposure, asthma and asthma like

406

M. Rochat and E. von Mutius

symptoms was therefore undertaken by Apelberg in 2001 who concluded that in children over 6 years of age there was a significant increase in the risk of asthma or wheezing, but in children younger than 6 years, exposure to pets had a protective effect [52]. Since then, there have been a number of prospective studies showing a reduced risk of allergic diseases or allergic sensitization in children exposed to cats or dogs in infancy, but consistency among these studies is lacking. Parental, mostly maternal history of asthma or atopy seems to exert significant effect modification with pet exposure being a risk factor in high risk children and a protective factor in low risk children. Additionally, there seems to be marked differences between different animal species, with exposure to dogs showing a more consistent pattern of protection than exposure to cats [53]. An interesting question in analyzing the relationship between pet exposure and allergic sensitization or allergic disease is whether it is exposure to high levels of allergens given off by the pet or exposure to an undefined environmental factor(s) related to the pet that contribute(s) protectively to the determination of the outcome, presumably by effects on the maturation of the immune system [54]. Furthermore, these results must be regarded with caution because of the possibility of reverse causation due to already implemented avoidance strategies in families with atopic heredity. As of today, the available literature does not provide conclusive guidance regarding the effects of pet exposure early in life.

Family Size/Day Care Among the most consistent associations is Strachan’s original observation that exposure to siblings reduces the risk of developing allergic diseases such as hay fever and eczema [55]. Whether this effect is attributable to an increase of the number of infections transmitted by “unhygienic” contact with older siblings or due to other unknown factors associated with an increased number of pregnancies is unknown. In the absence of a large family, exposure to children in early child care seems to have a similar protective effect [56]. Several observational studies have confirmed these findings in recent years [57, 58]. One cross-sectional study from Kramer et al. found an association between daycare attendance in the first year of life and the development of allergic diseases in single child families [59]. Positive associations were reported in two prospective birth cohorts. Celedon et al. found an inverse association between day care attendance in the first year of life and total serum IgE levels at the age of two [60], and eczema, as well as asthma and recurrent wheezing in the first 6 years of life among high risk children. This effect was not seen among offsprings of mothers with a history of asthma, where day care attendance was associated with an increased risk of wheezing [61]. In the Tucson birth cohort, young children’s exposure to other children in or out of the home was found to result in more frequent wheezing in the first few years of life and subsequently to decreased levels of serum IgE concentrations, skin test reactivity and to protection against the development of asthma and frequent wheezing later in childhood [62].

Birth Cohort Studies for the Prevention of Allergy

407

Infections Few prospective birth cohorts have investigated the potential effect of early infections on the development of atopy [63–66]. Three studies showed a protective effect, while no effect was seen in one survey. With respect to wheeze and asthma, studies investigating the effect of early life respiratory tract infections must be interpreted with caution. Bias by reverse causation is likely to occur since viral infections are the most potent trigger of asthma exacerbations. Respiratory syncitial virus (RSV) may, however, be particularly associated with asthma. A number of studies have consistently shown that children with a history of RSV bronchiolitis have an increased risk of developing repeated wheezing and asthma up to school age. Whether the RSV infection is the culprit or whether the determining factor is an asthmatic’s susceptibility to develop (severe) bronchiolitis after RSV infection remains unresolved. A recent cohort study provided some evidence that both arguments may be justified [67]. Findings from cross-sectional studies, mainly based on serological results, have suggested that other infectious agents such as hepatitis A, herpes, EBV, salmonella, helicobacter pylori, mycobacteria and lactobacilli [68] may be linked to the development of allergies. However, little is known from prospective studies.

Microbial Exposures in the Environment There is increasing evidence from cross-sectional studies to suggest that an environment rich in microbial compounds may protect from the development of allergic diseases. So far, few prospective studies have investigated the role of such exposures and these studies have focussed on assessing endotoxin, the cell wall component of gram negative bacteria. Two prospective birth cohorts found that endotoxin exposure in infancy among high risk children was associated with an increased incidence of wheeze and inconsistently with an increased incidence of atopic dermatitis, but not rhinitis or atopy in the first years of life [69, 70]. In contrast, another study showed that prenatal exposure to endotoxin was associated with a reduction in cord blood immunoglobulin E production suggesting that maternal cytokine production modulates the foetal immune cells [71]. But the infant’s exposure to endotoxin had no protective effect on the development of atopy until the age of 2 years [72]. These discrepancies between studies might be explained by recent data from a birth cohort showing that exposure to endotoxin exerts a protective effect only in individuals with a particular genetic background (CC genotype for CD14/_159) [73].

Antibiotics/Vaccinations/Paracetamol Antibiotics and vaccinations have been postulated to interfere with the immune response in the developing immune system and thus to enhance the development of allergic diseases. But here again, results from observational cohort studies are conflicting.

408

M. Rochat and E. von Mutius

While no association has been found between antibiotics and the subsequent development of asthma in a number of prospective birth cohorts and recently summarised in a meta-analysis [74], some prospective birth cohorts have shown a positive association between antibiotics administered during pregnancy or lactation and the development of allergic diseases in the offspring [75, 76]. According to the hygiene hypothesis, infections might confer protection from the development of allergic illnesses. Following this argument, it was proposed that vaccinations may play a role in the incidence of allergic disorders. However, two recent reviews of the literature came to the conclusion, that there is no epidemiological evidence to suggest an association between infant vaccinations and the development of allergic diseases [77, 78]. Since 2000, cross sectional, case control and ecologic studies have analysed and consistently reported a dose response association between paracetamol (acetaminophen) use and the development of wheeze and asthma. One possible mechanism might be mediated by an imbalance in the oxidant/antioxidant equilibrium leading to oxidant damage in the lung [79]. Reverse causation may, however, significantly bias these associations. Since paracetamol is given for fever and infectious diseases, the reported associations may merely reflect the strong relation between viral infections and asthma. In this context it is interesting to note that a prospective birth cohort found an association between paracetamol administered during late pregnancy and the development of asthma, wheeze and elevated total IgE by the age of 6–7 years [80].

Multifaceted Interventional Studies The studies described above used a monofaceted approach, studying one protective exposure or one preventive measure. Overall, the results of theses studies are rather disappointing. One explanation might be that the development of complex diseases, such as allergic illnesses, is attributable to a number of environmental influences. Accordingly, the avoidance of one single factor may not be sufficient. Some studies have therefore used a multifaceted approach, asking the parents to avoid or eliminate various known risk factors. All were performed among high risk children. The Isle of Wight study started the intervention postnatally. The investigators combined dietary restrictions in the lactating mothers and their children during the first year of their life with HDM reduction measures. The results at the age of 8 years suggest that such a combined approach is mostly effective for reducing atopy and may prevent some cases of childhood asthma depending on the phenotypic characteristic of the child [81]. The Canadian Childhood Asthma Primary Prevention Study used a combination of dietary restrictions in the mothers during pregnancy and lactation and encouraged them to breast-feed and delay the introduction of solid foods during the first year of life of their children. Additionally, intervention measures introduced before birth and during the first year of life included avoidance of HDM, pets, environmental tobacco smoke and day care facilities. The results showed a significant reduction in the prevalence of asthma and asthma symptoms, but not allergic rhinitis, atopic dermatitis, atopy or bronchial hyperresponsiveness at 7 years

Birth Cohort Studies for the Prevention of Allergy

409

of age. Since there was no difference between the groups for the objective parameters and since the controls could not be blinded towards the intervention, the preventive effect may at least in part be attributable to some underreporting in the active arm [82]. The Prevention of Asthma in Children study (PREVASC) combined prenatal HDM and pet allergen avoidance strategies with dietary interventions and restrictions in passive smoking. The results showed no effective reduction in asthmalike symptoms at the age of two years [83]. The Australian Childhood Asthma Prevention Study (CAPS) combined a reduction in HDM allergen measures with dietary fatty acid supplementation. The results at 5 years showed that the measures did not prevent the onset of asthma, eczema or atopy. As in other studies the reduction of HDM increased the risk of eczema [84].

Secondary and Tertiary Prevention in Cohort Studies There have been a number of studies investigating the potential of secondary and tertiary preventive measures through medications aiming at either preventing the onset of disease among predisposed subjects such as the Early Treatment of the Atopic Child (ETAC) study or at the prevention of a chronic course of asthma. The ETAC study, a multi-centre European double-blind, randomised, placebo-controlled study, investigated the potential of cetirizine (antihistamine) to prevent the development of asthma in infants with atopic dermatitis. However, this trial failed since no effect on asthma prevention was seen in the active arm [85]. The hypothesis that the treatment with inhaled corticosteroids at the onset of infant asthma might improve long-term asthma outcome is built on the observation that in many asthmatic children an ongoing chronic inflammatory process is associated with a loss of lung function by early childhood which extends into adult life. Within a birth cohort, a subsample of infants was randomised after either one prolonged (> 1 month) or two medically confirmed wheezy episodes to a treatment with Fluticasone propionate twice daily or to a control group. At the age of 5 years, the results showed that the early use of inhaled corticosteroids had no effect on the natural history of asthma or wheeze later in childhood and did not prevent lung function decline or reduce airway reactivity [86]. Likewise, a nested interventional study of another cohort showed that early intermittent inhaled budesonide therapy had no effect on the progression from episodic to persistent wheezing and no short-term benefit during episodes of wheezing in the first three years of life [87].

Conclusion Birth cohort studies investigating determinants of allergic illnesses have substantially contributed to our understanding of the natural course of allergic diseases and associated features. They have identified a number of potential harmful and protective determinants, but consistency across populations is often lacking. Recommendations on a

410

M. Rochat and E. von Mutius

population level, based on these findings, can in our opinion, only be issued for tobacco smoke avoidance for the prevention of asthma and other respiratory conditions. With respect to eczema and food allergy, the administration of hypoallergenic milk formula can be recommended for high risk children if prolonged breastfeeding is not possible. All other strategies have to be scrutizined in view of the results obtained so far.

Where do we go from now? The lack of understanding of the significant determinants of allergic illnesses may be attributable to a number of reasons [1]. A basic requirement for the demonstration of a causal relation between an exposure and a disease is the temporal sequence of events. Only exposures occurring before the first symptoms of an illness can influence its inception. Birth cohorts have the advantage of documenting temporal sequences and thus facilitating conclusions on causal relations. But the disparity and heterogeneity of findings in the literature are remarkable, and reflect the complexity of allergic diseases. Environmental exposures potentially causing the new onset of allergies are likely to occur during fetal life and early childhood. Any potential risk factor is likely to interact with an underlying, genetically determined pathway resulting in the manifestation of disease. But the mechanisms underlying allergic illnesses are not fully understood. This lack of understanding may in part be attributable to the fact that allergic illnesses are a syndrome of many diseases rather than one entity. The context in which exposures occur and interact with a subject’s individual pathophysiological pathways is another important factor in the causation of allergies. Variation in these pathways is determined by genes. Environmental exposures interact with these pathways. However, these interactions do not occur in isolation. Pathways have more than one component and the function of each component is determined by the gene or genes contributing to and regulating the processes. If in fact more than one pathway leads to the development of allergies, then not only many genes with small individual contributions, but also many environmental factors and gene–environment interactions will eventually be found to contribute to disease manifestation. Hence, different contexts in which a number of different exposures interact with various genetic backgrounds in a range of racial or ethnic groups will eventually result in changes in the incidence of allergies. The challenge in the years to come will be to integrate complex interactions between multiple exposures and numerous genetic variants to achieve an understanding of the causation of asthma.

References 1. Eder W, Ege MJ, von Mutius E (2006) The asthma epidemic. N Engl J Med 355(21): 2226–35 2. Sly RM (1999) Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol 82(3):233–48; quiz 248–52

Birth Cohort Studies for the Prevention of Allergy

411

3. Schultz Larsen F (1996) Atopic dermatitis: an increasing problem. Pediatr Allergy Immunol 7(9 Suppl):51–3 4. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, Williams H (2006) Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368(9537):733–43 5. Host A, Halken S (2002) Can we apply clinical studies to real life? Evidence-based recommendations from studies on development of allergic diseases and allergy prevention. Allergy 57(5):389–97 6. Webb P, Bain C, Pirozzo S (2005) Essential Epidemiology, an introduction for Students and Health Professionals. Second ed, Cambridge, Cambridge University Press, pp 7. Frost WH (1995) The age selection of mortality from tuberculosis in successive decades. 1939. Am J Epidemiol 141(1):4–9; discussion 3 8. Stevenson MD, Sellins S, Grube E, Schroer K, Gupta J, Wang N, Khurana Hershey GK (2007) Aeroallergen sensitization in healthy children: racial and socioeconomic correlates. J Pediatr 151(2):187–91 9. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC (2004) Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 113(5):832–6 10. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ (1995) Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 332(3):133–8 11. Prescott SL (2006) Maternal allergen exposure as a risk factor for childhood asthma. Curr Allergy Asthma Rep 6(1):75–80 12. Rowe J, Kusel M, Holt BJ, Suriyaarachchi D, Serralha M, Hollams E, Yerkovich ST, Subrata LS, Ladyman C, Sadowska A, Gillett J, Fisher E, Loh R, Soderstrom L, Ahlstedt S, Sly PD, Holt PG (2007) Prenatal versus postnatal sensitization to environmental allergens in a highrisk birth cohort. J Allergy Clin Immunol 119(5):1164–73 13. Hagendorens MM, Ebo DG, Bridts CH, Van de Water L, De Clerck LS, Stevens WJ (2004) Prenatal exposure to house dust mite allergen (Der p 1), cord blood T cell phenotype and cytokine production and atopic dermatitis during the first year of life. Pediatr Allergy Immunol 15(4):308–15 14. Wahn U (2000) What drives the allergic march? Allergy 55(7):591–9 15. Nickel R, Lau S, Niggemann B, Gruber C, von Mutius E, Illi S, Kulig M, Wahn U (2002) Messages from the German Multicentre Allergy Study. Pediatr Allergy Immunol 13(Suppl 15):7–10 16. Illi S, von Mutius E, Lau S, Nickel R, Gruber C, Niggemann B, Wahn U (2004) The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 113(5):925–31 17. Vadas P, Wai Y, Burks W, Perelman B (2001) Detection of peanut allergens in breast milk of lactating women. Jama 285(13):1746–8 18. Edelbauer M, Loibichler C, Nentwich I, Gerstmayr M, Urbanek R, Szepfalusi Z (2004) Maternally delivered nutritive allergens in cord blood and in placental tissue of term and preterm neonates. Clin Exp Allergy 34(2):189–93 19. Falth-Magnusson K, Kjellman NI (1992) Allergy prevention by maternal elimination diet during late pregnancy--a 5-year follow-up of a randomized study. J Allergy Clin Immunol 89(3):709–13 20. Lilja G, Dannaeus A, Foucard T, Graff-Lonnevig V, Johansson SG, Oman H (1989) Effects of maternal diet during late pregnancy and lactation on the development of atopic diseases in infants up to 18 months of age--in-vivo results. Clin Exp Allergy 19(4):473–9 21. Hattevig G, Sigurs N, Kjellman B (1999) Effects of maternal dietary avoidance during lactation on allergy in children at 10 years of age. Acta Paediatr 88(1):7–12 22. Lovegrove JA, Hampton SM, Morgan JB (1994) The immunological and long-term atopic outcome of infants born to women following a milk-free diet during late pregnancy and lactation: a pilot study. Br J Nutr 71(2):223–38

412

M. Rochat and E. von Mutius

23. Kramer MS, Kakuma R (2006) Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. Cochrane Database Syst Rev 3:CD000133 24. Sausenthaler S, Koletzko S, Schaaf B, Lehmann I, Borte M, Herbarth O, von Berg A, Wichmann HE, Heinrich J (2007) Maternal diet during pregnancy in relation to eczema and allergic sensitization in the offspring at 2 y of age. Am J Clin Nutr 85(2):530–7 25. Hoppu U, Rinne M, Lampi AM, Isolauri E (2005) Breast milk fatty acid composition is associated with development of atopic dermatitis in the infant. J Pediatr Gastroenterol Nutr 41(3):335–8 26. Stoney RM, Woods RK, Hosking CS, Hill DJ, Abramson MJ, Thien FC (2004) Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants. Clin Exp Allergy 34(2):194–200 27. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA, Host A, Kuitunen M, Olsen SF, Skerfving S, Sundell J, Wille S (2003) Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 58(9):833–43 28. Saarinen UM, Kajosaari M (1995) Breastfeeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old. Lancet 346(8982):1065–9 29. Bergmann RL, Diepgen TL, Kuss O, Bergmann KE, Kujat J, Dudenhausen JW, Wahn U (2002) Breastfeeding duration is a risk factor for atopic eczema. Clin Exp Allergy 32(2):205–9 30. Matheson MC, Erbas B, Balasuriya A, Jenkins MA, Wharton CL, Lai-Kuan Tang M, Abramson MJ, Walters EH, Hopper JL, Dharmage SC (2007) Breast-feeding and atopic disease: A cohort study from childhood to middle age. J Allergy Clin Immunol 31. Kramer MS, Matush L, Vanilovich I, Platt R, Bogdanovich N, Sevkovskaya Z, Dzikovich I, Shishko G, Mazer B (2007) Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial. Bmj 32. Osborn DA, Sinn J (2006) Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev(4):CD003664 33. von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grubl A, Wichmann HE, Bauer CP, Reinhardt D, Berdel D (2007) Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German Infant Nutritional Intervention Study. J Allergy Clin Immunol 119(3):718–25 34. Bjorksten B, Naaber P, Sepp E, Mikelsaar M (1999) The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 29(3):342–6 35. Halken S (2004) Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention. Pediatr Allergy Immunol 15 Suppl 16:4–5, 9–32 36. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E (2001) Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357(9262):1076–9 37. Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, Kuitunen M (2007) Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 119(1):192–8 38. Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, Oldaeus G (2007) Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 119(5):1174–80 39. Taylor AL, Dunstan JA, Prescott SL (2007) Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 119(1):184–91 40. Moro G, Arslanoglu S, Stahl B, Jelinek J, Wahn U, Boehm G (2006) A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 91(10):814–9

Birth Cohort Studies for the Prevention of Allergy

413

41. Strachan DP (1989) Hay fever, hygiene, and household size. Bmj 299(6710):1259–60 42. Tatum AJ, Shapiro GG (2005) The effects of outdoor air pollution and tobacco smoke on asthma. Immunol Allergy Clin North Am 25(1):15–30 43. Morgenstern V, Zutavern A, Cyrys J, Brockow I, Gehring U, Koletzko S, Bauer CP, Reinhardt D, Wichmann HE, Heinrich J (2007) Respiratory health and individual estimated exposure to traffic-related air pollutants in a cohort of young children. Occup Environ Med 64(1):8–16 44. Brauer M, Hoek G, Smit HA, de Jongste JC, Gerritsen J, Postma DS, Kerkhof M, Brunekreef B (2007) Air pollution and development of asthma, allergy and infections in a birth cohort. Eur Respir J 29(5):879–88 45. Lau S, Illi S, Sommerfeld C, Niggemann B, Bergmann R, von Mutius E, Wahn U (2000) Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 356(9239):1392–7 46. Wahn U, Lau S, Bergmann R, Kulig M, Forster J, Bergmann K, Bauer CP, GuggenmoosHolzmann I (1997) Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 99(6 Pt 1):763–9 47. Illi S, von Mutius E, Lau S, Niggemann B, Gruber C, Wahn U (2006) Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet 368(9537):763–70 48. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, Simpson A, Custovic A (2004) Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 170(4):433–9 49. Horak F, Jr., Matthews S, Ihorst G, Arshad SH, Frischer T, Kuehr J, Schwieger A, Forster J (2004) Effect of mite-impermeable mattress encasings and an educational package on the development of allergies in a multinational randomized, controlled birth-cohort study – 24 months results of the Study of Prevention of Allergy in Children in Europe. Clin Exp Allergy 34(8):1220–5 50. Brunekreef B, Smit J, de Jongste J, Neijens H, Gerritsen J, Postma D, Aalberse R, Koopman L, Kerkhof M, Wilga A, van Strien R (2002) The prevention and incidence of asthma and mite allergy (PIAMA) birth cohort study: design and first results. Pediatr Allergy Immunol 13 Suppl 15:55–60 51. Morgan WJ, Crain EF, Gruchalla RS, O’Connor GT, Kattan M, Evans R, 3rd, Stout J, Malindzak G, Smartt E, Plaut M, Walter M, Vaughn B, Mitchell H (2004) Results of a homebased environmental intervention among urban children with asthma. N Engl J Med 351(11):1068–80 52. Apelberg BJ, Aoki Y, Jaakkola JJ (2001) Systematic review: Exposure to pets and risk of asthma and asthma-like symptoms. J Allergy Clin Immunol 107(3):455–60 53. Gern JE, Reardon CL, Hoffjan S, Nicolae D, Li Z, Roberg KA, Neaville WA, Carlson-Dakes K, Adler K, Hamilton R, Anderson E, Gilbertson-White S, Tisler C, Dasilva D, Anklam K, Mikus LD, Rosenthal LA, Ober C, Gangnon R, Lemanske RF, Jr. (2004) Effects of dog ownership and genotype on immune development and atopy in infancy. J Allergy Clin Immunol 113(2):307–14 54. Ownby DR, Johnson CC (2003) Does exposure to dogs and cats in the first year of life influence the development of allergic sensitization? Curr Opin Allergy Clin Immunol 3(6):517–22 55. Karmaus W, Botezan C (2002) Does a higher number of siblings protect against the development of allergy and asthma? A review. J Epidemiol Community Health 56(3):209–17 56. Marks GB (2006) Environmental factors and gene-environment interactions in the aetiology of asthma. Clin Exp Pharmacol Physiol 33(3):285–9 57. Biagini JM, LeMasters GK, Ryan PH, Levin L, Reponen T, Bernstein DI, Villareal M, Khurana Hershey GK, Burkle J, Lockey J (2006) Environmental risk factors of rhinitis in early infancy. Pediatr Allergy Immunol 17(4):278–84 58. Infante-Rivard C, Amre D, Gautrin D, Malo JL (2001) Family size, day-care attendance, and breastfeeding in relation to the incidence of childhood asthma. Am J Epidemiol 153(7):653–8

414

M. Rochat and E. von Mutius

59. Kramer U, Heinrich J, Wjst M, Wichmann HE (1999) Age of entry to day nursery and allergy in later childhood. Lancet 353(9151):450–4 60. Celedon JC, Litonjua AA, Ryan L, Weiss ST, Gold DR (2002) Day care attendance, respiratory tract illnesses, wheezing, asthma, and total serum IgE level in early childhood. Arch Pediatr Adolesc Med 156(3):241–5 61. Celedon JC, Wright RJ, Litonjua AA, Sredl D, Ryan L, Weiss ST, Gold DR (2003) Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am J Respir Crit Care Med 167(9):1239–43 62. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL (2000) Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 343(8):538–43 63. Illi S, von Mutius E, Lau S, Bergmann R, Niggemann B, Sommerfeld C, Wahn U (2001) Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. Bmj 322(7283):390–5 64. Zutavern A, von Klot S, Gehring U, Krauss-Etschmann S, Heinrich J (2006) Pre-natal and post-natal exposure to respiratory infection and atopic diseases development: a historical cohort study. Respir Res 7:81 65. Nafstad P, Brunekreef B, Skrondal A, Nystad W (2005) Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort. Pediatrics 116(2):e255–62 66. Ramsey CD, Gold DR, Litonjua AA, Sredl DL, Ryan L, Celedon JC (2007) Respiratory illnesses in early life and asthma and atopy in childhood. J Allergy Clin Immunol 119(1):150–6 67. Gern JE, Brooks GD, Meyer P, Chang A, Shen K, Evans MD, Tisler C, Dasilva D, Roberg KA, Mikus LD, Rosenthal LA, Kirk CJ, Shult PA, Bhattacharya A, Li Z, Gangnon R, Lemanske RF, Jr. (2006) Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life. J Allergy Clin Immunol 117(1):72–8 68. Schaub B, Lauener R, von Mutius E (2006) The many faces of the hygiene hypothesis. J Allergy Clin Immunol 117(5):969–77; quiz 978 69. Park JH, Gold DR, Spiegelman DL, Burge HA, Milton DK (2001) House dust endotoxin and wheeze in the first year of life. Am J Respir Crit Care Med 163(2):322–8 70. Gillespie J, Wickens K, Siebers R, Howden-Chapman P, Town I, Epton M, Fitzharris P, Fishwick D, Crane J (2006) Endotoxin exposure, wheezing, and rash in infancy in a New Zealand birth cohort. J Allergy Clin Immunol 118(6):1265–70 71. Heinrich J, Bolte G, Holscher B, Douwes J, Lehmann I, Fahlbusch B, Bischof W, Weiss M, Borte M, Wichmann HE (2002) Allergens and endotoxin on mothers’ mattresses and total immunoglobulin E in cord blood of neonates. Eur Respir J 20(3):617–23 72. Bolte G, Bischof W, Borte M, Lehmann I, Wichmann HE, Heinrich J (2003) Early endotoxin exposure and atopy development in infants: results of a birth cohort study. Clin Exp Allergy 33(6):770–6 73. Simpson A, John SL, Jury F, Niven R, Woodcock A, Ollier WE, Custovic A (2006) Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am J Respir Crit Care Med 174(4):386–92 74. Marra F, Lynd L, Coombes M, Richardson K, Legal M, Fitzgerald JM, Marra CA (2006) Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis. Chest 129(3):610–8 75. Kummeling I, Stelma FF, Dagnelie PC, Snijders BE, Penders J, Huber M, van Ree R, van den Brandt PA, Thijs C (2007) Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics 119(1):e225–31 76. Jedrychowski W, Galas A, Whyatt R, Perera F (2006) The prenatal use of antibiotics and the development of allergic disease in one year old infants. A preliminary study. Int J Occup Med Environ Health 19(1):70–6 77. Gruber C, Nilsson L, Bjorksten B (2001) Do early childhood immunizations influence the development of atopy and do they cause allergic reactions? Pediatr Allergy Immunol 12(6):296–311

Birth Cohort Studies for the Prevention of Allergy

415

78. Koppen S, de Groot R, Neijens HJ, Nagelkerke N, van Eden W, Rumke HC (2004) No epidemiological evidence for infant vaccinations to cause allergic disease. Vaccine 22(25–26): 3375–85 79. Allmers H (2005) Frequent acetaminophen use and allergic diseases: is the association clear? J Allergy Clin Immunol 116(4):859–62 80. Shaheen SO, Newson RB, Henderson AJ, Headley JE, Stratton FD, Jones RW, Strachan DP (2005) Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood. Clin Exp Allergy 35(1):18–25 81. Arshad SH, Bateman B, Matthews SM (2003) Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomised controlled study. Thorax 58(6):489–93 82. Chan-Yeung M, Ferguson A, Watson W, Dimich-Ward H, Rousseau R, Lilley M, Dybuncio A, Becker A (2005) The Canadian Childhood Asthma Primary Prevention Study: outcomes at 7 years of age. J Allergy Clin Immunol 116(1):49–55 83. Schonberger HJ, Dompeling E, Knottnerus JA, Maas T, Muris JW, van Weel C, van Schayck CP (2005) The PREVASC study: the clinical effect of a multifaceted educational intervention to prevent childhood asthma. Eur Respir J 25(4):660–70 84. Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, Ampon RD, Crisafulli D, Belousova EG, Mellis CM, Peat JK, Leeder SR (2006) Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol 118(1):53–61 85. Wahn U (1998) Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Early Treatment of the Atopic Child. Pediatr Allergy Immunol 9(3):116–24 86. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A (2006) Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): doubleblind, randomised, controlled study. Lancet 368(9537):754–62 87. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F (2006) Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 354(19):1998–2005

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma Susan L. Prescott

Introduction As asthma and allergic diseases reach epidemic proportions, there is an urgent need to identify early the logical targets for strategies to reverse this trend. The frequent onset of disease within the first months of life necessitates early interventions. While it has been well recognized that allergic disease is multifactorial, conventional allergy prevention strategies have largely centered around avoidance of allergens and irritants with disappointing results. More recently, there has been a shift in focus to the role of immunomodulatory factors both as aetiologic factors and as possible avenues of early treatment and/or prevention [88]. Preliminary studies suggest that other environmental exposures (such as infection [1], maternal diet [2, 3], and smoking [3, 4]) can modify early immune function, although the mechanisms are not clear (Fig. 1). While potential genetic polymorphisms are of great importance in understanding the complex gene-environmental interactions during this period, genomic programming cannot account for the rising rates of disease. There has been a consequential shift in interest to environmental factors that may influence early immune development potentially through epigenetic modification in gene expression. This includes potentially environment-driven changes in the patterns of DNA methylation in proximal gene promoters, chromatin remodeling, histone modifications, and/or non-coding RNA interactions that can alter the patterns of gene expression and clinical phenotype (Fig. 1) [89]. With rising disease rates, there is a continuing urgency to identify the pathways involved and to explore and monitor the effects of early interventions that could

S.L. Prescott () School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia Princess Margaret Hospital, P.O. Box D184, Perth, WA, 6001, Australia e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_25, © Springer 2010

417

418

S.L. Prescott

Environmental Factors

Diet Microbes

Pollutants

Allergens OTHER?

Epigenetic modification

Genetic predisposition

Effects on Immune Development Clinical Phenotype

Fig. 1 Effects of environmental factors on immune development

favorably influence immune development and prevent allergic disease. This review explores the role of a range of novel immunomodulatory strategies including dietary interventions (including fatty acids, antioxidants, and prebiotics), the use of microbial agents (including probiotics, mycobacteria and other bacterial adjuvants), as well as the role of allergen immunotherapy for the primary prevention of disease. In this context, “primary” prevention refers to measures that may reduce the development of manifest allergic disease in individuals who have not previously had any evidence of disease. This review does not address conventional strategies, or strategies to alter the expression of already established disease.

The Need for Early Interventions for Allergy Prevention Allergic disorders including atopic dermatitis, food allergies, allergic rhinitis, and asthma, are collectively among the most common diseases in western societies. Rates of allergic sensitization are now reaching 40% in industrialized regions, with the same concerning trends now apparent in many developing societies. This highlights the urgent need to determine underlying mechanisms and to develop effective, preferably non-invasive and cost effective strategies to prevent disease and reverse these trends. Any strategy that reduces the burden of disease (even slightly) could have an enormous impact in a global context.

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

419

Limitations of Current Strategies Until recently, most of the interest has focused on the role of allergens in the development of disease. Although evidence was limited, this was the basis for recommending avoidance of allergenic” foods and indoor allergens (particularly house dust mites and pets) for primary allergy prevention. However, the results of intervention studies using these strategies have been disappointing (as summarized elsewhere [5]) or even paradoxic [6]. It now appears more likely that other factors are likely to influence the development of sensitization rather than allergen encounter per se. This has led to a growing focus on the potential role of other immunomodulatory factors including microbial products and dietary nutrients. Other novel allergy prevention studies are focusing on the potential role of controlled allergen administration (immunotherapy) rather than on allergen avoidance (as above). Notably, there are also studies underway to assess the role of regular, early exposure to potentially allergenic foods (such as peanut) to induce tolerance. Although this approach is the exact opposite of existing “avoidance” approaches, there is a strong logical basis for pursuing this method of preventing allergic disease, as discussed further below.

Identifying Target Populations for Prevention Strategies - the Need for Better Allergy Predictors Children born into atopic families are more likely to develop allergic diseases (50–80% risk) compared to those with no family history of atopy (20%). These children are commonly described as “high risk” for the purpose of prevention strategies, as there are currently no other more accurate (e.g. biological) markers of allergic risk. As potentially more effective interventions for disease prevention are developed (such as primary sublingual immunotherapy), it will become more crucial to more accurately identify children who will develop disease. The development of allergic disease is frequently preceded by immunologic differences that are already evident in the neonatal period [7–12]. The most consistently observed difference has been reduced T cell production of IFNg [7–12], suggesting that relative T cell immaturity may be an important contributor to disease development. Although it is not clear whether this T cell “defect” is primary or secondary to antigen presenting cell immaturity, our findings (below) support the presence of intrinsic differences in T cells from neonates with subsequent allergic disease. Despite the relationships between Type 1 (Th1) IFNg production and allergy risk [7–12], this has not been a reliable predictive marker because it (along with other functional measures) relies on inherently variable in vitro culturing systems with potent polyclonal stimulants that potentially distort patterns of response [13]. There are currently no other biological markers that have any established predictive value [13]. Cord blood IgE (CB-IgE), the only neonatal marker to be extensively

420

S.L. Prescott

evaluated as a likely predictor context, was shown to be unreliable in this context (reviewed in [13]). Although the specificity of this test ranged between 60 and 70% in several studies, the sensitivity (26–47%) and positive predictive value (22–42%) were generally very poor in predicting allergic disease [14–17]. For the first time, we recently discovered that the ‘fingerprint’ pattern of neonatal T cell PKC isozyme expression significantly predicts subsequent allergic disease (as detailed in [18]), and that the predictive effect was stronger than any other biological marker. Moreover, we have demonstrated that an intervention designed to prevent allergic disease (maternal dietary supplementation with fish oil) significantly modified the expression of the same neonatal PKC pathway (discussed further below and in [18]). These findings provide a strong basis for investigating this pathway further as a potential neonatal screening test for allergy prediction and potential target for prevention. Until these and other markers are further investigated, “family history” of allergic disease remains the only crude predictor of allergic disease in use, with variable specificity (48–67%) and sensitivity (22–72%) and a positive predictive value generally less than 40% [14–16]. Using receiveroperator curves (ROC), we recently determined that a neonatal PKCz level of £ 62% of adult control levels was able to predict allergic disease with a sensitivity of 80% and a specificity of 63% (and an accuracy of 71%, the proportion of correctly classified individuals based on subsequent outcomes) [18] as shown on Fig. 2. We are now exploring the value of this parameter as a disease predictor in larger cohort studies. Using neonatal PKCζ in the prediction of subsequent allergic disease

ROC Cu rve 1.00

Sensitivity = 80%

.75

.50

.25

0.00 0.00

.25

.50

.75

1.00

1 - Specificity

Specificity = 63% PKCζ <62.3% (of control) predicted disease with optimal specificity and sensitivity

Fig. 2 Sensitivity and Specificity of PKCz in predicting allergic disease

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

421

Novel Non-Invasive Strategies Using Dietary Nutrients to Prevent Disease Dietary factors are among the leading candidates in the rising rates of allergic disease [19]. Modern diets differ in many respects from more traditional diets, with more complex, processed, and synthetic foods and less fresh fish, fruits, and vegetables. As a result, there have been many changes in the intakes of various dietary components. These changes include decreased consumption of omega 3 PUFA (n-3 PUFAs), antioxidants and nondigestable oligosaccarides (prebiotics), and fermented foods (containing probiotics). These factors are also of particular interest as they have the potential to modulate inflammatory responses, and may promote oral tolerance (Fig. 3). However, while most studies have focused on the specific role of individual factors, it is important to recognize that this “single component” approach does not fully address the “composite effects” of diets and dietary changes (or interaction with other environmental factors). It remains essential to recognize the overall complexity of dietary changes in the wider context. (1) The role of dietary fatty acids and fatty acid supplements Modern diets contain less essential n-3 PUFA and elevated levels of n-6 PUFA, and similar changes are seem in infant diets with parallel changes in breast milk composition [20]. The initial studies to link these trends to the rise in allergic disease noted protective relationships between the consumption of oily fish in childhood and the development of asthma and wheeze [21–23], although there has been some evidence to the contrary [24]. Several studies of maternal diet during pregnancy have also reported reduced risk of childhood eczema [25] and asthma [26, 27], with high maternal consumption of n-3 PUFA from fish oil. A large UK cohort (n = 1,238) also suggested a link between cord blood n-3:n-6 levels and higher risk for eczema and late onset wheeze, however that these associations were not significant after Dietary Factors that may influence tolerance:

Diet / Environment (Gut flora)

Systemic immune tolerance

• Pattern of food allergen exposure (timing, dose, interval) • Factors affecting colonisation - prebiotics - probiotics (gut maturity / permeability / pH) • Other immunomodulatory factors: - breast feeding - fatty acids - antioxidants - role of dietary contaminants?

Fig. 3 Dietary Factors that may influence tolerance

422

S.L. Prescott

adjustment for multiple comparisons [28]. Collectively, these studies indicate PUFA have immunological properties that may regulate early immune development. In keeping with this, a recent Boston cohort study reported associations between cord blood immune responses and maternal fatty acid levels in pregnancy [29]. There is also a strong immunological basis for the observations, including anti- inflammatory effects of n-3 PUFA on wide-ranging aspects cellular function including antigen presenting cell (APC) function, T cell function, and the production of inflammatory products (prostaglandins and leukotrienes), as reviewed elsewhere [30]. This logically stimulated interest in the potential benefits of n-3 PUFA (fish oil) supplementation in early life for modulating early immune function and preventing allergic inflammation. These notions have been supported by observed effects of maternal fish oil supplementation on neonatal immune function [2, 31]. Most recently, we have noted that maternal fish oil supplementation was associated with significantly higher neonatal expression of a key T cell intracellular signaling molecule (PKC zeta; P = 0.014), whereas most other isozymes were reduced by fish oil supplementation [32]. Most notably, increased PKC zeta expression was associated with significantly reduced risk of allergic disease in later infancy [32]. This marker may not only be of value as a “predictive tool”, but may also be of value in assessing effectiveness of interventions aimed at allergy prevention, and needs to be investigated further. Despite the immunological effects and epidemiologic associations, there have been few intervention studies to examine the role of fish oil supplementation in allergy prevention. Currently, there has only been one published study to specifically address this (although others are anticipated soon), and the results were disappointing. The Childhood Asthma Prevention Study (CAPS) studied the effects of a daily supplement of tuna fish oil (500 mg oil/day; along with margarines and cooking oils rich in n-3 fatty acids) in infants at high risk of allergy (based on family history). The control group received a placebo supplement plus polyunsaturated margarines and cooking oils. This intervention commenced at 6 months of age or at weaning (which ever occurred first). Although early assessment indicated a reduction of respiratory symptoms (wheeze, coughing) at 18 month [33] and 3-years [34], there was no reduction in the development of atopy, asthma, or other allergic disease by five years of age [35]. The only other randomized controlled trial to report effects of fish oil supplementation of allergy prevention was designed to assess the effects of maternal fish oil supplementation during pregnancy (3.7 g n-3 PUFA/day) on neonatal immune function. In addition to the immunomodulatory effects, there was also a threefold reduction in the clinical detection of egg sensitization (OR = 0.34, P = 0.055) by one year of age. Although there was no difference in the propensity to develop atopic dermatitis, infants in the fish oil group had significantly less severe disease (OR = 0.09, P = 0.045) [2]. However, this study was too small to be conclusive. A more recent study has now also shown a significant reduction both in food allergy and IgE-associated eczema in children fish oil whose mothers were supplemented with daily fish oil from the 25 weeks gestation to 3–4 months of breastfeeding (compared with a placebo group) [90]. The only study to assess long term allergy outcomes has been a recently published 16 year follow-up of children involved in a pregnancy fish oil supplementation study (originally performed to assess pregnancy outcomes such as gestational length {Olsen,

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

423

1992 #594}), which showed a reduction in subsequent asthma [91]. Currently there are several more studies in progress (in Europe and Australia), which are specifically designed to assess this, and the results are awaited with great interest. Until this has been addressed more definitively, fish oil supplementation cannot be recommended specifically for allergy prevention. (2) The role of antioxidants Recent dietary changes also included declining intakes of antioxidants (such as vitamin C, vitamin E, beta-carotene, zinc, and selenium). Although there is no evidence that these trends are “causally” associated, there have been preliminary epidemiological studies that suggest an association between lower intakes of antioxidant rich foods (such as fresh fruits and vegetables) with deficit effects on pulmonary function [36], and increased risk of wheeze in both adults [37] and children [38, 39]. It has been hypothesized that these epidemiological associations may reflect a protective effect of antioxidant rich diets in the development of allergic diseases such as asthma [40, 41]. Although the full effects of antioxidants in immune development have not been thoroughly documented, the immunological properties of antioxidants have supported this hypothesis. Dendritic cells have been shown to promote the development of regulatory T cells in vitro in the presence of vitamin C and E antioxidants [42]. Studies in humans have also demonstrated that by favorably altering the ‘redox’ status of cells, antioxidants can enhance IL-12 production by APC [43], favor development of T helper cell type 1 (Th1) responses, and inhibit the development of allergic type 2 (Th2) responses. Speculation that these dietary changes could possibly have beneficial effects on developing immune responses has been the rationale for examining the relationship between antioxidant exposure during pregnancy and early childhood. One of the first studies to examine this noted an inverse relationship between cord blood mononuclear cell proliferative responses to allergens and maternal vitamin E intake during pregnancy [3]. Although the significance of this is not clear, this provided preliminary evidence that maternal dietary factors could potentially have antenatal influences and could be implicated in the increasing propensity for allergic symptoms in early childhood. Since then, the same group has reported that low maternal intake of vitamin E in utero is associated with an increased risk of developing childhood wheeze, asthma, and eczema by two and five years of age [40, 44]. More recently, they have also shown that maternal vitamin D intake during pregnancy may have the potential to reduce early childhood wheezing [45]. A Boston study has also reported that maternal intakes of vitamin E and zinc were negatively associated with wheezing at two years of age, although they did not observe any correlations between antioxidant intake and the risks of eczema in the same children [46]. Relationships between allergic disease and other antioxidant levels, such as vitamin C, have been inconsistent. Some studies have suggested negative associations (increased risk of wheezing) with increased vitamin C intake [44], while others have demonstrated beneficial decreases in the risk of wheeze [38, 47]. It is likely that maternal antioxidant intake during pregnancy does influence the antioxidant status of the developing fetus and potentially modulates the risk and development of childhood atopy [3, 48, 49]. It is also possible that this could influence or

424

S.L. Prescott

alter developing immune functions in the neonate. However, without any randomized controlled trials, this is difficult to prove definitively. Until these concepts are better understood, and concerns about potential adverse effects of antioxidant supplementation [50] are addressed, there is currently no place for specific antioxidant vitamin supplementation specifically for allergy prevention. Importantly, it is likely that fresh foods (such as fruits and vegetables) may have additional ‘protective’ properties that cannot be replicated by specific vitamin supplements, many of which may be synthetic [51]. Thus, while the potential role of antioxidants in immune regulation is unclear, it is best to advocate a healthy balanced diet rather than specific vitamin supplementation. (3) The role of dietary prebiotic and probiotic supplements Colonization of the intestinal tract is essential for development of normal immune tolerance. This has generated great interest in the role of dietary supplements that can favorably modify intestinal flora. Animal models have clearly demonstrated that impaired intestinal colonization can lead to failed oral tolerance and predisposition to inflammatory diseases [52]. In humans, pre-symptomatic differences in perinatal intestinal colonization patterns have also been documented in children who subsequently develop allergic disease [53, 54]. “Probiotics” are the main dietary supplements that have been used to favorably influence colonization. These are live commensal micro-organisms that (at an optimal dose) exert health benefits. The first study to explore the effect of probiotics in allergy prevention was performed by a Finnish group [55]. They administered Lactobacillius rhamnosus (or a placebo) to mothers (starting 2–4 weeks before delivery) and to infants in the first 6 months of life. The probiotic was associated with a 50% reduction in the incidence of eczema [55]; although the cumulative effect on eczema was still evident at 4 years [56], there was no reduction in respiratory allergy, IgE levels, or allergic sensitization. However, a number of methodical concerns have been raised [57] making the results difficult to interpret. There are now more than 16 other published studies and at least four other studies in progress to examine the effects of various probiotic strains for allergy prevention, most using direct infant supplementation as recently reviewed [92, 93]. The first of these (using a Lactobacillus acidophilus) failed to show any reduction in allergic disease despite changes in colonization, but instead reported an increase in sensitization and in IgE-associated atopic eczema [58]. The second study used a combination of strains (and prebiotic galacto-oligosaccharides) to show a reduction in atopic eczema, but no effects on sensitization or other allergic disease [59]. The third study, showed no effect of Lactobacillus reuteri on the prevention of allergic disease or sensitization [60]. However, subgroup analyses showed that probiotics were associated with less IgE-associated atopic eczema and less sensitization in a subgroup with atopic mothers. The results of more recent studies have been summarised elsewhere [92, 93]. Explanations for the varied results between studies include host factors (including genetic differences in microbial responses and allergic predisposition) and other environmental factors, such as general microbial burden, individual microbiota, diet (including consumption of prebiotic substances), and treatment with antibiotics. As more studies are completed, these factors are likely to make robust meta-analyses problematic to

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

425

perform. Despite all the immunomodulatory effects described in experimental models, so far, none of these studies has shown any clear effect on preventive sensitization or any allergic disease other than eczema. One important concern is the potential for contamination of these supplements with milk antigens during the manufacture process, which may pose a risk for children highly allergic to milk proteins [61]. It seems unlikely that supplementation with a single strain can influence the complex intestinal microbial population. This has lead to a focus on dietary substrates that can influence the growth profile of intestinal microflora, most notably nondigestable, but fermentable oligosaccharides (prebiotics). These substrates favor beneficial bacterial species (including bifidobacteria and lactobacilli). The first trials for allergy prevention are only just emerging and show promising results [62]. Moro et al. recently reported that “prebiotic” supplementation with a mixture of galacto- and long chain fructo-oligosaccharides for the first six months of life in high risk formula fed infants significantly increased bifidobacteria colonization (but had no effect on lactobacilli). This effect on colonization was associated with a significant reduction in the development of atopic dermatitis. In summary, while there is a sound theoretical basis for exploring the preventative effects of probiotics and prebiotics, further studies are needed before specific recommendations are appropriate.

Novel Strategies using other Microbial Products Reduced early microbial exposure in early life has become a leading candidate to explain the escalating rate of allergic disease. Infants depend on “signals” from the microbial environment to mature both Th1 and regulatory immune function. These signals, mediated through pattern-recognition receptors such as toll like receptors (TLR), appear essential to achieving the immunological balance required for (a) pathogens protection and (b) normal immune tolerance. These strategies have been used very successfully in vaccines against infectious diseases, and may also logically play a future role in the prevention of noninfectious immune diseases. (a) The role of CpG and other adjuvants in allergy “vaccinations” Broadly speaking, bacterial adjuvants such as immunostimulatory sequences (ISS) unmethylated cytosine and guanosine CpG motifs have more “Th1 polarizing” effects in mature individuals. Although these are not presently used in current vaccines, there has been growing interest in the potential role of these adjuvants in promoting perinatal Th1 responses. This is clearly of interest not only in enhancing early protection from infection, but also, as a strategy, in inhibiting the development of Th2 allergic responses in high risk infants. This remains largely theoretical at present, and there is ongoing concern about other unpredictable effects on the developing immune system. In established allergic disease, bacteria have also been used as adjuvants in allergen immunotherapy for many decades [63]. There are now many studies that demonstrate that CpG immunostimulatory sequences of oligodeoxynucleotides (ISS-ODN) inhibit airways inflammation, eosinophilia, IgE responses,

426

S.L. Prescott

Th2 (IL-5) responses and bronchial hyper-reactivity, and remodeling [64–66]. In mice, the administration of ISS-ODN coupled to rag weed allergen (Amb a 1) induced a Type 1 sustained biased (IFNg) response to Amb a 1, with concurrent IgE suppression [67]. Notably, it appears that this strategy will be more effective in down-regulating developing rather than established immune responses [67]. (b) Potential concerns about the use of immune adjuvants in infants Bacterial-derived adjuvants are already used extensively in existing infant vaccines to enhance immune responses against infectious disease. While adjuvants are very broadly regarded as Th1 or Th2 promoters, responses are often mixed and not exclusively polarized. However, Recent studies in animals suggests that “Th1 adjuvants” (such as complete Freund’s adjuvant [CFA]) have paradoxical effects in neonatal animals [68] with inhibition of murine Th1 responses (IgG2a, IL-2, and IFNg responses) and enhanced Th2 (IL-5) responses. In human neonatal mononuclear cell cultures, we recently demonstrated that CpG motifs not only enhance Th1 IFNg responses to vaccines antigens (and other environmental proteins such as house dust mite antigen), but also result in significantly enhance Th2 responses to these proteins. This suggests that CpG may not have the same Th1 polarizing effects in neonates, and needs to be investigated further. Thus, ethical considerations and uncertainties about long term effects are likely to delay the investigation of similar strategies in children, particularly in the absence of existing disease. (c) The use of mycobacterial products As potent Th1 immunostimulants, mycobacteria antigens have also been considered as agents for both prevention and treatment of allergic disease (reviewed in [69]). In sensitized animals, mycobacteria have also been associated with improved pulmonary function [70], reduced airways inflammation [71], eosinophilia [72], and expression of adhesion molecules [73]. Although the mechanisms are not clear, there is some evidence in animals that mycobacterium give rise to allergen specific CD4+CD45B-low regulatory cells that mediate a reduction in airways inflammation through the production of TGFb and IL-10 [74]. In humans, BCG vaccination has also been associated with reduced total and specific IgE in allergic individuals [75–77], and improved lung function in asthmatics [78]. Intradermal administration of mycobacteria has previously been used therapeutically in children with existing atopic dermatis with some success [79]. In newborns, BCG can influence immune responses to other antigens (vaccine antigens) promoting both Th1 and Th2 responses [76]. Although BCG administration in the neonatal period does not appear to reduce the risk of developing allergic disease [80, 81], as with many other agents, the role of mycobacterial antigens for disease prevention still needs to be investigated further. (d) Role of bacterial endotoxin administration Natural exposure to endotoxin (typically in association with animals) has been associated with reduced allergy risk in some [82] but not all studies [83]. To the author’s knowledge, there is only one study, still in progress, that is investigating the effects of endotoxin administration in a randomized controled trial. The results are not yet known.

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

427

(e) Genetic polymorphisms in microbial recognition could influence effectiveness of these interventions Genetic studies presently provide evidence that functional variations in aspects of TLR microbial signaling may be associated with the expression of the allergic phenotype. Specifically, polymorphisms in the gene coding for CD14 (involved in LPS signaling through TLR4) have been linked to total serum IgE levels [84]. More recently, a TLR2 genetic polymorphism was shown to have a protective effect on asthma [85]. Notably, the “protective” effect was only seen when children were raised in environments with “high” microbial burden, illustrating the interactive effects of genetic and environmental factors on these pathways. Together these findings suggest that functional genetic polymorphisms in microbial recognition pathways could result in individual variation in the effectiveness of microbial products in disease prevention.

The Role of Allergen Immunotherapy Other new allergy prevention studies are focusing on the potential role of controlled allergen administration (immunotherapy) rather than allergen avoidance. Concepts of an integrated mucosal immune system have been used to explain the remote effects of both “natural” tolerance and tolerance “induced” by mucosal immunotherapy. In the respiratory tract, the bulk of ambient aeroallergen exposure occurs in the “upper” airway. Under normal conditions, this appears to result in the generation of a CD4+CD25+ regulatory T cells and low level Th1 responses. This is the basis for the therapeutic use of mucosal allergen administration to induce systemic tolerance, and has been most successful using a sublingual route (sublingual immunotherapy [SLIT]). There are a growing number of reports of clinical benefits in established disease, including those of children [86]. There is also preliminary evidence that SLIT may reduce the risk of asthma developing in children with allergic rhinitis [87]. Novel studies are now planned to examine the effects of SLIT for primary prevention of aeroallergen sensitization. In this proposed randomized controlled trial, 200 children (aged 18 months to 3 years and at high risk of developing allergic respiratory disease) will receive inhalant allergen SLIT (house dust mite, cat, and timothy grass) or a placebo for 12 months. These children will already have evidence of allergic disease (food allergy or atopic dermatitis) but no sensitization to inhalants. The children will be monitored for 3 years, aiming to detect a 50% reduction in IgE and allergic Th2 responses to allergens, as well as a 50% reduction in asthma (www.immunetolerance.org/research/ allergy/trials/holt.html).

Future Directions Currently, our capacity to prevent allergic disease is constrained by limited understanding of disease pathogenesis and aetiological factors, particularly of the early exposures responsible for the recent increase in allergic disease. As the specific

428

S.L. Prescott

pathways involved in disease pathogenesis are more clearly defined, it will be possible to develop more efficient (possibly molecular) targets for intervention and more accurately identify infants who will otherwise go on to develop disease.

References 1. T Matsuoka, T Matsubara, K Katayama, K Takeda, M Koga, S Furukawa. Increase of cord blood cytokine-producing T cells in intrauterine infection. Pediatr Int 2001;43(5):453–7. 2. J Dunstan, TA Mori, A Barden, LJ Beilin, A Taylor, PG Holt, SL Prescott. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised controlled trial. J Allergy Clin Immunol 2003;112:1178–84. 3. G Devereux, RN Barker, A Seaton. Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy 2002;32(1):43–50. 4. PS Noakes, PG Holt, SL Prescott. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003;58(10):1053–8. 5. SL Prescott, ML Tang. The Australasian Society of Clinical Immunology and Allergy position statement: summary of allergy prevention in children. Med J Aust 2005;182(9):464–7. 6. A Woodcock, LA Lowe, CS Murray, BM Simpson, SD Pipis, P Kissen, A Simpson, A Custovic. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 2004;170(4):433–9. 7. MLK Tang, AS Kemp, J Thorburn, D Hill. Reduced interferon gamma secretion in neonates and subsequent atopy. Lancet 1994;344:983–85. 8. JA Warner, EA Miles, AC Jones, DJ Quint, BM Colwell, JO Warner. Is deficiency of interferon gamma production by allergen triggered cord blood cells a predictor of atopic eczema? Clin Exp Allergy 1994;24:423–30. 9. F Martinez, D Stern, A Wright, C Holberg, L Taussig, M Halonen. Association of interleukin-2 and interferon-g production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy. J Allergy Clin Immunol 1995;96:652–60. 10. N Kondo, Y Kobayashi, S Shinoda et al. Reduced interferon gamma production by antigenstimulated cord blood mononuclear cells is a risk factor of allergic disorders–6-year followup study. Clin Exp Allergy 1998;28(11):1340–4. 11. S Prescott, C Macaubas, T Smallacombe, B Holt, P Sly, R Loh, P Holt. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999;353(9148):196–200. 12. SL Prescott, C Macaubas, T Smallacombe, BJ Holt, PD Sly, R Loh, PG Holt. Reciprocal agerelated patterns of allergen-specific T-cell immunity in normal vs. atopic infants. Clin Exp Allergy 1998;28 Suppl 5:39–44; discussion 50–1. 13. JP Allam, O Zivanovic, Berg C., U Gembruch, T Bieber, N Novak. In search for predictive factors for atopy in human cord blood. Allergy 2005;60:743–50. 14. DW Hide, SH Arshad, R Twiselton, M Stevens. Cord serum IgE: an insensitive method for prediction of atopy. Clin Exp Allergy 1991;21:739–43. 15. RL Bergmann, G Edenharter, KE Bergmann et al. Predictability of early atopy by cord blood IgE and parental history. Clin Exp Allergy 1997;27:752–60. 16. LG Hansen, S Halken, A Host, K Møller, O Østerballe. Prediction of allergy from family history and cord blood IgE levels. Pediatr Allergy Immunol 1993;4(1):34–40. 17. S Croner, N-I Kjellman. Predictors of atopic disease: cord blood IgE and month of birth. Allergy 1986;41:68–70. 18. SL Prescott, J Irvine, J Dunstan, C Hii, A Ferrante. Protein kinase-C zeta: a novel “protective” neonatal T cell marker that can be up-regulated by allergy prevention strategies. J Allergy Clin Immunol 2007; (accepted February 2007).

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

429

19. P Black, S Sharpe. Dietary fat and asthma : Is there a connection? Eur Respir J 1997;10: 6–12. 20. M Makrides, K Simmer, M Neumann, R Gibson. Changes in the polyunsaturated fatty acids of breast milk from mothers of full-term infants over 30 wk of lactation. Am J Clin Nutr 1995;61(6):1231–3. 21. J Peat, C Salome, A Woolcock. Factors associated with bronchial hyper-responsiveness in Australian adults and children. Eur Respir J 1992;5:921–9. 22. L Poysa, M Korppi, K Remes, K Juntunen-Backman. Atopy in childhood and diet in infancy. A nine-year follow-up study. Allergy Proc 1991;12(2):107–11. 23. L Hodge, C Salome, J Peat, M Haby, W Xuan, A Woolcock. Consumption of oily fish and childhood asthma risk. Med J Aust 1996;164:137–40. 24. Y Takemura, Y Sakurai, S Honjo, A Tokimatsu, M Gibo, T Hara, A Kusakari, N Kugai. The Relationship between Fish Intake and the Prevalence of Asthma: The Tokorozawa Childhood Asthma and Pollinosis Study. Prev Med 2002;34(2):221. 25. WH Oddy, NH de Klerk, GE Kendall, S Mihrshahi, JK Peat. Ratio of omega-6 to omega-3 fatty acids and childhood asthma. J Asthma 2004;41(3):319–26. 26. S Sausenthaler, S Koletzko, B Schaaf et al. Maternal diet during pregnancy in relation to eczema and allergic sensitization in the offspring at 2 y of age. Am J Clin Nutr 2007;85(2):530. 27. MT Salam, YF Li, B Langholz, FD Gilliland. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma 2005;42(6):513–8. 28. RB Newson, SO Shaheen, AJ Henderson, PM Emmett, A Sherriff, PC Calder. Umbilical cord and maternal blood red cell fatty acids and early childhood wheezing and eczema. J Allergy Clin Immunol 2004;114(3):531–7. 29. DR Gold, BM Willwerth, KG Tantisira et al. Associations of cord blood fatty acids with lymphocyte proliferation, IL-13, and IFN-g. J Allergy Clin Immunol 2006;in press. 30. PC Calder. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids 2003;38(4):343–52. 31. JA Dunstan, TA Mori, A Barden, LJ Beilin, AL Taylor, PG Holt, SL Prescott. Maternal fish oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy. Clin Exp Allergy 2003;33(4):442–8. 32. SL Prescott, J Irvine, JA Dunstan, C Hii, A Ferrante. Protein kinase-C zeta: a novel “protective” neonatal T cell marker that can be up-regulated by allergy prevention strategies. J Allergy Clin Immunol 2007; (accepted February 2007). 33. S Mihrshahi, JK Peat, GB Marks, CM Mellis, ER Tovey, K Webb, WJ Britton, SR Leeder. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2003;111(1):162–8. 34. JK Peat, S Mihrshahi, AS Kemp, GB Marks, ER Tovey, K Webb, CM Mellis, SR Leeder. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. J Allergy Clin Immunol 2004;114. 35. GB Marks, S Mihrshahi, AS Kemp et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol 2006;118(1):53–61. 36. FD Gilliland, KT Berhane, Y-F Li, WJ Gauderman, R McConnell, J Peters. Children’s lung function and antioxidant vitamin, fruit, juice, and vegetable intake. Am J Epidemiol 2003;158(6):576–84. 37. C Bodner, D Godden, K Brown, J Little, S Ross, A Seaton. Antioxidant intake and adults onset wheeze: a case control study. Eur Respir J 1999;13:22–30. 38. F Forastiere, R Pistelli, P Sestini et al. Consumption of fresh fruit rich in vitamin C and wheezing symptoms in children. SIDRIA Collaborative Group, Italy (Italian Studies on Respiratory Disorders in Children and the Environment). Thorax 2000;55(4):283–8. 39. B Okoko, P Burney, R Newson, J Potts, S Shaheen. Childhood asthma and fruit consumption in South London. Eur Respir J 2007;1–24. 40. G Devereux, SW Turner, LCA Craig, G McNeill, S Martindale, PJ Harbour, PJ Helms, A Seaton. Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J Respir Crit Care Med 2006;174(5):499–507.

430

S.L. Prescott

41. F Nja, W Nystad, KC Lodrup Carlsen, O Hetlevik, K-H Carlsen. Effects of early intake of fruit or vegetables in relation to later asthma and allergic sensitization in school-age children. Acta Paediatr 2005;94(2):147–54. 42. PH Tan, P Sagoo, C Chan et al. Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. J Immunol 2005;174(12):7633–44. 43. M Utsugi, K Dobashi, T Ishizuka, K Endou, J Hamuro, Y Murata, T Nakazawa, M Mori. c-Jun N-terminal kinase negatively regulates lipopolysaccharide-induced IL-12 production in human macrophages: role of mitogen-activated protein kinase in glutathione redox regulation of IL-12 production. J Immunol 2003;171(2):628–35. 44. S Martindale, G McNeill, G Devereux, D Campbell, G Russell, A Seaton. Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Respir Crit Care Med 2005;171(2):121–8. 45. G Devereux, AA Litonjua, SW Turner et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 2007;85:853–9. 46. AA Litonjua, SL Rifas-Shiman, NP Ly et al. Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr 2006;84(4):903–11. 47. S Farchi, F Forastiere, N Agabiti, G Corbo, R Pistelli, C Fortes, V Dell’Orco, CA Perucci. Dietary factors associated with wheezing and allergic rhinitis in children. [see comment]. Eur Respir J 2003;22(5):772–80. 48. BE Lee, YC Hong, KH Lee et al. Influence of maternal serum levels of vitamins C and E during the second trimester on birth weight and length. Eur J Clin Nutr 2004;58(10):1365–71. 49. AR Scaife, G McNeill, DM Campbell, S Martindale, G Devereux, A Seaton. Maternal intake of antioxidant vitamins in pregnancy in relation to maternal and fetal plasma levels at delivery. Br J Nutr 2006;95(4):771–8. 50. C Murr, K Schroecksnadel, C Winkler, M Ledochowski, D Fuchs. Antioxidants may increase the probablility of developing allergic disease and asthma. Med Hypotheses 2005;64:973–7. 51. WL Stone, I LeClair, T Ponder, G Baggs, BB Reis. Infants discriminate between natural and synthetic vitamin E. Am J Clin Nutr 2003;77(4):899–906. 52. N Sudo, S Sawamura, K Tanaka, Y Aiba, C Kubo, Y Koga. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997;159(4):1739–45. 53. B Björkstén. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immunopathol 2004;25(3–4):257–70. 54. M Kalliomäki, P Kirjavainen, E Eerola, P Kero, S Salminen, E Isolauri. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001;107(1):129–34. 55. M Kalliomäki, S Salminen, H Arvilommi, P Kero, P Koskinen, E Isolauri. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001;357(9262):1076–9. 56. M Kalliomäki, S Salminen, T Poussa, H Arvilommi, E Isolauri. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003;361(9372):1869–71. 57. PM Matricardi. Probiotics against allergy: data, doubts, and perspectives Allergy 2002;57:185–7. 58. AL Taylor, JA Dunstan, SL Prescott. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 2007;119(1):184–91. 59. KK Kukkonen, KE Savilahti, KT Haahtela, KK Juntunen-Backman, KR Korpela, KT Poussa, KT Tuure, KM Kuitunen. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial. J Allergy Clin Immun 2007;119(1):192–8.

Novel Immunomodulatory Strategies for the Prevention of Atopy and Asthma

431

60. T Abrahamsson, T Jakobsson, M Böttcher, M Fredriksson, M Jenmalm, N Björkstén, G Oldaeus. Probiotics in prevention of IgE associated eczema; a double blind randomised placebocontroleld trial. J Allergy Clin Immunol 2007; in press. 61. TT Lee, M Morisset, C Astier et al. Contamination of probiotic preparations with milk allergens can cause anaphylaxis in children with cow’s milk allergy. J Allergy Clin Immunol 2007;119(3):746–7. 62. G Moro, S Arslanoglu, B Stahl, J Jelinek, U Wahn, G Boehm. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 2006;91(10):814–9. 63. HL Mueller, M Lanz. Hyposensitization with bacterial vaccine in infectious asthma. A double- blind study and a longitudinal study. Jama 1969;208(8):1379–83. 64. BK Choudhury, JS Wild, R Alam, DM Klinman, I Boldogh, N Dharajiya, WJ Mileski, S Sur. In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J Immunol 2002;169(10):5955–61. 65. S Sur, JS Wild, BK Choudhury, N Sur, R Alam, DM Klinman. Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides. J Immunol 1999;162(10):6284–93. 66. JN Kline, K Kitagaki, TR Businga, VV Jain. Treatment of established asthma in a murine model using CpG oligodeoxynucleotides. Am J Physiol Lung Cell Mol Physiol 2002;283(1):L170–9. 67. H Tighe, K Takabayashi, D Schwartz et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol 2000;106(1 Pt 1):124–34. 68. IT Tobagus, WR Thomas, PG Holt. Adjuvant costimulation during secondary antigen challenge directs qualitative aspects of oral tolerance induction, particularly during the neonatal period. J Immunol 2004;172(4):2274–85. 69. R Beasley, P Shirtcliffe, JL Harper, S Holt, G Le Gros. Mycobacterium-based vaccines for the prevention of allergic disease: a progress report. Clin Exp Allergy 2002;32(8):1128–30. 70. MT Hopfenspirger, DK Agrawal. Airway hyperresponsiveness, late allergic response, and eosinophilia are reversed with mycobacterial antigens in ovalbumin-presensitized mice. J Immunol 2002;168(5):2516–22. 71. JJ Tsai, YH Liu, HD Shen, SH Huang, SH Han. Prevention of Der p2-induced allergic airway inflammation by Mycobacterium-bacillus Calmette Guerin. J Microbiol Immunol Infect 2002;35(3):152–8. 72. T Major, G Wohlleben, B Reibetanz, KJ Erb. Application of heat killed Mycobacterium bovisBCG into the lung inhibits the development of allergen-induced Th2 responses. Vaccine 2002;20(11–12):1532–40. 73. X Yang, Y Fan, S Wang, X Han, J Yang, L Bilenki, L Chen. Mycobacterial infection inhibits established allergic inflammatory responses via alteration of cytokine production and vascular cell adhesion molecule-1 expression. Immunology 2002;1. 74. C Zuany-Amorim, E Sawicka, C Manlius et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae- induced allergen-specific regulatory T-cells. Nat Med 2002;8(6):625–9. 75. GP Cavallo, M Elia, D Giordano, C Baldi, R Cammarota. Decrease of specific and total IgE levels in allergic patients after BCG vaccination: preliminary report. Arch Otolaryngol Head Neck Surg 2002;128(9):1058–60. 76. MO Ota, J Vekemans, SE Schlegel-Haueter et al. Influence of Mycobacterium bovis bacillus Calmette-Guerin on antibody and cytokine responses to human neonatal vaccination. J Immunol 2002;168(2):919–25. 77. IB Barlan, F Tukenmez, NN Bahceciler, MM Basaran. The impact of in vivo Calmette-Guerin Bacillus administration on in vitro IgE secretion in atopic children. J Asthma 2002;39(3):239–46. 78. IS Choi, YI Koh. Therapeutic effects of BCG vaccination in adult asthmatic patients: a randomized, controlled trial. Ann Allergy Asthma Immunol 2002;88(6):584–91.

432

S.L. Prescott

79. PD Arkwright, TJ David. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001;107(3):53 80. JS Alm, G Lilja, G Pershagen, A Scheynius. Early BCG vaccination and development of atopy. Lancet 1997;350(9075):400–3. 81. IL Strannegård, LO Larsson, G Wennergren, Ö Strannegård. Prevalence of allergy in children in relation to prior BCG vaccination and infection with atypical mycobacteria. Allergy 1998;53(3):249–54. 82. E von Mutius, C Braun-Fahrländer, R Schierl, J Riedler, S Ehlermann, S Maisch, M Waser, D Nowak. Exposure to endotoxin or other bacterial components might protect against the development of atopy. Clin Exp Allergy 2000;30(9):1230–4. 83. G Bolte, W Bischof, M Borte, I Lehmann, HE Wichmann, J Heinrich. Early endotoxin exposure and atopy development in infants: results of a birth cohort study. Clin Exp Allergy 2003;33(6):770–6. 84. M Baldini, IC Lohman, M Halonen, RP Erickson, PG Holt, FD Martinez. A Polymorphism in the 5’ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999;20(5):976–83. 85. W Eder, W Klimecki, L Yu, E von Mutius, J Riedler, C Braun-Fahrlander, D Nowak, FD Martinez. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004;113(3):482–8. 86. SM Sopo, M Macchiaiolo, G Zorzi, S Tripodi. Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature. Arch Dis Child 2004;89(7):620–4. 87. E Novembre, E Galli, F Landi et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004;114(4):851–7. 88. SL Prescott, VL Clifton. Asthma and Pregnancy: emerging evidence of epigenetic interactions in utero. Curr Opin Allergy Clin Immunol 2009;9(5):417–26. 89. D Martino, SL Prescott. Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease. Allergy 2009; in press. 90. C Furuhjelm, K Warstedt, J Larsson, M Fredriksson, MF Bottcher, K Falth-Magnusson, et al. Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy. Acta Paediatr 2009;98(9):1461–7. 91. SF Olsen, ML Osterdal, JD Salvig, LM Mortensen, D Rytter, NJ Secher, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registrybased follow-up from a randomized controlled trial. Am J Clin Nutr 2008;88:167–75. 92. H Johannsen, SL Prescott. Practical prebiotics, probiotics and synbiotics for allergists: how useful are they? Clin Exp Allergy 2009; in press. 93. SL Prescott, B Björkstén. Probiotics for the prevention or treatment of allergic diseases. J Allergy Clin Immunol 2007;120:255–62.

Recombinant Allergens for Therapy and Prevention: Molecular Design and Delivery of Allergy Vaccines Shyam S. Mohapatra and Shawna A. Shirley

Introduction Advances in the knowledge of the cellular and molecular basis of immunity have led to a thorough understanding of the immunologic features that characterize an allergic response. All humans can mount an IgE antibody (Ab) response to a parasite, but some genetically predisposed or atopic individuals mount this response to common antigens to which they are exposed either by inhalation, ingestion or by contact with the skin [1]. These non-parasitic antigens, called allergens, induce persistently elevated levels of specific IgE Ab and stimulate a Type-I immediate hypersensitivity [2, 3]. Common allergens include dust, plant and tree pollens, pet dander and food. Although a specific sample of pollen or house dust contains numerous antigens, only a few of them induce a specific IgE Ab response and are considered allergens. The epitope structure will determine if an antigen is an allergen [2–7]. Some, but not all antigens have epitopes that stimulate a Th2-like response, which induces an IgE Ab response [6]. Several factors contribute to the immune response to the allergens including the amount and the route of antigen exposure [4, 5, 7], the type of antigen-presenting cell [1, 8, 9], and the cytokine milieu. IFN-g will promote a Th1-like immune response, whereas IL-4 will promote a Th2-like response. Other factors to consider are the host immune response genes and environmental cofactors, such as adjuvants. These may bias the immune response to allergens towards a Th2-type response.

S.S. Mohapatra () Division of Allergy and Immunology, Joy Culverhouse Airway Disease and Nanomedicine Research Center, Department of Internal Medicine, University of South Florida, College of Medicine and James A. Haley Veteran’s Hospital, Tampa, FL, USA e-mail: [email protected] S.A. Shirley Department of Molecular Medicine, University of South Florida, College of Medicine and James A. Haley Veteran’s Hospital, Tampa, FL, USA

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_26, © Springer 2010

433

434

S.S. Mohapatra and S.A. Shirley

Recombinant Allergens Recombinant allergens provide a safe alternative to traditional natural allergens used for immunotherapy. They can be consistently produced as defined molecules of high purity and quality in unlimited amounts with defined physiochemical, biological and immunologic characteristics [10]. There are several disadvantages to the traditional allergens used in allergen immunotherapy. They are contaminated with unwanted materials or allergens from other sources which may prime Th2 responses and induce new sensitizations. Their compositions vary widely from batch-to-batch, and may lack or contain important allergens in lower amounts, overall, making the results of such therapy not predictive and often leading to decreased efficacy (Table 1). Recombinant allergens were first described by Thomas et al. in 1988 when they cloned and expressed Der p 1 in E. coli [11]. To date, more than 100 of the major allergens have been cloned from diverse sources, such as mites, animals, molds, insects, foods and grass, weed and tree pollens using bacterial or phage vectors [12–14]. The emergence of gene cloning, gene expression, DNA sequencing, the polymerase chain reaction (PCR), peptide synthesis, and peptide sequencing technologies in the late 1980s, have allowed the characterization and study of allergens and helped in determining their primary structures. The cloning of some of the allergen-cDNAs enabled the production in virtually unlimited amounts of the corresponding recombinant allergens in E. coli for use in basic and clinical studies [15]. The recombinant allergens that are synthesized by yeast and the baculovirus systems efficiently bind to IgE Abs, presumably due to

Table 1 Critical factors involved in recombinant allergen synthesis Steps involved in synthesis Critical factors for success Step 1 Clone cDNAs for relevant allergen Characterize native allergens Characterize physiochemically and Identify the isoallergens (if any) immunologically Compare with the native allergens Determine if it is a major AL. and their isoforms Characterize epitopes Step2 Produce rALs in large quantities in Confirm the allergen(s) glycosylation either E. coli, yeast, insect cells or mammalian cells Step 3 Modify allergens and test in animal Test in one small and one large animal models. Structure-modified model and/or relevant human cell allergens (only T cell epitopes or culture models T cell epitopes with modified B cell epitopes) Step 4 Formulate vaccine and test single Singly or in combined form should or multiple allergens. Perform decrease significant (>70%) Ab and safety study (phase I) and in T cell response for that group of vitro and in vivo study of human allergens responses Step 5 Clinical efficacy (phase-II) Randomized DBPC trials are needed Ab, antibody; AL, allergen; rAL, recombinant allergen; DBPC, double-blind placebo-controlled

Recombinant Allergen Vaccines

435

the glycosylation of the recombinant proteins, which allows for appropriate folding, similar to that of the native proteins. For a majority of allergens, their precise function is unknown. However, for allergens with a known primary structure or with available amino acid sequence data, their homology with other known proteins in the database is known [16, 17]. Recombinant allergens can be produced as wildtype allergens that exactly mimic the properties of the natural allergens or as modified variants with enhanced properties such as increased immunogenicity and decreased allergic reactivity. They can also be produced as hybrid molecules that represent complex allergen sources by incorporating the epitopes of several allergens into a single molecule [18]. The production of overlapping recombinant and synthetic peptides in milligram amounts has allowed the determination of the complete repertoire of epitopes, which recognize B and T cell lymphocytes for many allergens, such as mites, cat and the pollens of trees, ragweeds and grasses. Furthermore, site-directed mutagenesis, in conjunction with PCR, permits the synthesis of allergens and peptides with the desired amino acid substitutions, which are devoid of IgE binding ability [19]. The B cell epitopes, utilizing the human IgE binding epitopes, are identified by analyses including antibody binding, molecular modeling, and X-ray crystallography. The T cell epitopes of many allergens have been identified by T cell proliferation assay, using peripheral blood mononuclear cells, and/or T cell lines and clones. Further, the knowledge of the primary structures of allergens and their B and T cell epitopes led to the determination of cross-reactivities among different allergens [20–23]. These studies indicate that: (1) the major allergens have a number of epitopes, (2) the B and T cell epitopes appear to overlap, and (3) the epitopes recognized by various individuals differ. Whereas some epitopes are immunodominant, other epitopes are of minor importance in mounting a persistent allergen-specific immune response [13]. In sharp contrast to natural allergen vaccines, the recombinant allergen vaccines possess well-defined physicochemical and immunologic properties and can be produced with consistently reproducible characteristics that permit monitoring of treatment and investigation of mechanisms. However, each allergen will be a separately regulated product, similar to other recombinant cytokines and proteins used as therapeutics. The risks involved in using recombinant allergens are associated with their production in E. coli or insect cells and the potential for mutations to be caused during the production process. However, recombinant allergens offer tremendous potential for allergy diagnostics as multi-allergen tests using marker allergens can be developed to facilitate the faster diagnosis and accurate prescription of immunotherapy [13, 24].

Recombinant Allergy Vaccines The availability of recombinant allergens make it possible to monitor, diagnose and treat allergic patients. They also allow the creation of novel allergy vaccines. The rationale is that, modified recombinant allergen vaccines provide a safer and more

436

S.S. Mohapatra and S.A. Shirley

effective vaccine with fewer injections than what is currently available with natural allergen extracts. A list of recombinant allergen-based vaccines can be found in a review article by Lindhart and Valenta [25]. In a mouse model, vaccination with a multi-epitopic recombinant allergen induced allergen-specific immune deviation from a Th2-like to a TH1-like response [26]. In another study, the treatment of primed mice with a recombinant allergen vaccine did not decrease IgE Ab responses; however it increased specific IgG1 and IgG2a Ab isotypes [27]. Interestingly, recombinant allergen treatment enhanced IgG2a and IgG1 Ab production to crude Kentucky Blue grass allergens (kALs). A comparison of the cytokine responses showed that the recombinant allergens induced significantly higher levels of IFN-g and specific IgG2a Abs compared to kALs [27]. In the clinical realm, the potential advantages of recombinant allergens include the administration of allergens in optimal doses, an increase in the safety of allergen immunotherapy by mutating allergens to modify or eliminate IgE binding epitopes by using aqueous, enteric coated, liposome-packed, polymerized, or N-formylmethionyl-leucyl-phenylalanine-conjugated allergen vaccines for immunotherapy [28–31]. The clinical studies with recombinant allergens conducted to date are listed in Table 2. Grass allergen vaccines comprise a few major allergens, each of which contributes significantly to the allergic response. In an elegant study, a cocktail of recombinant allergens were used to substitute extract-based immunotherapy of grass allergy and provided the proof of concept for the feasibility of patient-tailored immunotherapy. The clinical benefit of the treatment was associated with the promotion of IgG4 and reduction of IgE antibodies consistent with the induction of IL-10-producing Treg cells reported for extract-based specific immunotherapy [32]. Similar studies have been performed with recombinant birch allergens using either a combination of recombinant allergens or their modified derivatives [33– 36]. Most of these studies have been performed in Europe for grass and tree pollen allergens in a limited number of patients. None of these studies has shown significantly greater improvement compared to natural allergen mixtures. Further studies need to be conducted to indicate their reproducibility.

Molecular Design of Allergy Vaccines It is important to consider the underlying mechanisms of allergen-specific immunotherapy when designing allergy vaccines. One approach could be to modulate the T helper cell response to promote a Th1-like response as opposed to the Th2 response or inducing immunosuppressive Treg cells to promote tolerance. Another approach could be to use active vaccination that promotes the IgG response while suppressing or eliminating the IgE response. DNA-based allergen (AL-DNA) vaccines may be useful to treat allergic patients [26, 37–39]. Allergens cloned into suitable plasmids (pAL), would be utilized. In mice, such therapy shifts allergen-specific immunity from a Th2- response to a

Compare rBet v 1 fragments, rBet v 1 trimers and placebo(1 pre-seasonal Rx)

Compared rBet v 1 fragment variants with Bet v mix

DBPC

Open

n = 51

Single

Multi

Multi

Center Single

Results Increase IgG4 Decreased IgE Increased IL-10 and Treg cells rBet v 1 and nBet v 1 are equally effective Blunting of seasonal IgE, Robust IgG response. Decreased cutaneous and nasal sensitivity to rBet v 1 fragments. Increased Th1 response to rBet v 1 trimers Increase in IgG1 and IgG4 A 53% lower medication score compared to control group

rALs, recombinant allergens; rBet v 1, recombinant major Birch pollen allergen; nBet v 1, natural Birch pollen allergen

Birch

Birch

n = 124

n = 147

Compare rBet v 1 and nBet v 1

DBPC

Birch

No. of patients n = 62

Table 2 Immunotherapy trials with recombinant allergens Study Allergen design Study description (pollen) DBPC Compare a mixture of rALs with placebo Timothy grass

[36]

[33–35]

[44]

Ref. [32]

Recombinant Allergen Vaccines 437

438

S.S. Mohapatra and S.A. Shirley

Th1-like response, similar to the cytokine changes that occur in allergic patients after allergen immunotherapy. Although, allergen-DNA vaccines may be advantageous, clinical trials involving these vaccines have not been completed and the potential adverse effects of these vaccines in humans are unknown. Hybrid vaccines contain fusion molecules of two or more allergen epitopes or derivatives from single or multiple sources in a single vaccine. These molecules are engineered using recombinant DNA technology [40] and studies reveal they show low IgE binding activity, but retain the complexity of their T cell epitopes [41–43]. Although no clinical trials with hybrid vaccines have been carried out, animal models show promising results [42]. Wild-type allergen vaccines are engineered to resemble the natural allergen. They will have the same relevant B and T cell epitopes and allergenic properties of the natural molecules. Clinical studies have shown that these recombinant allergen vaccines are just as effective as the natural allergen [44]. Hypoallergenic allergen derivatives are recombinant allergens that have been modified to reduce the allergenic activity of the molecule, but preserve the immunogenicity and T cell epitopes. The decrease in allergenicity reduces the IgE effects, which allow higher doses of the derivatives to be given in comparison to the natural counterpart. The steps toward designing a recombinant allergen-based vaccine are outlined in Fig. 1. First, the source of allergen must be selected followed by the isolation of the cDNAs coding for the relevant regions. This is done by extracting RNA, transcribing it into cDNA and expressing it in a phage library which is then screened with IgE from allergic patients. This yields a mixture of allergens that equal the natural allergens of the source. The clinical relevance of each allergen is evaluated by skin testing in different populations; then relevant recombinant allergens are selected for vaccine formulation. Preclinical evaluations are carried out based on mixtures of allergens, hybrid molecules consisting of recombinant allergens equaling the natural allergens or genetically engineered derivatives having reduced allergenic activity. The final step is to carry out double-blind, placebo-controlled (DBPC) immunotherapy trials [25].

Delivery of Allergy Vaccines Recombinant allergens are less immunogenic than natural allergens, therefore it is essential to use an adjuvant to deliver the vaccine. Some examples of adjuvants used for recombinant allergen delivery include emulsions such as aluminum hydroxide (alum), cytokines, nanoparticles, and CpG DNA. One important aspect of treatment of allergic disease is the method of administration of the drugs to patients. While traditional immunotherapy utilizes a parenteral route, new approaches involving administration of allergen to specific tissues, such as local nasal, sub-lingual and local lung immunotherapy have been investigated.

Recombinant Allergen Vaccines

439

Fig. 1 Steps involved in designing recombinant allergen-based vaccines

Cytokines Th1-like cytokines IFN-g and IL-12 have the potential to convert allergen-specific Th2-like responses to Th1-like responses [26, 45–47]. IL-12 has been suggested as an adjuvant for vaccination against diseases in which the Th2 profile predominates. The administration of a fusion protein vaccine consisting of ovalbumin (OVA) and

440

S.S. Mohapatra and S.A. Shirley

IL-12p40 reduced OVA-specific IgE responses in vivo [48]. IFNg is a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR). Since allergic subjects produce relatively low amounts of IFNg, we investigated the ability of chitosan-IFNg pDNA nanoparticles (CIN) for in situ production of IFN-g and examined its in vivo effects [49]. In a mouse model of allergy, CIN reduced OVA-induced inflammation and AHR. Production of IFN-g was increased after CIN treatment, while the Th2-cytokines, IL-4 and IL-5, and OVA-specific serum IgE were reduced compared to controls. AHR and eosinophilia are also significantly reduced by CIN therapy. CIN was found to inhibit epithelial inflammation within 6 hours of delivery by inducing apoptosis of goblet cells.

CpG DNA Prokaryotic DNA sequences are rich in unmethylated cytosine-phosphoguanosine (CpG) dinucleotides. CpG DNA can be co-administered with antigen in the form of synthetic oligonucleotides which are able to activate both innate and adaptive immune responses through toll-like receptor 9 (TLR9) signaling. For natural allergens, CpG oligos have to be injected with the allergen; however, they can be directly linked with recombinant allergen cDNA. Utilization of CpG oligos as an adjuvant has been reported in a murine model of allergy and asthma [50]. The immunostimulatory profile of these adjuvants can be adjusted by chemical modifications. These sequences tend to induce a Th1-like cytokine response [51]. Synthetic CpG motifs linked to the major ragweed allergen Amb a 1 redirected ragweed-specific Th2 responses to Th1 responses as evidenced by increased IFN-g, CXCL-9 and CXCL-10 expression in a placebo-controlled clinical study [52].

Live Bacillus Calmette-Guerin BCG Bacillus Calmette-Guerin (BCG) has been suggested as an adjuvant for allergen immunotherapy. Vaccination simultaneously with live BCG and a recombinant grass allergen [37] induced allergen-specific immuno-deviation, i.e., a fivefold decrease of total IgE Abs and a tenfold decrease in specific IgE Abs, with a concomitant tenfold increase in IgG2a Ab synthesis (Mohapatra et al., unpublished data). Splenocytes of mice stimulated in vitro with Kentucky blue-grass allergens after the mice had been vaccinated with BCG and then 21 days after with the recombinant allergen, produced significantly higher amounts of IFN-g (unpublished data). Also, a live vaccine to treat allergic diseases using a recombinant (BCG) expressing allergens has been proposed [37].

Recombinant Allergen Vaccines

441

Live Vectors Allergen genes expressed in the appropriate hosts may be used as live vaccines, which stimulate the immune system toward a Th1-like response. For example, oral immunization with Salmonella typhimurium expressing a Bet v 1-cDNA promoted IgG2a instead of the default IgE Ab responses [39]. However, IgG2a responses specific for Bet v 1 could be detected in only 10% of the immunized mice. These experimental approaches appear promising and may lead to effective allergy vaccines.

Nanoparticles The application of nanotechnology for targeting drugs and macromolecules to specific tissues or cells is one of the most important areas in nanomedicine research [53]. Evidence shows that chitosan, a natural biocompatible cationic polysaccharide extracted from crustacean shells, has the potential to be a safe and effective carrier for genes and drugs. It has strong immunostimulatory properties, low immunogenicity [54], anticoagulant activity [54], wound-healing properties [55], and antimicrobial properties [55]. Chitosan is nontoxic, nonhemolytic, slowly biodegradable and has been widely used in controlled drug delivery [56–60]. Chitosan also increases transcellular and paracellular transport across the mucosal epithelium [61] and, thus, may facilitate mucosal allergen delivery and modulate immunity of the mucosal and bronchus-associated lymphoid tissue (Fig. 2.). Research from our laboratory has shown that plasmid DNAs can be encapsulated in chitosan to effectively transfer and express genes in lung cells [49]. Chitosan is also effective in delivering peptides. We have successfully encapsulated the allergen OVA in chitosan. These particles when delivered to mice orally desensitize the animals (data unpublished).

Nanocomplexes

Lung GFP Expression

Fig. 2 Nanocomplexes effectively deliver DNA to lungs after oral administration

442

S.S. Mohapatra and S.A. Shirley

Roy et al. reported an immunoprophylactic strategy using oral allergen-gene immunization to modulate peanut antigen-induced murine anaphylactic responses. Plasmid DNA encoding a dominant peanut allergen gene was coupled to chitosan and delivered orally resulting in transduced gene expression in the intestinal epithelium. Nanoparticle delivery of the allergen resulted in reduced anaphylaxis. This shows oral chitosan−DNA nanoparticles are effective in modulating murine anaphylactic responses, and may be useful as a prophylactic for food allergy [62]. Chitosan, therefore, appears to be a good candidate for the safe mucosal delivery of recombinant allergen molecules for immunotherapy. Modifications can be made to chitosan that will enhance its muco-adhesiveness and overall efficacy [63, 64]. Also, the complexes are thermally stable and can be stored at room temperature and reconstituted with water when needed.

Future of Immunotherapy Recombinant allergens and their corresponding cDNAs could be used to prevent allergen-specific IgE responses. As stated previously, vaccination of mice with a multi-epitopic recombinant allergen, induced an allergen-specific Ab response that was long lasting, despite several booster immunizations [27]. Alternatively, plasmids expressing allergens could also be utilized for prophylactic vaccination. The immunization of rats with a mite allergen-cDNA cloned in a plasmid vehicle resulted in an AL-specific IgG2a and a Th1-like response with no detectable IgE. This was in marked contrast to immunization with an allergen, which induced an IgE antibody response [65]. These studies suggest that immunization with allergencDNA(s) may provide a novel type of prophylactic vaccine against allergic diseases. About a quarter of the population is genetically predisposed to develop allergic disease and with advances in the identification of genes it may be possible to develop methods to predict atopic predisposition. This, in turn, may allow for vaccination of predisposed individuals to prevent sensitization from exposure to specific allergens.

Concluding Remarks Molecular cloning of allergens has advanced the knowledge of their primary structures and has enabled them to be produced in virtually unlimited quantities for potential diagnosis and treatment of allergic disease. Furthermore, availability of these recombinant allergens has led to the possibility that new ways to prevent or treat allergy may utilize them or even plasmid DNAs that encode allergens. It will be necessary to demonstrate the effectiveness and safety of these vaccines in humans before these new forms of therapy can be used in routine treatment. Allergic conditions are complex, and it is naive to think that one form of AL-specific

Recombinant Allergen Vaccines

443

immunotherapy will be effective to treat all allergic conditions. Nonetheless, it is prudent that all new technologies be explored for the diagnosis and treatment of allergic diseases. Acknowledgement The authors would like to thank the support by Joy McCann Culverhouse endowment to the division of Allergy and Immunology and Mabel and Ellsworth Simmons Professorship to SSM.

References 1. Yang, M., Wang, Y.Y., Zhang, L., Chong, P., Mohapatra, S.S. (1996). Host genetic and adjuvant factors influence epitope specificity to a major recombinant grass allergen. Int Arch Allergy Immunol 111, 173–181 2. Marsh, D.G. (1996). Genetics of asthma and other atopic diseases. 52nd Annual Conference AAAAI, New Orleans, 7 3. Romagnani, S. (1994). Regulation of the development of type 2 T-helper cells in allergy. Curr Opin Immunol 6, 838–846 4. Blaser, K. (1996). Allergen dose dependent cytokine production regulates specific IgE and IgG antibody production. Adv Exp Med Biol 409, 295–303 5. Finkelman, F.D. (1995). Relationships among antigen presentation, cytokines, immune deviation, and autoimmune disease. J Exp Med 182, 279–282 6. Parronchi, P., et al. (1991). Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A 88, 4538–4542 7. Schneider, T., Dudler, T., Annand, R.R., Gelb, M.H., King, T.P. Suter, M. (1997). Comparison of the antibody response to bee venom phospholipase A2 induced by natural exposure in humans or by immunization in mice. J Mol Recogn 10, 93–100 8. Evavold, B.D., Williams, S.G., Hsu, B.L., Buus, S., Allen, P.M. (1992). Complete dissection of the Hb(64-76) determinant using T helper 1, T helper 2 clones, and T cell hybridomas. J Immunol 148, 347–353 9. Tsitoura, D.C., Verhoef, A., Gelder, C.M., O’Hehir, R.E., Lamb, J.R. (1996). Altered T cell ligands derived from a major house dust mite allergen enhance IFN-gamma but not IL-4 production by human CD4+ T cells. J Immunol 157, 2160–2165 10. King, T.P., Hoffman, D., Lowenstein, H., Marsh, D.G., Platts-Mills, T.A., Thomas, W. (1994). Allergen nomenclature. WHO/IUIS Allergen Nomenclature Subcommittee. Int Arch Allergy Immunol 105, 224–233 11. Thomas, W.R., Stewart, G.A., Simpson, R.J., Chua, K.Y., Plozza, T.M., Dilworth, R.J., Nisbet, A., Turner, K.J. (1988). Cloning and expression of DNA coding for the major house dust mite allergen Der p 1 in Escherichia coli. Int Arch Allergy Appl Immunol 85, 127–129 12. Mohapatra, S.S. (1994). Modulation of allergen-specific antibody responses by T-cell-based peptide vaccine(s). Principles and potential. Clin Rev Allergy 12, 3–22 13. Mohapatra, S.S., Mohapatra, S. (1996). Application of molecular biology to diagnosis and treatment of allergic diseases. Immunol Allergy Clin N Am 16, 591 14. Stewart, G.A., Thompson, P.J. (1996). The biochemistry of common aeroallergens. Clin Exp Allergy 26, 1020–1044 15. Mohapatra, S.S., Nicodemus, C., Schou C., Valenta, R. (1994). Recombinant allergens and epitopes. Allergy Clinical Immunology News 6, 45 16. Chua, K.Y., Kehal, P.K., Thomas, W.R., Vaughan, P.R., Macreadie, I.G. (1992). Highfrequency binding of IgE to the Der p allergen expressed in yeast. J Allergy Clin Immunol 89, 95–102

444

S.S. Mohapatra and S.A. Shirley

17. Tomalski, M.D., King, T.P., Miller, L.K. (1993). Expression of hornet genes encoding venom allergen antigen 5 in insects. Arch Insect Biochem Physiol 22, 303–313 18. Valenta, R., Niederberger, V. (2007). Recombinant allergens for immunotherapy. J Allergy Clin Immunol 119, 826–830 19. Nishiyama, C., Fukada, M., Usui, Y., Iwamoto, N., Yuuki, T., Okumura, Y., Okudaira, H. (1995). Analysis of the IgE-epitope of Der f 2, a major mite allergen, by in vitro mutagenesis. Mol Immunol 32, 1021–1029 20. Astwood, J.D., Mohapatra, S.S., Ni, H., Hill, R.D. (1995). Pollen allergen homologues in barley and other crop species. Clin Exp Allergy 25, 66–72 21. Mohapatra, S.S. (1993). Analysis of structural motifs of allergenic proteins as a tool in studies of crossreactivity among ALs. Mol Biol Immunol Allergens, 69 22. Mohapatra, S.S. (1994). Determinant spreading: implications in allergic disorders. Immunol Today 15, 596–597 23. Mohapatra, S.S., Mohapatra, S., Yang, M., Ansari, A.A., Parronchi, P., Maggi, E., Romagnani, S. (1994). Molecular basis of cross-reactivity among allergen-specific human T cells: T-cell receptor V alpha gene usage and epitope structure. Immunology 81, 15–20 24. Hiller, R., et al. (2002). Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment. Faseb J 16, 414–416 25. Linhart, B., Valenta, R. (2005). Molecular design of allergy vaccines. Curr Opin Immunol 17, 646–655 26. Cao, Y., Yang, M., Luo, Z., Mohapatra, S.S. (1997). Vaccination with a multi-epitopic recombinant allergen induces specific immune deviation via T-cell anergy. Immunology 90, 46–51 27. Cao, Y. (1996). Thesis. University of Manitoba, Winnipeg 28. Arora, N., Gangal, S.V. (1992). Efficacy of liposome entrapped allergen in down regulation of IgE response in mice. Clin Exp Allergy 22, 35–42 29. Maasch, H.J., Marsh, D.G. (1987). Standardized extracts modified allergens--allergoids. Clin Rev Allergy 5, 89–106 30. Wheeler, A.W., Henderson, D.C., Youlten, L.J., Al, J. II, Hickman, B.E., Taylor, I.H., Moran, D.M. (1987). Immunogenicity in guinea pigs and tolerance in grass pollen-sensitive volunteers of enteric-coated grass pollen allergens. Int Arch Allergy Appl Immunol 83, 354–358 31. Wheeler, A.W., Whittall, N., Cook, R.M., Spackman, V.M., Moran, D.M. (1987). T cell reactivity of conjugates of N-formyl-methionyl-leucyl-phenylalanine and rye-grass pollen allergens. Int Arch Allergy Appl Immunol 84, 69–73 32. Jutel, M., Jaeger, L., Suck, R., Meyer, H., Fiebig, H., Cromwell, O. (2005). Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 116, 608–613 33. Niederberger, V., et al. (2004). Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A 101 Suppl 2, 14677–14682 34. Reisinger, J., Horak, F., Pauli, G., van Hage, M., Cromwell, O., Konig, F., Valenta, R., Niederberger, V. (2005). Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity. J Allergy Clin Immunol 116, 347–354 35. Gafvelin, G., et al. (2005). Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1. Int Arch Allergy Immunol 138, 59–66 36. Klimek, L., Bachert, C., Doemer, C., Meyer, H., Narkus, A. (2005). Specific Immnotherapy with recombinant birch pollen allergen rBet v 1-FV is clinically efficacious. Allergy Clin Immunol Int Suppl 1, 15 37. Kumar, M., Behera, A., Matsuse, H., et al. (1998). Development of a BCG-based allergen vaccine. J Allergy Clin Immunol 101, 333 38. Raz, E., Tighe, H., Sato, Y., et al. (1996). Inhibition of specific IgE antibody formation by naked plasmid DNA immunization. Proc Natl Acad Sci U S A 93, 5141 39. Vrtala, S., Grote, M., Ferreira, F., Susani, M., Stocker, B., Kraft, D., Valenta, R. (1995). Humoral immune responses to recombinant tree pollen allergens (Bet v I and Bet v II) in mice: construction of a live oral allergy vaccine. Int Arch Allergy Immunol 107, 290–294

Recombinant Allergen Vaccines

445

40. Linhart, B., Valenta, R. (2004). Vaccine engineering improved by hybrid technology. Int Arch Allergy Immunol 134, 324–331 41. Kussebi, F., et al. (2005). A major allergen gene-fusion protein for potential usage in allergenspecific immunotherapy. J Allergy Clin Immunol 115, 323–329 42. Karamloo, F., et al. (2005). Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes. Eur J Immunol 35, 3268–3276 43. Linhart, B., et al. (2005). A hybrid molecule resembling the epitope spectrum of grass pollen for allergy vaccination. J Allergy Clin Immunol 115, 1010–1016 44. Pauli, G., Malling, H., Rak, S., Pastorello, E., Purohit, A., Larsen, T., et al. (2006). Clinical efficacy of subcutaneous immunotherapy in birch pollen allergic patients: a randomized, double-blind, placebo-controlled study with recombinant Bet v 1 versus natural Bet v 1 or standardised birch extract. In 25th Congress of the European Academy of Allergology and Clinical Immunology (Valenta, R., Akdis, C., Bohle, B., eds), p. 28, Vienna, Austria 45. Afonso, L.C., Scharton, T.M., Vieira, L.Q., Wysocka, M., Trinchieri, G., Scott, P. (1994). The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263, 235–237 46. Mohapatra, S.S. (1995). IL-12 possibilities. Science 269, 1499 47. Parronchi, P., Mohapatra, S., Manetti, R., et al. (1996). Modulation by IFN-a of cytokine profile and eptiope specificity of allergen-specific T cells. Eur J Immunol 26, 697 48. Kim, T.S., DeKruyff, R.H., Rupper, R., Maecker, H.T., Levy, S., Umetsu, D.T. (1997). An ovalbumin-IL-12 fusion protein is more effective than ovalbumin plus free recombinant IL-12 in inducing a T helper cell type 1-dominated immune response and inhibiting antigen-specific IgE production. J Immunol 158, 4137–4144 49. Kumar, M., Kong, X., Behera, A.K., Hellermann, G.R., Lockey, R.F., Mohapatra, S.S. (2003). Chitosan IFN-gamma-pDNA Nanoparticle (CIN) Therapy for Allergic Asthma. Genet Vaccines Ther 1, 3 50. Sato, Y., et al. (1996). Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352–354 51. Roman, M., et al. (1997). Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat Med 3, 849–854 52. Simons, F.E., Shikishima, Y., Van Nest, G., Eiden, J.J., HayGlass, K.T. (2004). Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 113, 1144–1151 53. Ebbesen, M., Jensen, T.G. (2006). Nanomedicine: techniques, potentials, and ethical implications. J Biomed Biotechnol 2006, 51516 54. Kneuer, C., Sameti, M., Bakowsky, U., Schiestel, T., Schirra, H., Schmidt, H., Lehr, C.M. (2000). A nonviral DNA delivery system based on surface modified silica-nanoparticles can efficiently transfect cells in vitro. Bioconjug Chem 11, 926–932 55. Ezekowitz, R.A., Williams, D.J., Koziel, H., Armstrong, M.Y., Warner, A., Richards, F.F., Rose, R.M. (1991). Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature 351, 155–158 56. Behera, A.K., Kumar, M., Lockey, R.F., Mohapatra, S.S. (2002). Adenovirus-mediated interferon gamma gene therapy for allergic asthma: involvement of interleukin 12 and STAT4 signaling. Hum Gene Ther 13, 1697–1709 57. Ferkol, T., Mularo, F., Hilliard, J., Lodish, S., Perales, J.C., Ziady, A., Konstan, M. (1998). Transfer of the human Alpha1-antitrypsin gene into pulmonary macrophages in vivo. Am J Respir Cell Mol Biol 18, 591–601 58. Ferkol, T., Perales, J.C., Mularo, F., Hanson, R.W. (1996). Receptor-mediated gene transfer into macrophages. Proc Natl Acad Sci U S A 93, 101–105 59. Rojanasakul, Y., Wang, L.Y., Malanga, C.J., Ma, J.K., Liaw, J. (1994). Targeted gene delivery to alveolar macrophages via Fc receptor-mediated endocytosis. Pharm Res 11, 1731–1736 60. Wrobel, I., Collins, D. (1995). Fusion of cationic liposomes with mammalian cells occurs after endocytosis. Biochim Biophys Acta 1235, 296–304 61. Kumar, M., Behera, A.K., Matsuse, H., Lockey, R.F., Mohapatra, S.S. (1999). Intranasal IFNgamma gene transfer protects BALB/c mice against respiratory syncytial virus infection. Vaccine 18, 558–567

446

S.S. Mohapatra and S.A. Shirley

62. Roy, K., Mao, H.Q., Huang, S.K., Leong, K.W. (1999). Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 5, 387–391 63. Lee, D., Zhang, W., Shirley, S.A., Kong, X., Hellermann, G.R., Lockey, R.F., Mohapatra, S.S. (2007). Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene delivery. Pharm Res 24, 157–167 64. Lee, D.W., Shirley, S.A., Lockey, R.F., Mohapatra, S.S. (2006). Thiolated chitosan nanoparticles enhance anti-inflammatory effects of intranasally delivered theophylline. Respir Res 7, 112 65. Hsu, C.H., Chua, K.Y., Tao, M.H., Lai, Y.L., Wu, H.D., Huang, S.K., Hsieh, K.H. (1996). Immunoprophylaxis of allergen-induced immunoglobulin E synthesis and airway hyperresponsiveness in vivo by genetic immunization. Nat Med 2, 540–544

Prevention of Allergic Diseases Leena von Hertzen and Tari Haahtela

Introduction Accumulating evidence indicates that an environment rich in microbes in childhood reduces the risk of developing atopic disease in later life [1]. Along with urbanization, the perpetual coexistence of environmental microorganisms with man has been severely disturbed, with unexpected consequences. It has been elegantly shown that continuous stimulation of the innate immunity cells by commensals and saprophytes is necessary for the proper development and maintenance of mucosal homeostasis [2]. Such continuous stimulation of the immune system through the skin, respiratory tract and gut is thought to activate the regulatory network, which in turn seems to be decisive in the development of tolerance and in the prevention of inflammation associated with atopic conditions and harmful Th2 responses [3, 4]. Allergy and asthma epidemic still continues in many western countries [5], whereas in some other, less affluent areas, it may have only started [6, 7]. Numerous studies have provided evidence that allergen avoidance is not the right strategy to reverse the rising trends in asthma and allergy prevalence. Avoidance of inhalant allergens is difficult, often impossible, and the results from avoidance interventions have not been encouraging [8–10]. As to food antigens, excessive avoidance in early life can be harmful and prevent or weaken the development of regulatory mechanisms. Virtually, the only possibility to reduce the allergy burden in a population is to strengthen those mechanisms that are involved in the development and maintenance of tolerance. Patients must be treated, but the strategies to reduce the allergy burden should focus on prevention and preventive treatment. In this chapter, the development of tolerance in the context of environmental factors, and the means by which allergies might be reduced at the national level are discussed.

L. von Hertzen () and T. Haahtela Skin and Allergy Hospital, Helsinki University Central Hospital, P.O. Box 160, 00029 HUS, Finland e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_27, © Springer 2010

447

448

L. von Hertzen and T. Haahtela

Factors in the Environment that May Confer Protection Epidemiological studies have identified a number of factors that may confer protection against allergies, most associated, more or less, with the hygiene hypothesis. These studies have been extensively reviewed earlier (e.g., in [11, 12]), and are not repeated here. Nonetheless, the strongest and most consistent evidence comes probably from studies performed among farmers’ children and those living in nonaffluent areas in simple living conditions. Currently more than 30 studies have shown that farming environment, particularly in early life is associated with reduced risk for atopic disease in later life [1]. Similarly, data from the former socialistic countries indicate that atopic diseases are inversely related to affluence and urbanization [13, 14]. Common to both farming and nonaffluent environment is the heavy daily exposure to saprophytes and other microorganisms. Along with increasing affluence and urbanization, a dramatic shrinking in the diversity of ecosystems and species has occurred [15], and this concerns, not only macrobiology but microbiology as well. Thus far, the focus in microbial exposure-allergy – studies has largely been on endotoxin (lipopolysaccharide, LPS), the major cell wall component of gram-negative bacteria, and numerous studies have reported an inverse association between endotoxin levels in house dust and occurrence of atopic disease, although dose, route and timing of exposure may significantly affect the outcome [16, 17]. However, gramnegative bacteria are likely to represent only a minor part of all bacteria in the environment, as gram-positive bacteria, particularly members of the phylum Actinobacteria (including genera such as Streptomyces, Mycobacterium, Corynebacterium, Bifidobacterium), have been found to predominate in soils and natural waters in different geo-climatic areas [18–20]. The other phylum of gram-positive bacteria, Firmicutes (e.g., genera such as Staphylococcus, Streptococcus, Lactobacillus, Lactococcus), are also widely distributed in the environment and animals [21]. The significance of endotoxin as an environmental immunomodulator may have been overestimated, while the role of gram-positive bacteria largely ignored. The concept of the crucial role of saprophytes particularly from the gram-positive lineage in conferring protection against allergies has gained further momentum from several dietary studies. These include studies on (1) farm milk, (2) raw vegetable and fresh fruit, and (3) natural water consumption.

Farm Milk Consumption A large body of data [22–27], albeit not all [28] have revealed the unpasteurized milk/ farm milk may confer protection against sensitization and atopic disease. Riedler [24] and Barnes [27] in two independent studies were among the first to show that farm milk consumption in early life is associated with reduced rates of sensitization and/or atopic disease. After that the results have been replicated in four more studies [22, 23, 25, 26], two of which in large populations. A British study among nearly 4,800 school children [23] showed that current unpasteurized milk consumption was inversely associated with eczema symptoms and atopy. The effect was seen in all children,

Prevention of Allergic Diseases

449

independent of whether farmers’ children or not, and present regardless of the frequency of farm milk consumption. By contrast, farming status, early or current farm animal exposure, barn/stable exposure and endotoxin exposure were not associated with atopy in that study. Further, the most recent study with 15,000 European school children [22] revealed that farm milk consumption ever in life was associated with reduced rates of atopic diseases and sensitization to pollens and food allergens. The associations were, in line with the study by Perkin [23], found in all children and independent of farm-related coexposure. No other farm products inversely associated with atopic diseases or related symptoms, could be identified [22]. Which factor(s) in farm milk might mediate this relative strong protection against atopy and atopic diseases? It is well established that raw milk from a healthy cow after milking includes saprophytes derived from the cow (udders), soil or milking equipments. The microbial content normally is at the level of 100–1000 bacteria/ml, and the proportion of gram-positive bacteria of all those bacteria in milk is as high as >80%, Micrococcus (phylum Actinobacteria) and Staphylococcus (phylum Firmicutes) being the dominant genera. The proportion of gram-negative bacteria is very low, <10%, as is that of fungi (<10%) [29]. By contrast, the shoppurchased milk is likely to lose its immunomodulatory capacity during processing comprising separation, pasteurization and homogenization, of which separation (gathering of fat and microbial cell wall components considered as “rubbish”) may have the greatest impact in this respect.

Raw Vegetable and Fresh Fruit Consumption Another line of evidence of the impact of environmental saprophytes comes from studies investigating the relationship between raw vegetable and fresh fruit consumption and the occurrence of atopic disease. Data are accumulating to support the notion that consumption of such vegetables/fruits may reduce the risk of atopic disease [28, 30–34]. Remes [28] went further and found that the inverse association between vegetable consumption and atopy was stronger for vegetables grown on the own or a nearby farm than for vegetables bought from the grocery store. By contrast, the consumption of boiled vegetables showed no association with atopy. These findings suggest that soil saprophytes associated with recently collected vegetables rather than various phytochemicals or even vitamins are involved in this protective effect [28]. Indeed, intake of vitamin supplementation or cod liver oil in infancy has even been associated with increased sensitization rates in later life [32].

Natural Water Consumption We found recently, as part of the Karelia Allergy Study that the numbers of microorganisms in drinking water collected from school kitchens was inversely associated with atopy among children in the respective schools [35], in line with the limited

450

L. von Hertzen and T. Haahtela

earlier data [36–38]. Most Russian Karelians use untreated surface water from lake Ladoga as domestic water. This water may be brought to a boil, but major bacterial components, e.g., endotoxin, teichoic acids, muramic acids, are heat-resistant [35], and are to a large extent likely to retain their immunobiological activity after heating. Several studies have indeed shown that both viable and nonviable bacteria and their components are immunologically active [39, 40]. Analysis of chemical markers (muramic acids; a marker of peptidoglycan, 3-OH-fatty acids; a marker of endotoxin) of the bacteria in Karelian drinking waters revealed that the content of muramic acids was 3-fold higher as compared with that of 3-OH-fatty acids, pointing further to the significance of gram-positive bacteria rich in peptidoglycan as environmental immunomodulators [35]. Saprophytes in natural waters largely reflect the microbiota in soil (members in the phylum Actinobacteria), as soil bacteria have been found to gain access to waters even during low run periods [41] As shown earlier, the Russian Karelians are protected from atopy and atopic diseases [14]. Drinking water may have great impact on the development of tolerance as the exposure occurs on a daily basis throughout the life. In sum, the urban man-made environment clearly cannot provide all the microbial stimulation, in terms of quantity and diversity, that appears to be necessary for the proper development of the immune system and tolerance, nor the modern man’s immune system been able to adapt to this kind of microbial deprivation in this short time. Microbial deprivation concerns not only saprophytic bacteria but also fungi, protozoans, helminths and microscopic mites as well.

Tolerance In guidelines and consensus reports concerning asthma and allergy, hardly any attention has thus far been paid to tolerance. Currently, tolerance is one of the hot topics in allergy research worldwide, information is growing exponentially and many breakthroughs in tolerance-immunology research have recently been made (reviewed e.g., in [42–44]). The concept of T cells that have the ability to actively suppress the function and proliferation of many other cells is not new [45, 46]. However, only 30 years later, the specific role of these suppressive T cells, renamed regulatory T cells, in the development of tolerance could be unraveled.

Definition of Tolerance Tolerance can be categorized as immunological and clinical tolerance. Immunological tolerance refers to an antigen-induced condition, in which the immune response is greatly silenced. This can be primary tolerance, acquired prenatally or in infancy through the first contacts with the antigen/allergen, or secondary tolerance, in which an earlier developed allergy disappears transiently or permanently.

Prevention of Allergic Diseases

451

Clinical tolerance refers to a condition, in which there are no clinical symptoms, irrespective of sensitization to the allergen. In the following, the term “tolerance” refers to immunological tolerance.

Mechanisms Involved in the Development of Tolerance The development of tolerance may involve several different mechanisms, depending e.g., on the dose and route of exposure. The mechanisms include (1) anergy (under particular conditions, T cells do not die but persist as functionally inactive effector cells), (2) clonal deletion (activation-induced T cell death), (3) immune deviation and, (4) active suppression by T reg cells [47, 48], of which especially the last one, has been the subject of an intensive research worldwide during the past years. Recent data suggest that both thymus-derived natural T reg cells expressing the transcription factor Foxp3, and peripherally induced T reg cells (with or without Foxp3) acting via cytokines IL-10 and/or TGF-b have a physiological role in protection against allergic disease in humans [49]. For the induction of the latter, mucosal surfaces and skin provide a favorable environment [50]. There are several excellent reviews that have outlined the most recent data of T reg cells and the regulatory network (e.g., [49, 51–53]). Here, we will highlight some recent findings of major relevance to tolerance.

Bell-Shaped Curve It was earlier widely believed that the dose-response curve for different allergens/ bioparticles is different. For example, for house dust allergen, the occurrence of sensitization and respiratory symptoms was considered to increase linearly with increasing exposure, whereas for cat allergen, a nonlinear dose-response curve was proposed [54]. The emerging picture, however, now is that a nonlinear doseresponse curve (Fig. 1) may be a rather universal phenomenon, although the matter is still debated [55]. To date, a bell-shaped curve has been identified for endotoxin [56], fungal 1-3-b-glucans [57], cat and dog allergens [55, 58, 59], rat and mouse allergens [60–62] and house dust mite allergens [59, 63, 64]. Even the relationship between parasites and atopic diseases appear to be nonlinear; at low levels of exposure, atopic diseases and related symptoms are positively associated with exposure whereas at high levels of exposure, parasites appear to confer protection against atopic disease. In addition to dose, type of the parasite and duration of the infection (stage of chronicity) are likely to be involved [65]. This nonlinearity in doseresponse curve may partly explain discrepancies between some studies of helminths/pets and allergy [65, 66].

452

L. von Hertzen and T. Haahtela Prevalence of atopy/ atopic disease

Exposure

Fig. 1 The bell-shaped curve in the development of tolerance

Toll-Like Receptors in the Development of Tolerance Identification of microorganisms in environmental exposure (e.g., those in house dust, drinking water, milk) is pivotal from the perspective of their immunomodulatory capacity, and is the prerequisite for the development of novel bacteria-based prevention strategies. Toll-like receptors are a family of conserved receptors that recognize microbial molecular patterns. These Toll-like receptors (at least 10 in humans) are particularly expressed by antigen presenting cells (APC) of the innate immune system, and capture microbes and microbe-derived components as part of the first line immune defense system. As discussed above, bacteria particularly from the gram-positive lineage appear to predominate in the environment; in soil, natural waters, raw milk, and even in house dust of people living in a microbe-rich area [67]. The role of gram-positive bacteria as immunomodulators must thus be significant. The main immunostimulatory cell wall components in gram-positive bacteria are (lipo)teichoic acids and peptidoglycans [68–70]. Peptidoglycan is present in virtually all bacteria, but in high amounts, up to 50% of the dry weight of cell walls, in gram-positives. It consists of a polymeric glycan chain with alternating N-acetylmuramic acid and N-acetylglucosaminyl monomers cross-linked by short peptide subunits [1, 70]. Teichoic acids are water soluble polymers containing ribitol or glycerol residues joined through phosphodiester linkages. In lipoteichoic acids there is a single lipid side chain anchored to the ribitol or glycerol backbone [1]. Similarly to endotoxin, peptidoglycan and lipoteichoic acids induce the release of proinflammatory cytokines including TNF-a, IL-1, and IL-6 [68, 70]. It is now well established that gram-positive bacteria and their cell wall components are captured by TLR2 (albeit small fragments of peptidoglycan appear to be recognized by cytosolic intracellular receptors NOD1 (nucleotide-binding oligomerization domain) and NOD2 [71, 72]. TLR2 also recognizes mycobacteria,

Prevention of Allergic Diseases

453

various mycobacterial cell wall components and fungal zymosan [73] and b-glucan [74–76], all these structures are abundantly found in soil and natural waters. In addition, protozoan glycosylphosphatidyl-inositol anchors are recognized by TLR2 [70]. Indeed, TLR2 is the member of the TLR family with the highest number of different ligands identified to date. Early analyses in humans revealed significantly increased TLR2 mRNA accumulation in the lung, spleen and peripheral blood mononuclear cells (PBMC) as compared to other tissues [70]. Several lines of evidence suggest that TLR2 and probably also TLR9 (the receptor for bacterial DNA (CpG motifs)) are particularly involved in the development of tolerance [77–80], although differences between respiratory and oral tolerance in this respect may exist [81]. TLR2 ligation on human DCs was shown to lead to a rapid release of IL-10, the cytokine central to the development of tolerance [82, 83], and in higher concentrations than in TLR4 or TLR7 ligation [77]. Further, only TLR2, but not TLR4 or TLR9, ligation on regulatory T (T reg) cells resulted in T reg cell proliferation, clonal expansion and changes in their function in murine models [78, 84]. Interestingly, ligation of TLR2 on PBMNs from atopic individuals was found to prevent the Th2 immune response after exposure to allergen ex vivo [79]. The significance of TLR2 expression and polymorphism in conferring protection against atopic disease among farmers’ – but not among nonfarmers’children- has been shown earlier [85, 86], underscoring the impact of environment in determing the risk of the disease for certain polymorphism [87]. We have found that nasal administration of microbe-rich barn dust to BALB/c mice, induced significantly higher TLR2 mRNA expression in lung epithelial cells as compared with urban house dust. The difference was also significant, albeit of lower magnitude, for TLR9 expression, whereas for TLR4 expression, no significant differences between these two dusts could be found [M Leino, unpublished], which, in line with the studies by Eder and Lauener [85, 86], suggests a central role of TLR2 in a microbe-rich environment and in the development of tolerance. Most recently, a German study [88] showed that TLR2 controls mucosal inflammation by restoring epithelial barrier function. Oral treatment of mice with intestinal injury using a TLR2 ligand was able to suppress mucosal inflammation and restore mucosal homeostasis. Not only T reg cells but also dendritic cells (DCs) (and their secreted cytokines IL-10 and TGF-b), are the key players in the regulatory network. A prominent role in determining whether tolerance is induced or not, has been found for DCs, in close interplay with T cells [89, 90]. There is now considerable evidence that the lack/presence of costimulatory and other signals (lack referring to immature DCs) and the lack/presence of regulatory cytokines IL-10 and TGF-b at the site of induction contribute to DCs’ ability to induce Treg cells and tolerance [90]. Pulmonary DCs, accumulating immediately above and beneath the basement membrane of the respiratory epithelium [89], comprise a unique subset of DCs, called plasmacytoid DCs (pDCs), which appear to be crucial in maintaining tolerance to inhaled harmless antigens. Murine models have shown that when pDCs have been depleted, inhalation of normally inert OVA led to the development of all the major features of asthma. In addition, when transfer of allergen-pulsed pDCs prior to sensitization to

454

L. von Hertzen and T. Haahtela

allergen was performed, asthma could not be induced (reviewed in [89]). In humans, only the plasmacytoid subset, not conventional DCs, express TLR9 [91], the receptor of unmethylated DNA (CpG oligonucleotides) abundant in bacteria, mites and other invertebrates [92, 93]. Accumulating data indicate a role for TLR9 particularly in the development of respiratory tolerance [80, 94]. Moseman et al. [80] showed in human cells ex vivo that TLR9 stimulation on pDCs by its ligand, CpG-oligonucleotides, generated T reg cells which suppressed T-cell proliferation in an antigen-nonspecific manner, expressed Foxp3 and produced a T reg cell cytokine profile.

Healthy Immune Response vs. Allergic Immune Response The normal immune response to harmless antigens/allergens is tolerance without the appearance of Th2 cytokines and specific IgE antibodies [89, 90]. In high/ repeated antigen exposure, antigens are not able to fully activate the DCs which in turn may lead to T cell deletion and the development of T reg cells [89]. This tolerance in healthy individuals is mediated by dendritic cells, T reg cells and the suppressive cytokines IL-10 and TGF-b [82]. It is now widely accepted that the balance between allergen-specific T reg cells and Th2 cells is decisive in the development of allergy. After exposure, both healthy individuals and those with allergy show Th1, Th2 and T reg cells, but the relative proportions of these subsets vary; in healthy individuals, specific T reg cells are consistently found to be the dominant subset, whereas in atopics, the proportions of specific Th2 cells are greatly increased [95, 96]. In addition, the function of T regs may be impaired in allergic conditions [97]. Successful specific immunotherapy (SIT) has been found to largely restore the balance in T cell subsets [82]. IL-10 is induced and increasingly secreted by SIT, which, in addition to inducing the generation of T reg cells, suppresses both total and specific IgE and simultaneously increases IgG4 production [96]. A healthy immune response to an allergen (Der p1) is characterized by increased specific IgA and IgG4 levels, low levels of specific IgG1 and trace amounts, if any, of specific IgE [98]. T reg cells, through their secretion of IL-10 and/or TGF-b, are involved in the development of tolerance in several ways: they (1) suppress the function of DCs (and other APCs) to become inactive, tolerogenic, (2) suppress the function and proliferation of Th1 and Th2 cells, (3) suppress specific IgE but increase specific IgG4 and/or IgA production, (4) suppress mast cells, basophils and eosinophils, and (5) interact with resident tissue cells [96]. However, in addition to IL-10 and/or TGF-b, T reg cells may use different mechanisms to regulate T cell proliferation/ function and to control immunopathologies; this may be related to the level of inflammation [83, 99]. An interesting question remains as to whether there are differences in mechanisms involved in the development of tolerance between individuals who are sensitized

Prevention of Allergic Diseases

455

but otherwise healthy (clinical tolerance; a condition frequently seen e.g., among the Russian Karelian children) and those without any sensitization at all.

Can Tolerance Be Restored in Atopic Individuals? Data obtained thus far, mainly from animal models have provided evidence that administration of an antigen systemically under certain conditions can restore tolerance and prevent the development of respiratory allergic disease in sensitized animals (reviewed in [90]). Even allergen-induced inflammation in murine models of asthma could have been ameliorated by repeated administration of allergen locally into the respiratory tract, although results obtained from murine models need to be taken cautiously [90]. Dose and duration of antigen exposure may be the crucial determinants here. Nonetheless, recent results from studies of sublingual immunotherapy among sensitized children have been encouraging and support the view obtained from animal models; tolerance could be restored and the development of asthma prevented at least in children [100].

Primary Prevention An initiative “Prevention of Allergy and Allergic Asthma” was taken up some years ago by the World Allergy Organization (WAO), in collaboration with the World Health Organization (WHO), to prepare strategic guidelines that would provide a sound basis for practical action for authorities, health care professionals, patient organizations, and patients, to decrease the burden of allergy and asthma at a national level [101]. The general principles presented in the paper was targeted to act as a draft for local guidelines to be developed, and was based on scientific evidence and the WHO categorization on the strength of evidence. Preventive measures concerning primary, secondary and tertiary prevention are comprehensively considered in the WAO/WHO guidelines [101]. The focus of this discussion is on primary prevention, i.e., how to strengthen tolerance against allergens and prevent sensitization at the population level. Primary prevention measures by WAO/WHO and the strength of evidence are presented in Table 1. The evidence is strongest in showing that there is no need of special diet for lactating mothers. Convincing evidence also indicates that smoking in pregnancy and exposure to environmental tobacco smoke in early life is deleterious with respect to allergies, whereas breast-feeding for 4–6 months may prevent or dampen – although not consistently shown in all studies- the development of atopic disease in later life (reviewed in [101]). As to the avoidance of pets in high risk families, recent data show that even in genetically predisposed children, tolerance to inhalant allergens may develop, provided that the exposure is high enough [59].

456

L. von Hertzen and T. Haahtela

Table 1 Primary prevention measures (WAO/WHO) Measure Smoking and exposure to environmental tobacco smoke should be avoided, particulary during pregnancy and early childhood Tobacco smoke should be removed from work places Damp housing conditions should be avoided, and indoor air pollutants should be reduced Breast-feeding should be continued until 4–6 months No special diet is needed for the lactating mother In high-risk children, exposure to inhalant allergens should be reduced. Note: the most recent data, however, indicate that even high-risk children may develop tolerance against allergens; the dose-response curve appears to be bell-shaped [59] Highly irritant agents in occupational settings should be avoided. In case this is not possible, measures to prevent employee exposure should be implemented

Category of evidence (B) (B) (C) (C) (B) (A) (B)

(C)

A Evidence from meta-analysis of several or at least one randomized controlled trial(s) B Evidence from at least one controlled study without randomization or from other type of quasiexperimental study, or extrapolated recommendation from category A evidence C Evidence from nonexperimental descriptive studies, such as comparative, correlation and casecontrol – studies, or extrapolated recommendation from category A or B evidence

Measures for secondary prevention and the strength of evidence are shown in Table 2. Thus far, evidence is vague, and mostly no direct evidence-based data are available. Reduction of exposure to indoor allergens in the case of sensitized young children is recommended to prevent onset of allergic disease. Monosensitization to indoor allergens has been suggested to be the intermediate phase from nonatopy to polysensitisation and overt allergic disease [102]. This is, however, unlikely to be a universal pattern, as occurrence of atopic disease and atopy in general has remained low e.g., in Russian Karelia in repeated surveys [14, 103] and in generational analyses [14], irrespective of relatively high monosensitisation rates to house dust mite allergen among Russian children. Altogether, effective means for primary and secondary prevention are either lacking or are too vague to make a change. From the public health point of view, the preventive measures should be effective, easy to implement and cause no harm. This is difficult to achieve, and at the moment no active preventive measures are recommended anywhere. Giving child-bearing mothers, infants and children preand probiotics is an interesting approach. The first results of probiotic studies were quite promising [104], but the issue has become controversial as negative results have also been published [105, 106]. It must be emphasized that the term “probiotic” does not refer to any single bacterium species, and the effects are strainspecific. Recently, two studies with moderately positive results have been published [107, 108]. Modulation of the innate immunity by microbial, saprophytic components along with the most important airborne allergens (e.g., grass and birch pollen, cat and dog) in high-risk infants may offer a promising option. It could even be

Prevention of Allergic Diseases

457

Table 2 Secondary prevention measures (WAO/WHO) Measure Atopic eczema in infants and children should be treated to prevent respiratory allergy Upper respiratory disease (rhinoconjunctivitis) should be treated to reduce risk of development of asthma In young children already sensitized to indoor allergens, exposure should be reduced to prevent onset of allergic disease Employees should be removed from occupational exposure if they have developed symptoms associated with occupational allergic sensitization

Category of evidence (D) (D) (B) (C)

B Evidence from at least one controlled study without randomization or from other type of quasiexperimental study, or extrapolated recommendation from category A evidence C Evidence from nonexperimental descriptive studies, such as comparative, correlation and casecontrol – studies, or extrapolated recommendation from category A or B evidence D Expert opinion of the Prevention of Allergy and Allergic Asthma working group [100] or extrapolated recommendation from category A, B or C evidence

possible to treat drinking water and milk with immunostimulatory saprophytic components without risking the population with infections.

The Finnish Allergy Programme 2008–2018 Launched Occurrence of allergic diseases in Finland, similar to many other western countries, has reached alarming high levels. This rise in prevalence has continued for more than 40 years, without any changes in trends [109]. Sensitization rates to one or more common allergens among Finnish school children are currently approaching 50% [14]. Already in the early 1990s, the situation for asthma was considered serious enough to give an impetus for a National 10-year Asthma Programme, carried out in 1994–2004. This concrete, pragmatic action plan with simple goals resulted in improvements in several outcome measures and showed that a change for the better can be achieved with this kind of public health action plan [110]. In the wake of the successful asthma programme, the time for a national allergy programme to decrease the burden and costs of allergy has now been considered to be highly opportune. It is necessary to unify diagnostics and treatment practices nationally. In addition, the issue of allergy is associated with much of imagined allergy and unnecessary avoidance of allergens, both of which should be reduced in the population. It has become increasingly clear that the rising prevalence of allergic disease cannot be reversed by allergen avoidance. Tolerance against allergens must be strengthened in the population, in addition to strengthening treatment to control the allergy in those with true and severe allergic disease. The Finnish Allergy Programme was launched in April 2008.

458

L. von Hertzen and T. Haahtela

Goals and Focus Generally, the Programme is targeted to (1) decrease the burden of allergic disease on individuals and society, (2) decrease costs attributable to allergic disease, and to (3) improve treatment and control of patients with severe allergies. The Finnish Allergy Programme focuses on endorsing health and tolerance. It includes six ambitiously defined goals, tools to achieve the goals and an evaluation plan to assess the outcome and process [111]. The key messages of the Programme are: (1) (2) (3) (4) (5)

Endorse health, not allergy Strengthen tolerance Adopt a new attitude to allergy. Avoid allergens only if mandatory Recognize and treat severe allergies early. Prevent exacerbations Improve indoor air quality. Stop smoking

In allergy, there is now “law of worsening,” i.e., a mild allergy does not commonly develop to a severe one. Many children also outgrow their allergies. Adopting a new attitude – from avoidance to tolerance – is necessary. On the other hand, patients with severe disease must be treated better than before. The Allergy Programme emphasizes the importance of early recognition and treatment of patients with severe allergies. An important, albeit often neglected issue in allergy, is psychological tolerance. Imagined (pseudo-) allergy is common among people, and the Finnish Allergy Programme aims at reducing even this by strengthening psychological tolerance; mild allergy can be considered as a personal trait or characteristic rather than a disease that needs specific measures.

Conclusion An urban environment appears to lack elements that are necessary for the proper development of tolerance. Accumulating evidence indicates that the interplay between dose, timing and nature of exposure and the genetic composition of the host is decisive in determining the immune response in an individual. Much attention during the past 10 years has been devoted to endotoxin as an environmental immunomodulator. However, gram-negative bacteria appear to play only a minor part of the microbiota in different environments, and the role of bacteria of the gram-positive lineage as well as other microorganisms, fungi, protozoans, mites, algae etc., should in this respect be examined. Nonetheless, one of the key issues in the development of tolerance seems to be the diversity of microorganisms in our environment. Could occurrence of allergies be reduced in western populations? A large body of data shows that allergen avoidance – besides the fact that it is often impossible – seems not to be the right strategy. Animal models have provided encouraging

Prevention of Allergic Diseases

459

evidence that broken tolerance can be restored, and second-generation probiotic products (mixtures of four or more probiotic strains completed possibly with yeasts) and other bacteria-based prevention products may be the more successful tools in the future. Meanwhile, a 10 year Allergy Programme targeted to reduce the burden of allergies through education of health professionals and population is implemented in Finland. The focus of this Programme is on prevention and children, and the main issue will be the strengthening of tolerance in early life. To change the old dogmas is the major challenge. Acknowledgments The authors thank Professor Tapani Alatossava, University of Helsinki, for fruitful discussions, and the Allergy Foundation for partly funding this work.

References 1. von Hertzen L, Haahtela T (2006) Disconnection of man and the soil – reason for the asthma and atopy epidemic? J Allergy Clin Immunol 117:334–44 2. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118:229–41 3. van Oosterhout A, Bloksma N (2005) Regulatory T-lymphocytes in asthma. Eur Respir J 26:918–32 4. Rook G, Adams V, Hunt J, Palmer R, Martinelli R, Brunet LR (2004) Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders. Springer Semin Immunol 25:237–55 5. von Hertzen L, Haahtela T (2005) Signs of reversing trends in prevalence of asthma. Allergy 60:283–92 6. Raukas-Kivioja A, Raukas E, Loit HM, Kiviloog J, Ronmark E, Larsson K, Lundback B (2003) Allergic sensitisation among adults in Tallin, Estonia. Clin Exp Allergy 33:1342–48 7. Annus T, Riikjärv MA, Rahu K, Björksten B (2005) Modest increase in seasonal allergic rhinitis and eczema over 8 years among Estonian schoolchildren. Pediatr Allergy Immunol 16:315–20 8. Gotzsche PC, Johansen HK, Schmidt LM, Burr ML (2005) House dust mite control measures for asthma. The Cochrane Database of Systematic Reviews. The Cochrane Collaboration 3 9. Sheikh A, Hurwitz B (2003) House dust mite avoidance measures for perennial allergic rhinitis: a systematic review of efficacy. Br J Gen Pract 53:318–22 10. Kilburn S, Lasserson TJ, McKean M (2006) Pet allergen control measures for allergic asthma in children and adults. Cochrane Database Syst Rev 1 11. von Hertzen L, Haahtela T (2004) Asthma and atopy – the price of affluence? Allergy 59:124–37 12. von Mutius E (2004) Influences in allergy: epidemiology and the environment. J Allergy Clin Immunol 113:373–79 13. Björksten B, Dumitrascu D, Foucard T, Khetsuriani N, Khaitov R, Leja M, Lis G, Pekkanen J, Priftanji A, Riikjarv MA (1998) Prevalence of childhood asthma, rhinitis and eczema in Scandinavia and Eastern Europe. Eur Respir J 12:432–37 14. von Hertzen LC, Mäkela MJ, Petäys T, Jousilahti P, Kosunen TU, Laatikainen T, Vartiainen E,Haahtela T (2006) Growing disparities in atopy between the Finns and the Russians – a comparison of two generations. J Allergy Clin Immunol 117:151–57 15. Hanski I (2005) The Shrinking World: Ecological Consequences of Habitat Loss – Excellence in Ecology 14. International Ecology Institute: Germany

460

L. von Hertzen and T. Haahtela

16. Liu AH (2002) Endotoxin exposure in allergy and asthma: reconciling a paradox. J Allergy Clin Immunol 109:379–92 17. Gehring U, Bolte G, Borte M, Bischof W, Fahlbusch B, Wichmann HE, Heinrich J (2001) Exposure to endotoxin decreases the risk of atopic eczema in infancy: a cohort study. J Allergy Clin Immunol 108:847–54 18. Gisi U, Schkendel R, Schulin R, Standelman F, Sticker H (1997) Bodenökologie. Stuttgart: Georg Thieme Verlag 19. Sekar R, Pernthaler A, Pernthaler J, Warnecke F, Posch T, Amann R (2003) An improved protocol for quantification of freshwater Actinobacteria by fluorescence in situ hybridization. Appl Environ Microbiol 69:2928–35 20. Glöckner F, Zaichikov E, Belkova N, Denissova L, Pernthaler J, Pernthaler A, Amann R (2000) Comparative 16S rRNA analysis of lake bacterioplankton reveals globally distributed phylogenetic clusters including an abundant group of actinobacteria. Appl Environ Microbiol 66:5053–65 21. Balows A, Hausler WJ Jr, Herrmann KL, Shadomy HJ (eds) (1991) Manual of Clinical Microbiology. American Society for Microbiology: Washington DC, pp 222–224, 238–257 22. Waser M, Michels KB, Bieli C, Flöistrup H, Pershagen G, von Mutius E, Ege M, Riedler J, Schram-Bijkerk D, Brunekreef B, van Hage M, Lauener R, Braun-Fahrländer C (2007) Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe. Clin Exp Allergy 37:661–70 23. Perkin MR, Strachan DP (2006) Which aspects of the farming lifestyle explain the inverse association with childhood allergy? J Allergy Clin Immunol 177:1374–81 24. Riedler J, Braun-Fahrländer C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, Schierl R, Nowak D, von Mutius E (2001) Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358:1129–33 25. Radon K, Windststter D, Eckart J, Dressel H, Leitritz L, Reichert J, Schmid M, Praml G, Schosser M, von Mutius E, Nowak D (2004) Farming exposure in childhood, exposure to markers of infections and the development of atopy in rural subjects. Clin Exp Allergy 34:1178–83 26. Wickens K, Lane JM, Fitzharris P, Siebers R, Riley G, Douwes J, Smith T, Crane J (2002) Farm residence and exposures and the risk of allergic diseases in New Zealand children. Allergy 57:1171–79 27. Barnes M, Cullinan P, Athanasaki P, Macneill S, Hole AM, Harris J, Kalogeraki S, Chatzinikolau M, Drakonakis N, Bibaki-Liakou V, Newman Taylor AJ, Bibakis I (2001) Crete: does farming explain urban and rural differences in atopy? Clin Exp Allergy 31:1822–28 28. Remes ST, Iivanainen K, Koskela H, Pekkanen J (2003) Which factors explain the lower prevalence of atopy amongst farmers’ children? Clin Exp Allergy 33:427–34 29. Roginski H, Fuquay JW, Fox PF (eds) (2003) Encyclopedia of Dairy Sciences. Academic Press: Cornwall, pp 1786–96 30. Chatzi L, Apostolaki G, Bibakis I, Skypala I, Bibaki-Liakou V, Tzanakis T, Kogevinas M, Cullinan P (2007) Protective effect of fruits, vegetables and the Mediterranean diet on asthma and allergies among children in Crete. Thorax 62:677 31. Wong GW, Ko FW, Hui DS, Fok TF, Carr D, von Mutius E, Zhong NS, Chen YZ, Lai CK (2004). Factors associated with difference in prevalence of asthmain children from three cities in China: multicentre epidemiological survey. BMJ 329:1–4 32. Nja F, Nystad W, Carlsen L, Hetlevik O, Carlsen KH (2005) Effects of early intake of fruit or vegetables in relation to later asthma and allergic sensitization. Acta Pediatrica 94:147–54 33. Romieu I, Varraso R, Avenel V, Leynaert B, Kauffmann F, Clavel-Chapelon F (2006) Fruit and vegetable intakes and asthma in the E3N study. Thorax 61:209–15 34. Butland BK, Strachan DP, Anderson HR (1999) Fresh fruit intake and asthma symptoms in young British adults: confounding or effect modification by smoking? Eur Respir J 13:744–50

Prevention of Allergic Diseases

461

35. von Hertzen L, Laatikainen T, Pitkänen T, Vlasoff T, Mäkelä MJ, Vartiainen E, Haahtela T (2007) Microbial content of drinking water in Finnish and Russian Karelia – implications for atopy prevalence. Allergy 62:288–92 36. Cooper PJ, Chico ME, Rodriguest LC, Strachan DP, Anderson HR, Rodriguez EA, Gaus DP, Griffin GE (2004) Risk factors for atopy among school children in a rural area of Latin America. Clin Exp Allergy 34:845–52 37. Haileamlak A, Dagoye D, Williams H, Venn AJ, Hubbard R, Britton J, Lewis SA (2005) Early life risk factors for atopic dermatitis in Ethiopian children. J Allergy Clin Immunol 1154:370–6 38. Flohr C, Tuyen LN, Lewis S, Quinnell R, Minh TT, Liem HT, Campbell J, Pritchard D, Hien TT, Farrar J, Williams H, Britton J (2006) Poor sanitation and helminth infection protect against skin sensitisation in Vietnamese children: A cross-sectional study. J Allergy Clin Immunol 118:1305–11 39. Boasen J, Chrishol D, Lebet L, Akira S, Horner AA (2005) House dust extract elicit Toll-like receptor-dependent dendritic cell responses. J Allergy Clin Immunol 116:185–91 40. Hessle C, Andersson B, Wold AE (2000). Gram-positive bacteria are potent inducers of monocytic interleukin-12 (IL-12) while gram-negative bacteria preferentially stimulate IL-10 production. Infect Immun 68:3581–86 41. Lindström ES, Bergström AK (2005) Community composition of bacterioplankton and cell transport in lakes in two different drainage areas. Aquat Sci 67:210–19 42. Battaglia M, Gregori S, Bacchetta R, Roncarolo MG (2006) Tr1 cells: from discovery to their clinical application. Semin Immunol 18:120–27 43. Feleszko W, Jaworska J, Hamelmann E (2006) Toll-like receptors – novel targets in allergic airway disease (probiotics, friends and relatives). Eur J Pharmacol 533:308–18 44. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–95 45. Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21:903–14 46. Gershon RK, Cohen P, Hencin R, Liebhaber SA (1972) Suppressor T cells. J Immunol 108:585–90 47. Romagnani S (2006) Regulation of the T cell response. Clin Exp Allergy 36:1357–66 48. Umetsu D, DeKruyff R (2006) The regulation of allergy and asthma. Immunol Rev 212:238–55 49. Harylowicz CM, O’Garra A (2005) Potential role of interleukin-10 – secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5:271–83 50. Vigouroux S, Yvon E, Biagi E, Brenner M (2004) Antigen-induced regulatory T cells. Blood 104:26–33 51. Robinson DS, Larche M, Durham SR (2004) T regs and allergic diseases. J Clin Invest 114:1389–97 52. Umetsu DT, Akbari O, DeKruyff RH (2003) Regulatory T cells control the development of allergic disease and asthma. J Allergy Clin Immunol 112:480–87 53. Mills KHG (2004) Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 4:841–55 54. Platts-Mills TAE, Woodfolk JA, Erwin EA, Aalberse R (2004) Mechanisms of tolerance to inhalant allergens: the relevance of a modified Th2 response to allergens from domestic animals. Springer Semin Immun 25:271–79 55. Platts-Mills T (2007) The role of indoor allergens in chronic allergic disease. Presented at the World Immune Regulation Meeting, 11–15 April, Davos, Switzerland, Abstr: 26 56. Braun-Fahrländer C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Bufe A, Lauener RP, Schierl R, Renz H, Nowak D, von Mutius E (2002) Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 347:869–77 57. Iossifova YY, Reponen T, Bernstein DI, Levin L, Kaira H, Campo P, Villareal M, Lockey J, Hershey GK, LeMasters G (2007) House dust (1-3)-b-D-glucan and wheezing in infants. Allergy 62:504–13

462

L. von Hertzen and T. Haahtela

58. Custovic A, Hallam CL, Simpson BM, Craven M, Smpson A, Woodcock A (2001) Deacreased prevalence of sensitisation to cats with high exposure to cat allergen. J Allergy Clin Immunol 108:537–39 59. Cullinan P, MacNeill SJ, Harris JM, Moffat S, White C, Mills P, Newman Taylor AJ (2004) Early allergen exposure, skin prick responses, and atopic wheeze at age 5 in English children: a cohort study. Thorax 59:855–61 60. Jeal H, Draper A, Harris J, Taylor AN, Cullinan P, Jones M (2006) Modified Th2 responses at high-dose exposures to allergen – using an occupational model. Am J Respir Crit Care Med 174:21–25 61. Matsui EC, Eggleston PA, Breysse PN, Rand CS, Diette GB (2007) Mouse-allergen-specific antibody responses in inner-city children with asthma. J Allergy Clin Immunol 119:910–15 62. Pacheo KA (2007) New insights into laboratory animal exposures and allergic responses. Curr Opin Allergy Clin Immunol 7:156–61 63. Holt PG, Thomas WR (2005) Sensitization to airborne environmental allergens: unresolved issues. Nat Immunol 6:957–60 64. Schram-Bijkerk D, Doekes G, Boeve M, Douwes J, Riedler J, Üblagger E, von Mutius E, Budde J, Pershagen G, van Hage M, Wickman M, Braun-Fahrländer C, Waser M, Brunekreef B (2006) A non-linear relation between mite allergen levels and sensitisation in farm and nonfarm children. Allergy 61:640–47 65. Yazdanbakhsh M, Wahyuni S (2005) The role of helminth infections in protection from atopic disorders. Curr Opin Allergy Clin Immunol 5:386–91 66. Simpson A, Custovic A (2003) Early pet exposure: friend or foe? Curr Opin Allergy Immunol 3:7–14 67. Pakarinen J, Hyvärinen A, Salkinoja-Salonen M, Laitinen S, Nevalainen A, Mäkelä MJ, Haahtela T, von Hertzen L The predominance of Gram-positive bacteria in house dust in the low-allergy risk Russian Karelia. Environ Microbiol 2008;10:3317–25 68. Heumann D, Barras C, Severin A, Glauser MP, Tomasz A (1994) Gram-positive cell walls stimulate synthesis of tumour necrosis factor alpha and interleukin-6 by human monocytes. Infect Immun 62:2715–21 69. De Kimpe S, Kengatharan M, Thiemermann C, Vane J (1995) The cell wall components peptidoglycan and lipoteichoic acid from Staphylococcus aureus act in synergy to cause shock and multiple organ failure. Proc Natl Acad Sci USA 92:10359–63 70. Kirsching CJ, Schumann RR (2002) TLR2: cellular sensor for microbial and endogenous molecular patterns. Curr Top Microbiol Immunol 270:21–44 71. Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori MA, Werts C, Boneca IG. (2004) Toll-like receptor 2 – dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Reports 5:1000–06 72. Boneca IG (2005) The role of peptidoglycan in pathogenesis. Curr Opin Microbiol 8:46–53 73. Heine H, Lien E (2003) Toll-like receptors and their function in innate and adaptive immunity. Int Arch Allergy Immunol 130:180–92 74. Girardin SE, Philpott DJ, Lemaitre B (2003) Sensing microbes by diverse hosts. EMBO Reports 4:932–36 75. Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S (2003) Dectin-1 mediates the biological effect of b-glucans. J Exp Med 197:1119–24 76. Gantner BN, Simmons RM, Canavera SI, Akira S, Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 197:1107–17 77. Re F, Strominger JL (2004) IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J Immunol 173:7548–55 78. Sutmuller RPM, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, Joosten LA, Akira S, Netea MG, Adema GJ (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116:485–94

Prevention of Allergic Diseases

463

79. Taylor R, Richmond P, Upham JW (2006) Toll-like receptor 2 ligands inhibit Th2 responses to mite allergen. J Allergy Clin Immunol 117:1148–54 80. Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W (2004) Human plasmacytoid dendritic cells activated by CpG oligonucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 173:4433–42 81. Bashir ME, Louie S, Shi HN, Nagler-Anderson C (2004) Toll-like receptor 4 signalling intestinal microbes influences susceptibility to food allergy. J Immunol 172:6978–87 82. Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA (2006) Mechanisms of immune suppression by interleukin-10 and transforming growth factor-b: the role of T regulatory cells. Immunology 117:433–42 83. O’Garra A, Vieira P (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10:801–05 84. Liu H, Komai-Koma M, Xu D, Liew FY (2006) Toll-like receptor 2 signalling modulates the functions of CD4+CD25+ regulatory T cells. Proc Natl Acad Sci USA 103:7048–53 85. Lauener RP, Birchler T, Adamski J, Braun-Fahrländer C, Bufe A, Herz U, von Mutius E, Nowak D, Riedler J, Waser M, Sennhauser FH (2002) Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 360:465–6 86. Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun-Fahrländer C, Nowak D, Martinez FD (2004) Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 113:482–88 87. Martinez FD (2007) Genes, environment, development and asthma: a reappraisal. Eur Respir J 29:179–84 88. Cario E, Gerken G, Podolsky DK (2007) Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132:1359–74 89. Lambrecht BN (2005) Denritic cells and the regulation of the allergic immune response. Allergy 60:271–82 90. Tourney KG, van Hove C, Grooten J, Moerloose K, Brusselle GG, Joos GF (2006) Animal models of allergen-induced tolerance in asthma: are T-regulatory-1 cells (Tr-1) the solution for T-helper-2 cells (Th-2) in asthma? Clin Exp Allergy 36:8–20 91. Kaisho T, Akira K (2006) Toll-like receptor function and signalling. J Allergy Clin Immunol 117:979–87 92. Bird AP, Taggart MH (1980) Variable patterns of total DNA and rDNA methylation in animals. Nucleic Acids Res 8:1485–97 93. Antequera F, Tamame M, Villanueva JR, Santos T (1984) DNA methylation in the fungi. J Biol Chem 259:8033–36 94. de Heer HJ, Hammad H, Soullie T, Hijdra D, Vos N, Willart AM, Hoogssteden C, Lambrecht BN (2004) Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 200:89–98 95. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Schmidt-Weber C, Blaser K, Akdis CA (2004) Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 199:1567–75 96. Akdis M, Akdis CA (2006) Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 119:780–89 97. Ling EM, Smith T, Nguyen D, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS (2004) Relation of CD4+CD25+ regulatory T cell suppression of allergen-driven T cell activation to atopic status and expression of allergic disease. Lancet 363:608–15 98. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA (2003) IL-10 and TGF-b cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 33:1205–14 99. Sun-Payer E, Cantor H (2001) Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4+CD25+ T cells. J Autoimmun 16:115–23

464

L. von Hertzen and T. Haahtela

100. Pham-Thi N, de Blic J, Scheinmann P (2006) Sublingual immunotherapy in the treatment of children. Allergy 61(Suppl 81):7–10 101. Johansson SGO, Haahtela T (2004) World Allergy Organization Guidelines for prevention of allergy and allergic asthma. Int Arch Allergy Immunol 135:83–92 102. Bousquet J, Anto JM, Bachert C, Bousquet PJ, Colombo P, Crameri R, Daëron M, Fokkens W, Leynaert B, Lahoz C, Maurer M, Passalacqua G, Valenta R, van Hage M, van Ree R (2006) Factors responsible for differences between asymptomatic subjects and patients presenting an IgE sensitisation to allergens. A GA2LEN project. Allergy 61:671–80 103. Vartiainen E, Petäys T, Haahtela T, Jousilahti P, Pekkanen J (2002) Allergic diseases, skin prick test responses and IgE levels in North Karelia, Finland, and the Republic of Karelia, Russia. J Allergy Clin Immunol 109:643–48 104. Kalliomäki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E (2001) Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357:1057–59 105. Taylor AL, Dunstan JA, Prescott SL (2007) Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitisation in high-risk children: a randomised controlled trial. J Allergy Clin Immunol 119:184–91 106. Helin T, Haahtela S, Haahtela T (2002) No effect of oral treatment with an intestinal bacterial strain, Lactobacillus rhamnosus (ATCC53103), on birch-pollen allergy: a placebo-controlled double-blind study. Allergy 57:243–46 107. Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, Tuure T, Kuitunen M (2007) Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 119:192–98 108. Abrahamsson TR, Jacobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, Oldaeus G (2007) probiotics in prevention of IgE-associated eczema: a double-blind, randomised, placebo-controlled trial. J Allergy Clin Immunol 119:1174–80 109. Latvala J, von Hertzen L, Lindholm H, Haahtela T (2005) Trends in prevalence of asthma and allergy in Finnish young men: a nationwide study from 1966 to 2003. BMJ 330:1186–87 110. Haahtela T, Tuomisto LE, Pietinalho A, Klaukka T, Erhola M, Kaila M, Nieminen MM, Kontula E, Laitinen LA (2006) A 10-year asthma programme in Finland: major change for the better. Thorax 61:663–70 111. Haahtela T, von Hertzen L, Mäkelä M, Hannuksela M (2008) The Allergy Programme Working Group. Finnish Allergy Programme 2008–2018 – time to act and change the course. Allergy 63:634–45

Emerging Nonsteroidal Anti-Inflammatory Therapies Targeting Specific Mechanisms in Asthma and Allergy Leif Bjermer and Zuzana Diamant

Introduction Our current understanding of asthma pathophysiology has changed considerably during the last 20 years. From being regarded as an inflammatory disorder mainly affecting the central airways, asthma is now recognized as a heterogeneous, systemic disorder, involving the respiratory tract from nose to peripheral airways. Chronic inflammation in asthma is associated with the development of structural changes within the airways (the so-called “remodelling”) and airway hyperresponsiveness. While most asthma phenotypes are easily controlled with fairly low doses of corticosteroids, others appear more or less steroid-resistant. Inflammation involving mast cells and neutrophils is an example of such underlying mechanisms. Another example of corticosteroid resistance is over production of cysteinyl leukotrienes or tumour necrosis factor (TNF) -a in other asthma phenotypes [1, 2]. All together, this motivates the search for more systemic therapies, complementary to corticosteroid treatment. In this chapter, we will highlight some present and future nonsteroidal therapies, all given by systemic route.

Anti-Leukotrienes In 1940, Kellaway and Trethewie discovered the “slow reacting substance of anaphylaxis”, which appeared to constitute leukotrienes. Leukotrienes are metabolites of the arachidonic acid, constituent of the membrane phospholipids, via the

L. Bjermer () Department of Respiratory Medicine and Allergology, Heart and Lung Division, University Hospital of Lund, 221 85 Lund, Sweden e-mail: [email protected] Z. Diamant Departments of Allergology and Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_28, © Springer 2010

465

466

L. Bjermer and Z. Diamant

5-lipoxygenase (LO) pathway [3]. Apart from their bronchoactive properties, leukotrienes have been shown to induce several other features of asthma, such as airway hyperresponsiveness, airway inflammation and potentially, even airway remodelling both in healthy and asthmatic individuals [4–6]. The discovery of leukotrienes introduced a new target for the treatment of asthma. In the second half of the 1990s, the leukotriene synthesis inhibitor (LTSI), zileuton, and the leukotriene receptor antagonists (LTRAs), pranlukast, zafirlukast and montelukast entered into clinical practice representing a novel class of anti-asthma therapy [7]. Through antagonism of cysteinyl leukotrienes (cysLTs) at the CysLT1-receptor within the airways and on inflammatory cells, LTRAs combine anti-inflammatory – mainly anti-eosinophilic – activity with mild bronchodilator and bronchoprotective properties [4]. In asthma, while both LTSI and LTRA have been shown to be similarly effective, blocking the synthesis of both the cysLTs and leukotriene (LT)B4, LTSI may have additional potential in LTB4-driven conditions, such as the more severe asthma, COPD and cardiovascular disease [8, 9]. Presently, LTRAs are implicated in all treatment steps for asthma, mainly as add-on therapy [10]. Recently, their application has been extended to virally induced bronchoconstriction in children and to the “combined allergic rhinitis and asthma syndrome” (CARAS) [11, 12]. Moreover, more specific applications of LTRAs imply the mainly cysLTs-driven asthma phenotypes including the Aspirin-Exacerbated Airway Disease (AERD) and smoking or obese asthmatics [1, 2, 13].

Anti-Prostanoids Prostanoids are also derived from arachidonic acid through the cyclooxygenase (COX) pathway. Both thromboxane A2 (TxA2) and prostaglandin D2 (PGD2) have shown to be involved in allergic inflammation, and the effects are mediated mainly through three different receptors: TP (Thromboxane A2-receptor), DP (D-prostanoid receptor) and CRTH2 (chemoattractant receptor homologous-molecule expressed on T-helper type-2 cells). TxA2 is produced through the enzyme thromboxane synthase, and the primary target for its action is the TP-receptor. Introduced to the market in Japan in 1992, Ozagrel was the first TxA2 synthesis inhibitor reducing airway hyperresponsiveness to acetylcholine and leukotriene D4 [14]. Another anti-TxA2 drug, Seratrodast, is available for the treatment of asthma in Japan since 1997 [15, 16]. Both the DP and the CRTH2 receptors can be stimulated by PGD2 and both receptors are often expressed on the same cells. While the CRTH2 receptor on eosinophils, mast cells and basophils has a pro-inflammatory action, the DP receptor counteracts the CRTH2 effect. However, the interaction between these two receptors is very complex and there are examples of opposite effects, i.e., antagonizing DP receptor acting pro-inflammatory and vice versa [17]. Interestingly, even though PGD2 cannot discriminate between DP and CRTH2 receptors, there are several selective CRTH2 receptor antagonists being developed. Ramatroban was initially developed as a TP-receptor antagonist, but was found to

Nonsteroidal Therapy in Asthma & Allergy

467

act also as a CRTH2 receptor antagonist. Modest, though beneficial effects have been reported when applied in allergic rhinitis and asthma, the drug has been registered in Japan as a controller of allergy [18]. Presently, more potent and selective CRTH2 receptor antagonists are being tested in clinical trials of asthma, with promising effects [19, 20].

Phosphodiesterase Inhibitors Phosphodiesterase (PDE) includes 11 isoenzymes with various biological activities [21]. In pulmonary medicine, PDE4 and PDE5 are of particular interest. The latter exhibits its mode through interaction with cGMP, and together with PDE1, they are mainly responsible for breaking down gCMP in vascular smooth muscle cells [22]. Sildenafil is a potent PDE5 inhibitor and has been found to be effective in the treatment of pulmonary hypertension. It is conceivable to assume that the same drug may have effect in preventing vascular remodelling, a common phenomenon in both asthma and COPD [21]. The mode of PDE4 action is primarily by converting cAMP to 5’AMP and the different enzymes exert different biological effects dependent on localisation in different cell compartments. PDE4 is a family of 4 distinct sub-enzymes: PDE4A, B, C and D where PDEA, B and D are expressed on various inflammatory cells and structural cells [21]. The PDE4 antagonists were initially believed to be a further development of theophylline, used in asthma and COPD treatment since 1937 [23]. The aim was to find a drug with fewer side effects and drug interactions. Two PDE4 antagonists, Cilomilast (Ariflo®) and Roflumilast (Daxas®), have made it all the way to phase III trials. Both drugs have been shown to modestly reduce early and late inflammatory responses after allergen challenge and to improve airway hyperresponsiveness and lung function [24].

Anti-IgE Subcutaneous Omalizumab (a humanized monoclonal antibody, RhuMab-E25) has recently been registered as add-on therapy for the treatment of therapy-resistant, severe allergic asthma*. The mechanisms of action comprise reducing circulating serum IgE and down-regulating high-affinity IgE-receptors (FceRI) on mast cells and basophils [25]. Dosing is based on total serum IgE levels in combination with body weight. Since too high levels of anti-IgE may induce the formation of immune complexes, the cut-offs for these parameters have been set at 700 IE mL−1 and 150 kg, respectively [26]. In early clinical trials of asthma, Omalizumab has been shown to effectively reduce both the early and late phase responses following inhaled allergen [27]. In phase III trials, Omalizumab effectively improved disease control and allowed reduction of (topical) corticosteroids in two-thirds of the patients with allergic * 2002 in Australia, 2003 in US and 2007 in Europe.

468

L. Bjermer and Z. Diamant

asthma and/or allergic rhinitis [28–30]. However, despite its proven effectivity, the major drawbacks of this novel treatment modality comprise its subcutaneous administration (every 2–4 weeks) and high costs. Future applicability of anti-IgE in combination with immunotherapy is presently being explored for its immunotherapy-saving and (hence) safety-enhancing potential in allergic asthmatics [31, 32]. Presently, anti-IgE treatment is under investigation for another potential indication: food allergy [33].

Allergen Specific Immunotherapy Allergen specific immune therapy (ASIT) has been introduced by Noon in 1911 to induce tolerance to relevant allergens. The first successful attempt to induce tolerance to pollen allergens by sub-dermal injections was performed by Freeman at the Saint Maries hospital in London [34]. ASIT has been found to be effective not only in hay fever but also in asthma with allergy for pollen or house-dust mite that cannot be controlled by standard therapy [35]. ASIT is mostly administered by specialists as sub-dermal injections, requiring a building-up period followed by a maintenance period of 3–5 years. The protocol used varies depending on local tradition and the number and type of allergens delivered. Rush desensitization may be applied in mono-allergy and it is important to quickly reach a maintenance dose and a certain degree of protection. Examples of different protocols are shown in table (Table ASIT-number). Ultra-rush desensitization, reaching the maintenance dose already on day one, may also be applied in specific settings both as injectable and sub-lingual therapies [36, 37]. Concomitant uncontrolled asthma (FEV1 lower than 70% of predicted) is a relative contraindication to ASIT as asthma may temporarily deteriorate, especially during the step-up phase [38]. On the other hand, ASIT may decrease asthma severity and if started early, even prevent the development of asthma in susceptible patients with allergic rhinitis [39]. Today, ASIT both as injection and as sub-lingual therapies, is documented for allergic rhinitis with or without concomitant asthma. When safety instructions and protocols are followed, both treatments are safe and well-tolerated. Although sub-lingual therapy has the advantage of being simpler to administrate and requires less safety precautions, overall, the documented efficacy is considerably less than for subcutaneous ASIT [40, 41].

Anti-Cytokine Therapy The production of cytokines is regulated by regulatory T-cells (T-reg cells) and until recently two major pathways were considered: the T-helper (TH) type 1 and 2 pathways, with the latter being more associated with allergic sensitization, production of IgE and activation of eosinophils [42, 43]. Thus, the therapeutic strategy should

100 SQ 100 SQ 1,000 SQ 1,000 SQ 1,0000 SQ 1,0000 SQ 1,0000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ

0.2 0.8 0.3 0.8 0.2 0.4 0.4 0.1 0.2 0.4 0.6 0.8 1.0 week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 8 week 9 week 10 week 11 week 12

100 SQ 1,000 SQ 10,000 SQ 10,000 SQ 10,000 SQ 10,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ

0.2 0.2 0.1 0.2 0.4 0.8 0.15 0.3 0.6 0.8 1.0

day 1 day 1 day 1 day 4 day 4 day 7 week 2 week 3 week 4 week 5 week 6

time

Increase interval length 2 weeks 4 weeks 6 weeks Example of dosing schedules for allergen specific immunotherapy. The strategy should be chosen depending on the number of extracts used. However, other factors such as type of allergen and clinical factors (concomitant asthma, disease severity, etc) must also be considered.

week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 8 week 9 week 11 week 12 week 13 week 14 week 15 week 16

ml

0.2 0.4 0.6 0.2 0.4 0.8 0.15 0.3 0.6 0.8 0.1 0.2 0.4 0.6 0.8 1.0

time

100 SQ 100 SQ 100 SQ 1,000 SQ 1,000 SQ 1,000 SQ 10,000 SQ 10,000 SQ 10,000 SQ 10,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ 1,00,000 SQ

ml

Strength

Strength

ml

Strength

time

Quick(one allergen) (1 ½ month step-up)

Table 1 Allergen Specific Immunotherapy Step-up Schedule Standard-short(max 2 allergens) Standard(4 months step-up) (3 months step-up)

Nonsteroidal Therapy in Asthma & Allergy 469

470

L. Bjermer and Z. Diamant

be directed towards inhibiting type 2 associated cytokines such as IL-4, 5 and 13 and promoting type 1 associated cytokines, such as IL-9, 10, 12 and interferon (IFN)-gamma. Recently, the TH-1 and 2 hypotheses have been challenged with the discovery of other T-regulatory pathways, such as TH17 [44]. In asthma, the predominance of TH1 or TH2 pathway is also dependent on the individual phenotype: while the more mild allergic asthma is mainly of the TH2 type, the more severe sub-sets involve inflammatory mediators more linked to the TH1 pathway [45].

Anti-TNF-a TNF-a is stored in granulae of macrophages and mast cells and released via IgEdependent mechanisms [46]. Other important TNF sources are eosinophils, neutrophils and epithelial cells [47]. Increased expression of TNF-α has been found in bronchoalveolar lavage cells from asthmatic subjects [48]. In addition, increased levels of TNF-α have been measured in BAL fluid from allergic asthmatics following allergen challenge [49]. Anti-TNF-a therapy either by Infliximab, a chimeric anti-TNF antibody, or Etanercept, a soluble TNF-a receptor, has shown promising effects in several studies of severe persistent asthma, as these patients are relatively resistant to treatment with corticosteroids, expressing a T-helper-1 cell cytokines profile [50]. A recent study in patients with severe persistent asthma reported substantial improvement in airway hyperresponsiveness, quality of life scores and post-bronchodilator FEV1 following 10 weeks of treatment with subcutaneous Etanercept [51]. Another study in severe asthmatics showed similar results after 12 weeks of open label treatment [45]. Interestingly, Etanercept failed to protect against allergen-induced airway inflammation and airway hyperresponsiveness in patients with mild to moderate persistent asthma, who have a different TH-cell profile [52]. Thus, further studies are needed before this targeted treatment approach can be more widely recommended.

Anti-IL-5 Interleukin (IL)-5 is secreted by activated CD4 positive T-lymphocytes and has a central role in eosinophil activation and chemotaxis [53]. Inhalation of interleukin-5 is known to cause eosinophilic inflammation and to induce airway hyperresponsiveness in patients with asthma [54]. Thus, several in vitro and in vivo studies support the central role of IL-5 in both the allergic and asthmatic (airway) inflammations. In an allergen challenge study, Leckie and colleagues pre-treated 24 males with atopic mild persistent asthma with intravenously administrated monoclonal interleukin-5 antibody (SB-240563) in a randomized placebo-controlled design [55]. However, despite dramatic reduction in the number of eosinophils in both blood and induced sputum, anti-IL-5 treatment failed to reduce both the allergen-induced late response

Nonsteroidal Therapy in Asthma & Allergy

471

(LAR) and the allergen-induced airway hyperresponsiveness. These observations are in contrast with the pre-treatment with inhaled corticosteroids, reducing both the allergen-induced airway inflammation and the allergen-induced airway responses [56]. In a previous study in asthma, Haselden et al. already showed similar discrepancy between airway hyperresponsiveness and inflammatory reaction [57]. In this study, eight patients with a documented LAR to cat allergy were injected with cat allergen (Fel d 1) extract. However, no increase in eosinophils or TH2-type lymphocytes could be found in the bronchoalveolar lavage of these patients at 6 hours post-allergen [57]. These studies provided evidence that eosinophils may be merely an epi-phenomenon and hence may not play a predominant role in the pathophysiology of asthma, as was previously assumed. Another possible explanation could be that the anti-IL-5 effect on sputum and blood eosinophils does not fully reflect the situation within the deeper lung tissue. In a biopsy study, Flood-Page and co-workers found limited effect of anti-IL-5 treatment on tissue eosinophils in patients with active asthma [58]. In a more recent study, anti-IL-5 therapy with Mepolizumab failed to provide additional asthma control on top of moderate doses of inhaled corticosteroids in patients with persistent asthma, despite a significant reducing effect on sputum eosinophils [59]. Thus, the limited clinical efficacy of anti-IL-5 treatment may be due to the limited efficacy of the compounds tested so far or to a compensatory mechanism partly neutralizing the anti-IL-5 effect in the lung tissue. Alternatively, 2 recent placebo-controlled studies report beneficial effects of one year add-on treatment with intravenous mepolizumab in patients with severe refractory eosinophilic asthma [115,116]. In the first study with 9 patients with prednisone-dependent, eosinophilic asthma, mepolizumab reduced the number of sputum eosinophils and allowed tapering off prednisone [115]. Furthermore, in the other study in 61 asthmatics, add-on mepolizumab significantly reduced the number of blood and sputum eosinophilis along with significant reduction of the number of severe asthma exacerbations and improvement in quality of life (AQLQ scores) [116]. These data suggest that refractory airway eosinophilia may be a prerequisite for a potential response to (longterm) anti-IL-5 treatment.

Anti-IL-4 and Anti-IL-13 Parallel with IL-5, interleukin-4 (IL-4) is another key cytokine in the TH-2 dominated inflammation. IL-4 activates B-cells to differentiate into plasma cells secreting IgE [60, 61]. Furthermore, IL-4 enhances the secretion of eotaxin and increases the expression of adhesion molecules such as VCAM-1, which is known to be important for eosinophil recruitment and activation [62]. Increased serum levels of IL-4 have been reported in patients with allergic asthma, and allergen provocation has been shown to increase IL-4 levels in bronchoalveolar lavage [63]. Furthermore, inhalation of IL-4 has been shown to increase the numbers of eosinophils in induced sputum [64]. A free secreted form of IL-4 receptors naturally occurs in the serum of patients with active allergic asthma. This receptor has been shown to act as an antagonist to IL-4 and consequently prevents the activation of cells expressing IL-4 receptors [62]. A recombinant IL-4 receptor (RHUIL-4,

472

L. Bjermer and Z. Diamant

Nuvanc™; Immunex™) has been used in clinical studies in patients with allergic asthma. In one placebo-controlled parallel study, 62 patients with moderate persistent asthma, while on a maintenance dose of inhaled corticosteroids (ICS), were treated with inhaled RHUIL-4 (once per week for 12 weeks) and could successfully reduce or completely taper off their treatment with ICS [65]. Furthermore, treatment with recombinant IL-4 receptor resulted in a reduction of asthma symptoms and improved quality of life [65]. Presently, various anti-IL-4 approaches are being explored in allergic disease.

Anti-IL-13 The alpha chain of the IL-4 receptor forms an important signalling pathway for both IL-4 and IL-13 [66]. Thus, both cytokines share important biological activities. Interleukin-13 and IL-4 interact with respiratory epithelium, induce production of eotaxin and thus promote eosinophilic inflammation in animals [67]. They also interfere with COX-2 activity in epithelial cells, down-regulating the production of PGE2 [68]. Moreover, both cytokines increase the expression of VCAM, important for adherence and recruitment of T-lymphocytes and eosinophils to the lung tissue [69]. It has also been shown that both cytokines can induce similar biological activity independent of each other [70]. Thus, for optimal efficacy, it seems important to block both cytokines. Several combined anti-IL-4/IL-13 antibodies have shown promising results in animal models of asthma [71]. Until recently, there were no published human studies.

Anti-IL-9 Interleukin (IL)-9 was originally described as mast-cell growth factor due to its ability to enhance the survival of primary mast cells and to induce the production of their pro-inflammatory cytokine IL-6 [72, 73]. IL-9 induces mast-cell secretion of a number of proteases and the expression of high-affinity IgE receptor expression (FceRI-a) on T helper cell clones [74]. As mast cells are believed to play a crucial role in airway fibrosis and remodelling, IL-9 has received increased attention as a potential target in asthma therapy. Administration of anti-IL-9 systemically prevented the increase in airway hyperresponsiveness and eosinophilic response in mice after allergen challenge [75]. Presently, anti-IL-9 treatment is being tested in early clinical trials.

IL-10 Interleukin (IL)-10 is known to suppress the production of a number of proinflammatory cytokines such as IL-1b, TNF-a and GM-CSF and chemokines such as RANTES and eotaxin [76]. Furthermore, IL-10 inhibits the production of nitric oxide (NO) and appeared to block the effects of IL-5 [77]. Asthmatic patients have

Nonsteroidal Therapy in Asthma & Allergy

473

been shown to have a decreased ability to secrete IL-10 [78, 79]. Furthermore, a pronounced suppression was demonstrated in patients with difficult-to-treat asthma [80], while the levels of IL-10 increased in asthmatic children successfully treated with inhaled corticosteroids [81]. Until recently, recombinant IL-10 has only been shown to be effective in patients with Crohn’s disease [82]. No studies in asthma have been reported so far.

Recombinant IL-12 Interleukin (IL)-12 is mainly secreted by activated macrophages [83] and is also released by epithelial cells in asthmatics with active airway inflammation [84]. IL-12 stimulates TH0 lymphocytes towards the TH1 pathway and suppresses the TH2 response. It is known that subjects with allergic asthma have lower concentrations of IL-12 in their serum [85]. Low concentration of IL-12 has also been found in umbilical cord blood from infants predisposed to atopy [86]. These children also appeared to have low production of IFN-g, another important factor predisposing to TH-1 dominated inflammation [87, 88]. In vivo experiments in mice have shown that pre-treatment with IL-12 can prevent the increase of eosinophilic inflammation and the development of airway hyperresponsiveness following antigen challenge [89]. However, IL-12 may also have a dual response dependent on the timing of treatment. While IL-12 in the early phase of allergen sensitization may be protective, the introduction of IL-12 in a later stage may enhance even the allergic asthmatic reaction [90]. In a placebo-controlled study by Bryan and colleagues, 39 patients with allergic asthma were treated with recombinant IL-12 in weekly increasing doses for 4 weeks. In the group treated with IL-12, it was possible to prevent the allergen-induced eosinophilic inflammation. Furthermore, a tendency towards improvement in airway hyperresponsiveness after allergen provocation was seen together with a tendency to reduced late phase-induced inflammation. Unfortunately, the treatment was associated with a number of clinically relevant side effects, the most common one being flue-like symptoms occurring after each injection. Hence, 6 out of 19 subjects were withdrawn from the study due to unacceptable side effects [91].

Conclusion Anti-Cytokine Therapy The cytokine network in asthma is complex and dependent on the site, duration or timing of the intervention. The latter is exemplified by IL-12 with a potentially dual response. In addition, different asthma phenotypes may require different (customized) anti-cytokine therapy: an example is anti-TNF that seems to be effective in asthmatics with predominantly TH1 inflammatory mechanisms, including more severe disease, obese and/or smoking asthma patients [50, 92].

474

L. Bjermer and Z. Diamant

Probably, blocking more than one cytokine pathway is needed to obtain sufficient efficacy. Another challenge is the dosing, as has been demonstrated with anti-IL-5 treatment. This is a drawback for anti-cytokine treatment, since the production of monoclonals is expensive. Alternative strategies for antibody production have been tested, i.e., peptide-based vaccination and induction of neutralizing antibodies. These strategies require much lower doses and thus have a potential of being more cost effective [93–95].

Probiotics Following the concept of TH1 and TH2 imbalance and the hygiene hypothesis, immunostimulation with TH1 promoting microbes (i.e., probiotics) has been advocated during the last decade [96]. In this context, two major strategies have been tested: immunostimulating DNA sequences and active bacterial cultures, usually Lactobacilli (LB) and Bifid bacteria, given as food supplements. Probiotics delivered to high-risk mothers during the last months of pregnancy and during the first 6 months after delivery have been shown to reduce the risk for development of allergy and atopic dermatitis in newborns. This effect is maintained during the first years of life [97] and is of special interest as atopic dermatitis is a strong risk factor for later development of asthma in predisposed children [98]. Several species of Lactobacilli have been tested and the effect by one strain may not necessarily apply for another, i.e., it is not a “class effect”. In Kaliomäki’s studies, LB Rhamnosus GG (LGG) was used. In another recent study with a similar design, LB Streuveri reduced the number of IgE-related dermatitis, while the cumulative incidence of eczema was the same in both treatment groups [99]. In a third study using LB Acidophilus (LAVRI-A1), no difference in the incidence of atopic dermatitis could be found between the treatment groups. Unexpectedly, the degree of sensitization to allergens, including milk allergy, was higher in the probiotic group, despite a higher degree of Lactobacilli colonization [100]. Hence, this type of prevention of allergic diseases needs further research, considering both the lactobacillus strains but possibly the timing of intervention as well, before it can be generally recommended as a primary preventive tool, even in a risk population.

Heparins Heparin and related compounds have been shown to possess immunomodulator properties, attenuating the allergic airway inflammation in various species, including humans [101]. The anti-inflammatory properties may at least partly be explained by their anionic polyelectrolyte structure and are (mostly) not associated with anti-thrombotic activity [100,102]. In asthma, repeated doses of inhaled

Nonsteroidal Therapy in Asthma & Allergy

475

unfractionated heparin (UFH) have been shown to reduce the allergen-induced early and late asthmatic airway responses [103]. Similarly, in allergic rhinitis, intranasal UFH has been found to protect against adenosine monophosphate (AMP)and allergen-induced nasal symptoms and the associated nasal mast-cell release and eosinophilia/ECP, respectively [104, 105]. In the past decade, low molecular weight heparins (LMWH) have been introduced into clinical practice. LMWH possess superior pharmacological and immunomodulator properties to UFH. In (pre)clinical models of asthma, LMWH have been shown to possess potent (dose-dependent) anti-inflammatory effects (by reducing mast cell-induced mediator release and by reducing tissue eosinophilia by T-cell modulation) in various species in vivo [100 + refs therein, [106, 107]. In asthmatic patients, inhaled LMWH (5000 IU anti-FXa/daily, for 2 weeks) has been shown to reduce the number of inflammatory cells and mediators/cytokines in bronchoalveolar lavage fluid [108]. In another study, a dosedependent protection of ascending single inhaled dose of LMWH (enoxaparin) was found against exercise-induced bronchoconstriction (EIB) [109]. In this study, the maximum inhaled dose of LMWH (2 mg kg−1) was more effective than inhaled UFH (80,000 IU, equals 7.5 mg kg−1) against EIB and there were no anti-thrombotic effects at any of the doses tested [108]. A recent study by Duong and colleagues evaluated the effects of a single nebulized dose of a heparinderived hypersulfated disaccharide devoid of anti-coagulant activity (IVX-0142) on allergen-induced airway responses and airway inflammation [110]. Overall small and statistically not significant effects on all outcome parameters were observed – probably due to ineffective dosing. Application of heparin and related compounds for treatment of asthma and related disorders awaits further research.

Other Potential Anti-Asthma Targets Multiple signal transduction pathways are involved in airway inflammation with one of the key signalling pathways being phosphoinositide 3-kinase (PI3K). There are several isoforms of the PI3Ks, and especially the PI3Kg and d isoforms play an important role in the expression and activation of inflammatory mediators, inflammatory cell recruitment, immune cell function, airway remodelling and corticosteroid insensitivity in asthma and COPD [111, 112]. In this respect, these two isoforms may act as novel targets for therapeutic intervention in asthma and/or COPD. In vivo studies in these target populations are expected in the coming years. Other immunomodulator strategies in asthma are toll like receptor 9 (TLR-9) antagonists and CpG-, non-CpG- and antisense oligodeoxynucleotides [113, 114]. Some of these drugs have already entered phase I or II studies, but little data have been published so far.

476

L. Bjermer and Z. Diamant

Fig. 1 Different treatment strategies derived from the TH1/TH2 hypothesis. One strategy is to promote the immune system to direct towards the TH1 pathways, another to block TH2 promoting signals. A third strategy is to block disease specific (TH2 associated) mediators

Conclusion Since asthma was recognized as an inflammatory disease of the airways responsive to corticosteroids, our understanding of the concept of inflammation has changed considerably. As the inflammation has been found to extend beyond the airways and not all components appeared to respond to corticosteroid treatment, an urgent need came to find more disease-specific treatment modules devoid of disturbing side effects. The hygiene hypothesis, even though recently revised, has provided a base for constructing a large number of treatment strategies outlined in figure (Fig. 1) from TH1 promoting microbes and cytokines to blocking TH2 associated cytokines and disease-specific mediators, mainly amending the TH2 pathway. However, the nature of asthma is heterogeneous and complex, hence it requires totally different approaches for the prevention and treatment of early, mild and more severe disease.

References 1. Peters-Golden M, Swern A, Bird SS, et al. Influence of body mass index on the response to asthma controller agents. Eur Respir J. 2006; 27 (3):495–503 2. Lazarus SC, Chinchilli VM, Rollings NJ, et al. NHLBI’s Asthma Clinical Research Network. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;.175 (8):783–90

Nonsteroidal Therapy in Asthma & Allergy

477

3. Holtzman MJ. Arachidonic acid metabolism. Implications of biological chemistry for lung function and disease. American Review of Respiratory Disease 1991; 143:188–203 4. Diamant Z, Sampson AP. Anti-inflammatory mechanisms of leukotriene modulators. Clin Exp Allergy 1999; 29 (11):1449–1453 5. Panettieri RA, Tan EM, Ciocca V, Luttmann MA, Leonard TB, Hay DW. Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction In vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol. 1998; 19 (3):453–461 6. Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003; 111 (1 SUPPL):S18–34 7. Diamant Z, van der Molen T. Treating asthma: is there a place for leukotriene receptor antagonists? Respir Med. 2005; 99 (6):655–662 8. Bäck M, Sultan A, Ovchinnikova O, Hansson GK. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. Circ Res. 2007; 100 (7):946–949 9. Marian E, Baraldo S, Visentin A, Papi A, Saetta M, Fabbri LM, et al. Up-regulated membrane and nuclear leukotriene B4 receptors in COPD. Chest 2006; 129 (6):1523–1530 10. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2008; www.ginasthma.com 11. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et al. Montelukast reduces asthma exacerbations in 2–5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005; 171 (4):315–322 12. Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respir Med. 2006; 100 (11):1952–1959 13. Dahlén B, Nizankowska E, Szczeklik A, Zetterström O, Bochenek G, Kumlin M, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. Am J Respir Crit Care Med. 1998; 157 (4 PT 1):1187–1194 14. Fujimura M, Nishioka S, Kumabashiri I, Matsuda T, Mifune J. Effects of aerosol administration of a thromboxane synthetase inhibitor (OKY-046) on bronchial responsiveness to acetylcholine in asthmatic subjects. Chest 1990; 98 (2):276–279 15. Terao S, Shiraishi M, Matsumoto T, Ashida Y. Thromboxane A2 antagonist—discovery of seratrodast. Yakugaku Zasshi 1999; 119:377–390 16. Matsumoto T, Ashida Y, Tsukuda R. Pharmacological modulation of immediate and late airway response and leukocyte infiltration in the guinea pig. J Pharmacol Exp Ther. 1994; 269:1236–1244 17. Kostenis E, Ulven T. Emerging roles of DP and CRTH2 in allergic inflammation. Trends in Molecular Medicine 2006; 12:148–158 18. Motobayashi Y, Imagawa W, Saida K. [Ramatroban (Baynas): a review of its pharmacological and clinical profile]. Nippon Yakurigaku Zasshi Japanese J Pharmacol. 2001; 118:397–402 19. Uller L, Mathiesen J.M, Alenmyr L, Korsgren M, Ulven T, Högberg T, Andersson G, Persson C.G, Kostenis E. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respiratory Research 2007; 8:16 20. Ulven T, Kostenis E. Minor structural modifications convert the dual TP/CRTH2 antagonist ramatroban into a highly selective and potent CRTH2 antagonist. J Med Chem. 2005; 48:897–900 21. Fan Chung K. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol. 2006; 533:110–117 22. Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, Tang XB, Beavo JA. PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO Journal 2003; 22:469–478 23. Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med. 2003; 167:813–818 24. Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365:167–175

478

L. Bjermer and Z. Diamant

25. Nowak D. Management of asthma with anti-immunoglobulin E: a review of clinical trials of omalizumab. Respiratory Medicine 2006; 100:1907–1917 26. Novartis prescription information 2009; http://www.xolair.com/prescribing_information.html 27. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, Holgate ST, Fahy JV. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004; 170:583–593 28. Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M, Fox H, Surrey K. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004; 59:709–717 29. Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, Beeh K.M, Ramos S, Canonica GW, Hedgecock S, Fox H, Blogg M, Surrey K. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309–316 30. Bousquet J, Van Cauwenberge P, Ait Khaled N, et al. Pharmacologic and anti-IgE treatment of allergic rhinitis ARIA update (in collaboration with GA2LEN). Allergy 2006; 61 (9):1086– 1096 Review 31. Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006; 117 (1):134–140 32. Klunker S, Saggar LR, Seyfert-Margolis V, Asare AL, Casale TB, Durham SR, et al. Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding. J Allergy Clin Immunol. 2007;volume and pages?? 33. Chang TW, Wu PC, Hsu CL, Hung AF. Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol. 2007; 93:63–119 34. Freeman J. Furter observations on the treatment of Hay Fever by Hypodermic inoculations of pollen vaccine. Lancet 1911;178(4594):814–817 35. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003; 4:CD001186 36. Roll A, Hofbauer G, Ballmer-Weber BK, Schmid-Grendelmeier P. Safety of specific immunotherapy using a four-hour ultra-rush induction scheme in bee and wasp allergy. Journal of Investigational Allergology & Clinical Immunology 2006; 16:79–85 37. Tripodi S, Di Rienzo Businco A, Benincori N, Scala G, Pingitore G. Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children. International Archives of Allergy and Immunology 2006; 139:149–152 38. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol. 2006; 117:169–175 39. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, Koivikko A, Norberg LA, Valovirta E, Wahn U, Möller C. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007; 62:943–948 40. Abramson MJ, Puy R.M, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2003; 4:CD001186 41. Calamita Z, Saconato H, Pelá AB, Atallah AN. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006; 61:1162–1172 42. Coffman RL, Carty J. A T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma. J Immunol. 1986; 136:949–954 43. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 1986; 136:2348–2357

Nonsteroidal Therapy in Asthma & Allergy

479

44. Steinman L. A brief history of T (H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007; 13 (2):139–145 45. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, Beckett P, Al Ali M., Chauhan A, Wilson SJ, Reynolds A, Davies DE, Holgate ST. Tumor necrosis factor (TNF alpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005; 60:1012–1018 46. Ohkawara Y, Yamauchi K, Tanno Y, Tamura G, Ohtani H, Nagura H, et al. Human lung mast cells and pulmonary macrophages produce tumor necrosis factor-alpha in sensitized lung tissue after IgE receptor triggering. Am J Respir Cell Mol Biol. 1992; 7 (4):385–392 47. Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005; 109 (2):135–142 48. Cembrzynska-Nowak M, Szklarz E, Inglot AD, Teodorczyk-Injeyan JA. Elevated release of tumor necrosis factor-alpha and interferon-gamma by bronchoalveolar leukocytes from patients with bronchial asthma. Am Rev Respir Dis. 1993; 147 (2):291–295 49. Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005; 109 (2):135–142 50. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur Respir J. 2003; 22 (3):470–477 51. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006; 354 (7):697–708 52. Rouhani FN, Meitin CA, Kaler M, Miskinis-Hilligoss D, Stylianou M, Levine SJ. Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation. Respir Med. 2005; 99 (9):1175–1182 53. Lampinen M, Rak S, Venge P. The role of interleukin-5, interleukin-8 and RANTES in the chemotactic attraction of eosinophils to the allergic lung. Clin Exp Allergy 1999; 29 (3):314–322 54. Shi HZ, Xiao CQ, Zhong D, Qin SM, Liu Y, Liang GR, et al. Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics. Am J Respir Crit Care Med. 1998; 157 (1):204–209 55. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356 (9248):2144–2148 56. Kelly EA, Busse WW, Jarjour NN. Inhaled budesonide decreases airway inflammatory response to allergen. Am J Respir Crit Care Med 2000;162(3 PT 1):883–90. 57. Haselden BM, Larche M, Meng Q, Shirley K, Dworski R, Kaplan AP, et al. Late asthmatic reactions provoked by intradermal injection of T-cell peptide epitopes are not associated with bronchial mucosal infiltration of eosinophils or T(H)2-type cells or with elevated concentrations of histamine or eicosanoids in bronchoalveolar fluid. J Allergy Clin Immunol. 2001; 108 (3):394–401 58. Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med. 2003; 167:199–204 59. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007; 176 (11):1062–1071 60. Coffman RL, Ohara J, Bond MW, Carty J, Zlotnik A, Paul WE. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986; 136 (12):4538–4541 61. Sudowe S, Arps V, Vogel T, Kolsch E. The role of interleukin-4 in the regulation of sequential isotype switch from immunoglobulin G1 to immunoglobulin E antibody production. Scand J Immunol. 2000; 51 (5):461–471

480

L. Bjermer and Z. Diamant

62. Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir res. 2001; 2 (2):66–70 63. Leonard C, Tormey V, Burke C, Poulter LW. Allergen-induced cytokine production in atopic disease and its relationship to disease severity. Am J Respir Cell Mol Biol. 1997; 17 (3): 368–375 64. Shi HZ, Deng JM, Xu H, Nong ZX, Xiao CQ, Liu ZM, et al. Effect of inhaled interleukin-4 on airway hyperreactivity in asthmatics. Am J Respir Crit Care Med. 1998; 157 (6 PT 1):1818–1821 65. Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001; 107 (6):963–970 66. Zurawski SM, Vega F, Huyghe B, Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO Journal 1993; 12:2663–2670 67. Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunological Reviews 2004; 202:175–190 68. Trudeau J, Hu H, Chibana K, Chu HW, Westcott JY, Wenzel SE. Selective downregulation of prostaglandin E2-related pathways by the Th2 cytokine IL-13. J Allergy Clin Immunol 2006; 117:1446–1454 69. Fukushi J, Ono M, Morikawa W, Iwamoto Y, Kuwano M. The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13. J Immunol. 2000; 165:2818–2823 70. Perkins C, Wills-Karp M, Finkelman FD. IL-4 induces IL-13-independent allergic airway inflammation. J Allergy Clin Immunol. 2006; 118:410–419 71. Tomkinson A, Duez C, Cieslewicz G, Pratt J.C, Joetham A, Shanafelt MC, Gundel R, Gelfand EW. A murine IL-4 receptor antagonist that inhibits IL-4- and IL-3-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J Immunol. 2001; 166:5792–5800 72. Hultner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, Rude E, et al. Mast cell growthenhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol. 1990; 20 (6):1413–1416 73. Renauld JC, Kermouni A, Vink A, Louahed J, Van Snick J. Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis. J Leukoc Biol. 1995; 57 (3):353–360 74. Louahed J, Kermouni A, Van Snick J, Renauld JC. IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. J Immunol. 1995; 154 (10):5061–5070 75. Cheng G, Arima M, Honda K, Hirata H, Eda F, Yoshida N, Fukushima F, Ishii Y, Fukuda T. Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med. 2002; 166:409–416 76. Pretolani M, Goldman M. Cytokines involved in the downregulation of allergic airway inflammation. Res Immunol. 1997; 148 (1):33–38 77. Staples KJ, Bergmann M, Barnes PJ, Newton R. Stimulus-specific inhibition of IL-5 by cAMP-elevating agents and IL-10 reveals differential mechanisms of action. Biochem Biophys Res Commun. 2000; 273 (3):811–815 78. Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996; 97 (6):1288–1296 79. Matsumoto K, Gauvreau GM, Rerecich T, Watson RM, Wood LJ, O’Byrne PM. IL-10 production in circulating T cells differs between allergen-induced isolated early and dual asthmatic responders. J Allergy Clin Immunol. 2002; 109 (2):281–286 80. Hawrylowicz C, Richards D, Loke TK, Corrigan C, Lee T. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol. 2002; 109 (2):369–370 81. Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of the effect of glucocorticoid, antileukotriene and beta-agonist treatment on IL-10 serum levels in children with asthma. Clin Exp Allergy 2002; 32 (2):264–269

Nonsteroidal Therapy in Asthma & Allergy

481

82. Van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroidrefractory Crohn’s disease. Crohn’s Disease Study Group. Gastroenterology 1997; 113 (2):–9 83. Zeibecoglou K, Ying S, Meng Q, Poulter LW, Robinson DS, Kay AB. Macrophage subpopulations and macrophage-derived cytokines in sputum of atopic and nonatopic asthmatic subjects and atopic and normal control subjects. J Allergy Clin Immunol. 2000; 106 (4): 697–704 84. Walter MJ, Kajiwara N, Karanja P, Castro M, Holtzman MJ. Interleukin 12 p40 production by barrier epithelial cells during airway inflammation. J Exp Med. 2001; 193 (3):339–351 85. van der Pouw Kraan TC, Boeije LC, de Groot ER, Stapel SO, Snijders A, Kapsenberg ML, et al. Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma. J Immunol 1997; 158 (11):5560–5565 86. Blanco-Quiros A, Gonzalez H, Arranz E, Lapena S. Decreased interleukin-12 levels in umbilical cord blood in children who developed acute bronchiolitis. Pediatr Pulmonol. 1999; 28 (3):175–180 87. Rinas U, Horneff G, Wahn V. Interferon-gamma production by cord-blood mononuclear cells is reduced in newborns with a family history of atopic disease and is independent from cord blood IgE-levels. Pediatr Allergy Immunol. 1993; 4 (2):60–64 88. Chou CC, Huang MS, Hsieh KH, Chiang BL. Reduced IL-12 level correlates with decreased IFN-gamma secreting T cells but not natural killer cell activity in asthmatic children. Ann Allergy Asthma Immunol. 1999; 82 (5):473–484 89. Schwarze J, Hamelmann E, Cieslewicz G, Tomkinson A, Joetham A, Bradley K, et al. Local treatment with IL-12 is an effective inhibitor of airway hyperresponsiveness and lung eosinophilia after airway challenge in sensitized mice. J Allergy Clin Immunol. 1998; 102 (1):86–93 90. Meyts I, Hellings PW, Hens G, Vanaudenaerde BM, Verbinnen B, Heremans H, Matthys P, Bullens DM, Overbergh L, Mathieu C, De Boeck K, Ceuppens JL. IL-12 contributes to allergen-induced airway inflammation in experimental asthma. J Immunol. 2006; 177:6460–6470 91. Bryan SA, O’Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356 (9248):2149–2153 92. Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2008;121 (1):5–10; quiz 11–2. Epub 2007 Nov 26. Review. 93. Ma Y, Hayglass KT, Becker AB, Halayko AJ, Basu S, Simons FE, Peng Z. Novel cytokine peptide-based vaccines: an interleukin-4 vaccine suppresses airway allergic responses in mice. Allergy 2007; 62:–682 94. Ma Y, Hayglass KT, Becker AB, Fan Y, Yang X, Basu S, Srinivasan G, Simons FE, Halayko AJ, Peng Z. Novel Recombinant IL-13 Peptide-based Vaccine Reduces Airway Allergic Inflammatory Responses in Mice. Am J Respir Crit Care Med. 2007 95. Peng Z, Liu Q, Wang Q, Rector E, Ma Y,Warrington R. Novel IgE peptide-based vaccine prevents the increase of IgE and down-regulates elevated IgE in rodents. Clinical and Experimental Allergy 2007; 37:1041–1048 96. Yoo J, Tcheurekdjian H, Lynch SV, Cabana M, Boushey HA. Microbial manipulation of immune function for asthma prevention: inferences from clinical trials. Proc Am Thorac Soc. 2007; 4:–282 97. Kalliomäki M, Salminen S, Poussa T, Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007; 119:1011–1021 98. Del Giudice MM., Rocco A, Capristo C. Probiotics in the atopic march: highlights and new insights. Digestive and Liver Disease 2006; 38 (Suppl 2):S–S290. 99. Abrahamsson TR, Jakobsson T, Böttcher MF, Fredrikson M, Jenmalm MC, Björkstén B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebocontrolled trial. J Allergy Clin Immunol 2007; 119 (5):1–80

482

L. Bjermer and Z. Diamant

100. Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol. 2007; 119 (1):–91 101. Diamant Z, Page CP. Heparin and related molecules as a new treatment for asthma. Pulm Pharmacol Ther. 2000; 13:1–4 102. Ludwig RJ, Alban S, Boehncke WH. Structural requirements of heparin and related molecules to exert a multitude of anti-inflammatory activities. Mini Rev Med Chem. 2006; 6 (9):1–23 103. Diamant Z, Timmers MC, Van der Veen H, et al. Effect of inhaled heparin on allergeninduced early and late asthmatic responses in patients with atopic asthma. Am J Respir Crit Care Med. 1996; 153 (6 Pt 1):1–5 104. Vancheri C, Mastruzzo C, Armato F, et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol. 2001; 108 (5):–8 105. Zeng D, Prosperini G, Russo C, Spicuzza L, Cacciola RR, Di Maria GU, et al. Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation. J Allergy Clin Immunol. 2004; 114 (2):–20 106. Seeds AE, et al. The effect of inhaled heparin and related glycosaminoglycans on allergeninduced eosinophil infiltration in guinea-pigs. Pulm Pharmacol. 1995; 8(2–3):97–105 107. Zeng D, Prosperini G, Russo C, Spicuzza L, Cacciola RR, Di Maria GU, et al. Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation. J Allergy Clin Immunol. 2004; 114 (2):–20 108. Passowicz-Muszynska E, Jankowska R, Krasnowska M. [The effect of inhaled low molecular weight heparin on cell composition in bronchoalveolar lavage fluid and serum levels of soluble receptor IL-2 in bronchial asthma patients] Pol Merkuriusz Lek 2002; 12 (69):–20(Polish) 109. Ahmed T, Gonzalez BJ, Danta I. Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin Am J Respir Crit Care Med. 1999; 160 (2):–81 110. Duong M, Cockcroft D, Boulet LP, Ahmed T, Iverson H, Atkinson DC, Stahl EG, Watson R, Davis B, Milot J, Gauvreau GM, O’Byrne PM. The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma. Allergy 2008; 63 (9):1–201 111. Doukas J, Eide L, Stebbins K, Racanelli-Layton A, Dellamary L, Martin M, Dneprovskaia E, Noronha G, Acevedo LM, Soll R, Wrasidlo W, Cheresh DA. Aerosolized Phosphoinositide 3-Kinase {gamma}/{delta}Inhibitor TG–115 as a Therapeutic Candidate for Asthma and Chronic Obstructive Pulmonary Disease. J Pharmacol Exp Ther. 2008; [Epub ahead of print] 112. Park SJ, Min KH, Lee YC. Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma. Respirology. 2008; 13 (6):–71 113. Dorn A, Kippenberger S. Clinical application of CpG-, non-CpG-, and antisense oligodeoxynucleotides as immunomodulators. Curr Opin Mol Ther. 2008; 10 (1):10–20 Review 114. Kline JN, Krieg AM. Toll-like receptor 9 activation with CpG oligodeoxynucleotides for asthma therapy. Drug News Perspect. 2008;21 (8):–9 115. Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O’Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985–93 116. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009 Mar 5;360(10):973–84

Part II Special Considerations in Children, Elderly and Pregnancy

Asthma and Rhinitis in Pregnancy Vanessa E. Murphy and Peter G. Gibson

Introduction Asthma and rhinitis are common medical conditions that complicate pregnancy. Asthma can have an adverse impact on pregnancy outcomes, and pregnancy can modify the clinical status of pre-existing asthma and rhinitis. Coordinated medical and antenatal care that combines optimal medication use with self-management skills and careful monitoring of the mother and her baby form the basis of effective management of asthma and rhinitis in pregnancy.

Asthma During Pregnancy Asthma prevalence is around 10% in the adult female population, and between 8 and 12% of pregnant women in the UK and Australia report asthma during pregnancy. The clinical status of asthma is often altered by pregnancy. Women may experience a worsening of asthma during pregnancy, an improvement in asthma, or no change in clinical asthma status [1, 2]. Exacerbations of asthma are also common and affect many pregnant women with asthma [3, 4].

Asthma Control Asthma control is an important variable to assess during pregnancy, since changes in asthma control may necessitate changes in asthma therapy [5,6] (Table 1). A large prospective study of changes in asthma symptoms during and immediately

V.E. Murphy and P.G. Gibson () Hunter Medical Research Institute, Level 3, John Hunter Hospital, Locked Bag #1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_29, © Springer 2010

485

486

V.E. Murphy and P.G. Gibson Table 1 Clinical assessment of asthma during pregnancy Asthma control Night waking Daytime symptoms Activity limitation Reliever use Exacerbations Frequency Severity Lung function Airflow limitation Co-morbidity Rhinitis Gastroesophageal reflux Obesity Self-management skills Inhalation device technique Education Adherence Self-monitoring Action plan

after pregnancy found that there was a significant increase in asthma symptoms such as wheezing, sleep disturbance, and activity limitation from asthma between 25 and 32 weeks of gestation in those women whose asthma worsened [2]. Among women whose asthma improved during pregnancy, there was a decrease in wheeze and little change in sleep/activity interference. However, in all women, there was a significant improvement in wheezing and interference with sleep, and activity from asthma between 37 and 40 weeks of gestation. More than half of the women who had worsening of asthma during pregnancy showed an improvement in the postpartum period, while worsening of asthma at postpartum was observed in 87% of women who had improvements in pregnancy [2].

Asthma Exacerbations Asthma exacerbations occur during pregnancy and can be severe requiring hospitalization in up to 6% of women [4]. Preventing exacerbations is an important goal of asthma treatment. During pregnancy, between 20 and 36% of women have exacerbations of asthma requiring medical intervention [3, 7]. Exacerbations can occur at any time during gestation, but are more common in the late second trimester [1, 3, 8]. Severe exacerbations during labor are rare. The exacerbation rate during pregnancy increases with increasing asthma severity [1, 3, 7]. Murphy et al. described severe exacerbations among 8% of women with mild asthma, 47% of women with moderate asthma, and 65% of women with severe asthma [3]. Other risk factors for asthma exacerbation during pregnancy include inadequate prenatal care, viral infection [3],

Asthma and Rhinitis in Pregnancy

487

rhinitis [9], obesity [10], medication nonadherence, and the lack of appropriate treatment with inhaled corticosteroids (ICS) during pregnancy [3, 8, 11]. Conditions such as gastroesophageal reflux, rhinitis, and sinusitis may worsen during pregnancy, in turn exacerbating asthma. Treatment of these conditions is recommended as a component of asthma management during pregnancy [5]. Changes in asthma during pregnancy are variable and are not necessarily consistent from one pregnancy to another. When successive pregnancies in women with asthma were examined, only 60% of women followed the same course of asthma in the second pregnancy as the first, suggesting that there is a determinant of asthma which differed in the two pregnancies [2]. Interestingly, the course of rhinitis during pregnancy correlated with the course of asthma during pregnancy, with rhinitis worsening or improving in more than 50% of patients whose asthma had also worsened or improved, respectively [9]. Systemic factors such as IgE which can affect both the upper and lower airways may, therefore, be an important determinant of changes that occur in asthma and rhinitis during pregnancy [9]. Fetal sex has also been suggested as a relevant factor, where female fetal sex has been associated with deteriorating asthma in pregnancy [12].

Lung Function During Pregnancy Several studies of airway function during pregnancy report no changes in spirometry, but improvements in methacholine airway responsiveness are observed to occur in asthmatic women during the second trimester of pregnancy [13]. Pregnancy itself leads to changes in lung volumes that do not appear to have a major impact on asthma. These changes include decreases in total lung capacity and functional residual capacity, reduced chest wall compliance, and increased tidal volume and minute ventilation resulting in decreased arterial pCO2 concentration as an effect of progesterone-induced heightened respiratory drive.

Rhinitis During Pregnancy Symptoms of rhinitis are common during pregnancy. Between 18 and 30% of pregnant women report rhinitis symptoms during pregnancy. These symptoms may represent pre-existing rhinitis, the development of pregnancy rhinitis, or less common causes of rhinitis such as viral or bacterial infection, eosinophilic non-allergic rhinitis, nasal polyposis, or rhinitis medicamentosa. The course of rhinitis may vary during pregnancy. In patients with co-existing asthma and rhinitis, there is reasonable concordance between pregnancy-induced changes in asthma and changes in rhinitis [9] (Fig. 1).

488

V.E. Murphy and P.G. Gibson 60

% of women

50 40 Rhinitis Improved

30

Rhinitis Same

20

Rhinitis Deteriorated

10 0 Asthma Improved

Asthma Worse

Fig. 1 Change in rhinitis among women with asthma who experienced an improvement or worsening of asthma during pregnancy (Adapted from [9]).

Allergic Rhinitis Allergic rhinitis is common in pregnancy, and like asthma, the course can vary with up to one-third of women experiencing a deterioration in allergic rhinitis symptoms during pregnancy [14]. In women with pre-existing rhinitis, disease severity may change as a result of pregnancy. For example, a worsening of nasal symptoms was observed in 34% of pregnant women with pre-existing rhinitis, an improvement in 15%, and no change in 45% [9]. The recently revised international consensus panel, ARIA (Allergic Rhinitis and Its Impact on Asthma), has developed a rhinitis classification, and has recommended a step-wise approach to the treatment of allergic rhinitis based on the severity and duration of symptoms [15].

Pregnancy Rhinitis There is a specific form of rhinitis that develops during gestation. Pregnancyassociated rhinitis is defined as symptoms of nasal obstruction and rhinorrhea that develop during pregnancy, lasting for at least 2 months, and disappearing postpartum. The incidence of rhinitis associated with pregnancy was estimated to be 9% [16]. The mechanisms of pregnancy rhinitis are not known, but may be hormonally induced or due to changes in nasal hyperreactivity. The treatment of pregnancy rhinitis involves simple measures such as sleeping with the head of the bed elevated to avoid the increase in nasal congestion that occurs in the supine position, nasal saline washings, and nasal alar dilation using external devices.

Asthma and Rhinitis in Pregnancy

489

Snoring and Rhinitis in Pregnancy There is an emerging recognition that snoring and obstructive sleep apnea (OSA) can be important complications during pregnancy [17, 18]. Additionally, OSA is linked to pre-eclampsia [17, 19]. Rhinitis can impact on these associations. While the nose does not usually contribute substantially to total upper airway resistance, the swelling of the nasal mucosa due to congestion of the submucosal capacitance vessels that occurs during pregnancy may significantly reduce nasal airflow. With pregnancy there is also a reduction in upper airway dimensions, and pre-existing nasal conditions such as structural defects and rhinitis can increase nasal resistance. The consequences of this are nasal obstruction and an impairment of nasal breathing, especially when supine and during sleep. Treatment of allergic rhinitis with nasal corticosteroid reduced the apnea–hypopnea index and improved nasal resistance in OSA patients [20]. These studies suggest that in addition to an assessment of rhinitis and its severity, it is important to enquire about snoring and daytime sleepiness in pregnant women with rhinitis, as this may indicate accompanying OSA. If OSA occurs during pregnancy, treatment with nasal continuous airway pressure is well tolerated and effective.

Maternal and Fetal Complications of Asthma in Pregnancy Epidemiological studies provide varying results for the risk of maternal complications in pregnant women with asthma. The effect of asthma control and treatment may explain these differing results, with increased risks of complications generally associated with poor asthma control, asthma exacerbations, or undertreatment of asthma during pregnancy (Table 2).

Low Birth Weight Women with an exacerbation of asthma during pregnancy have a 2.5-fold increased odds of delivering a low birth weight baby (<2,500 g) [4]. An increased risk of intrauterine growth restriction or low birth weight in asthmatic pregnancies was found in Table 2 Pregnancy adverse effects associated with complicated asthmaa Low birth weight Pre-term labor Pre-eclampsia Severe asthma exacerbation a Complicated asthma is identified by poor control, need for oral corticosteroid, or severe exacerbation

490

V.E. Murphy and P.G. Gibson

a meta-analysis of four studies where women did not use ICS for asthma treatment during pregnancy [21]. Conversely, a meta-analysis of data where some or all women had used ICS during pregnancy found no significantly increased risk of low birth weight compared to control [21]. These analyses suggest that the use of ICS medication for asthma treatment during pregnancy may protect against low birth weight.

Preterm Birth Preterm labor is more common in pregnant women with severe asthma and in those needing oral corticosteroids for asthma exacerbations [22–24].

Pre-eclampsia and Pregnancy induced hypertension Pregnant women with asthma have been identified as being at increased risk of pre-eclampsia or pregnancy induced hypertension [8, 22, 25, 26]. The rate of preeclampsia was reported to be higher among oral steroid users compared to women with asthma who did not use oral steroids. Several studies have also found that the risk of pre-eclampsia is increased in women with poor asthma control [27–29]. In a large prospective study [30] where asthma was actively managed and subjects were well characterized, there was no effect of asthma on any of the outcomes examined, namely pre-eclampsia, perinatal mortality, low birth weight, preterm delivery, and congenital malformations. This study and others of women with closely managed asthma lead to the conclusion that well controlled asthma does not have significant adverse effects on either the mother or baby. Maternal allergic rhinitis has not been associated with adverse pregnancy outcomes [31].

Congenital Malformations The data on the effect of maternal asthma on congenital malformations is reassuring. Of the eight cohort studies examining congenital malformations among women with asthma, seven studies found no adverse effect and only one historical cohort study demonstrated a significantly increased odds of malformations in women with asthma compared to a control group of women without asthma [22].

Perinatal Mortality Although two studies in the 1970s found a significant effect of maternal asthma on perinatal mortality [32, 33], many of deaths were to women with severe asthma that

Asthma and Rhinitis in Pregnancy

491

was characterized by recurrent exacerbations during pregnancy. Since then, eight cohort studies have reported no increased risk of still birth and perinatal or neonatal mortality in women with asthma [8, 24, 30, 34–38].

Management of Asthma and Rhinitis During Pregnancy Managing Asthma and Rhinitis The goals of asthma and rhinitis management during pregnancy are to ensure normal fetal maturation while maintaining maternal quality of life by minimizing symptoms and limitations to activity, preventing exacerbations, maintaining near normal lung function and minimizing medication use and adverse side effects from medications [5]. Guidelines recommend the use of ICS for all women with persistent asthma, following a step-wise approach to therapy to achieve asthma control [5]. A randomized controlled trial that compared the use of inhaled beclomethasone and oral theophylline for the prevention of asthma exacerbations during pregnancy in women with moderate asthma found fewer side effects with inhaled beclomethasone and that the exacerbation rate was similar with both treatments [39]. Prospective studies also report that the risk of exacerbations of asthma during pregnancy was reduced by the use of ICS medication [8, 11]. Recommendations for asthma management during pregnancy include regular medical review and asthma monitoring with the obstetrician’s involvement. Education about how to self-manage asthma is an important component. Early detection of changes in lung function and asthma control is vital and women should receive education about asthma monitoring at home, and they should be provided with a written asthma action plan outlining how to respond to changes in their asthma and when to seek medical advice [5]. Monitoring and treatment of rhinitis is recommended to minimize complications. A simple visual analog scale has been found to be a useful tool to assess rhinitis symptoms in primary care [40] (Fig. 2).

Treatment of Asthma Exacerbations During Pregnancy Current guidelines on the management of asthma during pregnancy recommend treating exacerbations aggressively as a severe asthma attack presents more of a risk to the fetus than the use of asthma medications due to the potential for fetal hypoxia [5]. Studies suggest that pregnant women may be undertreated during severe exacerbations and consequently experience on-going symptoms of an asthma exacerbation. Management of an asthma emergency during pregnancy should involve both close monitoring of lung function and fetal activity. Oxygen saturation should be maintained above 95% with close cooperation between the

492

V.E. Murphy and P.G. Gibson

10 9 8 7 Visual 6 analogue 5 scale (cm) 4 3 2 1 0 intermittent

mild persistent mod persistent

Fig. 2 Visual analog scale values (cm) for categories of allergic rhinitis, assessed using ARIA guidelines. Solid line indicates cut-point for detecting more severe rhinitis (Adapted from [40]).

respiratory specialist and obstetrician [5]. In a randomized trial of therapy for severe asthma exacerbation during pregnancy, women received methylprednisolone with intravenous aminophylline or methylprednisolone alone at the time of admission to hospital [41]. Women receiving aminophylline reported more side effects, without any improvement in the length of hospital stay. On discharge, the women were randomized to receive inhaled b2-agonist with either oral steroid taper alone (40 mg reduced by 8 mg daily) or ICS (beclomethasone) plus oral steroid taper. The readmission rate was reduced by 55% with the inclusion of ICS on discharge [41]. This study supports the use of corticosteroids during and after hospitalization for asthma exacerbation in pregnancy.

Safety of Drug Treatments for Asthma and Rhinitis b2-Agonists There is a significant amount of reassuring data on the safety of short-acting b2-agonists, particularly albuterol during pregnancy [5]. Studies have found no significant differences in perinatal mortality, congenital malformations, preterm delivery, and low birth weight in asthmatic women who used short-acting b2-agonists compared to women who used no treatment for asthma during pregnancy [42]. A reduced risk of pregnancy induced hypertension, but not pre-eclampsia, was reported for women with asthma using rapid acting b2-agonists [28]. Limited data is available on the use of long-acting b2-agonists during pregnancy and no studies

Asthma and Rhinitis in Pregnancy

493

have addressed the use of combined inhaled corticosteroid and long-acting b2-agonist preparations in asthmatic pregnant women.

Inhaled Corticosteroids Inhaled corticosteroids have an acceptable safety profile among pregnant women with asthma and studies recommend that women whose asthma is well controlled on ICS should continue to use these during pregnancy [5, 43]. The majority of studies that address the safety of ICS use in pregnancy have been conducted in women using budesonide [5]. Other ICS drugs have not been shown to be unsafe and studies so far indicate that the use of ICS for asthma during pregnancy does not result in any adverse outcomes for the fetus [44]. In fact, by maintaining asthma control, ICS use may protect against some adverse outcomes, such as low birth weight [11, 21]. One study described a weak but significantly increased risk of malformations in women using any drugs for asthma during pregnancy, compared to the rate of malformations in the whole population [45]. A recent Canadian study of a large cohort of women with asthma found no increased risk of malformations in users of high-dose ICS [46]. Interestingly, there was a significantly reduced risk of malformations among users of moderate-dose ICS compared to nonusers [46].

Intranasal Corticosteroids Intranasal corticosteroids are recommended therapy for allergic rhinitis in pregnancy because of their acceptable safety profile and efficacy [47]. A recent review considered that the safety profile of intranasal budesonide was at least comparable to inhaled budesonide [48].

Oral Corticosteroids The effects of oral corticosteroids on pregnancy are not well described and the role of important variables such as the dose of oral steroid used, the timing and length of use during pregnancy remain unclear. Some cohort studies find a significant association between oral steroid use and pre-eclampsia [49], preterm delivery [23, 24], and reduced birth weight. Maternal oral corticosteroid use, particularly during the first trimester, appears to result in an increased risk of cleft lip in neonates [50]. None of the studies were specifically conducted in women with asthma. The current recommendation is that asthma be well managed so as to avoid the need for rescue oral steroid medication [43]. However, when required for the treatment of a severe exacerbation during pregnancy, the possible risks described are still less than the risks of severely uncontrolled asthma which may result in maternal and/or fetal death [5, 43].

494

V.E. Murphy and P.G. Gibson

Leukotriene Receptor Antagonists There is very limited data on the safety of leukotriene receptor antagonists in pregnancy. One study found no increased risk for preterm delivery, gestational diabetes, preeclampsia or pregnancy loss [51]; however, there was a small decrease in birth weight among users of leukotriene receptor antagonists, and in comparison to women without asthma, there was an increase in the prevalence of major structural anomalies. Leukotriene receptor antagonists are not specifically recommended for use during pregnancy in current guidelines due to the limited data available [5].

Antihistamines Antihistamines are effective therapy for allergic rhinitis, especially in treating nasal itch and discharge. The older agents have a longer history of use during pregnancy, and one review recommends these agents be used as first-line for rhinitis in pregnancy when an antihistamine is required [52]. A position statement recommended that cetirizine or loratadine could be considered for use in pregnancy, after the first trimester, in women who required topical antihistamine therapy and were not able to tolerate older antihistamines such as chlorpheniramine [53]. A practical approach is to use intranasal corticosteroids such as budesonide as first-line therapy of allergic rhinitis in pregnancy.

Nasal Decongestants While nasal decongestants are effective in relieving nasal obstruction, there is concern regarding their potential for causing rhinitis medicamentosa, and there have been concerns about their safety during pregnancy. More recent data is reassuring in this regard [54]. ARIA recommends that they be used with caution during pregnancy [15], and not as first-line therapy.

Conclusions Asthma and rhinitis are common problems in pregnancy. The clinical course of asthma and rhinitis may be altered by pregnancy, and uncontrolled asthma can have an adverse impact on outcomes for the mother and her baby. Optimal management of these conditions in pregnancy requires good communication between health professionals and patients, together with education, monitoring, and appropriate pharmacotherapy. There are research opportunities to identify the mechanisms of pregnancy-induced changes in asthma and rhinitis, as well as defining optimal management strategies for pregnant women with asthma and rhinitis.

Asthma and Rhinitis in Pregnancy

495

References 1. Gluck JC, Gluck PA (1976) The effects of pregnancy on asthma: a prospective study. Ann Allergy. 37:164–168 2. Schatz M, Harden K, Forsythe A, Chilingar L, Hoffman C, Sperling W, Zeiger RS (1988) The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol. 81 (3):509–517 3. Murphy VE, Gibson P, Talbot PI, Clifton VL (2005) Severe asthma exacerbations during pregnancy. Obstet Gynecol. 106 (5):1046–1054 4. Murphy VE, Clifton VL, Gibson PG (2006) Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes. Thorax 61 (2):169–176 5. NAEPP expert panel report. (2005) Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol. 115 (1):34–46 6. Global Initiative for Asthma (2006) Global strategy for asthma management and prevention. http://www.ginasthma.org 7. Schatz M, Dombrowski MP, Wise R, Thom EA, Landon M, Mabie W, Newman RB, Hauth JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, Varner MW, O’Sullivan M J, Thurnau GR, Conway D, McNellis D (2003) Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol. 112 (2):283–288 8. Stenius-Aarniala BS, Hedman J, Teramo KA (1996) Acute asthma during pregnancy. Thorax 51 (4):411–414 9. Kircher S, Schatz M, Long L (2002) Variables affecting asthma course during pregnancy. Ann Allergy Asthma Immunol. 89 (5):463–466 10. Hendler I, Schatz M, Momirova V, Wise R, Landon M, Mabie W, Newman RB, Kiley J, Hauth JC, Moawad A, Caritis SN, Spong CY, Leveno KJ, Miodovnik M, Meis P, Wapner RJ, Paul RH, Varner MW, O’Sullivan M J, Thurnau GR, Conway DL (2006) Association of obesity with pulmonary and nonpulmonary complications of pregnancy in asthmatic women. Obstet Gynecol. 108:77–82 11. Schatz M, Leibman C (2005) Inhaled corticosteroid use and outcomes in pregnancy. Ann Allergy Asthma Immunol. 95 (3):234–238 12. Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Bisits AM, Kessell CG, Clifton VL (2003) Maternal asthma is associated with reduced female fetal growth. Am J Respir Crit Care Med. 168 (11):1317–1323 13. Juniper EF, Daniel EE, Roberts RS, Kline PA, Hargreave FE, Newhouse MT (1989) Improvement in airway responsiveness and asthma severity during pregnancy. A prospective study. Am Rev Respir Dis. 140 (4):924–931 14. Blaiss MS (2003) Management of rhinitis and asthma in pregnancy. Ann Allergy Asthma Immunol. 90 (6 Suppl 3):16–22 15. Bousquet J, Van Cauwenberge P, Khaltaev N (2001) Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 108 (5 Suppl):S147–S334 16. Shushan S, Sadan O, Lurie S, Evron S, Golan A, Roth Y (2006) Pregnancy-associated rhinitis. Am J Perinatol. 23 (7):431–433 17. Edwards N, Middleton PG, Blyton DM, Sullivan CE (2002) Sleep disordered breathing and pregnancy. Thorax 57 (6):555–558 18. Pien GW, Fife D, Pack AI, Nkwuo JE, Schwab RJ (2005) Changes in symptoms of sleepdisordered breathing during pregnancy. Sleep 28 (10):1299–1305 19. Izci B, Riha RL, Martin SE, Vennelle M, Liston WA, Dundas KC, Calder AA, Douglas NJ (2003) The upper airway in pregnancy and pre-eclampsia. Am J Respir Crit Care Med. 167 (2):137–140 20. Kiely JL, Nolan P, McNicholas WT (2004) Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax 59 (1):50–55 21. Murphy VE, Gibson PG, Smith R, Clifton VL (2005) Asthma during pregnancy: mechanisms and treatment implications. Eur Respir J. 25 (4):731–750

496

V.E. Murphy and P.G. Gibson

22. Demissie K, Breckenridge MB, Rhoads GG (1998) Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med. 158 (4):1091–1095 23. Bracken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP (2003) Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol. 102 (4):739–752 24. Dombrowski MP, Schatz M, Wise R, Momirova V, Landon M, Mabie W, Newman RB, McNellis D, Hauth JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, Varner MW, O’Sullivan MJ, Thurnau GR, Conway DL (2004) Asthma during pregnancy. Obstet Gynecol. 103 (1):5–12 25. Mihrshahi S, Belousova E, Marks GB, Peat JK (2003) Pregnancy and birth outcomes in families with asthma. J Asthma. 40 (2):181–187 26. Kallen B, Otterblad Olausson P (2007) Use of anti-asthmatic drugs during pregnancy. 1. Maternal characteristics, pregnancy and delivery complications. Eur J Clin Pharmacol. 63:363–373 27. Schatz M, Dombrowski M, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Rouse DJ, Lindheimer M, Miodovnik M, Caritis SN, Leveno KJ, Meis P, Wapner RJ, Paul RH, O’Sullivan M J, Varner MW, Thurnau GR, Conway DL (2006) Spirometry is related to perinatal outcomes in pregnant women with asthma. Am J Obstet Gynecol. 194:120–126 28. Martel MJ, Rey E, Beauchesne MF, Perreault S, Forget A, Maghni K, Lefebvre G, Blais L (2007) Use of short-actine beta2-agonists during pregnancy and the risk of pregnancy-induced hypertension. J Allergy Clin Immunol. 119 (3):576–582 29. Martel MJ, Rey E, Beauchesne MF, Perreault S, Lefebvre G, Forget A, Blais L (2005) Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension: nested case-control study. Bmj 330 (7485):230 30. Schatz M, Zeiger RS, Hoffman CP, Harden K, Forsythe A, Chilingar L, Saunders B, Porreco R, Sperling W, Kagnoff M, et al. (1995) Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am J Respir Crit Care Med. 151 (4):1170–1174 31. Somoskovi A, Bartfai Z, Tamasi L, Kocsis J, Puho E, Czeizel AE (2007) Population-based case-control study of allergic rhinitis during pregnancy for birth outcomes. Eur J Obstet Gynecol Reprod Biol. 131 (1):21–27 32. Gordon M, Niswander KR, Berendes H, Kantor AG (1970) Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynecol. 106 (3):421–429 33. Bahna SL, Bjerkedal T (1972) The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol. 27 (5):397–406 34. Stenius-Aarniala B, Piirila P, Teramo K (1988) Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 43 (1):12–18 35. Jana N, Vasishta K, Saha SC, Khunnu B (1995) Effect of bronchial asthma on the course of pregnancy, labor and perinatal outcome. J Obstet Gynaecol. 21 (3):227–232 36. Wen SW, Demissie K, Liu S (2001) Adverse outcomes in pregnancies of asthmatic women: results from a Canadian population. Ann Epidemiol. 11 (1):7–12 37. Norjavaara E, de Verdier MG (2003) Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide. J Allergy Clin Immunol. 111 (4):736–742 38. Tata LJ, Lewis SA, McKeever TM, Smith CJ, Doyle P, Smeeth L, West J, Hubbard RB (2007) A comprehensive analysis of adverse obstetric and pediatric complications in women with asthma. Am J Respir Crit Care Med. 175 (10):991–997 39. Dombrowski MP, Schatz M, Wise R, Thom EA, Landon M, Mabie W, Newman RB, McNellis D, Hauth JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Varner MW, O’Sullivan MJ, Conway DL (2004) Randomized trial of inhaled beclomethasone dipropionate versus theophylline for moderate asthma during pregnancy. Am J Obstet Gynecol. 190 (3):737–744 40. Bousquet PJ, Combescure C, Neukirch F, Klossek JM, Mechin H, Daures JP, Bousquet J (2007) Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines. Allergy 62 (4):367–72

Asthma and Rhinitis in Pregnancy

497

41. Wendel PJ, Ramin SM, Barnett-Hamm C, Rowe TF, Cunningham FG (1996) Asthma treatment in pregnancy: a randomized controlled study. Am J Obstet Gynecol. 175 (1):150–154 42. Schatz M, Zeiger RS, Harden KM, Hoffman CP, Forsythe AB, Chilingar LM, Porreco RP, Benenson AS, Sperling WL, Saunders BS (1988) The safety of inhaled beta-agonist bronchodilators during pregnancy. J Allergy Clin Immunol. 82 (4):686–695 43. Schatz M (2005) Breathing for two: Now we can all breathe a little easier. J Allergy Clin Immunol. 115 (1):31–33 44. Silverman M, Sheffer A, Diaz PV, Lindmark B, Radner F, Broddene M, Gerhardsson de Verdier M, Pedersen S, Pauwels RA (2005) Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide. Ann Allergy Asthma Immunol. 95:566–570 45. Kallen B, Otterblad Olausson P (2007) Use of anti-asthmatic drugs during pregnancy. 3. Congenital malformations in the infants. Eur J Clin Pharmacol. 63 (4):383–388 46. Blais L, Beauchesne MF, Rey E, Malo JL, Forget A (2007) Use of inhaled corticosteroids during the first trimester of pregnancy and the risk of congenital malformations among women with asthma. Thorax 62:320–328 47. Gilbert C, Mozzotta P, Loebstein R, Koren G (2005) Fetal safety of drugs used in the treatment of allergic rhinitis: a critical review. Drug Saf. 28 (8):707–719 48. Gluck JC, Gluck PA (2005) Asthma controller therapy during pregnancy. Am J Obstet Gynecol. 192 (2):369–380 49. Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D (1997) The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol. 100 (3):301–306 50. Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, Friesen MH, Jacobson S, Kasapinovic S, Chang D, Diav-Citrin O, Chitayat D, Nulman I, Einarson TR, Koren G (2000) Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 62:385–392 51. Bakhireva LN, Jones KL, Schatz M, Klonoff-Cohen HS, Johnson D, Slymen DJ, Chambers CD (2007) Safety of leukotriene receptor antagonists in pregnancy. J Allergy Clin Immunol. 119 (3):618–625 52. Yawn B, Knudtson M (2007) Treating asthma and comorbid allergic rhinitis in pregnancy. J Am Board Fam Pract. 20:289–298 53. The use of newer asthma and allergy medications during pregnancy. (2000) The American College of Obstetricians and Gynecologists (ACOG) and The American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy Asthma Immunol. 84 (5):475 54. Kallen BA, Olausson PO (2006) Use of oral decongestants during pregnancy and delivery outcome. Am J Obstet Gynecol. 194 (2):480–485

Asthma in the Elderly Charles E. Reed

Introduction Despite the similarity of national and international guidelines for diagnosis and treatment of all ages, asthma in the elderly is a very different problem than asthma in children or younger adults. Diagnosis in this age group is particularly difficult because elderly patients frequently have coexisting lung diseases that contribute to the development of irreversible airway obstruction. Treatment is more difficult because of adverse effects of medications, especially on the heart. And death from asthma and other complicating lung diseases increases with age. There are three kinds of questions about asthma in the elderly: WHAT? HOW? and WHY? WHAT? questions are about epidemiology: What is the frequency, age of onset, death rate? HOW? questions are about the diagnosis and treatment: How do we diagnose and treat asthma in the elderly? WHY? questions are about pathogenesis: Why is the airway obstruction incompletely reversible in so many elderly patients? Why do they develop it when they do? Why do older individuals more often develop asthma that is intrinsic rather than allergic? Why in severe asthma are some segmental bronchi completely occluded with mucus plugs? The WHAT and HOW questions have been reasonably well answered [1–5]. Some answers to the WHY questions may be found in the innate immune response to agents from the environment.

Diagnosis National and international guidelines concur on the criteria for diagnosis of asthma and that these criteria are similar at all ages. The history includes episodic shortness of breath, cough and sputum, and wheezing. These symptoms are typically worse at

C.E. Reed () Emeritus Professor of Medicine, Mayo Medical School 9193 Bald Eagle Road, P.O. Box 158, Boulder Junction, WI 54512, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_30, © Springer 2010

499

500

C.E. Reed

night and often disturb sleep. Shortness of breath and wheezing after exercise or exposure to cold air or airborne irritants is a frequent symptom. Association with allergen exposure is less common in mature adults and when it develops in the middle-aged and elderly it is often occupational. Intrinsic asthma is often associated with rhinosinusitis and polyps and acute exacerbations from aspirin and related nonsteroidal anti-inflammatory drugs. In addition to the laboratory tests appropriate for all elderly individuals, blood tests should include a complete blood count and IgE level. Asthma is typically associated with eosinophilia unless it is under treatment with corticosteroids. Most elderly patients have moderately elevated IgE even if skin tests are negative. As a minimum, pulmonary function tests include spirometry before and after bronchodilators. If there is a suspicion of emphysema or interstitial lung diseases, then diffusing capacity should be added. Methacholine challenge is rarely indicated – only if the spirogram is normal and the diagnosis is in doubt. Chest X-ray, electrocardiograms, and cardiac ultrasound are needed to define other lung and heart diseases. Airway obstruction is often incompletely reversible, even after a course of corticosteroids. If the irreversible component is severe, computerized tomography (CT) is indicated to define the presence of additional lung diseases. Guidelines also stress that the diagnosis should include an evaluation of severity (mild, moderate, or severe) because management is linked to severity. The NAEPP working group report, Considerations for Diagnosing and Managing Asthma in the Elderly, summarizes their recommendations as follows: DIFFERENTIAL DIAGNOSIS OF ASTHMA IN THE ELDERLY • • • •

The differential diagnosis of episodic chest symptoms in the elderly expands as cardiovascular disease and other forms of chronic lung disease become more prevalent. In addition, the coexistence of asthma with other chronic cardiovascular or lung diseases may complicate the diagnosis. It is important not to misdiagnose asthma as COPD because asthma has a different natural history and a better prognosis with treatment. Because elderly patients with asthma can also have chronic, persistent airflow obstruction with poor bronchodilator responsiveness, a trial of therapy with corticosteroids may be necessary to establish that there is reversible airflow obstruction [1].

After the diagnosis of asthma is established the history must probe into possible environmental causes. These include outdoor allergens, pets, damp or water damaged houses or other buildings, and past or present occupational exposures. Skin tests or serum IgE antibody tests confirm the history of asthma provoked by allergy. It is my personal opinion that allergy tests should be done on all elderly patients to identify environmental exposures that can be controlled. Also, they provide reassurance if they are negative. In the past decades, asthma was underdiagnosed in the elderly [6], but now it is often overdiagnosed, either in patients with COPD with no reversibility or eosinophilia, or in patients whose only symptom is chronic day-time cough. Thus, epidemiological studies based on physicians’ diagnosis or patients’ recollection of asthma are

Asthma in the Elderly

501

difficult to interpret. Also, for studies of the epidemiology of a disease it is traditionally assumed that a patient has only one disease – for example, either asthma or COPD. In the elderly, this assumption is simply not true, as the Dutch hypothesis stated many years ago [7]. After all, many asthmatic patients smoke, and nothing prevents a person with COPD from developing asthma too. Furthermore, many environmental exposures include both bacterial endotoxin (a well described occupational cause of chronic bronchitis and emphysema) and allergens. Cigarette smoke itself contains endotoxin [8].

Onset and Prevalence Asthma may have begun early in life and persisted into old age, or it may begin late in life. Most individuals who had mild to moderate asthma in earlier years have a remission, but more severe disease tends to persist or recur. The incidence rate for elderly individuals is the same as younger adults, about one per thousand per year [9]. The reasons for late onset asthma have not yet been fully defined. Unlike asthma beginning in childhood there is no familial correlation. It has been generally considered that asthma beginning after the fourth decade is more often intrinsic, and not likely to be IgE-mediated unless the exposure to the agent is new. However, some, but not all, studies of patients who developed asthma after age 65 reported that many had allergy and elevated IgE [10–13]. Smoking is a risk factor, both for onset and persistence. Living or working in damp or water damaged buildings is an important risk factor for asthma development in children and working adults [14, 15]. Presumably this extends to the elderly. An important aspect of the onset of asthma in the elderly is that the obstruction becomes irreversible shortly after diagnosis or even before [16, 17]. Asthma prevalence in the elderly is about 6.5% [18]. Prevalence is somewhat greater than in young adults, presumably because the incidence rate exceeds the remission rate. Retrospective studies about whether incidence and prevalence of asthma in recent years has increased in the elderly are difficult because of changing criteria for diagnosis. In the Rochester, MN, community study based on information in the medical record rather than physicians’ diagnosis, the incidence in the elderly did not change between the years 1964 and 1984 [19].

Course Asthma that persists from earlier years remains fairly stable. However, asthma beginning in the elderly is more severe, more progressive, and less reversible [17, 20]. In the Tucson community-based longitudinal study, the FEV1 declined rapidly shortly after diagnosis, but then remained relatively stable with treatment. The rate of decline increases with age. Quality of life is impaired, even in those patients with good bronchodilator response. Remission is less common than it is in younger adults [18].

502

C.E. Reed

Death The death rate of individuals with asthma is similar to the general population; it increases strikingly with age [21]. Unfortunately, epidemiological studies of deaths caused by asthma that are based on death certificates are unreliable [22]. In the Rochester community study, a death certificate diagnosis of asthma had a high specificity (99%), but low sensitivity (42%) [23]. Patients who have coexisting lung diseases have a higher death rate [24, 25]. Death from the cardiac effects of asthma medications enhanced by hypoxemia remains a problem, though less now that large doses of theophylline are no longer used [26, 27].

Management and Treatment The goal is to maintain the best quality of life possible. Patient (or caregiver) education is the key to success since achievement of optimum results requires the patient to take responsibility for day-to-day management. Details of the treatment program and criteria for evaluating its success in meeting the goal are, of course, individualized, carefully tailored to the patient’s social and physical environment, to the severity of the asthma, and to the presence of coexisting lung and heart diseases. Guidelines recommend that each patient be given individualized written instructions. The NAEPP working group report lists the following key points to consider [1]. MANAGEMENT OF ASTHMA IN THE ELDERLY • Quality of life and the ability to live independently are important considerations in asthma management plans for the elderly. Each patient’s personal objectives should be explored and incorporated in treatment goals. • Desired therapeutic and clinical outcomes may be more difficult to achieve in elderly patients with asthma. Normal lung function may either be unattainable or be attainable only with potentially dangerous, high pharmacologic doses. Treatment goals may need to be modified to maintain a desirable quality of life. Conversely, some elderly patients do not appreciate the possibilities treatment offers, and they may have unnecessarily accommodated their lifestyles to their perceived limitations. It is important, therefore, to set realistic goals for therapy. • Medication for asthma management is similar for all ages, but ipratropium bromide may be useful, especially for those elderly patients who have chronic obstructive pulmonary disease or who experience tremor, angina, or arrhythmia from beta-2 agonists. • Because compliance with multiple therapies – for both asthma and coexisting diseases and conditions – may be difficult, elderly patients often need special education and training in using asthma medications and devices. • The potential for drug interactions is greater in elderly patients with asthma because these patients are likely to be on multiple medications for other conditions, particularly heart disease. — Beta-2 agonist and theophylline use should be monitored carefully because they can cause tachyarrhythmias and aggravate ischemic heart disease. — If theophylline is used, it should be used with caution, especially in patients with congestive heart failure. — Systemic corticosteroids may aggravate congestive heart failure and lower serum potassium with potentially adverse cardiac effects. — Corticosteroids in high doses may reduce bone mineral content and may accelerate development of osteoporosis.

Asthma in the Elderly

503

INTERACTIONS AMONG EFFECTS OF AGING, ASTHMA, AND COEXISTING DISEASES • Differentiating the normal physiologic, psychologic, and psychosocial changes that accompany aging processes from abnormal changes that accompany age-associated diseases or asthma is difficult. • Normal aging-associated changes in lung structure are likely to exaggerate asthma symptoms. These changes sometimes make it difficult to distinguish clearly between asthma and COPD, especially in patients who have smoked. • Patients with COPD often have a reversible component to their condition, and asthma medications may relieve some symptoms and improve the patient’s quality of life. • Elderly patients may have a decreased response to influenza immunization as well as to pneumococcal vaccine and tetanus toxoid. • Patient education and asthma management plans for elderly patients should take into consideration possible decreased ability to handle multiple complex stimuli, memory problems, loss of coordination, and muscle strength that make it difficult to use metereddose inhalers, hearing and visual difficulties, sleep disturbances that may impair cognitive function, and depression. • Adverse asthma reactions from medications related to polypharmacy are greater in the elderly. It is important to ask what other medications the elderly patient with asthma is taking. Particularly hazardous are beta adrenergic blocking agents (even ophthalmologic preparations) and, in some patients, nonsteroidal anti-inflammatory drugs and antidepressants.

Several points deserve elaboration. • The environment should be considered and optimized. Avoid active or passive smoking. Control exposure to household allergens. Identify and correct water damage and dampness in the home. See below for a more detailed discussion of the effects that airborne agents in these environments have on the innate immune inflammatory response. • Because many patients have glaucoma and cardiovascular diseases they are taking beta adrenergic blocking drugs that increase the severity of the asthma. Even eye drops may do so in some patients. • Learning how to inhale aerosol medications is difficult, although dry powder inhalers are easier to use than metered-dose inhalers. The patient’s inhalation technique should be checked at each follow-up visit. Elderly people tend to forget and often need several coaching sessions. • Anticholinergic aerosols are valuable bronchodilators for the elderly because they have less cardiovascular effects than beta adrenergic agonists. The long acting beta agonists are somewhat more likely to cause adverse cardiac effects, both because they are long acting and because they are less beta-2 selective [26, 27]. Unfortunately though, studies in younger adults have shown that while most asthmatic patients respond as well to anticholinergic as to beta-2 adrenergic agonists, as many as 25–30% of patients do not respond at all Therefore, the individual’s response must be validated by spirometry before and 20–30 min after inhalation. • Although bronchodilating levels of theophylline have been responsible for fatal cardiotoxicity, lower levels inhibit mast cell degranulation and inflammation [27a].

504

C.E. Reed

• As discussed below mast cell proteases and cytokine production play a major role in airway inflammation and fibrosis. Therefore, levels not greater than 5 mg/L should be considered as anti-inflammatory supplements to aerosol corticosteroids. • Many guidelines recommend that asthma control be monitored with daily peak flow measurements at home. However, the guidelines specifically for the elderly indicate that in this age group the usefulness of home peak flow monitoring is limited [1]. However, spirometry at each follow-up visit is indicated. Inexpensive hand-held instruments make this as simple in the examining room as blood pressure measurements for hypertension. • Overdosage with oral corticosteroids can occur in patients with coexisting irreversible airway obstruction in the attempt to maximize lung function. The peripheral blood eosinophil count is a useful guide in this circumstance. Optimal anti-inflammatory efficacy is attained when the total eosinophil count is about 50–100/mm3. If it is lower the corticosteroid dose may be too high. • Coexisting lung diseases that should be identified and considered in the management of patients with irreversible airway obstruction include: COPD, bronchiectasis (including allergic bronchopulmonary aspergillosis, ABPA), linear fibrosis, and even carcinoma of the lung [28]. Computerized tomography (CT) is indicated to identify the cause of irreversibility.

Irreversibility The majority of elderly patients with asthma have a substantial degree of irreversibility. In a random sample of Mayo Clinic patients 65 years of age or older with asthma, only about 20% achieved an FEV1 better than 80% of predicted value; another 20% achieved less than 50% predicted. This impairment was not related to the duration of the illness [17]. Why is the airway obstruction irreversible in so many elderly asthmatics? It is due to several distinctly different pathologies. 1. 2. 3. 4.

Airway remodeling from the inflammation of asthma Coexistence of COPD with centilobular and paraseptal emphysema Bronchiectasis Segmental linear pulmonary fibrosis

Although studies employing high-resolution CT scans have not been specifically designed to assess the reasons for irreversibility in the elderly, considerable information has been published about irreversibility in adults irrespective of age. Airway remodeling with collagen deposition beneath the basement membrane, smooth muscle hypertrophy, and hyperplasia of mucus glands affects the entire airway from main stem bronchi to bronchioles. Edema, vascular dilatation, and increased number of blood vessels also contribute to the thickening of the airway wall [29]. CT reveals the bronchial wall thickening and alveolar air trapping. The obstruction from remodeling increases with the severity and duration of asthma.

Asthma in the Elderly

505

Although treatment with aerosol corticosteroids reduces it in the large airways, aerosol corticosteroids have less effect in the small peripheral bronchioles. This treatment may not prevent the loss of reversibility in all patients [30]. Emphysema, characteristic of COPD and distinguishable from air trapping, is present in the CT scans of many patients with irreversible asthma, especially those who smoke. In nonsmokers emphysema in elderly asthmatic patients is associated with the duration of the disease [31]. Bronchiectasis is characteristic of the complication of asthma, ABPA. In this disease, the high-resolution CT of the chest demonstrates multiple areas of bronchiectasis and is a useful radiologic tool. Some other asthma patients have bronchiectatic airways, but not to the extent seen in or of the same character as those in ABPA [32]. In ABPA, the bronchiectasis typically is central while in other asthmatic patients bronchiectasis more often occurs in more peripheral bronchi. CT scans of patients with long standing severe asthma showed that many had both central and peripheral bronchiectasis, and that these abnormalities were more common in intrinsic than allergic asthma [33]. Segmental linear fibrosis is a common complication of lung infections including ABPA. Rarely, it is a result of Churg Strauss syndrome. Why do some patients with asthma develop emphysema? Because they smoke, of course. But another cause of emphysema is occupational exposure to airborne endotoxin [34, 35]. So the history of elderly patients with irreversible asthma should include enquiry into occupations with endotoxin exposure. In addition, endotoxin is present in many indoor environments, particularly homes with dogs or high humidity, so the present home environment should be considered, too [36]. The innate immune response to endotoxin involves the binding of the lipopolysaccaride molecule to CD14 on the cell membrane where it activates toll-like receptor 4 leading to production of cytokines like TNFa and chemokines like IL-8. IL-8 attracts and activates neutrophils and the neutrophil elastase destroys the elastic tissue of the alveoli causing emphysema. Patients with asthma, particularly intrinsic asthma, have increased frequency of MZ and SZ alpha-1 antitrypsin phenotypes [37]. This deficiency presumably increases the frequency of emphysema, but direct studies are yet to be done. Why do only some individuals develop asthma, especially intrinsic asthma? And why do they develop it when they do? Asthma probably has the most complex pathogenesis and cell biology of any disease in medicine. It has no single cause. It results from the interaction between many different agents in the environment and many different genes. Expression of many of these genes and function of their products is influenced by exposure to environmental agents [38]. After the environmental stimuli enter the airways they initiate the airway hyperresponsiveness and inflammation through multiple complex interacting inter- and intracellular signaling pathways [39]. Damp or water damaged buildings is the source of many of these stimuli [14, 40–43]. Microorganisms and mites growing in the damp environment not only produce allergens but also molecules that act through innate rather than humoral immunity.

506

C.E. Reed

In addition to the innate immune inflammation resulting from endotoxin inhalation, a second form of innate immunity resulting from the action of serine and cysteine proteases stimulating on specific receptors has emerged as an important mechanism of rhinitis and asthma. Endogenous proteases (thrombin, trypsin, and tryptase), acting on specific cell membrane molecules, protease-activated receptors (PARs), activate platelets and play a critical role in angiogenesis and fibrosis of wound healing, including airway remodeling. Information about exogenous proteases has expanded our understanding of allergic inflammation [44]. Proteases are present in many airborne allergenic particles. These proteases are not only allergens evoking an IgE response, but also promote production of IgE antibodies to proteins that otherwise would not elicit a Th2-type response [45, 46]. In addition, they can cause inflammation directly via PARs. This stimulation of inflammation includes recruitment and activation of eosinophils and degranulation of mast cells. In this respect, it can be considered as a variety of innate immunity directed particularly against parasites and arthropods [47, 48]. It is similar to toll-like receptor innate immunity in not requiring antibody production. But it differs in being directed against pathogens too large to be phagocytosed. The toxic products of eosinophils and the proteases of mast cell granules attack multicellular parasitic organisms directly. The important airborne proteases are from mites and molds. When molds germinate their hyphae produce digestive enzymes including proteases. Mite proteases are closely related between species. Group 1 (e.g., Der p1) are cysteine proteases; groups 3, 6, and 9 are serine proteases. All of them stimulate cytokine production by epithelial cells and degranulate eosinophils [49–51]. Molds not only grow in damp indoor environments, but can also germinate on the respiratory epithelium. Ponikau and associates have reported that 96% of nasal cultures of patients with chronic rhinosinusitis are positive for common fungi, particularly alternaria, aspergillus, and cladosporium [52]. Normal control subjects had similar frequency of positive cultures, but the chronic hyperplastic rhinitis patients had hyphae in the mucus of 86% of specimens, indicating that the fungi were growing on the mucosa [53]. Subsequently, they reported that extracts of mucus and nasal tissue from these patients attracted peripheral blood eosinophils in a tissue culture, and that the eosinophils from patients with chronic rhinosinusitis were more responsive than those from healthy controls [54]. Protease stimulation of PARs presumably is the mechanism for rhinosinusitis and polyp formation. Proteins in extracts of molds, especially alternaria, induced activation, IL-8 production, and degranulation of normal eosinophils through Ga protein pathways [55]. Proteases from aspergillus and alternaria stimulate respiratory epithelial cells to produce IL-6 and IL-8 [56, 57]. Do molds geminating on the bronchial epithelium similarly cause asthma? And could localized superficial germination of aspergillus produce the localized bronchial gland hyperplasia that leads to segmental bronchial occlusion by mucus plugs? Aspergillus is cultured from the sputum of many patients with asthma who do not have ABPA, so the hypothesis is worth testing. Environmental proteases act primarily on the epithelial cells and mast cells. Expression of PAR-2 is increased on respiratory cells of asthmatics, and presumably

Asthma in the Elderly

507

Table 1 Brief summary of innate immunity Th1-like Stimulus Endotoxin Airborne sources Target organisms Receptors

Gram-negative bacteria Bacteria and viruses Toll-like receptors (TLRs)

Primary cells involved Cytokines generated Chemokines generated Adhesion molecules generated Leucocytes attracted

Macrophages/monocytes TNFa, INFg, IL-6, IL-10, IL-12 IL-8 ICAM-1

Th-2 like Serine and cysteine proteases Mites and molds Helminths and arthropods Protease-activated receptors (PARs) Epithelial cells, mast cells IL-6,IL-4, IL-13 Eotaxins ICAM-1, VCAM-1

Neutrophils, monocytes, lymphocytes Neutrophils IgG

Eosinophils, monocytes, lymphocytes Eosinophils, mast cells IgE

Loss of alveolar elastic tissue, goblet cell hyperplasia

Basement membrane collagen production, smooth muscle hypertrophy, bronchial gland hypertrophy, angiogenesis, increased noxioception

Granulocytes activated Increased immunoglobulin production Tissue effects

increases the response to airborne proteases. It is not yet known whether this occurs before or after the development of asthma [58]. Much research is still needed about the genetics of these pathways, and how they may differ from “normal.” Table 1 summarizes the effect of these two pathways of innate immunity on asthma, COPD, and the combination of the two. One of the important effects is increased ICAM-1 on the respiratory epithelium that binds rhinovirus and increases viral respiratory infections.

Summary and Conclusions Asthma is a common and complex illness in the elderly. Unlike asthma in children and young adults it often occurs in combination with other lung diseases – COPD, bronchiectasis, and linear segmental fibrosis. Even patients with recent onset of asthma have a substantial degree of irreversible airway obstruction. It is important to determine the reasons for the irreversibility. Management is also complicated by coexisting cardiovascular and other problems. Current evidence-based guidelines provide valuable basis for individualizing management, but in my opinion do not stress sufficiently on the importance of controlling environmental exposures. Although the studies linking damp or water damaged buildings to development of asthma have included only children and working adults, it is reasonable to assume

508

C.E. Reed

that these exposures also make asthma worse in the elderly and can even cause its onset. Agents growing in water damaged or even just humid environments can cause airway inflammation and emphysema through two pathways of innate immunity: gram-negative bacterial endotoxin and mite and mold digestive proteases. At present the most practical way for physicians to check the on this is to ask the patient to look for it in their houses. Measurements of endotoxin and proteases in both settled dust and airborne particles are available, but only in research laboratories. Studies of the clinical value of these assays are needed. In order to reduce its severity, management of asthma in the elderly, particularly control of smoking and damp environment, needs to begin much earlier in life.

References 1. National Asthma Education and Prevention Program Coordinating Committee (1996) Considerations for diagnosing and managing asthma in the elderly. Publication No. 96-3662 2. Barbee RA, Bloom JW (Eds) (1997) Asthma in the Elderly. Marcel Dekker, New York 3. Barbee RA, Murphy S (1998) The natural history of asthma. J. Allergy Clin. Immunol. 102:S65–S72 4. Reed CE (1999) The natural history of asthma in adults: the problem of irreversibility. J. Allergy Clin. Immunol. 103:539–547 5. Bousquet J, Clark TJ, Hurd S, Khaltaev N, Lenfant C, O’Byrne P, Sheffer A (2007) GINA guidelines on asthma and beyond. Allergy 62:102–112 6. Banerjee DK, Lee GS, Malik SK, Daly S (1987) Underdiagnosis of asthma in the elderly. Brit. J. Dis. Chest 81:23–29 7. Sluiter HJ, Koeter GH, de Monchy JG, Postma DS, de Vries K, Orie NG (1991) The Dutch hypothesis (chronic non-specific lung disease) revisited. Eur. Respir. J. 4:479–489 8. Sebastian A, Pehrson C, Larsson L (2006) Elevated concentrations of endotoxin in indoor air due to cigarette smoking. J. Environ. Monit. 8:519–522 9. Bauer BA, Reed CE, Yunginger JW, Wollan PC, Silverstein MD (1997) Incidence and outcomes of asthma in the elderly. A population-based study in Rochester, Minnesota. Chest 111:303–310 10. Ariano R, Panzani RC, Augeri G (1998) Late onset asthma clinical and immunological data: importance of allergy. J. Invest. Allergol. Clin. Immunol. 8:35–41 11. Braman SS, Kaemmerlen JT, Davis M (1991) Asthma in the elderly. A comparison between patients with recently acquired and long-standing disease. Am. Rev. Respir. Dis 143:336–340 12. Dow, Coggon D, Campbell MJ, Osmond C, Holgate ST (1992) The interaction between immunoglobulin E and smoking in airflow obstruction in the elderly. Am. Rev. Respir. Dis. 146:402–407 13. Tracey M, Villar A, Dow L, Coggon D, Lampe FC, Holgate ST (1995) The influence of increased bronchial responsiveness, atopy, and serum IgE on decline in FEV1. A longitudinal study in the elderly. Am. J. Crit. Care Med. 151:656–662 14. Park JH, Cox-Ganser J, Rao C, Kreiss K (2006) Fungal and endotoxin measurements in dust associated with respiratory symptoms in a water-damaged office building. Indoor Air 16:192–203 15. Bornehag CG, Sundell J, Hagerhed-Engman L, Sigsggard T, Janson S, Aberg N (2005) ‘Dampness’ at home and its association with airway, nose, and skin symptoms among 10,851 preschool children in Sweden: a cross-sectional study. Indoor Air 15 Suppl 10:48–55 16. Burrows B, Lebowitz MD, Barbee RA, Cline MG (1991) Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample. J. Allergy Clinl. Immunol. 88:870–877

Asthma in the Elderly

509

17. Reed CE (1999) The natural history of asthma in adults: the problem of irreversibility. J. Allergy Clin. Immunol. 103:539–547 18. Barbee RA (1987) The epidemiology of asthma. Monogr. Allergy 21:21–41 19. Yunginger JW, Reed CE, O’Connell EJ, Melton LJ III, O’Fallon WM, Silverstein MD (1992) A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983. Am. Rev. Respir. Dis. 146:888–894 20. Reed, CE (2006) The natural history of asthma. J. Allergy Clin. Immunol. 118:543–548 21. Silverstein MD, Reed CE, O’Connell EJ, Melton LJ III, O’Fallon WM, Yunginger, JW (1994) Long-term survival of a cohort of community residents with asthma. N. Engl. J. Med. 331:1537–1541 22. Capewell S (1993) Asthma in Scotland: epidemiology and clinical management. Health Bull. 51:118–127 23. Hunt LW Jr, Silverstein MD, Reed CE, O’Connell EJ, O’Fallon WM, Yunginger JW (1993) Accuracy of the death certificate in a population-based study of asthmatic patients. JAMA 269:1947–1952 24. McCoy L, Redelings M, Sorvillo F, Simon P (2005) A multiple cause-of-death analysis of asthma mortality in the United States, 1990-2001. J. Asthma 42:757–763 25. Cluroe AD, Beasley R, Lorimer S, Holloway L (1994) The relationship between pulmonary interstitial emphysema and clinical features in fatal asthma. J. Asthma 31:65–69 26. Bremner P, Burgess CD, Crane J, McHaffie D, Galletly D, Pearce N, Woodman K, Beasley R (1992) Cardiovascular effects of fenoterol under conditions of hypoxaemia. Thorax 47:814–817 27. Martinez FD (2006) Serious adverse events and death associated with treatment using longacting beta-agonists. Clin. Rev. Allergy Immunol. 31:269–278 27a.Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ (1995) Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Resp Crit Care Med 151:1907–14 28. Brown DW, Young KE, Anda RF, Giles WH (2005) Asthma and risk of death from lung cancer: NHANES II Mortality Study. J. Asthma 42:597–600 29. Fish JE, Peters SP (1999) Airway remodeling and persistent airway obstruction in asthma. J. Allergy Clin. Immunol. 104:509–516 30. Dompeling E, van Schayck CP, van Grunsven PM, van Herwaarden CL, Akkermans R, Molema J, Folgering H, van Weel C (1993) Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study. Ann. Intern. Med. 118:770–778 31. Yilmaz S, Ekici A, Ekici M, Keles H (2006) High-resolution computed tomography findings in elderly patients with asthma. Eur. J. Radiol. 59:238–243 32. Greenberger PA (2002) Allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 110:685–692 33. Paganin F, Seneterre E, Chanez P, Daures JP, Bruel JM, Michel FB, Bousquet J (1996) Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am. J. Respir. Crit. Care Med. 153:110–114 34. Simpson JC, Niven RM, Pickering CA, Fletcher AM, Oldham LA, Francis HM (1998) Prevalence and predictors of work related respiratory symptoms in workers exposed to organic dusts. Occup. Environ. Med. 55:668–672 35. Reed CE, Milton DK (2001) Endotoxin-stimulated innate immunity: A contributing factor for asthma. J. Allergy Clin. Immunol. 108:157–166 36. Park JH, Spiegelman DL, Gold DR, Burge HA, Milton DK (2001) Predictors of airborne endotoxin in the home. Environ. Health Perspect. 109:859–864 37. Prados M, Monteseirin FJ, Carranco MI, Aragon R, Conde A, Conde (1995) Phenotypes of alpha1-antitrypsin in intrinsic asthma and ASA-triad patients. Allergol et Immunopathol. 23:24–28 38. Martinez FD (2007) Gene-environment interactions in asthma: with apologies to William of Ockham. Proc. Am. Thorac. Soc. 4:26–31 39. Bjornsson E, Norback D, Janson C, Widstrom J, Palmgren U, Strom G, Boman G (1995) Asthmatic symptoms and indoor levels of micro-organisms and house dust mites. Clin. Exp. Allergy 25:423–431

510

C.E. Reed

40. Etzel R, Rylander R (1999) Indoor mold and children’s health. Environ. Health Perspect. 107 Suppl 3:463 41. Dangman KH, Bracker AL, Storey E (2005) Work-related asthma in teachers in Connecticut: association with chronic water damage and fungal growth in schools. Conn. Med. 69:9–17 42. Rao CY, Riggs MA, Chew GL, Muilenberg ML, Thorne PS, Van Sickle D, Dunn KH, Brown C (2007) Characterization of airborne molds, endotoxins, and glucans in homes in New Orleans after Hurricanes Katrina and Rita. Appl. Environ. Microbiol. 73:1630–1634 43. Jaakkola MS, Nordman H, Piipari R, Uitti J, Laitinen J, Karjalainen A, Hahtola P, Jaakkola JJ (2002) Indoor dampness and molds and development of adult-onset asthma: a populationbased incident case-control study. Environ. Health Perspect. 110:543–547 44. Reed CE, Kita H (2004) The role of protease activation of inflammation in allergic respiratory diseases. J. Allergy Clin. Immunol. 114:997–1008 45. Gough L, Campbell E, Bayley D, Van Heeke G, Shakib F (2003) Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model. Clin. Exp. Allergy 33:1159–1163 46. Kheradmand F, Kiss A, Xu J, Lee SH, Kolattukudy PE, Corry DB (2002) A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J. Immunol. 169:5904–5911 47. Donnelly S, Dalton JP, Loukas A (2006) Proteases in helminth- and allergen-induced inflammatory responses. Chem. Immunol. Allergy 90:45–64 48. Pollock KG, McNeil KS, Mottram JC, Lyons RE, Brewer JM, Scott P, Coombs GH, Alexander J (2003) The Leishmania mexicana cysteine protease, CPB2.8, induces potent Th2 responses. J. Immunol. 170:1746–1753 49. Miike S, Kita H (2003) Human eosinophils are activated by cysteine proteases and release inflammatory mediators. J. Allergy Clin. Immunol. 111:704–713 50. Tomee JF, van Weissenbruch R, De Monchy JG, Kauffman HF (1998) Interactions between inhalant allergen extracts and airway epithelial cells: effect on cytokine production and cell detachment. J. Allergy Clin. Immunol. 102:75–85 51. Iraneta SG, Duschak VG, Rodriguez SM, Seoane MA, Albonico JF, Alonso A (1999) Proteinase and gelatinolytic activities of house dust mite and cockroach extracts. J. Investig. Allergol. Clin. Immunol 9:235–240 52. Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA, Roberts GD (1999) The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin. Proc. 74:877–884 53. Taylor MJ, Ponikau JU, Sherris DA, Kern EB, Gaffey TA, Kephart G, Kita H (2002) Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein. Otolaryngol. Head Neck Surg. 127:377–383 54. Wei JL, Kita H, Sherris DA, Kern EB, Weaver A, Ponikau JU (2003) The chemotactic behavior of eosinophils in patients with chronic rhinosinusitis. Laryngoscope 113:303–306 55. Inoue Y, Matsuwaki Y, Shin SH, Ponikau JU, Kita H (2005) Nonpathogenic, environmental fungi induce activation and degranulation of human eosinophils. J. Immunol. 175: 5439–5447 56. Borger P, Koeter GH, Timmerman JA, Vellenga E, Tomee JF, Kauffman HF (1999) Proteases from Aspergillus fumigatus induce interleukin (IL)-6 and IL-8 production in airway epithelial cell lines by transcriptional mechanisms. J. Infect. Dis. 180:1267–1274 57. Kauffman HF, Tomee JF, van de Riet MA, Timmerman AJ, Borger P (2000) Proteasedependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production. J. Allergy Clin. Immunol. 105:1185–1193 58. Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ (2001) Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J. Allergy Clin. Immunol. 108:797–803

The Natural History of Childhood Asthma Miles Weinberger and Dirceu Solé

Introduction The natural history of a disease is defined as a set of interactive processes that involves the underlying defect, the susceptible individual, and the environment. These three variables influence the global process that results in the human response. The result is persistence of the pathophysiology, recovery, or death [1]. Two sequential phases can be identified, the pre-pathogenic period (dependent on the host, the environment and the agent) and the pathogenic period. Asthma is a complex disease with several rather distinct clinical patterns that make the study and discussion of its natural history a challenging task.

Definition of Asthma In order to discuss the natural history of asthma, it first becomes necessary to define the clinical entities that we call asthma. There is by no means universal acceptance of a definition for asthma. Moreover, there are sufficiently different clinical patterns, clinical manifestations, and natural history that it is best to refer to specific asthma phenotypes when discussing the natural history [2]. This chapter will address specifically the natural history of the most common phenotypes that begin in childhood. What is asthma? This question is of particular importance in evaluating respiratory disease in the young child, where euphemisms for asthma including reactive

M. Weinberger () Pediatric Department, University of Iowa Hospital, 200 Hawkins Drive, Iowa City, IA 52242, USA e-mail: [email protected] D. Solé Division of Allergy, Clinical Immunology and Rheumatology, Federal University of São Paulo, São Paulo, Brazil

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_31, © Springer 2010

511

512

M. Weinberger and D. Solé

airway disease (RAD), wheezy bronchitis, obstructive bronchitis, recurrent bronchiolitis, etc. have been common. Sometimes, describing or defining asthma is like the parable of the blind men describing the elephant who felt it was like a tree, a snake, or a rope depending on whether they were feeling a leg, the trunk, or the tail. As with the perception of the blind men examining only one part of the elephant, asthma is sufficiently diverse that its perception depends on the experience of the observer. Some have suggested that, like love, it can’t be defined, but it’s recognizable when confronted [3]. The complexity and challenge of defining asthma have been discussed extensively by Sears [4]. In examining the 12 definitions and references in his review, a common theme to all is the presence of airway disease that varies over time either spontaneously or as a result of treatment. A committee of the American Thoracic Society agreed upon the definition that “Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that change in severity either spontaneously or as a result of therapy” [5]. This definition was expanded by a subsequent committee of the American Thoracic Society to include “The major symptoms of asthma are paroxysms of dyspnea, wheezing and cough, which may vary from mild and almost undetectable to severe and unremitting...” [6]. That definition and others, most notably that of Simon Godfrey, added to the definition that the airflow obstruction and clinical symptoms are largely or completely reversed by treatment with bronchodilators or corticosteroids [7]. Inflammation was introduced into the definition by Hargreave [8] and subsequently incorporated into the National Asthma Education Program Expert Panel Reports from the US National Institute of Health [9, 10]. However, a definition based on inflammation is not helpful in differential diagnosis or early disease identification since noninvasive measures of inflammation are neither readily available nor well-validated. This is especially true for young children in whom even the ability to make physiologic measurements is limited. Moreover, inflammation is not persistent in the common nonatopic asthma phenotype characterized by an intermittent viral respiratory infection-induced pattern of illness [11]. For a definition of a disease to be useful, it should provide a basis for making the diagnosis. While airway inflammation is certainly a characteristic for chronic phenotypes of asthma, the value of including this as a major component of the definition has been challenged. McFadden and Gilbert commented, “Airway inflammation and hyperresponsiveness....are not unique to this illness. The usefulness of these characteristics in defining asthma is unclear” [12]. This issue is discussed further by Brusasco et al. who argued that airway narrowing in asthma is not necessarily related to airway inflamation [13]. Asthma has thus proved challenging to define because of the diversity in its clinical presentation, variability of its clinical course, and absence of any specific diagnostic test. The ability to define asthma is essential for both study of the disease and for diagnosis. The reported prevalence and natural history of childhood asthma vary greatly depending on how asthma is defined for the purpose of diagnosis in epidemiologic and natural history studies [14, 15]. The challenge of defining asthma

The Natural History of Childhood Asthma

513

becomes greatest in the very young child. While there is an absence of an internationally accepted criteria for the definition of asthma in early childhood, birth cohort studies have nonetheless been attempted using various criteria to define asthma or potential asthma [16]. Martinez has emphasized the heterogeneity of asthma and the identification of specific phenotypes based on patterns of natural history and presence of early allergic sensitization [17].

When does Asthma begin?

Number per 10,000 children

While asthma can begin at almost any age, the childhood asthma phenotypes most commonly begin in infancy with a viral respiratory infection that causes the lower airway inflammatory disease with consequent wheezing and coughing that is commonly known as bronchiolitis. The most common cause of this initial wheezing episode is respiratory syncytial virus (RSV), but rhinovirus, parainfluenza, and metapneumovirus are other common cold viruses that can also initiate the first episode of lower airway disease in susceptible infants [18]. As many as 3% of infants in the U.S. have been hospitalized annually because of lower respiratory illness from these infections [19]. While it is premature to call the first episode of such symptoms asthma, this initial viral respiratory infection induced lower airway obstruction in infancy is often the harbinger of more to come, consistent with a diagnosis of asthma. In fact, when the onset of symptoms consistent with asthma was examined in an epidemiologic study of the population in the vicinity of Rochester Minnesota by investigators at Mayo clinic, the predominance of children with asthma had their onset during the first year of life (Fig. 1) [20].

7000 6000 5000 4000 3000 2000 1000 0 <1

1-4 Age of onset (years) Girls

5 - 14

Boys

Fig. 1 Age- and sex-adjusted incidence of asthma onset in a population-based epidemiologic study in Rochester, Minnesota (adapted from Yunginger et al) [20]

514

M. Weinberger and D. Solé

When an Infant Gets a VRI

Genetic and prenatal factors

URI only

Bronchiolitis No recurrent LRI with VRI Atopy

Recurrent LRI with VRI ( intermittent asthma )

Chronic

(persistent)

asthma

Fig. 2 Clinical consequences of initial infection following one of the common cold viruses in infancy. URI – upper respiratory illness; LRI – lower respiratory illness; VRI – viral respiratory infection (reproduced with permission) [24]

Thus, when a healthy baby becomes infected with one of these common cold viruses, as virtually all of them eventually do, most get only the typical coryza. A substantial minority experience bronchiolitis, the most common cause of hospitalization during the first year of life. Of those who experience bronchiolitis, about 25–50% subsequently have symptoms of an intermittent pattern of asthma manifested by recurrent wheezing only in association with subsequent viral respiratory infections [21, 22]. While clinical experience and natural history studies suggest that the majority of such children remit later in childhood, some continue to have recurrent or chronic symptoms consistent with a diagnosis of asthma throughout childhood, and some also continue into adult life [23] (Fig. 2) [24].

Who gets Asthma? A component of the natural history of asthma is identifying who is at risk for having asthma. An asthma phenotype is present in approximately 25% of the offspring of a parent with asthma [25]. Further evidence for a genetic influence on the asthma phenotype is seen in twin studies wherein there is a higher concordance in monozygotic twins compared with dizygotic twins, even though both twins share the same environment [26, 27]. But the concordance even in identical twins is not much over 50%. Both genetics and environment therefore appear to contribute to asthma.

The Natural History of Childhood Asthma

515

The genetics are complex with apparently separate contributions to airway hyperresponsiveness and IgE mediated sensitivity to inhalant allergens [28]. Airway reactivity or hyperresponsiveness is considered a hallmark of asthma [29]. Persistence of asthma beyond the pre-school years has been found to be associated with increased airway responsiveness in early life [30]. However, airway hyperresponsiveness is not diagnostic of asthma. Airway hyperresponsiveness to a cholinergic stimulus is found with increased frequency in nonasthmatic parents of children with asthma at a frequency, suggesting that such responsiveness is transmitted as an autosomal-dominant trait that is a necessary but not sufficient biologic variable to cause clinical asthma [31, 32]. Total IgE production appears to have strong genetic determination based on the observations of very high concordance in monozygotic twins and lesser concordance in dizygotic twins, both of whom should have similar environmental exposures [33]. However, less well studied is the genetics of antigen specific IgE. Other genetic variables that can affect the phenotypic manifestations of atopic sensitization include the affinity of IgE receptors on target cells, the interaction of IgE with the receptors, IgE-induced release of mediators, and end-organ responsiveness. Despite their clinical usefulness as an aid to the assessment of diseases affected by atopic sensitization, neither the size of allergy skin tests nor the titer of antigen-specific IgE on in vitro tests reliably predicts either disease or severity. Although IgE mediated inhalant sensitivity tends to develop later than ingestant sensitivity in early childhood, Wilson et al. found cockroach sensitivity in 29%, dust mite in 10%, cat in 10%, and Alternaria in 4% among 49 asthmatic infants under one year of age [34]. Arshad and Hide examined the development of atopic related findings in a prospective study of 1,167 infants [35]. They found that dust mite positive skin tests were more prevalent in formula fed infants. While positive skin tests to animal epidermals were more prevalent among infants exposed to the respective animals, they did not find that exposure to animals influenced the prevalence of clinical disorders. However, Lindfors et al., in a case control study of 193 children with asthma aged one to 4 years, did find that high dose exposure to cat and/or dog resulted in an increased risk of asthma with indoor dampness and exposure to environmental tobacco smoke having apparent synergistic effect [36]. In a subsequent report, they described a dose-response relationship between cat exposure and sensitization to cat but not to dog [37]. Sears et al. found a relationship between children born in winter and sensitization to cats and house dust mites [38]. Sherrill et al., in a prospective longitudinal study in Tucson, found an association between sensitization before age 8, as determined by skin testing, and symptoms of asthma, whereas those who developed positive skin tests only after age 8 did not differ in frequency of asthmatic symptoms from those never sensitized [39]. Similar results were reported in a longitudinal study of 2,166 children by Chen et al [40]. While Nelson et al. found an association of many positive skin tests among 1,041 school age children with “mild to moderate” asthma, these investigators found that only dog, cat, and Alternaria mold correlated independently with increased lower airway hyperresponsiveness as measured by methacholine challenge, though not with decreased pulmonary function [41]. Although this latter study did not involve

516

M. Weinberger and D. Solé 70

% wheezing at year 3

60 50 40 30 20 10 0 RSV Season (Dec-Jan) None

Both Seasons RV Season (Mar-Nov)

Season of First Wheezing as Infant

Fig. 3 Wheezing illnesses consistent with asthma at age 3 as predicted by initial viral respiratory infection induced lower wheezing illness in infancy (adapted from Lemanske et al) [42]

pre-school age children, it indicates that some inhalant allergens appear to be more asthmagenic than others. Thus, getting asthma is a function of genetic and environmental variables, not all of which are known. While those with a viral respiratory infection-induced intermittent pattern appear to have a familial predisposition, the genetics of that pattern are not well-studied. Both airway hyperresponsiveness and IgE mediated sensitivity to inhalant allergens in infancy appear to be predictors of those who eventually have persistent symptoms.

Natural History of Early Childhood Asthma While a viral respiratory infection is the cause of common first wheezing episodes in an infant (Fig. 2) and as respiratory syncytial virus (RSV) receives considerable attention because of its major contribution to seasonal epidemics of bronchiolitis, it is rhinovirus-induced bronchiolitis that appears to be a better predictor of those infants likely to experience recurrent wheezing episodes consistent with asthma [42]. When a wheezing illness was associated with the seasons for RSV or rhinovirus during the first year of life, rhinovirus was identified as a greater predictor for recurrent symptoms consistent with asthma than RSV when evaluated at age 3 (Fig. 3). Rhinovirus-induced bronchiolitis has also been reported to be associated with a high risk of asthma at 6 years of age [43].

The Natural History of Childhood Asthma

517

Fig. 4 Hospital discharge rates for asthma from the National Center for Health Statistics, Center for Disease Control, as the first-listed, by age group and year – United States, 1980–1999 (adapted from Akinbami et al) [51]

Beyond the first episode of viral respiratory infection induced wheezing in infancy, viral respiratory infections continue to be a major cause of subsequent asthma exacerbations at all ages [44–48]. These recurring viral respiratory infections appear to be the major risk factor for the large increase in hospital admissions for asthma that occurs in every autumn [49]. Pre-school age children have a particularly high frequency of viral respiratory infections, with most getting 3–8 infections per year and 10–15% getting 12 or more per year [50]. This is the likely explanation for a frequency of asthma hospitalization in the pre-school age group that far exceeds that of older children and adults. The rate of hospitalization for asthma among the U.S. children of age 1–4 years has been about 1 in 200 children compared with 1 in 500 children 5–14 years, and 1 in 1000 for individuals 15–24 years of age (Fig. 4) [51]. Various studies have evaluated factors associated with persistence of asthma from infancy (Table 1). The longest-term clinical course of asthma in young children was a prospective study with repeated evaluations for up to 35 years [52]. In 1963, all children entering first grade in Melbourne Australia had a medical examination that included a short questionnaire and interview. As part of that questionnaire, parents were asked if their child had experienced episodes of wheezing or asthma during their pre-school years and whether that had been associated with a viral respiratory infection. Based on that survey, an overall community prevalence for asthma symptoms in childhood was estimated to be about 20%, a rate similar to that described more recently in the U.S [14, 53, 54]. A stratified sample was then randomly selected in the following year from the approximately 30,000 7-year-old children previously surveyed. This included 105 2nd graders who had never wheezed to serve as controls, 75 with less than 5 episodes of wheezing with viral respiratory infections, 104 with 5 or more episodes of wheezing with viral respiratory infections, and 113 with recurrent wheezing not limited to association with viral respiratory infections. Three years later, the investigators entered 83 children

Sample type BC

BC

BC

BC

Children with wheezing and control subjects

BC

Location Dunedin [59]

Manchester [71]

Perth [72]

Tucson [73]

Melbourne [52]

Isle of Wight [74]

1,456

168

826

156

690

N subjects 613

Table 1 Longitudinal studies of childhood asthma persistencea [59]

0–10

7–42

0–22

0–11

0–5

Age at entry and conclusion (y) 9–26

Summary of factors related to persistence Early age of onset of wheezing Airway hyperresponsiveness Persistently low lung function Sensitization to house dust mites Female sex Smoking Poor lung function at age 3 y Maternal asthma, maternal smoking during pregnancy Increased airway responsiveness Reduced airway function in early infancy Atopy Parental asthma Reduced airway function in early infancy Transient early and persistent wheezers have lower flows at multiple time points than never wheezers. Level of lung function stabilized in all groups by age 6y Atopy more prevalent in persistent and late-onset wheezers than never or transient wheezers, along with more eczema, rhinitis eosinophils, parental asthma. Episodic childhood asthma tends to resolve in adolescence and adulthood with no lung impairment. Persistent asthma in childhood more likely to show modest lung function impairment, seen by age 14 y and not progressive. Atopy increases risk for more severe disease. Never atopic Recurrent URI at age 2y, Maternal asthma, Parental smoking at age 2y, Nasal symptoms at age 1y Chronic childhood atopic (up to 4y)

518 M. Weinberger and D. Solé

High risk of asthma newborns

Children hospitalized due to wheezing and control subjects

High atopy risk newborns

Risk factors for asthma

BC

Brigham [75]

Göteborg [76]

Poole [77]

ECRHS Study Group [78–80]

Germany [62]

a

0–7

Age at entry and conclusion (y)

1,314

18,156

100

0–13

0–44

0–22

101 patients and < 2 to 17–20 401 controls

505

N subjects

N = number, BC = Birth cohort, PD = Physician-diagnosed, y = year Modified from [81]

Sample type

Location

Summary of factors related to persistence Male sex, Eczema at age 4ys, Family history of eczema, Parental smoking at age 4y Delayed childhood atopic (up to 10y) Family history of urticaria, Maternal asthma Dog ownership at age 4y PD-croup and more than 2 episodes of PD-ear infections (1st y of life) inversely associated with atopy at school age. PD-bronchiolitis before age of 1y was significantly associated with asthma at age 7 y. More than 3 episodes of runny nose in the 1st y of life was associated with allergic rhinitis at age 7 y Asthma in childhood Female gender, Passive smoking Asthma in early adulthood Early wheezing disorder, Current allergy Bronchial hyperresponsiveness Female gender Persistent wheezing at age 11 y Early sensitization to inhalant allergens in infancy Bronchial hyperresponsiveness at age 11y Parents with asthma Female gender Moderate to persistent asthma has early deterioration of lung function Sensitization to perennial allergens in the first 3 y of life was associated with a loss of lung function at school age. High exposition to aeroallergens was associated with bronchial hyperresponsiveness

The Natural History of Childhood Asthma 519

520

M. Weinberger and D. Solé

Percent of patients

from the same population who had chronic asthma. These children with severe chronic asthma, now 10-years-old, had a history of onset before age 3 with persistent symptoms at the time of entry with barrel chest deformity and/or FEV1 that was 50% or less than the forced vital capacity. All groups of children were re-evaluated at ages 14, 21, 28, 35, and 42 years [55–58]. The subsequent spot prevalence of continued wheezing episodes was 12% at ages 14 and 21. However, 75% percent of the stratified samples followed longitudinally, an estimated 15% of all children, had infrequent episodes, while 25%, an estimated 5% of all children, had frequent episodes. Only an estimated 0.5% of all children had chronic or persistent asthma based on their survey. Forty percent of the initial children followed were free of respiratory symptoms by age 10, and 50% were asymptomatic by age 14. The remainder continued into adult life, but symptoms were rarely troublesome, usually only present with viral respiratory infections or exercise. However, 10% who had ceased wheezing in childhood had recurrences as young adults, and some of those had troublesome symptoms. Those with chronic or persistent wheezing had growth failure and delayed puberty but eventually attained normal adult height. While 50% of this group improved considerably at puberty, most did not become totally asymptomatic. When the subjects were examined at 42 years of age, a correlation between the nature of the symptoms in childhood and the subsequent outcome was apparent (Fig. 5). Over half of those with symptoms of asthma limited to an association with viral respiratory infection prior to age 7 were asymptomatic at age 42. A substantial

100 80 60 40 20 0 <5 w VRI 5+ w VRI w/o VRI chronic Childhood pattern of asthma at age 7 Persistent asthma Frequent episodic asthma Infrequent episodic asthma No recent asthma

Fig. 5 Clinical expression of childhood asthma at age 42 years among a stratified random sample from a population of 30,000 children surveyed at entry to 1st grade, about 20% of whom had symptoms consistent with asthma. The sample included 105 2nd graders who never wheezed, 75 with less than 5 episodes of wheezing with viral respiratory infections (<5 w VRI), 104 with 5 or more episodes of wheezing with viral respiratory infections (5+ w VRI), 113 with recurrent wheezing not associated with viral respiratory infections (w/o VRI), and 83 children from the same population who had severe chronic asthma (chronic). (adapted from Phelan et al) [52]

The Natural History of Childhood Asthma

521

number were still having episodic asthma, and a few had developed persistent asthma. Nevertheless, the frequency of all patterns of active asthma at age 42 years was greater among those in whom wheezing without viral respiratory infection had been reported in childhood. About half of those with chronic asthma as children continued to have persistent symptoms at age 42, with only 11% reporting no recent asthma. Repeated measurements of forced expiratory volume at one second (FEV1) to age 42 did not differ significantly from controls among the two groups of children who had only wheezing with viral respiratory infection. Those with chronic asthma generally had significant decrements in the FEV1 that persisted but were not progressive (Fig. 6). It is notable that the patients in this 35 year study who began with asthma in their pre-school years had, for the most part, little in the way of what today would be considered optimal treatment. The initial identification of these patients occurred prior to the introduction of inhaled corticosteroids, cromolyn, or even optimal use of oral theophylline. The investigators did not intervene in the patients’ care, limiting their involvement to the interval assessments and recommendations communicated only to the patients’ physicians. However, the authors commented that the recommendations were rarely followed. This longitudinal study therefore provides unique data regarding the natural history of asthma, beginning in the pre-school years, that was generally untreated by current standards. Another longitudinal study of childhood asthma followed to adulthood was performed in New Zealand [59]. This study involved a complete birth cohort born in

Percent of predicted

110 100 90 80 70 60 7

10

14

21 28 Age in years

Controls

<5 w VRI

5+ w VRI

w/o VRI

35

42

Chronic

Fig. 6 One second forced expiratory volume (FEV1 expressed as percent of predicted) for children over time by classification of childhood asthma at the time of recruitment. The categories of asthma at the time of entry into the study included those with <5 wheezing episodes with viral respiratory infections (<5 w VRI), those with ³ 5 episodes with VRI (5+ w VRI), those with episodic wheezing without VRI (w/o VRI), and those with severe persistent asthma (chronic), and controls from the same cohort (adapted from Phelan et al) [52]

522

M. Weinberger and D. Solé 50

Percentage of patients

40

30

20

10

0 Relapsed Wheezing Persistent Wheezing Remission

Intermittent wheeze Never or once

Fig. 7 Outcomes at age 26 years among 613 study members who provided respiratory data at every assessment (adapted from Sears et al) [59]

Dunedin, New Zealand from April 1972 to March 1973. Of 1128 children born during that period, 1037 were available at age 3 and were seen every 2 years between 3 and 15 years of age and then at 18, 21, and 26 years of age. Of those, 613 completed every assessment. These 613 were considered to be generally representative of the base cohort. Persistent wheezing at age 26, defined as wheezing reported at each of the visits, was reported in almost 15% of that 613. Wheezing that stopped and then relapsed, defined as reported at two or more visits followed by the absence of reporting at one or more visits and then reported as present at all previous visits, occurred in 12%. Wheezing in remission at age 26, reported at two or more visits followed by the complete absence at all subsequent visits, occurred in 9.5% (Fig. 7). Those with reported wheezing at each visit and those identified as having relapsed were found to be more likely to have allergic sensitivity to dust mites and cat allergen, increased airway hyperresponsiveness, and lower lung function that those whose wheezing did not persist or relapse. While pulmonary function was somewhat lower in those with persistent or relapsed wheezing, the rate of decline was similar for all (Fig. 8). These data appear to be consistent with other cohort studies [52, 60, 61]. In the German Multicentre Allergy Study that followed birth cohort of 1,314 children born in 1990 in five German cities from birth to 13 years of age, Illi et al. studied the role of allergic sensitization and allergen exposure early in life on the development and clinical course of asthma [62]. Consistent with previous studies, they demonstrated that early exposure and sensitization, as evidenced by determination of the presence of specific IgE, were predictive of persistent symptoms

The Natural History of Childhood Asthma

523

Fig. 8 Mean ({+/−}SE) FEV1:FVC ratios measured at 9, 11, 13, 15, 18, 21, and 26 years in male (Panel A) and female (Panel B) study members, according to the pattern of wheezing (reproduced with permission from Sears et al) [59]

Fig. 9 Prevalence of wheeze from birth to age 13 years in children with any wheezing episode at school age (5–7 years), stratified for atopy at school age (reproduced with permission from Illi et al) [62]

beyond age 5 (Fig. 9). Decreased lung function was also apparent in those who were sensitized by age 5. Subsequent to age 5, sensitization and exposure had much less effect.

524

M. Weinberger and D. Solé

In several studies of the natural history of asthma, female sex has been described as a risk factor for persistence of asthma from childhood to adulthood [59, 63–65]. In a sex-specific analysis of airway responsiveness over time utilizing data from 941 participants from the Children’s Asthma Management Program [66], who were enrolled in a 4 year observational study. Airway responsiveness to methacholine was observed to improve in males but not females after age 11 [67]. These data are consistent with the loss of male predominance for asthma prevalence postpuberty.

Can the Natural History of Asthma be Altered? Two studies represent major attempts to favorably alter the natural course of asthma in wheezy infants. In a British study with the acronym IFWIN (Inhaled Fluticasone propionate in Wheezy Infants), a randomized, double-blind controlled trial of 100 mg of fluticasone twice daily was started in young children, median age 1.2 years, at the first sign of wheeze [68]. The purpose was to test the hypothesis that loss of lung function and worsening asthma could be prevented. After the initial doses were started, subsequent increases based on clinical need or decreases because of absence of symptoms occurred while the children were followed until 5 years of age. Two hundred children began treatment of whom 173 (85 given fluticasone and 88 placebo) continued treatment until evaluation at age 5 years. No significant differences were seen between the fluticasone and placebo groups at 5 years of age in current wheeze, physician-diagnosed asthma, use of asthma medication, lung function, or airway reactivity. In a U.S. study identified by the acronym PEAK (Prevention of Early Asthma in Kids), 285 children of 2–3 years of age with a positive predictive index, defined by specific clinical characteristics [69], which placed them at risk for future persistent asthma, were randomized to fluticasone (2 inhalations of Flovent 44) delivered through a valved holding chamber or matched placebo [70]. During the 2 years of treatment, those receiving the inhaled corticosteroids (n = 143) had fewer symptoms than those receiving placebo (n = 142). However, when treatment was stopped at the end of 2 years, the frequency of symptoms in those receiving fluticasone gradually increased to match with that of those who had been receiving the placebo (Fig. 10). Thus, this study was consistent with the British study in demonstrating no alteration in the natural course of asthma. While treatment with an inhaled corticosteroid for a 2 year period was beneficial in decreasing the frequency of symptoms, there were no lasting effects once treatment was stopped.

Other Asthma Phenotypes in Childhood The previous discussions have addressed the natural history of essentially two very common asthma phenotypes, those whose asthma is limited to recurrent episodic illness wherein viral respiratory infections are the inciting factor and those who also

The Natural History of Childhood Asthma

525

Fig. 10 Bimonthly proportion of episode-free days during a two-year treatment period and a subsequent observation period following random assignment of pre-school age children (mean age 3 years) with a positive predictive asthma index [69] to fluticasone (n=143) or placebo (n=142) aerosol (reproduced with permission from Guilbert et al) [70]

develop inhalant allergy mediated by IgE to specific inhalant allergens. The former tends to remit or improve beyond age 6, while the latter are those most likely to continue with persistent symptoms. While published evidence for the natural history of other childhood asthma phenotypes is not available, at least two others clinical patterns of asthma can be identified. Children with no prior history can be seen developing asthma exclusively when exposed to inhalant allergens. No history of asthma or wheezing illnesses may be present early in life. Symptoms from this pattern of asthma may be manifest exclusively as seasonal allergic asthma from seasonal inhalants or asthma only upon exposure to a nonseasonal inhalant such as cat allergen. The long term pattern for this phenotype is less well-characterized although perhaps some of those are in the category described by Phelan [52] as wheezing without viral respiratory infections (Fig. 5).

526

M. Weinberger and D. Solé

Less frequent and even more poorly characterized with regard to the natural history is nonatopic asthma that begins in adolescence. This appears to be more common in girls than in boys and contributes to the gradual greater prevalence of asthma in boys than girls before puberty to the more equal distribution of asthma seen among the genders in adults.

Summary While diagnosis of asthma is essential for studying the epidemiology and natural history, there has been controversy regarding a precise definition. However, all of the various definitions refer to airway obstruction that is largely reversible, either spontaneously or as a result of treatment. While there has been an emphasis on including inflammation in the definition, it has not generally been useful as a means of identifying asthma for the purposes of diagnosis. Beyond the diagnosis of asthma is the requirement to characterize the clinical patterns of asthma that distinguishes the various phenotypes. The most common phenotypes of asthma in childhood begin with a viral respiratory infection in infancy, followed by recurrent episodes of lower airway disease from subsequent common cold viruses. The development of specific IgE to inhalant allergens is a major distinguishing factor for those most likely to have persistent disease that continues throughout childhood and often into adult life. For the majority of those early wheezers and coughers with viral respiratory infections who do not develop allergic antibody, improvement or remission by school age is common. Less is known of the natural history of other phenotypes, such as those who only have asthma during exposure to allergens. These include those with seasonal allergic asthma and others who experience asthma only upon specific environmental exposures. Another childhood phenotype less well-characterized with regard to the natural history is the onset of nonallergic asthma in adolescence, more common in girls than boys, which contributes to the evolvement of more equal numbers of asthma among the genders in adult compared with the greater prevalence among boys during childhood.

References 1. Leavell H, Clark EG (1976) Preventive Medicine. São Paulo, MacGraw-Hill, 744 2. Bel EH (2004) Clinical phenotypes of asthma. Curr Opin Pulm Med 10:44–50 3. Gross NJ (1980). What is this thing called love? – or, defining asthma. Am Rev Respir Dis 121:203–204 4. Sears MR (1993) The definition and diagnosis of asthma. Allergy 48:12–16 5. Meneely GR, Renzetti AD, Steele JD, Wyatt JP, Harris HW (1962) Chronic bronchitis, asthma and pulmonary emphysema. A statement by the committee on diagnostic standards for nontuberculous respiratory disease. Am Rev Respir Dis 85:762–768

The Natural History of Childhood Asthma

527

6. Dantzker DR, Pingleton SK, Pierce JA, Niewoehner DE, Thurlbeck WM, Buist AS (1987) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease and asthma. Am Rev Respir Dis 136 (Pt. 2):225–243 7. Godfrey S (1985) What is asthma? Arch Dis Child 60:997–1000 8. Hargreave FE, Gibson PG, Ramsdale EH (1990) Airway hyperresponsiveness, airway inflammation, and asthma. Immunol Allergy Clin N Am 10:439–448 9. Guidelines for th Diagnosis and Management of Asthma (1991) National Asthma Education Program Expert Panel Report, US Department of Health and Human Services, NIH publication 91–3042 10. National Heart, Lung, and Blood Institute, National Institutes of Health (1997) Guidelines for the diagnosis and management of asthma. Washington: US Government Printing Office. Publication No. 97–4051 11. Maclennan C, Hutchinson P, Holdsworth S, Bardin PG, Freezer NJ (2006) Airway inflammation in asymptomatic children with episodic wheeze. Pediatr Pulmonol 41:577–583 12. McFadden ER, Gilbert IA (1992) Asthma. N Engl J Med 327:1928–1937 13. Brusasco V, Crimi E, Pellegrino R (1998) Airway hyperresponsiveness in asthma: Not just a matter of airway inflammation. Thorax 53:992–998 14. Joseph CL, Foxman B, Leickly FE, Peterson E, Ownby D (1996) Prevalence of possible undiagnosed asthma and associated morbidity among urban schoolchildren. J Pediatr 129:735–742 15. Yeatts K, Shy C, Sotir M, Music S, Herget C (2003) Health consequences for children with undiagnosed asthma-like symptoms. Arch Pediatr Adolesc Med 157:540–544 16. Koopman LP, Brunekreef B, deJongste JC, Neijens HJ (2001) Definition of respiratory symptoms an disease in early childhood in large prospective birth cohort studies that predict the development of asthma. Pediatr Allergy Immunol 12:118–124 17. Martinez FD (2002). Development of wheezing disorders and asthma in preschool children. Pediatrics 109(2 Suppl):362–367 18. Pierangeli A, Gentile M, Di Marco P, Pagnotti P, Scagnolari C, Trombetti S, Lo Russo L, Tromba V, Moretti C, Midulla F, Antonelli G (2007) Detection and typing by molecular techniques of respiratory viruses in children hospitalized for acute respiratory infection in Rome, Italy. J Med Virol 79:463–468 19. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ (1999) Bronchiolitisassociated hospitalizations among US children, 1980-1996. JAMA 282:1440-1446 20. Yunginger JW, Reed CE, O’Connell EJ, Melton LJ 3rd, O’Fallon WM, Silverstein MD (1992) A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 146:888–894. 21. Welliver RC, Sun M, Rinaldo D, Ogra PL (1986) Predictive value of respiratory syncytial virusspecific IgE responses for recurrent wheezing following bronchiolitis. J Pediatr 109:776–780 22. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B (1995) Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: A prospective cohort study with matched controls. Pediatrics 95:500–505 23. von Mutius E (2001) Paediatric origins of adult lung disease. Thorax 56:153–157 24. Weinberger M (2003) Clinical patterns and natural history of asthma. J Pediatr 142:S15–20 25. Panhuysen CI, Bleecker ER, Koeter GH, Meyers DA, Postma DS (1998) Characterization of obstructive airway disease in family members of probands with asthma. An algorithm for the diagnosis of asthma. Am J Respir Crit Care Med 157:1734–1742 26. Edfors-Lubs ML (1971) Allergy in 7,000 twin pairs. Acta Allergol 26:249–285 27. Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD (1990) Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis 142:1351–1358 28. Wiesch DG, Meyers DA, Bleecker ER (1999) Genetics of asthma. J Allergy Clin Immunol 104:895–901 29. Weinberger MM (1991) Mechanisms and management of reactive airways in children. Current Opinion in Pediatrics 3:399–407 30. Palmer LJ, Rye PJ, Gibson NA, Burton PR, Landau LI, LeSouëf PN (2001) Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age. Am J Rev Respir Crit Care Med 163:37–42

528

M. Weinberger and D. Solé

31. Longo G, Strinati R, Poli F, Fumi F (1987) Genetic factors in nonspecific bronchial hyperreactivity. An epidemiologic study. Am J Dis Child 141:331–334 32. Hopp RJ, Bewtra AK, Biven R, Nair NM, Townley RG (1988) Bronchial reactivity pattern in nonasthmatic parents of asthmatics. Ann Allergy 61:184–186 33. Hopp RJ, Bewtra AK, Watt GD, Nair NM, Townley RG (1984) Genetic analysis of allergic disease in twins. J Allergy Clin Immunol 73:265–270 34. Wilson NW, Robinson NP, Hogan MB (1999) Cockroach and other inhalant allergies in infantile asthma. Ann Allergy Asthma Immunol 83:27–30 35. Arshad SH, Hide DW (1992) Effect of environmental factors on the development of allergic disorders in infancy. J Allergy Clin Immunol 90:235–241 36. Lindfors A, Wickman M, Hedlin G, Pershagen G, Rietz H, Nordvall SL (1995) Indoor environmental risk factors in young asthmatics: A case-control study. Arch Dis Child 73:408–412 37. Lindfors A, van Hage-Hamsten M, Rietz H, Wickman M, Nordvall SL (1999) Influence of interaction of environmental risk factors and sensitization in young asthmatic children. J Allergy Clin Immunol 104:755–762 38. Sears MR, Holdaway MD, Flannery EM, Herbison GP, Silva PA (1996) Parental and neonatal risk factors for atopy, airway hyperresponsiveness, and asthma. Arch Dis Child 75:392–398 39. Sherrill D, Stein R, Kurzius-Spencer M, Martinez F (1999) On early sensitization to allergens and development of respiratory symptoms. Clin Exp Allergy 29:905–911 40. Chen CM, Rzehak P, Zutavern A, Fahlbusch B, Bischof W, Herbarth O, Borte M, Lehmann I, Behrendt H, Krämer U, Wichmann HE, Heinrich J (2007) Longitudinal study on cat allergen exposure and the development of allergy in young children. J Allergy Clin Immunol 119:1148–1155 41. Nelson HS, Szefler SJ, Jacobs J, Huss K, Shapiro G, Sternberg AL (1999) The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the Childhood Asthma Management Program. J Allergy Clin Immunol 104:775–785 42. Lemanske RF, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, Kirk CJ, Reisdorf E, Roberg KA, Anderson EL, Carlson-Dakes KT, Adler KJ, Gilbertson-White S, Pattas TE, DaSilva DF, Tisler CJ, Gern JE (2005) Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 116:571–577 43. Kotaniemi-Syrjanen A, Vainionpaa R, Reijonen TM, Waris M, Korhonen K, Korppi M (2003) Rhinovirus-indued wheezing in infancy – the first sign of childhood asthma? J Allergy Clin Immunol 111:66–71 44. Rakes GP, Arruda E, Ingram JM, Hoover GE, Zambrano JC, Hayden FG, Platts-Mills TA, Heymann PW (1999) Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. IgE and eosinophil analyses. Am J Respir Crit Care Med 159:785–790 45. McIntosh K, Ellis EF, Hoffman LS, Lybass TG, Eller JJ, Fulginiti VA (1973) The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J Pediatr 82:578–590 46. Minor TE, Dick EC, DeMeo AN, Ouellette JJ, Cohen M, Reed CE (1974) Viruses as precipitants of asthmatic attacks in children. JAMA 227:292–298 47. Nicholson KG, Kent J, Ireland DC (1993) Respiratory viruses and exacerbations of asthma in adults. BMJ 307:982–986 48. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs, L, Symington P, O’Toole S, Myint SH, Tyrrell AJ, Holgate ST (1995) Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. BMJ 310:1225–1229 49. Dales RE, Schweitzer I, Toogood JH, Drouin M, Yang W, Dolovich J, Boulet J (1996) Respiratory infections and the autumn increase in asthma morbidity. Eur Respir J 9:72–7 50. Rosenstein N, Phillips WR, Gerber MA, Marcy SM, Schwartz B, and Dowell SF (1998) The Common Cold – Principles of Judicious Use of Antimicrobial Agents. Pediatrics 101:181–184 51. Akinbami LJ, Schoendorf KC (2002) Trends in childhood asthma: Prevalence health care utilization, and mortality. Pediatrics 110:315–322 52. Phelan PD, Robertson CF, Olinsky A (2002) The Melbourne asthma study: 1964–1999. J Allergy Clin Immunol 109:189–194

The Natural History of Childhood Asthma

529

53. Grant EN, Daugherty SR, Moy JN, Nelson SG, Piorkowski JM, Weiss KB (1999) Prevalence and burden of illness for asthma and related symptoms among kindergartners in Chicago public schools. Ann Allergy Asthma Immunol 83:113–120 54. Yawn BP, Wollan P, Kurland M, Scanlon P (2002) A longitudinal study of the prevalence of asthma in a community population of school-age children. J Pediatr 140:576–581 55. Williams HE, McNicol KN (1969) Prevalence, natural history and relationship of wheezy bronchitis and asthma in children. An epidemiological study. Br Med J 4:321–325 56. McNicol KN, Williams HE, Gillam GL (1970) Chest deformity, residual airway obstruction and hyperinflation and growth in children with asthma. I: Prevalence findings from an epidemiological study. Arch Dis Child 45:783–788 57. McNicol KN, Williams HB (1973) Spectrum of asthma in children – I. clinical and physiological components. Br Med J 4:7–11 58. Martin AJ, McLennan LA, Landau LI, Phelan PD (1980) Natural history of childhood asthma to adult life. Br Med J 280:1397–1400 59. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Silva PA, Poulton R (2003) A longitudinal, population-base cohort study of childhood asthma followed to adulthood. N Eng J Med 349:1414–1422 60. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles GG (1994) Factors in childhood as predictors of asthma in adult life. BMJ 309:90–93 61. Strachan DP, Butland BK, Anderson HR (1996) Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ 312:1195–1199 62. Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U (2006) Perennial allergen sensitisation early in life and chronic asthma in children: A birth cohort study. Lancet 368:763–770 63. Toelle BG, Xuan W, Peat JK, Marks GB (2004) Childhood factors that predict asthma in young adulthood. Eur Respir J 23:66–70 64. Fagan JK, Scheff PA, Hryhorczuk D, Ramakrishnan V, Toss M, Persky V (2001) Prevalence of asthma and other allergic diseases in an adolescent population: Association with gender and race. Ann Allergy Asthma Immunol 86:177–184 65. Kjellman B, Gustafsson PM (2000) Asthma from childhood to adulthood: Asthma severity, allergies, sensitization, living conditions, gender influence and social consequence. Respir Med 94:454–465 66. The Childhood Asthma Management Program Research Group (2000) Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 343:1054–63 67. Tantisira KG, Colvin R, Tonascia J, Strunk RC, Weiss ST, Fuhlbrigge AL (2008) Airway responsiveness in mild to moderate childhood asthma: Sex influences on the natural history. Am J Respir Crit Care Med 178:325–331 68. Murray CS, Woodcock A, Langley S, Morris J, Custovic A (2006) Secondary prevention of asthma by the use of inhlaed fluticasone propionate in wheezy infants. Lancet 368:754–762 69. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD (2000) A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 162:1403–1406 70. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Soehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF, Strung R, Allern DB, Bloomberg GR, Heldt G, Krawlec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Eng J Med 354:1985–1997 71. Lowe LA, Simpson A, Woodcock A, Morris J, Murray CS, Custovic A (2005) Wheeze pheonotypes and lung function in preschool children, Am J Respir Crit Care Med 171:231–237 72. Turner SW, Palmer LJ, Rye PJ, Gibson NA, Judge PK, Cox M, Young S, Goldblatt J, Landau LI, Le souef PN (2004) The relationship between infant airway function, childhood airway responsiveness, and asthma. Am J Respir Crit Care Med 169:921–927 73. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD (2003) Tucson children’s respiratory study: 1980 to present. J Allergy Clin Immunol 111:661–675

530

M. Weinberger and D. Solé

74. Kurukulaaratchy RJ, Matthews S, Arshad SH (2006) Relationship between childhood atopy and wheeze: What mediates wheezing in atopic phenotypes? Ann Allergy Asthma Immunol 97:84–91 75. Ramsey CD, Gold DR, Litonjua AA, Sredl DL, Ryan L, Celedon JC (2007) Respiratory illness in early life and asthma and atopy in childhood. J Allergy Clin Immunol 119:150–156 76. Goksör E, Amarak M, Alm B, Gustafsson PM, Wennergren G (2006) Asthma symptoms in early childhood – what happens then? Acta Paediatr 95:471–478 77. Rhodes HL, Thomas P, Sporik R, Holgate ST, Cogswell JJ (2002) A birth cohort study of subjects at risk of atopy: Twenty-two-year follow-up of wheeze and atopic status. Am J Respir Crit Care Med 165:176–180 78. deMarco R, Locatelli F, Cerveri I, Bugiani M, Marinoni A, Giammanco G (2002) Incidence and remission of asthma: A retrospective study on the natural history of asthma in Italy. J Allergy Clin Immunol 110:228–235 79. de Marco R, Pattaro C, Locatelli F, Svanes C (2004) Influence of early life exposures on incidence and remission of asthma throughout life. J Allergy Clin Immunol 113:845–852 80. de Marco R, Marcon A, Jarvis D, Accordini S, Almar E, Bugiani M, Carolei A, Cazzoletti L, Corsico A, Gislason D, Gulsvik A, Jõgi R, Marinoni A, Martínez-Moratalla J, Pin I, Janson C (2006) Prognostic factors of asthma severity: A 9-year international prospective cohort study. J Allergy Clin Immunol 117:1249–1256 81. Shapiro GG (2006) Among young children who wheeze, which children will have persistent asthma? J Allergy Clin Immunol 118:562–564

The Wheezing Infant and Young Child Peter J. Helms

Although the notion that childhood wheezing illnesses, particularly those presenting in infancy and early childhood (children less than 5 yrs), may have different causes is not new, studies in recent years have revealed and rediscovered a number of distinct wheezing conditions in this early phase of life [1] (Table 1). The highest prevalence of recurrent wheezing is found in the first years of life and according to long-term population-related prospective birth cohort studies, up to 50% of all infants and children below the age of 3 years will have at least one such episode [2]. Wheezing in this early period of life is often transient, and 60% of children with mild intermittent infantile wheeze will become asymptomatic in later childhood [3]. On the other hand infants with more severe recurrent wheezing have a higher risk of developing persistent asthma particularly if they are also atopic [4]. However, both the incidence and period prevalence of wheezing decreases significantly with increasing child age [5]. Wheezing, a required feature to make the diagnosis of asthma, is generated by turbulent airflow in an obstructed medium to large airways in which transitional or turbulent airflow can occur. In small peripheral airways where linear bulk flow is absent or minimal not enough energy is available to generate oscillation of the airway wall and hence wheezing occurs. However the narrowing of small peripheral airways is usually associated with gas trapping and hyperinflation, which can result in dynamic compression of larger airways, with consequent airflow obstruction and, if a critical airway diameter is reached, with wheezing. Wheezing may therefore be caused both by alterations in the large airways themselves or by changes in the balance of pressures that control airway diameter. If localized, these alterations are usually associated with monophonic wheezing, whereas generalized intraluminal or extraluminal airway involvement is associated with polyphonic wheezing.

P.J. Helms () Department of Child Health, University of Aberdeen; Royal Aberdeen Children’s Hospital, Westburn Road, Aberdeen, Scotland, AB25 2ZG, UK e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_32, © Springer 2010

531

532

P.J. Helms Table 1 “Asthma” syndromes in early childhood Infants(< 1 yr) Young children (1–5 yrs) Maternal smoking Atopic Asthma Prematurity Viral (Wheezy Bronchitis) Post Bronchiolitis Cough Viral wheeze Exercise induced

The airways of infants and young children are also more susceptible to obstruction because of their smaller size and the soft ribcage that offers poor support for the underlying lung, which recoils to volumes more likely to cause airway closure [6].

Interpretation of Wheeze Wheeze is commonly regarded by parents as a term describing many different respiratory sounds [7–10] which at least in part, explains the heterogeneity in outcomes for early wheeze reported in longitudinal studies [11, 12]. A large airway rattle is the noise most commonly confused with wheeze [7] and is thought to be independent of asthma [13]; hence the advice that wheeze should be confirmed and documented by a competent health care professional before assigning a diagnosis of asthma [14].

Infant Wheeze Although the highest incidence of asthma-like symptoms occurs during the first years of life and in most cases symptoms first develop during infancy and early childhood [15], early epidemiological studies performed in the 1950’s suggested that wheezing episodes occurring in infancy were largely unrelated to the persistence of symptoms during the school age years [16]. Whereas a proportion of symptomatic infants and very young children have pre-existing reductions in airway function [1], this clearly defined group in no way explains all the symptomatology present in this young population. Wheezing is a heterogeneous condition in infancy and most subjects who present at an early age will remit by school age with only a small proportion of approximately 20% progressing to classical atopic asthma in mid-childhood. If a strategy will ever be developed for the primary (or secondary) prevention of persistent wheezing in infancy and childhood, better characterisation of the main wheezing phenotypes of infancy will be required. Therefore, and until non-invasive markers that allow a better assessment of the nature of the inflammatory reaction in the airway become part of routine practice, only population risk factors that cannot be easily applied at the individual patient level can be used.

The Wheezing Infant and Young Child

533

The most important known risk factor for frequent symptoms and reduced lung function in early life is maternal smoking during pregnancy [17, 18] although most studies suggest that exposure to tobacco smoke products in-utero is mainly associated with an increased risk of wheezing in early life (see subsequent section on environmental factors).

Early Wheezing and Prematurity Associations among wheezing, lung function, and prematurity is unclear [19, 20]. There is evidence that infants born prematurely (especially those requiring mechanical ventilation) have both increased risk of wheezing during viral infections in early life and persisting lower levels of lung function. The association between prematurity and the development of persistent airway bronchial hyperresponsiveness (BHR) is less clear, and schoolchildren with a history of prematurity do not seem to be more atopic or to be more likely to exhibit non specific BHR [21]. Whether lower levels of lung function are the consequence of prematurity or are otherwise involved in the complex disease mechanisms contributing to premature delivery is not yet understood.

Wheezing after RSV Bronchiolitis In addition to the role of rhinovirus the respiratory syncytial virus (RSV) has continued to receive much attention as a possible contributor not just to exacerbations but also to the early origins of wheezing illness. Long term studies have confirmed that bronchiolitis (the main diagnosis associated with RSV infection in early life) is associated with continuing respiratory morbidity and airways hyperresponsiveness independent of atopy [22] and that infants with severe enough bronchiolitis to require hospital admission are likely to continue with symptoms into early adolescence [23]. However other studies have found that for less severe disease presenting in the community and not requiring hospital admission the increased prevalence of wheezing gradually diminishes with advancing child age so that by age 13 no additional risk is evident [24]. The possibility that RSV or other viruses may interact with the immune and respiratory systems in early life to initiate the complex mechanisms leading to asthma and allergic sensitisation continues to be a matter of considerable study and debate. RSV infection by itself cannot be a “cause” for asthma, as more than 90% of all children are infected with RSV during the first 3 years of life. It is more likely that, if RSV can trigger the “asthmatic process”, this will occur in subjects who are predisposed either by their genetic background or by events occurring before their first encounter with RSV that have “primed” systemic and/or local immune responses.

534

P.J. Helms

Recurrent Symptoms Beyond Infancy A sizeable proportion of young children who present with wheezing provoked by intercurrent infections or by exercise or with recurrent cough do have asthma, and careful attention to the clinical history and to the settings in which symptoms are reported can distinguish a number of distinct phenotypes. Treating all children as if there were destined to become atopic asthmatics and at risk of persistent disease is arguably unnecessary particularly as many symptomatic children will subsequently experience complete resolution during later childhood. However this optimistic note needs to be tempered by the observation that asthma has a labile long term course with a tendency for resolution and re-emergence in the same individual with time [25].

Atopic Asthma Early identification of classical atopic asthma with its associated chronic airway inflammation may be of great significance as this type of wheezing illness often persists into adult life [26] and is generally more severe than other wheezing and recurrent lower respiratory symptoms that present in infancy and early childhood. A family history of atopic disease has been found to predict persistence in some [27, 28] but not in all [29] long term follow-up studies. Attempts have been made to identify and monitor atopic status by assessment of the granular proteins, eosinophilic cationic proteins (ECP), and eosinophil protein X (EPX). However although this approach can identify individuals with active atopic disease it reflects eosinophil activation from all body sites not just the lung [30]and consequently has a limited role in predicting and following the development of asthma. There are as yet no reliable predictors available to confidently identify the risk of developing atopic asthma and the likelihood of persistence when an individual first presents with symptoms. Indeed studies in infants and young pre-school children [31, 32] confirm clinical impressions that the presence or absence of specific sensitisation to common inhaled allergens are poor predictors of the subsequent development of established asthma in contrast to the situation in school age children in whom BHR and atopy are strongly associated [33, 34].

Viral Associated Wheeze Until the 1980’s the terms wheezy bronchitis (WB) [35] and chronic bronchitis of childhood in North America [36], were commonly used to describe school age children with recurrent wheezing and cough predominantly provoked by intercurrent respiratory tract, presumed viral, infections, in contrast to children with multitrigger wheeze (MTW) more characteristic of atopic asthma.

The Wheezing Infant and Young Child

535

The “wheezy bronchitis” diagnostic label fell into disfavour during the 1970’s with the observation that asthma and wheezing illness were often unrecognised and therefore not afforded the benefit of medical treatment [37]. The move towards an all inclusive label of asthma was supported by an influential follow up study from Melbourne Australia which could not clearly separate children with wheezy bronchitis from children with classical atopic asthma [38]. However it needs to be remembered that the diagnostic label of wheezy bronchitis was originally used in children of school age rather than in infants and young children and that a more widely accepted term for such infants and young children is “viral associated wheeze”. The limited data from airway sampling that is available in this young symptomatic age group supports the separation of a viral wheeze syndrome from classical atopic asthma in that the types of airway inflammation appear to be different [39]. Although it has become fashionable to label all wheezy illnesses as asthma and assume that eosinophilic airway inflammation is present, it is clear that there are different outcomes for the different wheezing syndromes and that the historical separation of wheezy bronchitis or what has been termed “viral associated wheeze” (VAW) from the classical largely atopic one should be reconsidered [40].

Cough Cough without wheeze is a common finding in epidemiological studies in childhood and appears to decrease with age [41] and although a common feature of asthma has been shown to be responsive to anti asthma treatment in several small, highly selected groups [42–44] it is not clear whether these symptoms presenting on their own form part of the same syndrome [42, 45]. The epidemiological evidence, which shows approximately equal sex ratios for cough, in contrast to the male preponderance of wheeze, suggests that there are important differences in the determinants of recurrent cough alone and wheeze in this age group. The lack of association between cough without wheeze and atopy or BHR raises important questions as to whether this group should be considered alongside those children with wheeze, atopy, and BHR. Studies of bronchoalveolar lavage (BAL) [46] and induced sputum [47] also demonstrate that this type of airway inflammation is generally different from that seen in classical atopic asthma in that the major inflammatory cell type tends to be the neutrophil rather than the eosinophil. There is also evidence that a maternal history of bronchitis is a more significant risk factor for non wheezy cough than a paternal history of asthma [48]. Persistent cough may reflect an increased susceptibility to viral respiratory infection, which may have a heritable component. It is intriguing to speculate whether this susceptibility involves mechanisms related to those involved in virus-associated wheeze in infancy and to what extent the two groups of children with virus-associated wheeze in infancy and cough in later childhood may be linked. Although the short to medium term prognosis for those with cough alone appears to be good [49] the longer term implications of this pattern of lower respiratory illness (which may

536

P.J. Helms

previously have been described as “bronchitis” or “pneumonia”) for the development of adult obstructive lung disease may be less favourable [50, 51]. Such children may be at increased risk not only from viral infection but also from other factors such as environmental tobacco smoke [52] or air pollution. Standard asthma therapy for isolated and troublesome cough without wheeze has shown no better response than placebo [53] again suggesting that this symptom without associated wheeze is distinct from asthma. Any child with cough and persistent sputum production also needs careful assessment to exclude alternative diagnoses including late presenting cystic fibrosis, ciliary dyskinesia, inhaled foreign body, congenital lung malformations, and selective immune deficiency [54]. Further prospective studies of well characterised families are likely to help in the identification of the heritable and environmental influences contributing to this troublesome symptom and its relationship, if any, to adult obstructive lung disease.

Major Environmental Factors Human rhinoviruses are responsible for the majority of asthma exacerbations [55, 56] and respiratory syncytial virus is a common cause of severe symptoms in infants [57]. Severe respiratory infections are associated with persistence later in childhood [58], and such children should be protected from re-exposure if at all possible. Infection can damage the airway epithelium, induce inflammation, and stimulate both an immune reaction and airway hyperresponsiveness [59, 60]. Once the infection resolves, hyperresponsiveness remains for a considerable length of time [61]. Passive exposure to tobacco smoke is one of the strongest domestic and environmental risk factors for developing recurrent coughing/wheezing or asthma symptoms at any age during childhood [2]. Tobacco smoke increases oxidative stress and stimulates inflammation in both the lower and upper airways. In addition, maternal smoking during pregnancy results in impaired lung growth in the developing fetus, which may be associated with wheezing early in life [62]. In existing asthma, active smoking is associated with disease persistence [62, 63] and although tobacco smoke is harmful to everyone, its detrimental effects are relatively greater in younger children. Avoiding tobacco smoke is therefore one of the most important factors in asthma prevention and particularly in early childhood when dependence on parents or carers who are active smokers places the child at a greater risk of exposure [64].

Airway Inflammation and Remodelling Airway remodeling is a general term describing chronic, possibly non-reversible changes that occur in the airways of patients with asthma. These include smooth muscle hypertrophy, angiogenesis and increased vascularity, chronic inflammatory cell infiltration, goblet cell hyperplasia, collagen deposition, thickening of the basement

The Wheezing Infant and Young Child

537

membrane, and reduced elasticity of the airway wall [65]. Although such abnormalities have been described in both adults and children, they are less extensively characterized in childhood [66–68]. Evidence of remodeling has been described in children with post-viral wheeze, but there is evidence that the changes do not begin until after infancy [69]. Remodeling may be enhanced by elements of a Th2 immune response [70, 71] although early treatment (from 2 or 3 years of age) with ICS does not appear to change the course of the disease [72]. Although bronchial biopsy and BAL have proved useful in adult patients in clarifying pathogenic mechanisms, there are practical and ethical difficulties in performing similar studies in children.

Persistence and Resolution There are as yet no screening tests that can be used at first presentation to separate those individuals who are at risk of long term chronic airway inflammation and airway remodelling from those with transient symptoms associated only with viral infections although some features can be used to identify children with high or relatively low risk of persistent disease (Table 2). It is widely believed that the presence or absence of a family history of atopic disease has high positive and negative predictive value in establishing a diagnosis of asthma whatever the age of presentation. However this assertion, based as it is on large epidemiological studies and on the likelihood of familial transmission of the atopic trait, can only provide indications of the likely long term outcome. Evidence from serial cross-sectional and family studies in the same community suggests that much of the increase in the prevalence of childhood wheezing has come from what in the past would have been considered to be “low risk” families with little or no atopic history [73, 74] and from the youngest age group, under 5 years of age, where objective assessment of atopy with skin prick tests and/or specific RAST tests have a low predictive value for disease persistence at the individual patient level [75]. The large number of infants and young children presenting with recurrent symptoms suggestive of asthma, and with likely resolution of symptoms in the majority not only poses problems for the clinician in offering a long term prognosis but also in deciding the best initial therapy.

Table 2 Prognostic factors in early childhood For Resolution For Persistence Presentation in infancy Presentation after age 2–3 yrs Viral precipitants only Many provoking factors Male Female Intermittent episodes Persistent symptoms No personal atopy Personal Atopy (Eczema) No family atopy Family atopy Mild symptoms Severe symptoms

538

P.J. Helms

Implications for Therapy As the confident diagnosis of asthma remains difficult, particularly in young children, the timing of introduction of prophylactic therapy and in particular inhaled corticosteroids (ICS) remains a challenge. A significant proportion of recurrently wheezy infants and very young children appear to have impaired airway function rather than atopy, in contrast to the situation in later childhood where atopy is more strongly associated with wheezing illness. This uncertainty has to be set against the association of decline in lung function with atopy and the likelihood that this may be modulated by chronic airway inflammation and airway remodelling. The large number of infants and young children presenting with recurrent symptoms suggestive of asthma, and with likely resolution of symptoms in the majority, clearly poses problems for the clinician in offering a long term prognosis and in deciding the best initial therapy. For the young child or infant with episodic viral induced wheeze and no interval symptoms the LTRA Montelukast should be considered before initiating ICS [76]. The problem would be completely resolved if there were no concerns about the long term use of prophylactic ICS. However, with the recognition that asthma is a chronic inflammatory airway disease there is now widespread consensus for the early introduction of ICS [14]. Whole population data suggests that the early use of ICS protects against exacerbations leading to hospitalisation [77] and this appears to be supported by declining rates of hospital admissions despite increasing whole population prevalences [78]. These observations suggest that either asthma is less severe than it used to be or that it is being well controlled in primary care with appropriate doses of ICS. With the high population prevalence of asthma and wheezing illness in childhood it is not surprising that a large proportion of the whole child population are being prescribed ICS on a regular basis. Bearing in mind that the majority of pre-school children will become asymptomatic by mid-childhood there is an urgent need to identify those with chronic airway inflammation, and by inference, increased risks of airway remodelling, as the benefits of continuing long term ICS therapy may be most beneficial and possibly disease modifying in such children.

Conclusions Although wheezing illness is at its most prevalent in infancy and early childhood its self-limiting nature in the majority poses considerable challenges in offering a long term prognosis and in initiating long term prophylaxis. There is an urgent need to develop simple and reliable measures that can identify the presence of allergic airway inflammation as it is in this group of infants and young children that early use of ICS might modify the long term course of the disease. In the meantime when parents ask the question “will he/she grow out of it” all that can be offered in response are the relative risks based on the age of presentation, gender, and presence or absence of atopy (Table 2). Essentially this advice remains at the level of probability

The Wheezing Infant and Young Child

539

rather than certainty although several factors associated with both a good and poor long term prognosis can be identified. Factors associated with resolution include early age of presentation, exacerbations only in the presence of intercurrent respiratory infections, and no associated atopic features. Less favourable features include presence of atopy, multiple provoking factors for wheeze, and the acquisition of the smoking habit (Table 2). The recognition of the major types of recurrent symptoms often brought together under the diagnostic label of asthma and the risk factors that contribute to long term prognosis should be included in decisions as to the most appropriate therapy. Among these the early identification of sensitisation to common inhalent allergens is important as this pattern of sensitisation appears to be associated with persistent disease. Further understanding of the patho-physiology of the different wheezing syndromes in infancy and childhood, their natural histories, and responses to therapy are clearly required. In addition to the identification of the environmental and genetic determinants underlying asthma in its various forms, the relationship, if any, between the wheezing syndromes presenting in childhood and adult chronic obstructive pulmonary disease requires urgent answers.

References 1. Landau LI (2008) Wheezing phenotypes. Thorax 63:942–943. 2. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ (1995) Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 332:133–138. 3. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW et al (2005) Outcome of asthma and wheezing in the first 6 years of life: Follow-up through adolescence. Am J Respir Crit Care Med 172:1253–1258. 4. Illi S, von ME, Lau S, Niggemann B, Gruber C, Wahn U (2006) Perennial allergen sensitisation early in life and chronic asthma in children: A birth cohort study. Lancet 368:763–770. 5. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD (2003) Tucson Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol 111:661–675. 6. Chernick V and West J (2006) The functional basis of respiratory disease. In V. Chernick, T. Boat, R. Wilmott, and A. Bush, editors Kendig’s disorders of the respiratory tract in children Saunders, Philadelphia. 29–64. 7. Elphick HE, Sherlock P, Foxall G, Simpson EJ, Shiell NA, Primhak RA, et al (2001) Survey of respiratory sounds in infants. Arch Dis Child 84:35–39. 8. Cane RS, Ranganathan SC, McKenzie SA (2000) What do parents of wheezy children understand by “wheeze”?. Arch Dis Child 82:327–32. 9. Lowe L, Murray CS, Martin L, Deas J, Cashin E, Poletti G, et al (2004) Reported versus confirmed wheeze and lung function in early life. Arch Dis Child 89:540–3. 10. Saglani S, McKenzie SA, Bush A, Payne DN (2005) A video questionnaire identifies upper airway abnormalities in preschool children with reported wheeze. Arch Dis Child 90:961–4. 11. Stein RT, Holberg CJ, Morgan WJ, Wright AL, Lombardi E, Taussig L, et al (1997) Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 52:946–52. 12. Turner SW, Palmer LJ, Rye PJ, Gibson NA, Judge PK, Cox M, et al (2004) The relationship between infant airway function, childhood airway responsiveness and asthma. Am J Respir Crit Care Med 169:921–927.

540

P.J. Helms

13. Elphick HE, Ritson S, Everard ML (2002) Differential response of wheezes and ruttles to anticholinergics. Arch Dis Child 86:280–1. 14. British guideline on the management of asthma (2008) Thorax 63(Suppl 4):1–121. 15. Anderson HR, Pottier AC, Strachan DP (1992) Asthma from birth to age 23: Incidence and relation to prior and concurrent atopic disease. Thorax 47:537–542. 16. Boesen I. Asthmatic bronchitis in children (1953) Prognosis for 162 cases, observed 6–11 years. Acta Paediatrica 42:87–96. 17. Tager IB, Hanrahan JP, Tosteson TD, Castile RG, Brown RW, Weiss ST, et al (1993) Lung function, pre- and post-natal smoke exposure and wheezing in the first year of life. Am Rev Resp Dis 147:811–817. 18. Wang X, Wypij, D, Gold DR, Speizer FE, Ware JH, Ferris BG, et al (1994) A longitudinal study of the effects of parental smoking on pulmonary function in children 6–18 years. Am J Respir Crit Care Med 149:1420–1425. 19. Chan KN, Elliman A, Bryan E, Silverman M (1989) Respiratory symptoms in children of low birth weight. Arch Dis Child 64:1294–1304. 20. Chan KN, Noble-Jamieson CM, Elliman A, Bryan EM, Silverman M (1989) Lung function in children of low birth weight. Arch Dis Child 64:1284–1293. 21. von Mutius E, Nicolai T, Martinez FD (1993) Prematurity as a risk factor for asthma in preadolescent children. J Pediatr 123:223–229. 22. Murray M, Webb MS, O’Callaghan C, Swarbrick AS, Miiner AD (1992) Respiratory status and allergy after bronchiolitis. Arch Dis Child 67:482–487. 23. Sigurs N, Gustafsson PM, Bjarnason R, Lundberg F, Schmidt S, Sigurbergsson F et al (2005) Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 171:137–41. 24. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al (1999) Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 354:541–5. 25. Strachan D, Gerritsen J (1996) Long-term outcome of early childhood wheezing: Population data. Eur Resp J 9:42S–47S. 26. Martin AJ, Landau LI, Phelan PD (1981) Natural history of allergy in asthmatic children followed to adult life. Med J Aust 2:470–474. 27. Kelly WJ, Hudson I, Phelan PD, Pain MC, Olinsky A (1990) Atopy in subjects with asthma followed to the age of 28 years. J Allergy Clin Immunol 85:548–557. 28. Sibbald B, Horn ME, Gregg I (1980) A family study of the genetic basis of asthma and wheezy bronchitis. Arch Dis Child 55:354–357. 29. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles GG (1994) Factors in childhood as predictors of asthma in adult life. Brit Med J 309:90–93. 30. Renes S, Korppi M, Renes K, Savolainen K, Monoren I, Pekkaren J (1998) Serum eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in childhood asthma. Pediatr Pulmonol 25:167–174. 31. Sporik R, Holgate ST, Cogswell JJ (1991) Natural history of asthma in childhood - a birth cohort study. Arch Dis Child 66:1050–1053. 32. Brooke AM, Lambert PC, Burton PR, Clarke C, Luyt DK, Simpson H (1995) The natural history of respiratory symptoms in preschool children. Am J Resp Crit Care Med 152:1872–1878. 33. Pattemore PK, Asher MI, Harrison AC, Mitchell EA, Rea HH, Stewart AW (1990) The interrelationship among bronchial hyperresponsiveness, the diagnosis of asthma, and asthma symptoms. Am Rev Respir Dis 142:549–554. 34. Peat JK, Britton WJ, Salome CM, Woolcock AJ (1987) Bronchial hyperresponsiveness in two populations of Australian schoolchildren. II. Relative importance of associated factors. Clin Allergy 17:283–290. 35. Horn MEC, Brain EA, Gregg I, Inglis JM, Yealland SJ, Taylor P (1979) Respiratory viral infection and wheezy bronchitis in childhood. Thorax 34:23–8. 36. Taussig LM, Smith SM, Blumenfeld R (1981) Chronic bronchitis in childhood: What is it? Pediatrics 67:1–5.

The Wheezing Infant and Young Child

541

37. Speight ANP, Lee DA, Hey EN (1983) Underdiagnosis and undertreatment of asthma in childhood. Br Med J 286:1253–1256. 38. Williams H, McNicol KN (1969) Prevalence,natural history,and relationship of wheezy bronchitis and asthma in children. An Epidemiological study. Br Med J 4:321–325. 39. Stevenson EC, Turner G, Heaney LG, Schock BC, Taylor R, Gallagher T, Ennis M, Shields MD (1997) Bronchoalveolar lavage findings suggest two different forms of childhood asthma. Clin Exp Allergy 27:1027–1035. 40. Wilson NM (1989) Wheezy bronchitis revisited. Arch Dis Child 64:1194–1199. 41. Clifford RD, Howell JB, Radford M, Holgate ST (1989) Associations between respiratory symptoms, bronchial response to methacholine, and atopy in two age groups of schoolchildren. Arch Dis Child 64:1133–1139. 42. Anonymous (1988) Cough and Wheeze in Asthma: Are they Interdependent? Lancet 447–448. 43. Hannaway PJ, Hopper GDK (1982) Cough variant asthma in children. JAMA 247:206–208. 44. Corrao WM, Braman SS, Irwin RS (1979) Chronic cough as the sole presenting manifestation of bronchial asthma. N Engl J Med 300:633–637. 45. McKenzie S (1994) Cough – but is it asthma? Arch Dis Child 70:1–2. 46. Fitch PS, Brown V, Schock BC, Taylor R, Ennis M, Shields MD (2000) Chronic cough in children: Bronchoalveolar lavage findings. Eur Respir J 16:1109–14. 47. Gibson PG, Simpson JL, Chalmers AC, Toneguzzi RC, Wark PA, Wilson AJ et al (2001) Airway eosinophilia is associated with wheeze but is uncommon in children with persistent cough and frequent chest colds. Am J Respir Crit Care Med 164:977–81. 48. Duffy DL, Mitchell CA (1993) Lower respiratory tract symptoms in Queensland schoolchildren: Risk factors for wheeze, cough and diminished ventilatory function. Thorax 48:1021–1024. 49. Strachan DP, Anderson HR, Bland JM, Peckham C (1988) Asthma as a link between chest illness in childhood and chronic cough and phlegm in young adults. Brit Med J 296:890–893. 50. Shaheen SO, Barker DJ, Shiell AW, Crocker FJ, Wield GA, Holgate ST (1994) The relationship between pneumonia in early childhood and impaired lung function in late adult life. Am J Resp Crit Care Med 149:616–619. 51. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO (1991) Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. Brit Med J 303:671–675. 52. Burrows B, Knudson RJ, Cline MG, Lebowitz MD (1988) A reexamination of risk factors for ventilatory impairment. Am Rev Respir Dis 138:829–836. 53. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF (1998) A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 79:6–11. 54. Shields MD, Bush A, Everard ML, McKenzie S, Primhak R, on behalf of the British Thoracic Society Cough Guideline Group (2008) Thorax 63(Suppl 3):1–15. 55. Heymann PW, Carper HT, Murphy DD, Platts-Mills TA, Patrie J, McLaughlin AP et al (2004) Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol 114:239–247. 56. Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston SL et al (2006) Study of modifiable risk factors for asthma exacerbations: Virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 61:376–382. 57. Sigurs N (2002) Clinical perspectives on the association between respiratory syncytial virus and reactive airway disease. Respir Res 3(Suppl 1):S8–14. 58. Illi S, von ME, Lau S, Bergmann R, Niggemann B, Sommerfeld C et al (2001) Early childhood infectious diseases and the development of asthma up to school age: A birth cohort study. Brit Med J 322:390–395. 59. Papadopoulos NG, Bates PJ, Bardin PG, Papi A, Leir SH, Fraenkel DJ et al (2000) Rhinoviruses infect the lower airways. J Infect Dis 181:1875–1884.

542

P.J. Helms

60. Papadopoulos NG, Stanciu LA, Papi A, Holgate ST, Johnston SL (2002) A defective type 1 response to rhinovirus in atopic asthma. Thorax 57:328–332. 61. Xepapadaki P, Papadopoulos NG, Bossios A, Manoussakis E, Manousakas T, SaxoniPapageorgiou P (2005) Duration of postviral airway hyperresponsiveness in children with asthma: Effect of atopy. J Allergy Clin Immunol 116:299–304. 62. Moshammer H, Hoek G, Luttmann-Gibson H, Neuberger MA, Antova T, Gehring U et al (2006) Parental smoking and lung function in children: An international study. Am J Respir Crit Care Med 173:1255–1263. 63. Burrows B, Bloom JW, Traver GA, Cline MG (1987) The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engl J Med 317:1309–1314. 64. Halken S (2004) Prevention of allergic disease in childhood: Clinical and epidemiological aspects of primary and secondary allergy prevention. Pediatr Allergy Immunol 15(Suppl 16):4–32. 65. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM (2000) Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161:1720–1745. 66. Pohunek P, Warner JO, Turzikova J, Kudrmann J, Roche WR (2005) Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol 16:43–51. 67. Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Tura M et al (2003) Airway inflammation in childhood asthma. Am J Respir Crit Care Med 168:798–803. 68. Payne DN, Rogers AV, Adelroth E, Bandi V, Guntupalli KK, Bush A et al (2003) Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 167:78–82. 69. Saglani S, Malmstrom K, Pelkonen AS, Malmberg LP, Lindahl H, Kajosaari M et al (2005) Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction. Am J Respir Crit Care Med 171:722–727. 70. Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST (2003) Airway remodeling in asthma: New insights. J Allergy Clin Immunol 111:215–225. 71. Vignola AM, Gagliardo R, Siena A, Chiappara G, Bonsignore MR, Bousquet J et al (2001) Airway remodeling in the pathogenesis of asthma. Curr Allergy Asthma Rep 1:108–115. 72. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ et al (2006) Longterm inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354:1985–1997. 73. Russell G, Helms PJ (1997) Reporting of common respiratory and atopic symptoms has increased. Brit Med J 315:1014–1015. 74. Christie GL, Helms PJ, Godden DJ et al (1999) Asthma, wheezy bronchitis and atopy across two generations. Am J Resp Crit Care Med 159:125–129. 75. Wahn U, Lau S, Bergmann R et al (1997) Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 99:763–769. 76. Brand PLP, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al (2008) Definition, assessment and treatment of wheezing disorders in preschool children: An evidence-based approach. Eur Respir J 32:1096–1110. 77. Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, Platt R (1997) Inhaled steroids and the risk of hospitalization for asthma. JAMA 277:887–891. 78. Wennergren G, Kristjansson S, Strannegard IL (1996) Decrease in hospitalization for treatment of childhood asthma with increased use of antiinflammatory treatment, despite an increase in the prevalence of asthma. J Allergy Clin Immunol 97:742–748.

Acute Severe Asthma in Children Barbara P. Yawn

Definition “Acute asthma” is often used to describe an asthma exacerbation or asthma attack. Whatever term is chosen these are episodes of rapid onset and progressive worsening of breathlessness, wheezing, cough, and chest tightness, individually or in combination. Expiratory airflow as measured by spirometry (FEV1) or peak expiratory flow (PEF) decreases. Inflammatory cell influx into the lung assessed by sputum eosinophils and exhaled nitrous oxide increases [1–4]. In more severe attacks blood oxygenation levels measured by pulse oximetery or arterial blood gases will also fall [5, 6]. Acute asthma or an asthma exacerbation is not the same as loss of asthma control. The exacerbation is usually of rapid onset and progressive while loss of control is more gradual and often does not continue to progress [7–9]. Severe acute asthma can occur in children with good or poor control. The striking lack of PEF variation during exacerbations, as compared to increased variability usually seen with poor asthma control, suggests there may be differences in the beta2-adrenoceptor function between these conditions [7]. The severity of acute asthma is based on the level of functional disability (talking, ambulating, alertness), vital signs (respiratory rate, pulse and blood pressure and color), physical examination findings (wheezing and use of accessory chest wall muscles), lung function measurements, and measures of oxygenation in moderate to severe acute episodes [9–14]. The rapidity of symptom onset may also be useful in infants and young children unable to provide objective lung function measures [15]. Assessment of inflammatory markers adds little additional information [4, 16–20]. Table 1 [6, 10, 21–27] provides a summary of metrics to assess the severity of acute asthma. Infants and young toddlers are at greater risk of developing respiratory failure during a moderate or severe exacerbation because of greater peripheral airway resistance, fewer collateral channels of ventilation, airway smooth muscles extending further into the peripheral airways resulting in longer areas of airway narrowing, less elastic recoil of the alveoli, and a mechanical disadvantage of the diaphragm. B.P. Yawn () Adjunct Professor, University of Minnesota, Director of Research, Olmsted Medical Center e-mai: [email protected]; [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_33, © Springer 2010

543

544

B.P. Yawn

Table 1 Acute severe ASTHMA Severe Symptoms Breathlessness Talks in Alertness Signs Respiratory rate

Use of accessory suprasternal muscles; retractions Wheeze Pulse/minute

Pulsus paradoxus

Functional Assessment PEF % predicted or % personal best PaO2 (on air) and/or PCO2 SaO2% (on air) at sea level

While at rest (infant—stops feeding) Sits upright Words or short cries Usually agitated Often > 30/minute Guide to rates of breathing in awake children: Normal rate by age < 60/minute infants up to 1 year < 50/minute young children up to 2 years < 40/minute children up to 12 <30/minute older than 12 years Usually

Usually loud; throughout inhalation and exhalation > 120 Normal rate < 160/minute (infant) < 120/minute (child) < 110/minute (adult) Often present > 25 mm Hg (adult) 20–40 mm Hg (child) < 40% Note: FEV1 and PEF often cannot be obtained during severe exacerbations. < 60 mm Hg: possible cyanosis

Respiratory Arrest Imminent

Cannot speak Severe

Paradoxical thoracoabdominal movement Absence of wheeze Bradycardia

Absence suggests respiratory muscle fatigue < 25% Note: PEF testing may not be needed in very severe attacks

³ 42 mm Hg: possible respiratory failure (see text) < 90%

Epidemiology of Severe Acute Asthma in Children Most of the 6–18% of the world’s children [28–31] diagnosed with asthma will never have a severe acute asthma episode. However, 5–10% will have at least one severe exacerbation with 1–2% having multiple severe exacerbations. Black children

Acute Severe Asthma in Children

545

Table 2 Risk factors for life-threatening or fatal acute asthma include • • • • • • • • •

Prior intubation and mechanical ventilation for acute asthma [34] Two or more hospitalization for asthma in the past 12 months, Hospitalization or emergency department visit for asthma within the past 1 month, Lack of clear and accessible instructions for recognizing and dealing with deteriorating signs and symptoms (e.g. written asthma action plan) Use of rescue or reliever medications on average of 3 or more times each day [35] Sensitivity to Alternaria. Use of or recent discontinued use of daily oral steroids [9] No current use of inhaled corticosteroids [36] History of non-compliance with medication plan [9, 37–44]

and certain subgroups of Latino children (e.g. in the U.S., Puerto Rican children) appear to have more severe and more rapid onset acute asthma episodes [28, 32]. The scope of the impact of race and genetic receptor polymorphisms on symptoms perception, treatment failures, and disease progression remain controversial in adults and almost no information is available related to children [32–35]. The risk factors for life threatening asthma are shown in Table 2 [36–42]. Children with severe or difficult to control asthma are most likely to have a life threatening or severe exacerbation, yet most severe exacerbations occur in the 80% of children with mild to moderate asthma. This group of children with mild asthma and severe exacerbations have been identified as a potential distinct phenotype [43]. Risk factors for severe asthma include a previous episode of severe or life threatening asthma lower socio-economic status, poor access to medical services, use of illicit drugs, parent mental illness, and heavy exposure to major irritants and toxins such as biomass fuel use in poorly ventilated homes [9, 44–47]. Some biomarkers may suggest increased risk for severe exacerbations including increased number of circulating eosinophil progenitor cells [48] or the number of cytokines in bronchoalveloar lavage (BAL) fluid [49]. Neither is practical for daily practice and the only feasible assessment currently available, FeNO, is of limited value in predicting exacerbations and not recommended for primary care use [50, 51].

Recognition and Treatment of Severe Acute Asthma Early treatment of acute asthma requires early recognition by the child and parent. Treatment should be aimed toward rapid relief of airflow obstruction and hypoxemia. Early recognition (6 hours or less) may decrease the progression to severe acute asthma and hospitalization [26]. Treatment can begin at home or school but in any child with a history of severe exacerbation, treatment is best continued at an acute care facility such as an emergency department [52, 53]. Initial treatment will include use of the child’s rapid reliever. Increased doses of inhaled corticosterids (e.g. doubling the dose) have been shown to be of little value. Very high doses such as quadrupling may help but having a child use 8 or more puffs of an ICS is difficult [54–57].

546

B.P. Yawn

Children with a history of more than one moderate to severe exacerbation who live more than 30 minutes from acute care may benefit from having oral steroids at home. Some children with signs of moderate to severe exacerbations may present to the physician’s or nurse’s office. It is important that all office staff know the warnings signs of acute asthma and have protocols to follow to allow them to provide the necessary immediate evaluation and care including immediate access to an examination room to check vital signs, pulse oximetery, and provide oxygen if available. Staff must have permission to interrupt the medical staff to seek immediate support and care. Few clinics have the resources necessary to complete the monitoring and treatment of a severe exacerbation [58] and plans to transfer the child should be made immediately. The decision of what type of transport to use is based on local resources. Some parents will directly call for emergency transport [59]. In the office and emergency transport vehicle, treatment should include inhaled short acting bronchodilators and oxygen [60, 61]. A mask or holding chamber added to the inhaler or a nebulizer is often required because the child is unable to coordinate breathing and inhaler initiation because of his/her young age, rapid respirations, or marked distress [62–64]. Only in the most extreme situations and when no other resources are available should subcutaneous epinephrine or terbutaline be used [65, 66]. Treatment should never be delayed for transport [67]. Although three bronchodilator treatments within the first hour is considered maximal treatment, home treatment should be repeated in the office or ambulance since inhaled bronchodilator without mask or holding chamber may have delivered little if any effective therapy. Non-medical remedies such as pursed lip breathing may calm some children during an exacerbation but does not improve lung function [10]. Other home remedies such as drinking large volumes of liquids, breathing warm moist air or use of over the counter anti-histamines or cold remedies are NOT recommended and may aggravate the acute episode and frustrate the child who is unlikely to be willing to drink or use oral medications during a severe episode [10]. All emergency medical services transport or ambulance teams should have standardized protocols that allow treatment with therapy beyond short acting beta agonist therapy including use of ipratropium bromide and systemic corticosteroids [61, 68–70]. In addition, the transport team must be taught to assess for imminent respiratory failure and have skills and equipment to provide ventilatory assistance and support when required. Spirometry and peak flow assessment (PFA) are often impossible outside of the hospital [71].

Assessment in the Emergency Department or Acute Care Facility When a child arrives in the ED, basic therapy such as oxygen and bronchodilator therapy is begun while completing critical evaluation of vital signs, severity of episode, and oxygenation levels [Table 3]. While beginning treatment with the presumed diagnosis of asthma, other reasons for airflow obstruction must be ruled

Acute Severe Asthma in Children

547

Table 3 Therapies for severe asthma exacerbations Recommended: Always: Oxygen, Inhaled short acting broncho-dilators, oral corticosteroids As needed: Intravenous magnesium sulfate, Heliox Not recommended: Never use: Sedatives, Mucolytic drugs, Excessive hydration Rarely: Methylxanthines by any route of administration, Antibiotics

out including aspiration of a foreign body, anaphylaxis from something such as a peanut allergy, or a cardiovascular event (congenital heart disease) since beta agonists will not help these problems and may aggravate cardiovascular events. In older children, the use of illicit drugs or a severe panic attack should also be considered while initiating respiratory therapy [72–75]. A short set of questions directed to the parent(s) should explore asthma history including previous hospitalization or ICU admission for asthma, any history of severe food or insect sting allergy, recent history of choking on solid foods, or a history of congenital heart disease [76]. In some areas the label of asthma is seldom applied to infants and so it may be necessary to inquire about diagnoses of reactive airway disease or recurrent broncho-spasm [59]. The general goals of treatment are the same worldwide but are best adapted and implemented locally on the basis of available resources and community needs [77, 78]. When a child meets the criteria for a severe exacerbation, an immediate decision must be made whether to continue therapy in the ED or transfer the child to the hospital. Immediate transfer to an intensive care unit (ICU) if available, is appropriate for children at risk of death [Table 2] and for infants with severe exacerbations. A respiratory rate of 60 or greater, inspiratory plus expiratory wheezing, the rare child with a silent chest (too little air movement for auscultation) [79], or oxygen saturation of < 90% should lead to immediate hospitalization rather than treatment and evaluation in the emergency department. If a child is able to perform spirometry, any value < 25% of the predicted one that improves by < 10% within the first 15 minutes after the first bronchodilator treatment in office or in ED, is an indication for immediate transfer to the hospital and if available, an intensive care unit (ICU), bypassing extensive evaluation in the ED, regardless of other signs and symptoms [10]. Fever is not uncommon in infants with acute asthma as many asthma exacerbations result from viral infections. The presence of a fever in an infant with an asthma exacerbation does not automatically require either antibiotics or hospitalization [21].

First Line Care in the ED Figure 1 provides an overview of treatment once the immediate decision has been made to provide therapy in the ED. Most exacerbations will begin to improve with therapy over a period of 1–3 hours with a combination of oxygen, bronchodilators and systemic corticosteroids to combat inflammation.

548

B.P. Yawn

Fig. 1 Management of Severe Acute Exacerbation

Oxygen saturation should be kept > 95% in all infants and children. Hypoxemia may be obvious from nail bed or peri-oral cyanosis but usually requires an objective measure. Non-invasive measures such as pulse oximetery are appropriate for rapid initial assessment [7, 23, 80, 81], but may need to be followed by arterial blood gases to also assess acidosis in respiratory failure or when assisted ventilation is used. Oxygen delivery should be by face mask since most infants and children with severe acute asthma will be mouth-breathing and a nasal cannula will have little effect. Oxygen tents should not be used for acute therapy since the period of time required to raise the oxygen level in the tent can be quite extended.

Acute Severe Asthma in Children

549

The oxygen can be combined with nebulized short-acting beta-2-agonists given continuously over the first hour of therapy for rapid reversal of airflow obstruction [53, 82, 83]. Blow-by therapy is not recommended as the amount of drug inhaled into the lungs is usually quite low. A child who has already used multiple doses of beta2-agonist over the past few hours may still respond to the same therapy delivered more effectively. Use of leva-albuterol may increase the bronchodilator effect [55, 84–88]. Continuous and prolonged administration of bronchodilators provides some incremental bronchodilation [82, 89–95]. However, if additional therapy is required after three or more doses of short-acting beta2-agonists, short acting anticholinergic bronchodilators such as ipratropium bromide can be tried [89, 96]. The duration of action of a short-acting bronchodilator can be significantly shortened during an exacerbation [82], so continuous treatment is usually recommended [97]. After prolonged use of beta agonists, the possibility of lactic acidosis should be considered and appropriate monitoring of serum pH can be done using capillary blood [98].

The History and Physical Examination A brief but more thorough history and physical should be done making sure to include the child in any queries whenever possible [Table 4] [10, 99]. Despite the need for health professionals to move rapidly and monitor closely, it is important to address the child’s and family’s fears of death and treatments such as nebulizers and steroids. It is not difficult to imagine the fear and anxiety a child or parent is experiencing amidst all of the ED or hospital activities. The physical examination is an ongoing process that is done initially to determine the severity of the acute asthma response to immediate therapy and then to look for triggers and co-morbid conditions such as pneumonia, pneumothorax, pneumomediastinum [100, 101], congenital heart disease, epiglotitis, Respiratory Syntical Virus (RSV) infection, extrinsic and intrinsic tracheal narrowing, vocal cord dysfunction, gastro-intestinal reflux, anemia, non-respiratory infections such as parasites, or gastrointestinal infections which can be evaluated by chest radiograph, chest auscultation, a complete blood count, or other special tests.

Table 4 Brief history for severe acute asthma • • • • • •

Onset and possible triggers Rapidity of progression Current medications and all medications stopped or decreased recent Prior ED, urgent care or hospital visits for asthma in past 2 years Timing of prior severe episodes of asthma Any other current problems or illnesses–upper respiratory infections, heart disease, cystic fibrosis, tuberculosis, etc. • Any exposure that may have been related–tobacco smoke, food, animals • Specific child and parent concerns or fears

550

B.P. Yawn

Stress and systemic corticosteroids elevate the polymorphonuclear leukocyte count within 1–2 hours [102]. For oxygen saturation levels less 95% and children on assisted ventilation, arterial blood gases are required for monitoring levels of oxygen, carbon dioxide, and pH. Venous (capillary) PCO2 may be useful for identifying levels of > 45 mm but should be confirmed by arterial testing [25].

Ongoing ED Care As soon as feasible, such as after the completion of the first nebulizer treatment or as the nebulized drug is being prepared, the infant or child should receive glucocorticosteroids (0.5–1 mg of prednisolone/kg or equivalent) that can be given in a single dose (best in severe exacerbations) or divided over a 24-hour period [53, 102–105]. An estimated weight is sufficient for dosing the glucocorticosteroids. However, it is important to use doses determined by weight for all medications since the group defined as “children” can vary from a few kilograms to 50 or 60 kilograms. Inhaled corticosteroids, even at high doses, are not a substitute for oral or intravenous corticosteroids in children during a severe exacerbation [105]. Even children on daily oral steroids prior to the exacerbations benefit from a burst of high dose steroids [9]. During severe exacerbations additional therapies may be required such as a switch to anti-cholinergic bronchodilators [32, 89]. Epinephrine (adrenaline) is rarely indicated even for severe asthma exacerbations except when anaphylaxis or angioedema are also present [106]. Some data are available on magnesium sulfate and heliox and older therapies like theophylline [107–111]. There is no role for theophylline in treating severe asthma exacerbations. In fact any child who has been using theophylline for asthma should be evaluated for theophylline toxicity [110, 111]. Inhaled magnesium sulfate therapy has not been shown to be of value [107, 108], but intravenous magnesium sulfate (usually give as 2 gm over 20 minutes) can be used in children aged 8–12 and older with severe exacerbations, specifically those with initial FEV1 of 25%–30% of predicted and those whose FEV1 does not increase to above 60% of predicted after 1 hour of therapy [45, 100, 101, 105]. Magnesium sulfate is given intravenously (25–75 mg/kg with maximum does 2 grams over 20–30 minutes) to children with very severe or severe and worsening exacerbations. Two meta-analyses suggest that when added to conventional therapy it can be very helpful in children who present with FEV1 < 40% of predicted [52, 112]. Others report that magnesium sulfate is useful only in those with FEV1 < 25% of predicted [113]. Although not all studies have found positive results [114–116] the use of magnesium sulfate in a child with a very severe exacerbation who is not responding to other therapies, or is faced with impending respiratory failure, or who is intubated is appropriate. The therapy is a single dose. Because magnesium sulfate toxicity results in muscle paralysis checking reflexes and observing for rapidly increasing respiratory muscle “fatigue” is important in a child who is given

Acute Severe Asthma in Children

551

magnesium sulfate and is not intubated. The half life of magnesium sulfate can be quite long and the reflexes should be reassessed before considering extubation [114]. Nebulized magnesium sulphate combined with short acting beta agonist has not been shown to be of benefit [117]. Theoretically the low density of helium should improve the ability of an oxygenhelium mixture to get past marked airway obstruction [118]. However, two studies in children combined in a meta-analysis with 4 studies in adults, did not find any improvement in any outcome measures after use of heliox [119]. More recent work using a larger number of children, found some improvement in children given heliox driven nebulization of albuterol compared to children given only oxygen driven albuterol nebulization [109, 120–122]. Therefore, a trial of heliox in children with life threatening or worsening severe exacerbation appears indicated. Very little data is available regarding the benefits of heliox driven non-invasive bilevel positive pressure ventilation and what is available concludes that it is not helpful [123] but that it may show promise [124]. Use of intravenous beta agonist has failed to show definitive improvement over inhaled beta-agonists [125] and may increase the risks of cardio-toxicity. However, in the child who is intubated, intravenous beta-agonist may be tried if therapy continues to be ineffective even when the child has respiratory support [126]. Due to the risk of cardio-toxicity, intravenous isoproterenol is not recommended [127]. Intravenous montelukast is not readily available in most sites but when available may be tried in children with severe or life-threatening exacerbations when conventional therapy is not working or begins to cause side effects such as cardio-toxicity [128]. One study of IV montelukast found significant improvement in pulmonary function within 10 minutes [128]. Use of oral montelukast does not have a place in emergency treatment of a severe exacerbation or in respiratory failure because the onset of action is 90 minutes or longer [129, 130]. In refractory cases of respiratory failure with severe airway obstruction, human recombinant human deoxyribonuclease (rhDNase) has shown some promise in small trials but should only be used in the context of a trial [131]. Concurrent administration of multiple drugs by nebulization is not recommended but may be required in ‘real world” care. The interaction of multiple drugs administered simultaneously in the same nebulizer is not well understood [132]. If multiple drugs are being given simultaneously and the child is not responding as anticipated, the switch to administering one drug at a time should be considered. Despite the child’s agitation, sedatives should never be given to the child with acute severe asthma prior to use of assisted ventilation. Mucolytic drugs may increase coughing and decrease oxygenation. Chest physiotherapy and the Asian practice of coining may increase the child’s discomfort and restrict respiratory efforts. The need for hydration should be individually determined. Most older children (12 and above) seldom require significant rehydration and fluid overload must be avoided. However, mouth breathing can lose large volumes of fluids in infants and young children who may become dehydrated. In the concern over respiratory status, monitoring of other systems can be overlooked, which is why written protocols and assessment checklists can be helpful.

552

B.P. Yawn

Monitoring Response to Therapy Decisions to transfer a child to the hospital or to discharge the child can be complex decisions [Figure 1]. A child with marked hypoxemia who is unresponsive to oxygen and bronchodilator therapy within 15–30 minutes (oxygen saturation remains < 90%) should be hospitalized [6, 23, 81]. Unfortunately, objective lung function measurements can be helpful for children 5 years and older but difficult to obtain until the initial therapy has provided some relief for the child with a severe exacerbation [71]. One small study suggests that if a child’s peak flow remains at < 40% of predicted 15 minutes after initiation of therapy, he/she will require hospitalization [133]. None of the published severity assessment scores are perfect in predicting the need for hospitalization [6, 21, 71, 134–136]. Children who continue to meet the criteria for a severe exacerbation [Figure 1] after 1 hour of intensive therapy in the ED, should be considered for hospitalization (86% required hospital). For those infants and children who still meet the criteria for a moderate exacerbation after 1 hour of intensive therapy, the rate of eventual hospitalization is about as high as 84%. But for those who have improved sufficiently to meet the criteria for mild exacerbation after 1–2 hours in the ED, only 18% will require hospitalization [26]. In very busy emergency departments where staff observation cannot be continuous, asking parents to help in assessment is useful [22]. Using the multi-faceted assessments for judging the severity of the exacerbation (vital signs, child’s ability to do simple functions like talk or cry, the measure of oxygenation, and if possible lung function) guides monitoring continuously with formal reassessments every 15–60 minutes.

Consideration of Hospital Based Therapy When it is necessary to admit infants or children to the hospital for severe acute asthma, most cases are admitted to an intensive care unit where they can be closely monitored. In smaller hospitals, the ICU may not be familiar with care of infants and children. The decision to have the child remain in the local hospital versus transport to a center with more experience in caring for children should be made as soon as possible. If physicians are unsure regarding transfer, the referral center should be called to discuss possible transfer and method of transport.

Respiratory Failure On rare occassions an infant or child arrives at the care site in respiratory failure, with apnea, or in a coma requiring immediate intubation and ventilatory assistance. More commonly respiratory failure develops over minutes to hours despite therapy [Table 5]. The etiology may be failure to respond to therapy or worsening of the obstructive process owing to continuation of the triggering event such as pneumonia

Acute Severe Asthma in Children

553

Table 5 The signs of impending respiratory failure include • • • • •

Inability to speak or cry due to respiratory distress, Altered mental status such as failure to respond to parents, Intercostal muscle retractions with inhalation, Worsening fatigue often laying flaccid in parents arms or on the examination table Elevated PCO2 (> 42 mm Hg).

or respiratory muscle fatigue. Infants and very young children have limited respiratory muscle reserve and may develop respiratory failure suddenly. Without access to blood gases, clinical judgment alone must be used to determine when to intubate. If you are considering intubation it is best to proceed with intubation immediately. In any child respiratory failure can progress rapidly and is often difficult to reverse. Intubation with controlled oxygenation allows time to identify and treat the trigger(s) for the episode, prevent damaged to multiple organs from hypoxemia, and let the child to rest while reversing airway obstruction. External ventilation such as bagging may have very limited ability to move air sufficiently in and out of the lungs owing to the high pressures that can be required. As soon as intubation is considered a possibility, a physician experienced in intubation of infants or children should be consulted and arrangements to transfer to an intensive care setting should be made if feasible. Whenever possible, consultation should be done before an emergency intubation is required. Many hospitals now have evaluation teams that can be called for consultation prior to a respiratory or cardiac arrest and that help with not only evaluation but practical matters such as bringing the proper equipment for intubation of small children or infants and portable ventilator equipment. It is appropriate to intubate the child in the emergency department or regular hospital room and then transfer to an intensive care unit if immediate intubation is required. Transport of the child to an intensive care unit should never delay intubation. If intravenous access has not already been established it should be immediately after intubation. Management of mechanical ventilation of children with severe refractory asthma is complicated and beyond the scope of this chapter. Care of a child on a ventilator should be managed in consultation with an expert. If this expertise is not available within your hospital and transport to a hospital with this expertise is not feasible, consultation and support may be available by telephone and or internet interactions.

Prevention and Discharge Planning Once the child or infant is stabilized in either the emergency department or the hospital, it is important to identify the trigger for this episode, provide at least minimal education regarding early identification of severe asthma, identify and make follow up appointment, and consult other available support services. Figure 2 provides a check list that can be used to remind the physicians and nurses to complete all the tasks.

554

B.P. Yawn

Intervention Inhaled medications (MDI + spacer/holding chamber) Beta2-agonist Corticosteroids

Dose/Timing Select agent, dose, and . frequency (e.g., albuterol) 2-6 puffs q 3-4 hr prn Medium dose

Education/Advice

M.D./R.N. Initials

Teach purpose Teach technique Emphasize need for spacer/ holding chamber Check patient technique

Oral medications

Select agent, dose, and frequency (e.g., prednisone 20 mg bid for 3-10 days)

Teach purpose Teach side effects

Peak flow meter

Measure a.m. and p.m. PEF and record best of three tries each time

Teach purpose Teach technique Distribute peak flow diary

Follow-up visit

Make appointment for follow-up care with primary clinician or asthma specialist

Advise patient (or caregiver) of date, time, and location of appointment within 7 days of hospital discharge

Action plan

Before or at discharge

Instruct patient (or caregiver) on simple plan for actions to be taken when symptoms, signs, and PEF values suggest recurrent airflow obstruction

Fig. 2 Checklist for Discharge

Other services that should be considered include social services to explore insurance coverage or help with costs of needed medications, home visiting nurses to reaffirm education and help identify potential asthma irritants and triggers in the home, and mental health support if there are signs of depression or marked anxiety. Depending on the family structure, it may be important to include grandparents, siblings or other relatives, and care givers in this education. The education provided in the emergency department is often very limited. However, in the event of a severe exacerbation, staff should be available to educate the parents and, when appropriate, the child about the basics of asthma care, inhaler techniques, and reasons for use of medications including the concepts of antiinflammatory medications and those used for quick relief [Table 6]. After a severe exacerbation, no child or infant should leave the hospital or emergency department without medications or prescriptions for systemic corticosteroids, inhaled or nebulized

Acute Severe Asthma in Children

555

Table 6 Brief teaching should focus on • • • • • •

What asthma is The usual triggers for asthma Need for regular asthma visits in the outpatient setting Review of discharge medications, (check literacy levels) Plan to follow for worsening asthma (can use asthma action plan) [137] Peak flow meter may be helpful

corticosteroids, and, if old enough, long acting bronchodilators and either inhaler (with or without mask) for quick relief or nebulized quick reliever medication and a follow up appointment [137]. When feasible, an infant or child who has experienced a severe asthma exacerbation should consult an asthma specialist (allergist, pulmonologist, or general physician who has special training in asthma care) [10, 138–141]. All children who are discharged from the ED or hospital following a severe exacerbation should have both actual drugs and prescriptions for all required medications for at least 30 days. No ED or hospital personnel should assume that the children will receive their immediately needed asthma medications from their usual physician or any specialist to whom they have been referred. In several studies such follow up appointments occur less than 30% of the time in the U.S and seldom within less than 14–28 days [142, 143]. It is however, important to stress the need for regular office based follow up of asthma. Children with fewer general practice contacts in a year are at increased risk of fatal asthma [144], and having a follow-up visit within 30 days of an asthma emergency department visit decreased the ED and hospital readmission rate for the next 90 days [145]. Finding time and personnel with the training to educate parents and the child are often difficult. However, the rate of recurrence of severe exacerbations is also high (up to 50%) [143] and the time and stress required to care for a child with another severe asthma exacerbation is likely to be much greater than finding the time and staff to provide at least minimal prevention education before discharge from the first episode. Education in the intensive care unit when a child is intubated may be provided even to parents who appear too upset to learn. Providing some minimal information about how to prevent a re-visit to the ICU is often worth including during the time spent caring for and monitoring the child. Providing parents with support from pastoral staff or faith based support staff can also help with the treatment of the child and support for the family. Early recognition requires that parents and children know what signs and symptoms may herald an exacerbation, when those signs and symptoms suggest a severe exacerbation, and what action should be taken and how quickly the action should be initiated [26]. Written asthma action plans have been used for that purpose and appear to provide patients and families the needed support in deciding when and where to seek medical care and what treatment to begin while coming to medical care services [46, 47]. Similar education can be accomplished without written information and may be necessary in low literacy areas. Like written information, verbal instructions require repeated reinforcement, which requires repeated visits and may be difficult to achieve.

556

B.P. Yawn

Although the format of the written action plan may vary, the content has become relatively standard. For signs and symptoms, the ability to perform common activities helps patients, families, and health professionals determine the severity of the acute episode [See Figure 1]. For example, the level of breathlessness increases with severity from breathlessness during activity, breathlessness at rest precluding even the ability to speak more than one or two words at a time, and in infants precluding the ability to feed. Most children become very agitated with rapid breathing (over 30 breaths per minute), use of accessory respiratory muscles, and a pulse that may be twice the normal range. Drowsiness, confusion, and bradycardia are signs of impending respiratory failure and represent a medical emergency. Many parents and children learn to identify a typical pattern of acute asthma episodes that either begin slowly and build over hours or that begin and build over minutes [39, 47]. Identifying this pattern is important for any child with recurrent exacerbations since it provides a guide to the rapidity with which the family must react, whether they should transport the child by car or ambulance, whether they can go to the physicians office, or should immediately proceed to a hospital, emergency department, or acute care center. Children with severe exacerbations or those with rapidly deteriorating symptoms should be cared for in an acute or emergency medical setting where services for cardiac and respiratory support including ventilatory support are immediately available [53, 103]. Novel new therapies that are being tested to prevent recurrence of severe acute asthma include macrolides to reduce neutrophilic inflammation, perhaps by eliminating chronic lower respiratory track infection or carrier status [146], anti-IgE in older children with marked allergic disease [147–150], and anti-TNF-alpha therapy [151, 152]. The most invasive therapy that does not work on inflammatory pathway but directly on the lung tissue is bronchial thermoplasy that uses controlled heat from a high radio-frequency source [153] and has been used primarily in adults with moderate success.

Summary Early recognition and treatment is imperative to the successful resolution of a severe asthma exacerbation. Written protocols, flow algorithm and team evaluation management can facilitate care of acute severe asthma. The care of the exacerbation is not finished until plans have been initiated to prevent the next severe exacerbation.

References 1. Canonica GW (2006) Treating asthma as an inflammatory disease. Chest 130:21–28 2. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID (2002) Asthma exacerbations and sputum eosinophil counts: a randomized controlled trial. Lancet 360(9347):1715–21

Acute Severe Asthma in Children

557

3. Green RH, Brightling Ce,Wardlaw AJ, Avord ID (2003) Asthma exacerbations and sputum eosinophil counts. Lancet 361(9365):1303 4. Hanazawa T, Kharitonov SA, Barnes PJ (2000) Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am J Respir Crit Care Med 162:1273–1276 5. Higgins JC (2003) The ‘crashing asthmatic.’ Am Fam Phys 67:997–1004 6. Keahey L, Bulloch B, Becker AB, Pollack CV Jr, Clark S, Camargo CA Jr (2002) Initial oxygen saturation as a predictor of admission in children presenting to the emergency department with acute asthma. Ann Emerg Med 40(3):300–307 7. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A (1999) Differences between asthma exacerbations and poor asthma control. Lancet 353(9150):364–9 8. Busse WW, Lemanske RF Jr (2001) Asthma. N Engl J Med. 344(5):350–362 9. The Global Initiative for Asthma. http://www.ginasthma.com/ 10. National Heart, Lung, and Blood Institute. 2007. National Asthma Education and Prevention Expert Panel report 3: guidelines for the diagnosis and management of asthma. Bethesda (MD): National Institutes of Health. Available from URL: www.nhlbi.nih.gov/guidelines/ asthma/epr3/index.htm 11. National Institute for Health and Clinical Excellence. http://www.nice.org.uk/asthmas 12. Institute for Clinical Systems Improvement. http://www.icsi.org/guidelines/respiratory/ asthma__er_and_inpatient/asthma__er_and_inpatient_management_of_1444.html 13. Blake K (2006) Review of guidelines and the literature in the treatment of acute bronchospasm in asthma. Pharmacotherapy 26(9 Pt 2):148S–55S 14. FitzGerald JM, Grunfeld A (1996) Status asthmaticus. In: Lichtenstein LM, Fauci AS, eds. Current therapy in allergy, immunology, and rheumatology. 5th edition. St. Louis, MO:Mosby, pp 63–7 15. Chan-Yeung M, Chang JH, Manfreda J, Ferguson A, Becker A (1996) Changes in peak flow, symptoms score, and the use of medications during acute exacerbations of asthma. Am J Respir Crit Care Med 154(4 Pt 1):889–93 16. Gauvreau GM, Watson RM, O’Byrne PM (1999) Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 160: 640–647 17. Green RH, Brighting CE, McKenna S, et al (2002) Asthma exacerbations and sputum eosinophil counts: a randomized controlled trial. Lancet 360:1715–1721 18. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ (1994) Increased nitric oxide in exhaled air of asthmatic patients. Lancet 343:133–135 19. Lim S, Jatakanon A, John M, et al (1999) Effect of inhaled budesonide on lung function and airway inflammation. Am J Respir Crit Care Med 159:22–30 20. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR (2005) Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 352:2163–2173 21. Smith SR, Baty JD, Hodge D III (2002) Validation of the pulmonary score: An asthma severity score for children. Acad Emerg Med 9(2):99–104 22. Gorelick MH, Stevens MW, Schultz TR, Scribano PV (2004) Performance of a novel clinical score, the pediatric asthma severity score (PASS), in the evaluation of acute asthma. Acad Emerg Med 11(1):10–18 23. Wright RO, Santucci KA, Jay GD, Steele DW (1997) Evaluation of pre- and posttreatment pulse oximetry in acute childhood asthma. Acad Emerg Med 4(2):114–117 24. Chey T, Jalaludin B, Hanson R, Leeder S (1999) Validation of a predictive model for asthma admission in children: how accurate is it for predicting admissions? J Clin Epidemiol 52(12):1157–1163 25. Kelly AM, Kyle E, McAlpine R (2002) Venous PCO(2) and PH can be used to screen for significant hypercarbia in emergency patients with acute respiratory disease. J Emerg Med 22(1):15–19 26. Kelly AM, Powell C, Kerr D (2002) Patients with a longer duration of symptoms of acute asthma are more likely to require admission to hospital. Emerg Med (Fremantle) 14(2):142–145

558

B.P. Yawn

27. Keogh KA, Macarthur C, Parkin PC, Stephens D, Arseneault R, Tennis O, Bacal L, Schuh S (2001) Predictors of hospitalization in children with acute asthma. J Pediatr 139(2):273–277 28. American Lung Association (2005) Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology & Statistics Unit, Research and Program Services Available at: www.lungusa.org/atf/cf/{7A8D42C2-FCCA-4604-8ADE-7F5D5E762256}/ASTHMA1.PDF 29. Yawn BP, Wollan P, Kurland M, Scanlon P (2002) A longitudinal study of the prevalence of asthma in a community population of school-age children. J Pediatr 140(5):576–81 30. Brunner WM, Lindgren PG, Langner DM, Williams AN, Yawn BP (2005) Asthma among rural Minnesota adolescents. J Asthma 42(9):787–92 31. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, Williams H (2006) Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368(9537):733–43 32. El-Ekiaby A, Brianas L, Skowronski ME, Coreno AJ, Galan G, Kaeberlein FJ, Seitz RE, Villaba KD, Dickey-White H, McFadden ER (2006) Impact of race on the severity of acute episodes of asthma and adrenergic responsiveness. Am J Respir Crit Care Med 174(5):508–13 33. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E, Kraft M, Leone F, Martin RJ, Peters SP, Szefler SJ, Liu W, Israel E (2006) Beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 173(5):519–26 34. Choudhry S, Taub M, Mei R, Rodriguez-Santana J, Rodriguez-Cintron W, Shriver MD, Ziv E, Risch NJ, Burchard EG (2008) Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region. Hum Genet 123(5):455–69 35. Holloway JW, Yang IA, Holgate ST (2008) Interpatient variability in rates of asthma progression: can genetics provide an answer? J Allergy Clin Immunol 121(3):573–9 36. Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, FitzGerald JM (1998) Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med 157(6 Pt 1):1804–9 37. Suissa S, Blais L, Ernst P (1994) Patterns of increasing beta-agonist use and the risk of fatal or near-fatal asthma. Eur Respir J 7(9):1602–9 38. Ernst P, Spitzer WO, Suissa S, Cockcroft D, Habbick B, Horwitz RI, et al (1992) Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use. JAMA 268(24):3462–4 39. Verbruggen SC, Corel LJ, Tiddens HA, Joosten KF, de Hoog M (2006) [Fatal asthma in childhood preventable by recognizing risk factors and presenting features] Fataal astma op de kinderleeftijd te voorkomen door herkenning van risicofactoren en presentatiewijze. Ned Tijdschr Geneeskd 150(5):225–9 40. Kallenbach JM, Frankel AH, Lapinsky SE, et al (1993) Determinants of near fatality in acute severe asthma. Am J Med 95:265–72 41. Rodrigo C, Rodrigo G (1993) Assessment of the patient with acute asthma in the emergency department. A factor analytic study Chest 104:1325–8 42. Suissa S, Ernst P, Bolvin JF, et al (1994) A cohort analysis of excess mortality in asthma and the use of inhaled beta2-agonists. Am J Respir Crit Care Med 149(3 Pt 1):604–10 43. Carroll CL, Schramm CM, Zucker AR (2008) Severe exacerbations in children with mild asthma: characterizing a pediatric phenotype. J Asthma 5(6):513–7 44. O’Hollaren MT, Yunginger JW, Offord KP, et al (1991) Exposure to an aeroallergen as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 324:359–63 45. Greenberger PA, Miller TP, Lifschultz B (1993) Circumstances surrounding deaths from asthma in Cook County (Chicago) Illinois. Allergy Proc 14:321–6 46. Kikuchi Y, Okabe S, Tamura G, et al (1994) Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 330:1329–34 47. Hardie GE, Gold WM, Janson S, Carrieri-Kohlman V, Boushey HA (2002) Understanding how asthmatics perceive symptom distress during a methacholine challenge. J Asthma (7):611–618

Acute Severe Asthma in Children

559

48. Makowska JS, Grzegorczky J, Cieslak M, Bienkiewicz B, Kowalski ML (2008) Recruitment of CD34+ progenitor cells into peripheral blood and asthma severity. Ann Allergy Asthma Immunol 101(4):402–6 49. Brasier AR, Victor S, Boetticher G, Ju H, Lee C, Bleecker ER, Castro M, Busse WW, Calhoun WJ (2008) Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage-derived cytokines. J Allergy Clin Immunol 121(1):30–37.e6 50. Menzies D, Jackson C, Mistry C, Houston R, Lipworth BJ (2008) Symptoms, spirometry, exhaled nitric oxide, and asthma exacerbations in clinical practice. Ann Allergy Asthma Immunol 101(3):248–55 51. Bush A, Eber E (2008) The value of FeNO measurement in asthma management: the motion for Yes, it’s NO—or, the wrong end of the Stick! Paediatr Respir Rev 9(2):127–31 52. Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA Jr (2000) Intravenous magnesium sulfate treatment for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med 36(3):181–190 53. McFadden ER Jr (2003) Acute severe asthma. Am J Respir Crit Care Med 1;168(7):740–59 54. FitzGerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J (2004) Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 59(7):550–556 55. Schreck DM (2006) Asthma pathophysiology and evidence-based treatment of severe exacerbations. Am J Health Syst Pharm 63(10 Suppl 3):S5–13 56. McDonald MV, Gibson PG (2005) Inhalation-device polypharmacy in asthma. Med J Aust 182(5):250–1 57. Foresi A, Morelli MC, Catena E (2000) Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Chest 117(2):440–6 58. Santillanes G, Gausche-Hill M, Sosa B (2006) Preparedness of selected pediatric offices to respond to critical emergencies in children. Pediatr Emerg Care 22(11):694–8 59. Yawn BP (2003) The impact of childhood asthma on daily life of the family. General Practice Airways Group12(3):82–85 60. Fergusson, RJ, Stewart CM, Wathen CG, Moffat R, Crompton GK (1995) Effectiveness of nebulised salbutamol administered in ambulances to patents with acute severe asthma. Thorax 50:81–2 61. Markenson D, Foltin G, Tunik M, Cooper A, Treiber M, Caravaglia K (2004) Albuterol sulfate administration by EMT-Basics: results of a demonstration project. Prehosp Emerg Care 8(1):34–40 62. Cates CC, Bara A, Crilly JA, Rowe BH (2003) Holding chambers versus nebulisers for betaagonist treatment of acute asthma. Cochrane Database Syst Rev (3):CD000052 63. Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, Smaldone GC, Guyatt G (2005) American College of Chest Physicians; American College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest 127(1):335–371 64. Rodrigo GJ (2005) Delivery of beta-agonists in the emergency department setting: metereddose inhalers or nebulizers? Chest 128(3):1890 65. Sly RM, Badiei B, Faciane J (1977) Comparison of subcutaneous terbutaline with epinephrine in the treatment of asthma in children. J Allergy Clin Immunol 59:128–35 66. Smith PR, Heurich AE, Leffler CT, Henis MM, Lyons HA (1977) A comparative study of subcutaneously administered terbutaline and epinephrine in the treatment of acute bronchial asthma. Chest 71:129–34 67. Crago S, Coors L, Lapidus JA, Sapien R, Murphy SJ (1998) Prehospital treatment of acute asthma in a rural state. Ann Allergy Asthma Immunol 81(4):322–325 68. Anonymous (2006) A model protocol for emergency medical services management of asthma exacerbations. Prehosp Emerg Care 10(4):418–29 69. Knapp B, Wood C (2003) The prehospital administration of intravenous methlypredisolone lowers hospital admission rates for moderate to severe asthma. Prehosp Emerg Care 7(4):423–426

560

B.P. Yawn

70. Stead L, Whiteside T (1999) Evaluation of a new EMS asthma protocol in New York City: a preliminary report. Prehosp Emerg Care 3(4):338–342 71. Gorelick MH, Stevens MW, Schultz T, Scribano PV (2004) Difficulty in obtaining peak expiratory flow measurements in children with acute asthma. Pediatr Emerg Care 20(1):22–26 72. Li JR, O’Connel EJ (1996) Clinical evaluation of asthma. Ann Allergy Asthma Immunol 76:1–13 73. Martinati LC, Boner Al (1995) Clinical diagnosis of wheezing in early childhood. Allergy 50:701–710 74. Newman KB, Mason UG III, Schmaling KB (1995) Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med 152:1382–1386 75. Anonymous (1999) Pediatric Asthma Promoting Best Practice. Guide for Managing Asthma in Children. American Academy of Allergy Asthma & Immunology. Academic Services Consortium, University of Rochester, Rochester, New York 76. Struck RC (1987) Asthma deaths in childhood: identification of patients at risk and intervention. J Allergy Clin Immunol 80:472–477 77. Beasley R, Miles J, Fishwick D, Leslie H (1996) Management of asthma in the hospital emergency department. Br J Hosp Med 55(5):253–7 78. FitzGerald JM (1998) Development and implementation of asthma guidelines. Can Respir J 5 Suppl A:85–8S 79. Shim CS, Williams MH Jr (1980) Evaluation of the severity of asthma: patients versus physicians. Am J Med 68:11–3 80. Sole D, Komatsu MK, Carvalho KV, Naspitz CK (1999) Pulse oximetry in the evaluation of the severity of acute asthma and/or wheezing in children. J Asthma 36(4):327–333 81. Geelhoed GC, Landau LI, Le Souef PN (1994) Evaluation of SaO2 as a predictor of outcome in 280 children presenting with acute asthma. Ann Emerg Med 23(6):1236–41 82. Camargo CA Jr, Spooner CH, Rowe BH (2003) Continuous versus intermittent beta-agonists in the treatment of acute asthma. Cochrane Database Syst Rev (4):CD001115 83. Travers AH, Rowe BH, Barker S, Jones A, Camargo CA (2002) The effectiveness of IV betaagonists in treatment patients with acute asthma in the emergency department: a meta-analysis. Chest 122(4):1200–7 84. Nowak R, Emerman C, Hanrahan JP, Parsey MV, Hanania NA, Claus R, Schaefer K, Baumgartner RA (2006) A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults. Am J Emerg Med 24(3):259–67 85. Ameredes BT, Calhoun WJ (2006) (R)-albuterol for asthma: pro [a.k.a. (S)-albuterol for asthma: con] Am J Respir Crit Care Med 174(9):965–9; discussion 972–4 86. Berger WE, Milgrom H, Skoner DP, Tripp K, Parsey MV, Baumgartner RA (2006) Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial. Curr Med Res Opin 22(6):1217–26 87. Gupta MK, Singh M (2007) Evidence based review on levosalbutamol. Indian J Pediatr 74(2):161–7 88. Milgrom H (2006) Levosalbutamol in the treatment of asthma. Expert Opin Pharmacother 7(12):1659–68 89. Watanasomsiri A, Phipatanakul W (2006) Comparison of nebulized ipratropium bromide with salbutamol vs salbutamol alone in acute asthma exacerbation in children. Ann Allergy Asthma Immunol 96(5):701–6 90. Strauss L, Hejal R, Galan G, Dixon L, McFadden ER Jr (1997) Observations on the effects of aerosolized albuterol in acute asthma. Am J Respir Crit Care Med 155(2):454–458 91. Rodrigo C, Rodrigo G (1998) Salbutamol treatment of acute severe asthma in the ED: MDI versus hand-held nebulizer. Am J Emerg Med 16(7):637–642 92. Rodrigo G, Rodrigo C (1998) How often should beta-agonists be administered? Chest 113(5):1427–1428 93. Rodrigo G, Rodrigo C (1998) Nebulized fenoterol versus intravenous aminophylline treatment of acute severe asthma. Am J Emerg Med 16(1):95 94. Karpel JP, Aldrich TK, Prezant DJ, Guguchev K, Gaitan-Salas A, Pathiparti R (1997) Emergency treatment of acute asthma with albuterol metered-dose inhaler plus holding chamber: how often should treatments be administered? Chest 112(2):348–356

Acute Severe Asthma in Children

561

95. Hanania NA, Moore RH, Zimmerman JL, Miller CT, Bag R, Sharafkhaneh A, Dickey BF (2007) The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma. Respir Med 101(5):1007–14 96. Broadley KJ (2006) Beta-adrenoceptor responses of the airways: for better or worse? Eur J Pharmacol 533(1–3):15–27 97. Salo D, Tuel M, Lavery RF, Reischel U, Lebowitz J, Moore T (2006) A randomized, clinical trial comparing the efficacy of continuous nebulized albuterol (15 mg) versus continuous nebulized albuterol (15 mg) plus ipratropium bromide (2 mg) for the treatment of acute asthma. J Emerg Med 31(4):371–6 98. Koul PB Minarik M Totapally BR (2007) Lactic acidosis in children with acute exacerbation of severe asthma. Eur J Emerg Med 14(1):56–8 99. Ait-Khaled N, Enarson DA (2006) Managing acute attacks of asthma. Int J Tuberc Lung Dis 10(5):484–9 100. Ameh V, Jenner R, Jilani N, Bradbury A (2006). Spontaneous pneumopericardium, pneumomediastinum and subcutaneous emphysema: unusual complications of asthma in a 2-yearold boy. Emerg Med J 23(6):466–7 101. Egbagbe EE, Elusoji SO (2006) Pneumomediastinum and subcutaneous emphysema associated with asthma exacerbation. J Pak Med Assoc 56(6):287–9 102. Rachelefsky G (2003) Treating Exacerbations of asthma in children: the role of systemic corticosteroids. Pediatrics 112(2):382–397 103. Rowe BH, Edmonds ML, Spooner CH, Diner B, Camargo CA Jr (2004) Corticosteroid Therapy for Acute Asthma. Respir Med 98(4):275–284 104. Rowe BH, Edmonds ML, Spooner CH, Camargo CA (2001) Evidence-Based Treatments for Acute Asthma. Respir Care 46(12):1380–1390 105. Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH (2003) Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev (3):CD002308 106. Green SM (2003) Intravenous epinephrine in asthma? A word of caution. Ann Emerg Med 41(5):712–3 107. Blitz M, Blitz S, Beasely R, Diner B, Hughes R, Knopp J, et al (2005) Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev (4):CD003898 108. Blitz M, Blitz S, Hughes R, Diner B, Beasley R, Knopp J, et al (2005) Aerosolized magnesium sulfate for acute asthma: a systematic review. Chest 128(1):337–44 109. Rodrigo GJ, Rodrigo C, Pollack CV, Rowe B (2003) Use of helium-oxygen mixtures in the treatment of acute asthma: a systematic review. Chest 123(3):891–6 110. Parameswaran K, Belda J, Rowe BH (2000) Addition of intravenous aminophylline to beta2agonists in adults with acute asthma. Cochrane Database Syst Rev (4):CD002742 111. Mitra A, Bassler D, Goodman K, Lasserson TJ, Ducharme FM (2005) Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev (2):CD001276 112. Cheuk DKL, Chau TCH, Lee SL (2005) A meta-analysis on intravenous magnesium sulfate for treating acute asthma. Arch Dis Child 90:74–77 113.Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S (2002) IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest 122(2):489–97 114. Boonyavorakul C, Thakkinstian A, Charoenpan P (2000) Intravenous magnesium sulfate in acute severe asthma. Respirology 5(3):221–225 115. Porter RS, Nester, Braitman LE, Geary U, Dalsey WC (2001) Intravenous magnesium is ineffective in adult asthma, a randomized trial. Eur J Emerg Med 8(1):9–15 116. Scarfone RJ, Loiselle JM, Joffe MD, Mull CC, Stiller S, Thompson K, Gracely EJ (2000) A randomized trial of magnesium in the emergency department treatment of children with asthma. Ann Emerg Med 36(6):572–578 117. Aggarwal P, Sharad S, Handa R, Dwiwedi SN, Irshad M (2006) Comparison of nebulised magnesium sulphate and salbutamol combined with salbutamol alone in the treatment of acute bronchial asthma: a randomised study. Emerg Med J 23(5):358–62

562

B.P. Yawn

118. Gupta VK, Cheifetz IM (2005) Heliox administration in the pediatric intensive care unit: An evidence-based review. Pediatr Crit Care Med 6:204–211 119. Ho AM, Lee A, Karmakar MK, Dion PW, Chung DC, Contardi LH (2003) Heliox vs airoxygen mixtures for the treatment of patients with acute asthma: A systematic overview. Chest 123(3):882–890 120. Rivera ML, Kim TY, Stewart GM, Minasyan L, Brown L (2006) Albuterol nebulized in heliox in the initial ED treatment of pediatric asthma: a blinded, randomized controlled trial. Am J Emerg Med 24(1):38–42 121. Dhuper S, Choksi S, Selvaraj S, Jha G, Ahmed A, Babbar H, Walia B, Chandra A, Chung V, Shim C (2006) Room air entrainment during beta-agonist delivery with heliox. Chest 130(4):1063–71 122. Kim IK, Saville AL, Sikes KL, Corcoran TE (2006). Heliox-driven albuterol nebulization for asthma exacerbations: an overview. Respir Care 51(6):613–8 123. Venkataraman ST (2006) Heliox during mechanical ventilation. Respir Care 51(6):632–9 124. Levin DA (2008) Novel therapies for children with severe asthma. Curr Opin Pediatr 20(3):261–5 125. Travers A, Jones AP, Kelly K, Barker SJ, Camargo CA, Rowe BH (2001) Intravenous beta2agonists for acute asthma in the emergency department. Cochrane Database Syst Rev (2):CD002988 126. Browne GJ, Penna AS, Phung X, Soo M (1997) Randomised trial of intravenous salbutamol in early management of acute severe asthma in children. Lancet 349:301–305 127. Maguire JF, O’Rourke PP, Colan SD, Geha RS, Crone R (1991) Cardiotoxicity during treatment of severe childhood asthma. Pediatrics 88:1180–6 128. Camargo CA Jr, Smithline HA, Malice MP, Green SA, Reiss TF (2003) A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 167(4):528–33 129. Dockhorn RJ, Baumgartner RA, Leff JA, Noonan M, Vandormael K, Stricker W, Weinland DE, Reiss TF (2000) Comparison of the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax (4):260–5 130. Green SA, Malice MP, Tanaka W, Tozzi CA, Reiss TF (2004) Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax 59(2):100–4 131. Boogaard R, Smit F, Schornagel R, Vaessen-Verberne AA, Kouwenberg JM, Hekkelaan M, Hendriks T, Feith SW, Hope WC, de Jongste JC, Merkus PJ (2008) Recombinant human deoxyribonuclease for the treatment of acute asthma in children. Thorax 63(2):141–6 132. Berlinski A, Waldrep JC (2006) Nebulized drug admixtures: effect on aerosol characteristics and albuterol output. J Aerosol Med 19(4):484–90 133. Piovesan DM, Menegotto DM, Kang S, Franciscatto E, Millan T, Hoffmann C, Pasin LR, Fischer J, Barreto SS, Dalcin Pde T (2006) Early prognosis of acute asthma in the emergency room. J Bras Pneumol 32(1):1–9 134. McCarren M, Zalenski RJ, McDermott M, Kaur K (2000) Predicting recovery from acute asthma in an emergency diagnostic and treatment unit. Acad Emerg Med 7(1):28–35 135. Weber EJ, Silverman RA, Callaham ML, Pollack CV Jr, Woodruff PG, Clark S, Camargo CA Jr (2002) A prospective multicenter study of factors associated with hospital admission among adults with acute asthma. Am J Med 113:371–378 136. Pollack CV Jr, Pollack ES, Baren JM, Smith S, Woodruff PG, Camargo CA Jr (2002) A prospective multicenter study of patient factors associated with hospital admission from the emergency department among children with acute asthma. Arch Pediatr Adolesc Med 156:934–940 137. Zorc JJ, Scarfone RJ, Li Y, Hong T, Harmelin M, Grunstein L, Andre JB (2003) Scheduled follow-up after a pediatric emergency department visit for asthma: A randomized trial. Pediatrics 111(3):495–502 138. Zeiger RS, Heller S, Mellon MH, Wald J, Falkoff R, Schatz M (1991) Facilitated referral to asthma specialist reduces relapses in asthma emergency room visits. J Allergy Clin Immunol 87:1160–8

Acute Severe Asthma in Children

563

139. Sperber K, Ibrahim H, Hoffman B, Eisenmesser B, Hsu H, Corn B (1995) Effectiveness of a specialized asthma clinic in reducing asthma morbidity in an inner-city minority population. J Asthma 32(5):335–43 140. Harish Z, Bregante AC, Morgan C, Fann CS, Callaghan CM, Witt MA, Levinson KA, Caspe WB (2001) A comprehensive inner-city asthma program reduces hospital and emergency room utilization. Ann Allergy Asthma Immunol 86(2):185–9 141. Kelly AM, Powell C, Kerr D (2003) Snapshot of acute asthma: Treatment and outcome of patients with acute asthma treated in Australian emergency departments. Intern Med J 33(9–10):406–413 142. Smith SR, Jaffe DM, Fisher EB Jr, Trinkaus KM, Highstein G, Strunk RC (2004) Improving follow-up for children with asthma after an acute Emergency Department visit. J Pediatr 145(6):772–7 143. Baren JM, Boudreaux ED, Brenner BE, Cydulka RK, Rowe BH, Clark S, Camargo CA Jr (2006) Randomized controlled trial of emergency department interventions to improve primary care follow-up for patients with acute asthma. Chest 129:257–265 144. Sturdy PM, Butland BK, Anderson HR, Ayres JG, Bland JM, Harrison BD, Peckitt C, Victor CR (2005) National Asthma Campaign Mortality and Severe Morbidity Group.Deaths certified as asthma and use of medical services: a national case-control study. Thorax 60(11):909–95 145. Sin DD, Bell NR, Svenson LW, Man SF (2002) The impact of follow-up physician visits on emergency readmissions for patients with asthma and chronic obstructive pulmonary disease: A population-based study. Am J Med 112(2):120–125 146. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG (2008) Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 177(2):148–55 147. Humbert M, Berger W, Rapatz G, Turk F (2008) Add-on omalizumab improves day-to-day symptoms in inadequately controlled severe persistent allergic asthma. Allergy 63(5):592–6 148. Steiss JO, Strohner P, Zimmer KP, Lindemann H (2008) Reduction of the total IgE level by omalizumab in children and adolescents. J Asthma 45(3):233–6 149. Prenner BM (2008) Asthma 2008: targeting immunoglobulin E to achieve disease control. J Asthma 45(6):429–36 150. Niven R, Chung KF, Panahloo Z, Blogg M, Ayre G (2008) Effectiveness of omalizumab in patients with inadequately controlled severe persistent allergic asthma: an open-label study. Respir Med 102(10):1371–8 151. Brightling C, Berry M, Amrani Y (2008) Targeting TNF-alpha: a novel therapeutic approach for asthma 121(1):5–10; quiz 11–2 152. Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST (2008) The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomized, placebo controlled trial. Thorax 63(7):584–91 153. Wechsler ME (2008) Bronchial thermoplasty for asthma: a critical review of a new therapy. Allergy Asthma Proc 29(4):365–70

Best Estimates of Asthma Control in Children Megan E. Partridge and William K. Dolen

Asthma is a disease caused by the chronic inflammation with resulting airway hyper-responsiveness and reversible obstruction. Although the underlying pathophysiology of the condition is similar in adults and children, differences exist between these two populations because the pediatric lung is not just a smaller version of the adult lung. Because of a narrower airway, children may have asthma symptoms when exposed to stimuli that an adult may tolerate without symptoms. Since the pediatric lung is still developing, chronic inflammation may result not only in current asthma symptoms, but also in a permanent decrease in lung function [1]. On the global level, asthma prevalence is increasing at a disproportionate rate in children, compared to adults. Asthma has become the most common chronic disease of childhood, affecting approximately 9 million children less than 18 years of age [2].

Asthma Severity Versus Asthma Control Asthma severity and control are related, but different, concepts. The clinician assesses asthma severity prior to, and in the course of, treatment. It can be considered as an underlying personal characteristic of the disease that remains fairly constant despite therapy [3,4]. Severity is defined on the basis of asthma symptoms, frequency of rescue medication use, measures of pulmonary function, and the degree to which asthma interferes with daily activities. The term “severity” can refer to the overall severity of the disease or to the severity of a particular exacerbation. In those patients being treated with daily maintenance medications, severity is assessed by the amount of medication needed to sustain asthma control. In contrast, the concept of asthma control relates to the adequacy of the current asthma management [3]. Asthma control has been defined in a variety of ways. In general, asthma

M.E. Partridge and W.K. Dolen () Allergy-Immunology Section, Departments of Pediatrics and Medicine, Medical College of Georgia, 1120, 15th Street, Augusta, GA 30912, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_34, © Springer 2010

565

566

M.E. Partridge and W.K. Dolen

control refers to the control of disease manifestations, highlighting the dynamic nature of the disease by including response to therapy and triggers [5]. Unfortunately, there is no global consensus on the definition of asthma control and no single marker of adequate control [6]. According to the 2005 practice parameter on asthma control published by the Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology, the assessment of asthma control should be based on symptoms, sleep disturbance, use of rescue medications, limitations on daily activities, lung function, and patient and physician assessment of control [7]. Well-controlled asthma (Table 1) is defined by having asthma symptoms less than twice per week, rescue medication use twice a week or less, lack of nighttime symptoms, no limitations on daily activities, and normal lung function. The patient and physician should also agree that asthma is well controlled and physicians should frequently reassess their patients since asthma control will change over time [7]. Although they are two separate concepts, asthma severity and asthma control are closely related. For example, a patient who has severe asthma can still be well controlled, whereas a patient with mild asthma can be poorly controlled. This hypothetical inverse relationship has been demonstrated in a study of long-term asthma control using several markers of asthma severity, including use of oral steroids, frequency of hospitalizations for asthma, and number of unscheduled visits for asthma. Furthermore, in patients with severe asthma, asthma control is possible with effective control strategies [8]. As appreciation for the adverse health effects of asthma on the population has increased, so too has the need to identify patients at high risk of asthma exacerbations. It is important for clinicians caring for these patients to have a pragmatic approach to assess asthma so that they can identify high-risk patients. The 1991 National Heart, Lung, and Blood Institute (NHLBI) guidelines for the diagnosis and management of asthma emphasized that assessment of asthma severity is the best tool to guide asthma care [9]. The 1995 Global Initiative for Asthma (GINA) guidelines also focused on assessment of asthma severity. The GINA guidelines classify asthma into mild intermittent, mild persistent, moderate persistent, and severe persistent asthma on the basis of symptoms [10].

Table 1 Well-controlled asthma Asthma symptoms twice a week or less Rescue bronchodilator use twice a week or less No nighttime or early morning awakening No limitations on exercise, work, or school Well-controlled asthma by patient and physician assessment Normal or personal best PEF or FEV1 Modified from “National Asthma Education and Prevention Program Expert Panel Report: Guidelines for the Diagnosis” [7]

Best Estimates of Asthma Control in Children

567

In the past several years, an increasing focus on the importance of assessing asthma control, instead of asthma severity, has been reflected in newer guidelines [11]. The 2006 revision of the GINA guidelines was based on concepts of asthma control. The NHLBI asthma guidelines expected to be published in 2007 will probably include recommendations on the assessment of asthma control. Unlike past guidelines, these new guidelines are expected to provide recommendations on asthma management for children 0–4, 5–11, and ³12 years of age and will also provide recommendations on assessing asthma while on controller medications. Pediatric asthma is unique, making caring for this population of asthmatics a special challenge. Since reduction in the lung function starts early in life [12], it is essential to address asthma control before this decline begins. The prognosis of adult asthma may be determined at least in part by asthma control during childhood [13,14]. Estimates of pediatric asthma control should aid practitioners as they strive for optimal disease control in children.

Assessment of Asthma Control Using Subjective Measures Symptom Assessments Asthma symptom assessments (Table 2) alone are not a reliable measure of asthma control. The blunted perception of dyspnea found in chronic asthma is a contributing factor [15]. There is a poor correlation between perceived asthma symptoms and measured peak expiratory flow rates (PEFRs) in up to 60% of asthmatic adults (17–76 years) [16]. A similar lack of asthma perception has been found in children; less than 20% improvement in the visual analog scale scores after bronchodilator administration may identify a patient as a “poor perceiver.”[17] In contrast, other patients report significant asthma symptoms despite normal spirometry values. A study of more than 1,500 adults demonstrated a low correlation

Table 2 Interim asthma history for assessing asthma control How has your asthma been doing since your last visit? How has it been doing in the past week? Do asthma symptoms limit your exercise? What kind of exercise do you do? Do asthma symptoms affect school or play? How often do you cough? Is it due to asthma? How often do you wake up at night? Is it due to asthma? How often do you have other asthma symptoms? How often do you use your rescue inhaler? Do you feel that your asthma is in control? The Asthma Control Test [28] asks similar questions in a way that permits quantification of the response

568

M.E. Partridge and W.K. Dolen

between daytime symptoms and forced expiratory volume in 1 second (FEV1) and PEFR measurements in 40% of patients [18]. Thus, symptoms may improve without a corresponding improvement in lung function, and lung function may improve without an improvement in asthma symptoms [19]. Despite this lack of correlation, the assessment of perceived asthma symptoms is an important component in the overall assessment of asthma control. In a study of over 3,000 adults, symptom frequency was the major determinant of a patient’s perception of asthma burden. Severity of asthma symptoms, frequency of exacerbations, and interference with activity were less strongly associated with a patient’s perception of asthma burden [20]. This is a disturbing finding, from a management perspective, since physicians often rely on the assessment of patient symptoms for the diagnosis and treatment of asthma.

Quality of Life Measures Asthma affects overall quality of life in a number of ways. Surveys of children show that asthma limits their daily activities, causes them to miss school, and results in limitations on activity while at school. Asthma is the leading cause of childhood disability; its prevalence has increased at almost twice the rate of all other chronic illnesses of childhood combined [21]. Asthma patients are twice as likely as the general population to experience depression, and patients with depression are three times less likely to take prescribed medications; therefore, they have a higher risk of poor health outcomes in the future [1,22,23]. Depression is an important issue of asthma since it is related to quality of life, medication adherence, and risk of hospitalization [24]. Identifying and addressing these issues are important components of asthma care, and there are standardized measurement instruments to help clinicians achieve this goal. These tools attempt to quantify patient-reported symptoms in order to construct valid and reproducible measures of a subjective outcome. Tools available to physicians for the standardized assessment of an asthmatic’s quality of life include generic measures and asthma-specific measures. These health related quality of life (HRQOL) assessments focus primarily on disease burden in regards to overall physical and functional status, psychological status, effects on social interactions, and economic factors [25]. The 1992 Juniper Asthma Quality of Life Questionnaire (AQLQ) is an asthmaspecific tool used to assess quality of life impairment in adult asthmatics [26]. The Pediatric AQLQ was adapted from the Juniper AQLQ. Analysis of this clinical instrument demonstrated that this test could detect significant differences in the quality of life of patients whose asthma control had changed in one direction or the other. Furthermore, results were reproducible in patients with stable asthma followed over time [26,27]. Other validated tools can aid clinicians in assessing a patient’s subjective report of asthma symptoms. These include the Short Form-12 (SF-12) to assess generic

Best Estimates of Asthma Control in Children

569

quality of life, the Mini AQLQ and the Asthma Outcomes Monitoring System (AOMS) to assess asthma severity, and the Asthma Control Test (ACT) to assess asthma control. The ACT was first developed for the use in adults and children over 12 years of age. This test has also been validated for the use in children 4–11 years of age. Using input from caregiver and child, this questionnaire can identify children whose asthma is inadequately controlled (sensitivity 68%, specificity 74%) [28].

Healthcare Utilization Morbidity from asthma is a major contributor to health care costs in the United States. In 1998, the economic burden of asthma in the United States was estimated at 12.8 billion dollars annually [29]. A population-based survey done in 1987 found that children 1–17 years of age with asthma used 3.1 times as many prescriptions, had 1.9 times as many outpatient visits, 2.2 times as many emergency department visits, and 3.5 times as many hospitalizations as children without asthma. Costs incurred by these children from healthcare utilization were almost three times that of the nonasthmatic children surveyed, demonstrating the significant impact of asthma on healthcare costs [30]. More severe asthma and non-compliance with NHLBI guidelines is associated with increased healthcare utilization [29]. Although only 20% of asthmatics have frequent exacerbations, these patients account for over 80% of total direct asthma costs [29,31]. Tracking other healthcare utilization trends can be a way to monitor asthma control. In a retrospective observational study of over 60,000 patients, prescription claims for asthma medications and emergency room visits or hospitalizations were tracked in order to assess asthma control in this population. Patients were defined as well as controlled if they had fewer than four claims for beta-agonists, no oral steroid claims, and no ER visits or hospitalizations for asthma. During a 3-year period, 73% of patients had evidence of at least one episode of uncontrolled asthma. Fluctuations in asthma control occur even in patients with previously well-controlled asthma, which could be detected by monitoring resource utilization and administrative claims [32]. Healthcare utilization data can also be used to predict poor outcomes. A systematic review of the literature published between 1960 and 2004 on the risk factors associated with near fatal and fatal asthma in children and adults found several characteristics that predict a poor outcome. Increased use of medications such as beta-agonists via metered dose inhalers (OR = 1.67, 95% CI 0.99–2.84, P = 0.057), nebulizers (OR = 2.45, 95% CI 1.52–3.93, P = 0.0002), and oral steroids (OR = 2.71, 95% CI 1.34–5.51, P = 0.006) were predictors of fatal or near fatal asthma. A history of a hospital admission (OR = 2.62, 95% CI 1.04–6.58, P = 0.04) and/or intensive care unit admission (OR = 5.14, 95% CI 1.91–13.86, P = 0.001), and mechanical ventilation due to asthma (OR = 6.69, 95% CI 2.80–15.97, P = 0.0001) were also predictors of near fatal and fatal asthma [33].

570

M.E. Partridge and W.K. Dolen

Monitoring the asthma medication use alone can serve as a marker for asthma exacerbations. A review of Medicaid claims data by over 31,000 adults over a 2-year period observed a significant positive association between emergency room visits or hospital admissions for asthma and filling a prescription for a short acting beta-agonist in the immediate period following the visit [34].

Assessment of Asthma Control Using Objective Measures Monitoring the Peak Expiratory Flow Rate Monitoring the PEFR is a routinely used tool to assess airflow obstruction, since the various available devices are portable, inexpensive, and fairly easy to use (Table 3). There are, however, limitations to its use. The PEFR reflects the obstruction of the larger airways. PEFR monitoring is not reliable in children 3–5 years of age [35] and is not reproducible even when used in healthy children [36]. Nevertheless, past asthma guidelines have encouraged the use of PEFR in asthma home monitoring, and PEFR monitoring can result in fewer asthma exacerbations when used in combination with asthma education [36]. Children aged 7–14 years who were randomized to management based on monitoring either PEFR alone or PEFR plus symptom assessments had no differences in mean symptom score, lung function, PEF, and quality of life scores. During acute exacerbations, PEFR monitoring did not influence self-management decisions [37]. In some studies, PEFR monitoring is no more useful than monitoring asthma symptoms alone and is satisfactory as long as the results are applied to the individual’s asthma status at baseline [38,39]. Although the PEFR may function best as a temporary monitoring device in the setting of an acute asthma exacerbation, it provides only a rough estimate of lung function. When used alone, it may not contribute significantly to asthma management and is not useful in the majority of childhood asthmatics [36,40]. However, it may be useful in children who are poor perceivers to help identify triggers of their asthma [36] and provide a rough early warning of an asthma exacerbation. Use of a PEFR diary as an objective measure of lung function has been a recommendation by the asthma guidelines. Unfortunately, actual compliance with keeping an asthma diary has been estimated at approximately 20%, compared with patient reported compliance of 95%. Diaries can be inaccurate, falsified, and inconsistent [37].

Table 3 Selected objective measures of asthma control Home monitoring of peak expiratory flow rate and/or FEV1 Forced expiratory spirometry Impulse oscillometry Sputum eosinophil counts Measurement of eNO

Best Estimates of Asthma Control in Children

571

Forced Expiratory Spirometry Other measures of pulmonary function (Table 3), specifically the FEV1, provide objective and more reliable data to the provider regarding the current degree of airway obstruction. It is easy to perform, reproducible, and is considered the gold standard of lung function tests in asthma. There are relatively inexpensive hand-held devices that will measure the FEV1. The FEV1 may indicate the risk of a future exacerbation [41], may be used to predict progressive decline in lung function over time [42], and may predict persistence of obstructive disease later in life [43]. In children and adults, the absolute value of the FEV1 should be followed over time, since the prediction equations have an unavoidable amount of statistical noise and are substantially affected by errors in entering age or height. The predicted FEV1 values used in the NHLBI guidelines may not be sensitive enough to accurately classify pediatric asthma patients as mild intermittent or persistent, moderate persistent, and severe persistent categories. A study performed at National Jewish Medical and Research Center found that FEV1 values are lower than predicted throughout childhood and that most children with asthma have FEV1 values within the normal range for their age. The mean FEV1 value in this population of children, including severe asthmatics, evaluated at a tertiary care center was 84% of predicted, well within what is considered the normal range. Therefore, when used alone, FEV1 is not a reliable measure of obstructive lung disease in children [44]. Another method for assessing the lung function, impulse oscillometry, does not require active patient participation. It can measure airflow resistance even in children who are unable to cooperate with the conventional lung function testing. It is reproducible in children 3–6 years of age, and the lung function measures obtained correlate well with values obtained from spirometry [45]. It is not a widely available technique and is therefore not routinely used in the clinical setting.

Sputum Eosinophil Counts At this time, the counting of sputum eosinophils is primarily a research tool used in adults. Since there is correlation between the cellular components obtained in adult sputum analysis and those obtained in children, it is another potentially useful measure of asthma control in children [46]. Its use is limited to children older than 6 years of age, primarily due to the technical difficulties in cooperating with the maneuver and to low tidal volumes [47]. However, children with asthma, either well controlled or poorly controlled, have a significantly higher number of sputum eosinophils than children without asthma [48]. There is some correlation between sputum eosinophilia, defined as >2.5% eosinophils on sputum analysis [48], and an increase in the frequency of asthma exacerbations [49]. Reducing sputum eosinophils into the normal range with use of inhaled steroids can decrease the number of asthma exacerbations [50]. Sputum eosinophilia may also predict the need for future asthma treatment. The CAMP study established that children with higher sputum eosinophil counts had more steroid bursts than children with lower counts [51].

572

M.E. Partridge and W.K. Dolen

Difficulties associated with the performance of sputum analysis include the following: it is a time consuming procedure; there are time constraints since sample analysis must done with 2 h of collection; and there are few clinical laboratories that can perform sample analysis [52]. Until these limitations can be addressed, this will remain a research tool.

Measurement of Exhaled Nitric Oxide The level of exhaled nitric oxide (eNO) can be a useful marker of airway eosinophilia that, in contrast with analysis of induced sputum, is easier to perform. It is a potentially practical measure of airway inflammation in children, though its use is currently limited by equipment costs and questions about standardization and reproducibility. Currently, eNO has been primarily used in the diagnosis of asthma, being most valuable in differentiating asthma, in which eNO is elevated, from other conditions such as chronic obstructive pulmonary disease or gastroesophageal reflux disease, in which eNO is low. Measurement of eNO has been used to assess asthma control and to predict the clinical response to changes in the dosage of inhaled corticosteroids [53,54]. As a marker of asthma severity as outlined by the NHLBI guidelines [55], eNO levels increase with the loss of asthma control [56] and decrease in a linear manner with adequate treatment [57]. The precise role for eNO measurement in routine asthma follow-up is still being determined.

Is Asthma Control Possible? Asthma control is achievable in the majority of patients, despite the degree of asthma severity. Bateman and Bousquet analyzed eight randomized, double-blind parallel studies of nearly 2,800 patients with poorly controlled asthma on their current therapy and of all asthma severity classifications. Asthma control, as defined by the asthma guidelines, was assessed after treatment with fluticasone, salmeterol, or combination therapy. They found that the proportion of patients achieving asthma control for a given therapy was similar despite the asthma severity, suggesting that asthma control can be attained even in severe asthma [58]. The Gaining Optimal Asthma Control (GOAL) study was a randomized, stratified, double-blind, parallel-group study, of 3,421 patients who were treated with fluticasone propionate or salmeterol/fluticasone. Treatment decisions were made based on rigorous adherence to the asthma guidelines until total control or well controlled asthma was achieved. In patients treated with either salmeterol/fluticasone or fluticasone for 1 year, total control was achieved in 41 and 28%, respectively, while good control was achieved in 71 and 59%, respectively. Patients treated with salmeterol/fluticasone had fewer exacerbations in 1 year and had more significant improvements in the quality of life measures than those patients treated with fluticasone alone. The conclusion of this study was that a majority of patients

Best Estimates of Asthma Control in Children

573

with uncontrolled asthma can attain asthma control by the use of management strategies proposed in the asthma guidelines [59]. Although asthma control is possible in a majority of patients, variability in response to therapy is observed. This may be due to an array of factors that result in heterogeneity of the asthma phenotype [60]. These factors include, but are not limited to, presence of allergic sensitization, environmental triggers such as air pollution and viral infections, genetic polymorphisms that might affect response to therapy, and behavioral factors such as medication compliance [61,62]. As a result of the multiple factors involved, asthma control is variable not only between individual patients, but also within a single patient [19]. The complex nature of asthma requires the use of multiple approaches in the evaluation and management of these patients. Assessment of control should take multiple parameters into consideration since reliance on any single measure is likely to overestimate the level of control [58]. A more complete understanding of the genetic and environmental basis for this variability in asthma phenotypes might allow simpler approaches to maximizing therapy and assessing control.

Achieving Asthma Control The development of GINA and national guidelines has given physicians around the world access to specific expert opinions on best asthma management practices [10]. Despite the availability of these recommendations, the use of these guidelines in daily clinical practice has fallen short of the goals outlined in the guidelines. In a worldwide study published in 2006, asthma control in children was evaluated in relation to recommendations put forth by the GINA guidelines. Only a small percentage of children have a good control of their asthma. In addition, many patients are not being managed according to the recommendations of the guidelines. Internationally, there is wide variation in asthma management practices, such as use of written asthma action plans, performance of lung function testing, and use of inhaled steroids [6]. The Asthma Insights and Reality (AIR) survey was performed in 29 countries; it included 7,786 adults and 3,153 children [63]. In all of the countries studied, there was suboptimal control of asthma. Significant numbers of patients reported limitations in daily life, missed school and work days, continued asthma symptoms, and healthcare utilization.

Improving Asthma Control Another important finding from the AIR survey was that one of the reasons for suboptimal asthma control was that patients do not understand the basics of the disease or the management of their asthma [63]. This observation generated development of a global, quantitative survey, the Global Asthma Physician and Patient (GAPP) survey, to examine barriers to optimal asthma care. Results from interviews with

574

M.E. Partridge and W.K. Dolen

over 5,550 patients and physicians from over 16 countries found that perceptions about time spent on asthma education, the effectiveness of patient communication, and medications compliance issues differed between patients and physicians, highlighting a need for improvement in patient centered care [64]. Working toward asthma control in children should be a cooperative effort among the patient, parent, and physician. Education of patients, parents, and physicians is essential in attaining this goal. Patients and parents need to be able to recognize asthma symptoms and understand the treatments used in managing asthma at home. They also need to understand the importance of attaining optimal asthma control. Asthma education programs and events can be organized within communities to provide information on aspects of disease management and proper medication use [6]. Physicians need to address barriers to medication compliance, such as concerns about adverse effects of medications, in order maximize compliance. Early and aggressive treatment with anti-inflammatory medications should be initiated according to recommendations in published guidelines and should be reviewed regularly with patients [64]. Physicians should be aware that patient and parental perception of the level of asthma control can often be inaccurate, with overestimation of the level of control and underestimation of disease severity. Therefore, physicians may need to assess asthma control using several different measures (both subjective and objective) of control. Since physicians, parents, and patients can have inappropriately low expectations of the level of achievable asthma control, reexamination of asthma control goals with a more optimistic outlook may be needed [6]. Effective cooperation among the clinicians, parents, and patients provides the best chance for optimal asthma control and may reduce disease-related morbidity and mortality among children with asthma.

References 1. Rietveld S, Creer TL (2003) Psychiatric factors in asthma: implications for diagnosis and therapy. Am J Respir Med 2(1):1–10 2. Bloom, B. and A.N. Dey, Summary health statistics for U.S. children: National Health Interview Survey, 2004. Vital Health Stat 10, 2006. (227): p. 1–85 3. Vollmer, W.M., Assessment of asthma control and severity. Ann Allergy Asthma Immunol, 2004. 93(5): p. 409–13; quiz 414–6, 492 4. Cockcroft DW, Swystun VA (1996) Asthma control versus asthma severity. J Allergy Clin Immunol 98(6 Pt 1):1016–8 5. Humbert M et al (2007) Asthma control or severity: that is the question. Allergy 62(2):95–101 6. Gustafsson PM et al (2006) Poor asthma control in children: evidence from epidemiological surveys and implications for clinical practice. Int J Clin Pract 60(3):321–34 7. Li J et al (2005) Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol 116(5): p. S3–11 8. Schatz M et al (2006) Determinants of future long-term asthma control. J Allergy Clin Immunol 118(5):1048–53 9. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. National Asthma Education Program. Expert Panel Report. J Allergy Clin Immunol, 1991. 88(3 Pt 2): p. 425–534

Best Estimates of Asthma Control in Children

575

10. Von Mutius, E., Presentation of new GINA guidelines for paediatrics. The Global Initiative on Asthma. Clin Exp Allergy, 2000. 30 (Suppl 1): p. 6–10 11. Bousquet J et al (2007) GINA guidelines on asthma and beyond. Allergy 62(2):102–12 12. Covar RA et al (2004) Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med 170(3):234–41 13. Sears MR et al (2003) A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 349(15):1414–22 14. Morgan WJ et al (2005) Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 172(10):1253–8 15. Kikuchi Y et al (1994) Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 330(19):1329–34 16. Kendrick AH et al (1993) Accuracy of perception of severity of asthma: patients treated in general practice. BMJ 307(6901):422–4 17. Baker RR et al (2000) Poor perception of airway obstruction in children with asthma. J Asthma 37(7):613–24 18. Shingo S, Zhang J, Reiss TF (2001) Correlation of airway obstruction and patient-reported endpoints in clinical studies. Eur Respir J 17(2):220–4 19. Luskin AT (2005) What the asthma end points we know and love do and do not tell us. J Allergy Clin Immunol 115(4 Suppl):S539–45 20. Schatz M et al (2005) Relationships among quality of life, severity, and control measures in asthma: an evaluation using factor analysis. J Allergy Clin Immunol 115(5):1049–55 21. Newacheck PW, Halfon N (2000) Prevalence, impact, and trends in childhood disability due to asthma. Arch Pediatr Adolesc Med 154(3):287–93 22. Cohen P et al (1998) Prospective associations between somatic illness and mental illness from childhood to adulthood. Am J Epidemiol 147(3):232–9 23. DiMatteo MR, Lepper HS, Croghan TW (2000) Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med 160(14):2101–7 24. Kullowatz A et al (2007) Association of depression and anxiety with health care use and quality of life in asthma patients. Respir Med 101(3):638–44 25. Gandhi RK, Blaiss MS (2006) What are the best estimates of pediatric asthma control? Curr Opin Allergy Clin Immunol 6(2):106–12 26. Juniper EF et al (1992) Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 47(2):76–83 27. Juniper EF et al (1996) Measuring quality of life in children with asthma. Qual Life Res 5(1):35–46 28. Liu A et al (2007) Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 119(4):817–825 29. Gendo K, Lodewick MJ (2005) Asthma economics: focusing on therapies that improve costly outcomes. Curr Opin Pulm Med 11(1):43–50 30. Lozano P et al (1999) The economic burden of asthma in US children: estimates from the National Medical Expenditure Survey. J Allergy Clin Immunol 104(5):957–63 31. Malone DC, Lawson KA, Smith DH (2000) Asthma: an analysis of high-cost patients. Pharm Pract Manag Q 20(1):12–20 32. Stempel DA et al (2005) Patterns of asthma control: a 3-year analysis of patient claims. J Allergy Clin Immunol 115(5):935–9 33. Alvarez GG et al (2005) A systematic review of risk factors associated with near-fatal and fatal asthma. Can Respir J 12(5):265–70 34. Naureckas ET et al (2005) Short-acting beta-agonist prescription fills as a marker for asthma morbidity. Chest 128(2):602–8 35. Kanengiser S, Dozor AJ (1994) Forced expiratory maneuvers in children aged 3 to 5 years. Pediatr Pulmonol 18(3):144–9 36. Kamps AW, Brand PL (2001) Education, self-management and home peak flow monitoring in childhood asthma. Paediatr Respir Rev 2(2):165–9 37. Kamps AW, Roorda RJ, Brand PL (2001) Peak flow diaries in childhood asthma are unreliable. Thorax 56(3):180–2

576

M.E. Partridge and W.K. Dolen

38. Gibson PG (2000) Monitoring the patient with asthma: an evidence-based approach. J Allergy Clin Immunol 106(1 Pt 1):17–26 39. Kotses H, Harver A, Humphries CT (2006) Home monitoring in asthma self-management. J Asthma 43(9):649–55 40. Brand PL, Roorda RJ (2003) Usefulness of monitoring lung function in asthma. Arch Dis Child 88(11):1021–5 41. Fuhlbrigge AL et al (2001) FEV(1) is associated with risk of asthma attacks in a pediatric population. J Allergy Clin Immunol 107(1):61–7 42. Liu AH (2005) Biomarkers and childhood asthma: improving control today and tomorrow. Allergy Asthma Proc 26(4):249–54 43. Horak E et al (2003) Longitudinal study of childhood wheezy bronchitis and asthma: outcome at age 42. BMJ 326(7386):422–3 44. Paull K et al (2005) Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999–2002. Pediatr Pulmonol 39(4):311–7 45. Olaguibel JM et al (2005) Comparative analysis of the bronchodilator response measured by impulse oscillometry (IOS), spirometry and body plethysmography in asthmatic children. J Investig Allergol Clin Immunol 15(2):102–6 46. Papadopouli E et al (2006) Comparison of induced sputum inflammatory profiles between childhood and adult-onset asthma. Respir Med 100(8):1442–50 47. Riedler J, Robertson CF (1994) Effect of tidal volume on the output and particle size distribution of hypertonic saline from an ultrasonic nebulizer. Eur Respir J 7(5):998–1002 48. Cai Y et al (1998) Persistence of sputum eosinophilia in children with controlled asthma when compared with healthy children. Eur Respir J 11(4):848–53 49. Gibson PG et al (2003) Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma. Thorax 58(2):116–21 50. Green RH et al (2002) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360(9347):1715–21 51. Covar RA et al (2004) Safety and application of induced sputum analysis in childhood asthma. J Allergy Clin Immunol 114(3):575–82 52. Li AM et al (2005) Induced sputum in childhood asthma. Hong Kong Med J 11(4):289–94 53. Taylor DR (2006) Nitric oxide as a clinical guide for asthma management. J Allergy Clin Immunol 117(2):259–62 54. Smith AD et al (2005) Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 352(21):2163–73 55. Delgado-Corcoran C et al (2004) Exhaled nitric oxide reflects asthma severity and asthma control. Pediatr Crit Care Med 5(1):48–52 56. Jones SL et al (2001) The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 164(5):738–43 57. Jones SL et al (2002) Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship. Eur Respir J 20(3):601–8 58. Bateman ED, Bousquet J, Braunstein GL (2001) Is overall asthma control being achieved? A hypothesis-generating study. Eur Respir J 17(4):589–95 59. Bateman, E.D., et al., Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study [see comment]. Am J Respir Crit Care Med, 2004. 170(8): p. 836–44 60. Lemanske RF Jr (2002) Genetics and the variability of treatment response in asthma. J Allergy Clin Immunol 109(6 Suppl):S521–4 61. Israel E (2005) Genetics and the variability of treatment response in asthma. J Allergy Clin Immunol 115(4 Suppl):S532–8 62. Murphy KR (2005) Asthma: versatile treatment for a variable disease. J Asthma 42(3):149–57 63. Rabe KF et al (2004) Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol 114(1):40–7 64. Canonica GW et al (2007) Unmet needs in asthma: Global Asthma Physician and Patient (GAPP) Survey: global adult findings. Allergy 62(6):668–74

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids Hugo P. Van Bever, Lynette P. Shek, and Daniel Y.T. Goh

Inhaled corticosteroids (ICS) are now considered the most effective asthma therapy, and are first-line therapy for control of asthma in both children and adults [1–4]. In the past, ICS were mainly used in children with severe persistent asthma. Nowadays, they are also recommended for the treatment of mild to moderate persistent asthma, and in most countries, ICS have become first-line treatment, even for very young children [5]. However, ICS still fail to enjoy a favorable reputation in terms of safety and tolerability [6]. Many patients (and parents) have a “steroid phobia” that is based on the local and systemic adverse events from high-dose ICS or oral corticosteroids, leading to poor compliance [7–9]. A number of ICS have been developed and made available to treat asthma over the last 30 years. They include beclomethasone dipropionate (BDP), budesonide (BUD), fluticasone propionate (FP), triamcinolone acetonide (TA), flunisolide (FLUN), mometasone furoate (MF), and ciclesonide (CIC) [10]. Each has unique physiochemical properties that confer distinct pharmacologic characteristics regarding potency, efficacy, safety, tolerability, lung deposition, receptor binding, lipophilicity, and esterification (Table 1). In children, the best studied ICS to date are BPD and BUD [11]. Therefore, many of the data and references mentioned in this chapter will be from studies on BPD and BUD. The newest ICS is ciclesonide (CIC), of which many studies in asthmatic children were published [12] recently. A recent study by Pedersen et al. concluded that ciclesonide’s safety and efficacy profile in asthmatic children is similar to that of fluticasone propionate [13]. H.P. Van Bever () Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; Department of Paediatrics, National University Hospital, 5 Lower Kent Ridge Road, 119074 Singapore e-mail: [email protected] L.P. Shek Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore D.Y.T. Goh Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, University Children’s Medical Institute, National University Hospital, Singapore

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_35, © Springer 2010

577

578

H.P. Van Bever et al.

Table 1 Comparison of the pharmacokinetic and pharmacodynamic features of a number of ICS Parameters BPD BUD FP CIC MF Oral bioavailability <1% 11% <1% <1% < 1% Pulmonary deposition 51% 28% 16% 52% 14% On-site activation somewhat no no yes no Receptor binding affinity 53 935 1,800 12 1,235 Esterification no yes no yes no Lipophilicity moderate low high very high Protein binding: free fraction (%) 87; 13 88; 12 90; 10 99; 1 99; 1 *T ½ h 0.5 2.8 7.8 0.36 4.5 *Vd, L 20 183 318 207 Clearance, L/h 15 84 69 152 53.5 *T1/2 h = half-life / Vd = volume of distribution Modified from Cerasoli F. Developing the ideal inhaled corticosteroid. Chest, 2003, 130:54S–64S

Characteristics of Inhaled Corticosteroids Effects of Inhaled Corticosteroids Glucocorticoids are lipophilic molecules, exerting effects on many different cell types, and whose underlying mechanisms of action have been well described (Table 2) [14,15].

Similarities and Differences in Inhaled Corticosteroids The potency of ICS varies widely. Relative topical potencies of ICS are as follows: FP – CIC > BUD > BPD > TA. Agents demonstrating an improved pharmacokinetic Table 2 Effect of glucocorticoids on transcription of genes* Increased transcription – Lipocortin-1 – b2-adrenoceptor – Endonucleases – Secretory leukocyte inhibitory protein Decreased transcription – Cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-11, IL-12, IL-13, TNF-alfa, GM-CSF, RANTES, monocyte inhibiting protein-1-alfa) – Inducible nitric oxide synthetase (iNOS) – Inducible cyclo-oxygenase (COX-2) – Inducible phospholipase A2 (cPLA2) – Endothelin-1 – NK2 receptors – Adhesion molecules (ICAM-1) *Adapted from: Barnes PJ (1997) Glucocorticoids. In: Kay AB, editor. Allergy and allergic diseases. Blackwell Science Ltd, London, pp. 619–641

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

579

profile (i.e. high clearance rate, high volume of distribution, and a high level of protein binding, together with a short elimination half-life and a long terminal halflife) have the potential to offer an improved therapeutic index as a result of increased receptor affinity, slower absorption from the lung following inhalation, and rapid systemic clearance [11]. The amount of systemic absorption depends not only on the actual dose administered, but also on the mode of delivery [1,16,17]. In a study by Agertoft and Pedersen, lung deposition between BUD inhaled from a Turbuhaler and FP inhaled from a Diskus (GlaxoSmithKline, London, UK) was compared in asthmatic children [18]. The mean lung deposition of BUD from a Turbuhaler was 30.8%, and of FP from a Diskus was 8%. This study indicates that to make rational comparisons between various ICS preparations possible, knowledge of interaction of drug preparation and delivery device in determining oral versus lung deposition is essential. Metered-dose inhalers containing hydrofluoroalkane (HFA) propellants are now replacing inhalers containing chlorofluorocarbon (CFC) propellants [19]. A glucocorticoid administered by means of an HFA propellant will have enhanced deposition in the peripheral airways and will have a different benefit/risk ratio than the same glucocorticoid administered in the same dose by means of a chlorofluorocarbon propellant. BDP through a HFA-MDI produces a clinically equivalent therapeutic response at half the dose of BDP through CFC-MDI, but with similar or less systemic activity, measured by studies of the HPA axis [20]. Although various ICS are believed to have similar clinical efficacy when used at equivalent therapeutic doses, differences in pharmacokinetics affect their safety profiles. The percentage of drug that is systemically available after oral administration has been estimated to be less than 1% for FP, 10.6% for TA, 11% for BUD, and 41% for BPD. Studies in asthmatic children in which the efficacy of the five currently available ICS has been compared directly on a microgram per microgram basis are not available [10,21]. However, by extrapolating from published studies, it appears that ICS have similar clinical efficacy despite their distinct pharmacologic and pharmacokinetic profiles (Table 3). In contrast, they may differ with regard to their benefit/risk ratios.

Table 3 Clinical pharmacology of a number of ICS

BDP BUD FP TA FLUN

Oral bioavailability 15 11 <1 23 20

Inhalation bioavailability 25 28 16 22 39

Plasma elimination half-life after inhalation (h) 0.1 6.5* 2.3–2.8 3.7–14.4 1.5–3.6 1.6

Percent of glucocorticoid active after first-pass metabolism ? 6–13 <1 22 21

Topical: systemic Binding potency affinity** ratio 0.4 0.1 9.4 1.00 18 25.00 3.6 0.05 1.8 0.05

From: Simons FER (1998) Benefits and risks of inhaled glucocorticoids in children with persistent asthma. J Allergy Clin Immunol 102:S77–84 *Beclomethasone dipropionate (0.1) is hydrolyzed to beclomethasone monopropionate (6.5) in vivo **Binding affinities are relative to dexamethasone

580

H.P. Van Bever et al.

Benefits of Inhaled Corticosteroids in Children Overview of Efficacy of Inhaled Corticosteroids A large number of studies have been performed in asthmatic children, showing that ICS have an important role in the maintenance treatment of childhood asthma [1,2,22]. In short, ICS are able to inhibit asthmatic symptoms, to reduce the need for reliever treatment, to improve the lung function (short-term), and to decrease bronchial hyperresponsiveness [23]. The onset of effect of ICS is not immediately. Symptoms usually begin to improve within days, but obtaining optimal control of symptoms can take weeks. Improvement in pulmonary function takes even longer, and airway hyperresponsiveness continues to improve even after months or years of regular treatment [24,25]. However, both in preschoolers and in older children, effectiveness starts disappearing within weeks of discontinuing ICS [26,27]. Moreover, it was shown that continuous use of ICS has no effect on the course of an acute severe asthma attack [28]. ICS have also been successfully used in the treatment of acute asthma [29,30]. Data suggest that ICS have early beneficial effects (within 1–2 h) when they are used in multiple doses administered in time intervals < or = 30 min [31]. The efficacy is better with high doses given repeatedly during the initial phase of the exacerbation [32]. In comparison with oral prednisone, however, FP was found to be less effective in children with severe acute asthma [33]. Furthermore, it was shown that FEV1 in children with mild to moderate asthma, in the emergency department, improves faster on oral (prednisolone 2 mg/kg) than on a high dose of ICS (2 mg of FP) [34]. Similar findings were reported on FLUN, which happened to be less effective in acute asthma than prednisone [35].

Early Intervention with Inhaled Corticosteroids Based on theoretical grounds, it can be assumed that treatment with ICS may be more effective if started early during the course of childhood asthma, in an attempt to stop the inflammatory process, rather than after symptoms have been present for several years. In an open, but controlled study by Agertoft and Pedersen, a significant relationship between the duration of asthma at the start of BUD and the annual increase in FEV1 during BUD therapy was found. After 3 years of treatment with BUD, children who started this therapy later than 5 years after the onset of asthma had significantly lower FEV1 than the children who received BUD within the first 2 years after the onset of asthma [36]. In the START study is demonstrated that longterm, once-daily treatment with a low-dose of BUD decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset [37]. However, the START study was unable to show that early administration of ICS has major benefits as compared to administration during later

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

581

phases of asthma. Furthermore, many young children will outgrow their asthmatic symptoms spontaneously, and do not need ICS [38–40].

Failure to Respond to Inhaled Corticosteroids Persistent asthmatic symptoms in children usually respond extremely well to ICS treatment. If symptoms persist, despite ICS treatment, the following issues should be considered: (1) poor compliance to treatment, (2) poor inhalation technique, (3) family dysfunction and psychosocial problems, including inability to afford the medication, and (4) physician error (diagnosis is not asthma, but vocal cord dysfunction or hyperventilation syndrome, or there are untreated co-morbidities, such as chronic sinusitis or gastro-esophageal reflux) [41,42]. Rarely, persistent inflammation (i.e. undertreatment of extremely severe asthma), abnormal glucocorticoid pharmacokinetics, or true glucocorticoid resistance is responsible for the child’s persistent symptoms [43].

Risks of Inhaled Corticosteroids in Children Potential adverse effects of ICS have been reported and are listed in Table 4.

Effect of ICS on Linear Growth and Bone Metabolism For many years, systemic corticosteroids have been known to be potent inhibitors of linear growth, exerting their suppressive effects at virtually every level of a child’s growth axis [44]. Consequently, it was appropriate to carefully examine potential effects of ICS on childhood growth. However, it is important to emphasize that height measurements must be interpreted carefully because persistent severe

Table 4 Potential adverse effects of ICS in children – – – – – – – – –

Growth delay HPA axis dysfunction Bone turnover (breakdown, formation, density) Connective tissue effects: skin thinning, easy bruising Posterior subcapsular cataracts Metabolic changes (impaired insulin tolerance, increases glucose, hyperlipidemia) Disseminated or opportunistic infection (e.g., varicella) Behavioral/psychiatric effects Local effects: irritation (cough), oropharyngeal candidiasis, dysphonia

582

H.P. Van Bever et al.

asthma on itself may result in delayed onset of puberty and preadolescent deceleration of height velocity [45,46]. Mild-to-moderate asthma on itself of duration of 4–7 years seems not adversely affect linear growth. Significant growth suppression occurs only when asthma is persistent and of at least moderate severity [47]. Linear growth can be described as short-term (weeks to months), intermediate term (6–12 months), and long-term (final adult height) [46]. A delay in short-term growth has been reported during treatment with ICS, by using kenmometry studies of lower-leg length growth [10,46,48]. Knemometry measurements must be interpreted with caution, however, because their predictive value with regard to long-term growth is unknown. There are still conflicting data as to whether some children with mild to moderate asthma have delayed intermediate-term growth during treatment with ICS. A number of studies, including several with a randomized, double-blind, placebocontrolled design, have suggested that some delay may occur with BPD doses as low as 400 µg/day, and that this effect occurs within the first 6–12 weeks of treatment [25,49–58]. There are fewer intermediate-term growth studies of other ICS, although it seems that BUD and FP (200 µg/day) can exhibit potentially the same effects as BPD [54,55,57,59–61]. Most of the studies on the effects of ICS on growth have been performed in prepubertal, late school-aged children, and only a limited number of studies have been performed in young children [62]. A large prospective, randomized trial in asthmatic children aged 1–3 years (n = 625) compared 1-year safety and efficacy of FP (100 mg twice daily) to that of sodium cromoglycate, and added important knowledge in this area [63]. There was no significant difference in mean adjusted growth rates between the two groups. Delayed intermediate-term growth seems to be not associated with decreased growth hormone secretion or impaired HPA axis function [57,58]. Decreased concentrations of osteocalcin have been found, but correlations with linear growth delay were imperfect [58]. In contrast, the outcome of a meta-analysis, analyzing 21 studies, of the effects of ICS on intermediate-term growth showed that BPD did not have any effect, even at high doses for long therapy durations, or in children with severe asthma [64]. Early studies of BPD given for decades to children with moderate or severe asthma were also reassuring, as were more recent studies with BUD in which slight delay in linear growth was either found, or if found, was attributed to prepubertal growth deceleration rather than to ICS [36,65–68]. There are no prospective, randomized, rigorously controlled, double-blind studies on the effect of ICS on long-term linear growth. In one retrospective cohort study, it was suggested that the attainted adult height of asthmatic children treated with ICS is not significantly different from the adult height of those not treated with these medications [69]. A number of other studies came to similar conclusions [66,70–72]. ICS appear to have little effect on bone architecture or bone turnover [73–75]. Cross-sectional studies of children treated with ICS have reported normal bone mass or bone mineral density (BMD) and normal blood markers of bone

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

583

metabolism [75,76]. One cross-sectional study of 1,041 asthmatic children, 5–12 years old, examined whether mild-moderate asthma on itself sufficient to produce a decrease in baseline lung function is associated with an adverse effect on BMD, as determined by dual-energy x-ray absorptiometry (DEXA). In this group, the mean BMD was 0.65 ± 0.10 SD g/cm2 for the population. The use of oral corticosteroids within the previous 6 months did not adversely affect BMD. The authors concluded that mild-moderate asthma of duration as long as 4–7 years in children does not adversely affect BMD [77]. In another study, on 174 asthmatic children, treated with FP 200 mg/d or nedocromil sodium for 24 months, no differences were found in BMD, determined by DEXA measurements of the lumbar spine and femoral neck [78]. Finally, a large population-based cohort of children aged 4–17 years in the United Kingdom on incidence rates of fractures among children taking ICS, compared to a group only on bronchodilators and a reference group, could not find any increased risk for fractures in children taking ICS, after adjusting the results for indicators of asthma severity [79].

Effect of ICS on the HPA Axis During treatment with recommended doses of ICS, the risk of adrenal insufficiency is very low, as most routine tests of HPA axis function are normal [80,81]. However, more sensitive tests, such as serial early morning cortisol measurements, the area under the curve of 24-hour serum cortisol measurement, or 24-hour urine free cortisol measurements, might show evidence of HPA axis suppression [82,83]. A recent series of case reports from the United Kingdom of adrenal insufficiency showed the potential side effects of high doses of ICS [84].

Other Potential Adverse Effects of ICS Other systemic adverse effects of ICS treatment in recommended doses are extremely uncommon. Posterior subcapsular cataract was not detected in children with a median age of 13.8 years inhaling a median dose of BPD or BUD of 750 µg/ day (12.9 µg/kg/day) for a median duration of 5 years, with infrequent supplemental oral glucocorticoids [85]. Side effects, such as skin rash and conjunctivitis, occurred at low frequencies, similar to placebo or comparator drugs [86]. Rarely, reports of behavioral disturbances and other adverse central nervous system have been published [87]. Furthermore, disseminated infections, such as disseminated varicella, are extremely rare in children taking ICS, and the association between the two has never been proven [88]. An altered carbohydrate and lipid metabolism have been

584

H.P. Van Bever et al.

reported after high doses of ICS [89]. Rare cases of hypertrichosis have been reported that were associated with usage of ICS [90].

Maximizing the Benefits and Minimizing the Risks It is very important to maximize the benefits and minimize the risks of ICS in children with persistent asthma. The following guidelines may be helpful: (1) recommend the lowest dose that will achieve asthma control, (2) monitor height velocity and pulmonary function on a regular basis, and (3) for BDP and other ICS with little inactivation by first-pass metabolism, reduce oropharyngeal deposition and systemic absorption by encouraging children to rinse and expectorate after inhalation, and add a spacer device. According to the Global Initiative on Asthma (GINA), each individual asthmatic child should be assessed to establish his or her current treatment regimen, adherence to the current regimen, and level of asthma control [91].

Inhaled Corticosteroids in Infants Wheezing is a common symptom of infancy, affecting 25–30% of them [92,93]. However, not all wheezy infants have asthma, and most of them will outgrow their symptoms. On the other hand, it has been shown that chronic asthma can start during infancy [39]. Therefore, infantile wheezing has to be considered as a heterogeneous disease, in which, among others, two major types of wheezing can be distinguished: viral-induced wheezing and wheezing that is associated with allergy. [94]. The treatment of wheezing infants is largely ignored in the different asthma guidelines, such as The Global Initiative for Asthma (GINA), and there are no international guidelines for the management of acute bronchiolitis [95]. The general trend nowadays, however, is to prescribe ICS to young wheezy children, although the majority do not need that kind of treatment. Randomized, controlled studies on the long term effect of inhaled corticosteroids in those wheezy infants with an unfavorable prognosis are urgently needed. In a number of studies, the effectiveness of ICS in young asthmatic children was shown, although not all studies showed clinical beneficial effects [96–98]. Moreover, recent studies were unable to demonstrate significant long-term effects of ICS in young asthmatic children [27,99,100]. These findings are very similar to the findings in older asthmatic children, showing that once ICS are stopped, asthma symptoms do re-occur [26]. Moreover, in a recent study on the effect of FP, 200 µg/day, in preschool children with recurrent respiratory symptoms (i.e. cough, shortness of breath, wheeze) in a general practice setting, no effect was found during a 6 month treatment period [101]. ICS were also unable

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

585

to prevent post-bronchiolitic wheezing when given during the acute phase of bronchiolitis [102].

Combining Inhaled Corticosteroids with Long-Acting Beta-Agonists in Children For patients whose asthma is not controlled on ICS monotherapy, current recommendations advocate the addition of add-on therapy. For many clinicians, the preferred add-on is a long-acting b-agonist (LABA) such as formoterol or salmeterol. In the Pediatric Asthma Controller Trial (PACT), fluticasone monotherapy was superior to fluticasone/salmeterol combination therapy for asthma control in patients with mild to moderate persistent asthma [103]. In another study of 177 children aged 6–16 years, the authors found no additional benefit of adding salmeterol to a daily dose of 400 mg beclomethasone in a group of children with moderate persistent asthma who were compliant with medication [104]. However, another study of 630 children aged 4–11 years showed improved lung function in those treated with combination of budesonide and formoterol (whether in the same or separate inhaler) compared with ICS alone [105]. Overall, analysis of randomized control trials of LABAs in children showed little to no added protection from asthma exacerbations in patients treated with LABAs compared with ICS alone [106,107]. The use of LABAs has been brought to the spotlight recently because of the health advisory by the US Food and Drug Administration in 2005 (http://www.fda.gov/cder/ drug/advisory/LABA). The FDA mandated that all products containing LABAs are required to carry the warning that these medicines may increase the chance of severe asthma episodes, and death when these episodes occur. This advisory came about because of data from the Salmeterol Multicenter Asthma Research Trial (SMART), which showed that asthma-related death in adults was 4.4 times more likely in the salmeterol group compared to the placebo group [108]. With the current level of knowledge regarding LABAs, appropriate use of ICS first is recommended, which should be adequate in most patients with mild to moderate asthma [109].

Conclusion: Treatment with ICS in Asthmatic Children: Risk or Benefit? Except for a slight delay in short-term and intermediate-term growth, ICS are able to inhibit asthmatic symptoms, and to reduce the need for reliever treatment, without causing important systemic adverse effects when administered in recommended doses (Table 5). The only limitation found was that ICS seem to have no major positive effect on lung function parameters in asthmatic children. However, ICS are much less likely to cause adverse effects than are oral glucocorticoids, the only

586

H.P. Van Bever et al.

Table 5 Major messages on the usage of ICS in childhood asthma ICS in childhood asthma are... 1. Safe/effective/ not too expensive, and are therefore 1st choice treatment to prevent asthma symptoms 2. Free of major side effects when given in appropriate doses 3. The best medication to prevent symptoms of asthma, but have no major effect on existing symptoms 4. Not necessary in most infants with wheezing, as most of them will grow out of their wheezing and don’t need ICS 5. Preferred to be prescribed without a LABA, which should be avoided, especially in young children

other medications that prevent and control asthma symptoms to the same extent [47]. However, no ICS is absolutely free from adverse effects, especially when the manufacturer’s recommended doses are exceeded [110]. Treatment with ICS has allowed most children with persistent asthma, even those with severe disease, to be free of symptoms and to have a normal lung function. The considerable long-term benefits of ICS are worth the relatively minor risks, but the risks must be minimized as much as possible.

References 1. Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ (2003) Inhaled corticosteroids: past lessons and future issues. J Allergy Clin Immunol 112 (3 Suppl):S1-S40 2. Pedersen S (2006) Clinical safety of inhaled corticosteroids for asthma in children: an update of long-term trials. Drug Saf 29:599–612 3. Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, PlattR (1997) Inhaled steroids and the risk of hospitalization for asthma. JAMA 277:887–891 4. Tattersfield AE, Knox AJ, Britton JR, et al. (2002) Asthma. Lancet 360:1313–1322 5. White AJ, Richards DH (1997) Inhaled corticosteroid prescribing in very young children. J Allergy Clin Immunol 99:S325. 6. Irwin RS, Richardson ND (2006) Side effects with inhaled corticosteroids: the physician’s perception. Chest 130:S41-S53 7. Jones C, Santanello NC, Boccuzzi SJ, et al. (2003) Adherence to prescribed treatment for asthma: evidence from pharmacy benefits data. J Asthma 40:93–101 8. Connett GJ, Lee BW (1994) Treating childhood asthma in Singapore: when West meets East. BMJ 308:1282–1284 9. Chew FT, Goh DYT, Lee BW (1999) Under-recognition of childhood asthma in Singapore: evidence from a questionnaire survey. Ann Trop Paediatr 19:83–91 10. Kamada AK, Szefler SJ, Martin RJ, Boushey HA, Chinchilli VM, Drazen JM, et al. (1996) Issues in the use of inhaled glucocorticoids. Am J Respir Crit Care Med 153:1739–1748 11. Cerasoli F (2006) Developing the ideal inhaled corticosteroid. Chest 130:54 S-64 S 12. Colice GL (2006) The newly developed inhaled corticosteroid ciclesonide for the treatment of asthma. Expert Opin Pharmacother 15:2107–2117 13. Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R (2006) A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatr Pulmonol 41:954–961

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

587

14. Barnes PJ (1997) Glucocorticoids. In: Kay AB, editor. Allergy and allergic diseases. Blackwell Science, London, pp. 619–641 15. Schleimer RP, Beck L, Schwiebert L, Stellato C, Bochner BS (1997) Inhibition of inflammatory cell recruitment by glucocorticods: cytokines as primary targets. In: Schleimer RP, Busse WW, O’Byrne P, editors. Topical glucocorticoids in asthma: mechanisms and clinical actions. Marcel Dekker, New York, pp. 203–238 16. Bisgaard H (1998) Automatic actuation of a dry powder inhaler into a non-electrostatic spacer. Am J Respir Crit Care Med 157:518–521 17. Pedersen S (1995) Drug delivery. Am J Respir Crit Care Med 151:S27-S42 18. Agertoft L, Pedersen S (2003) Lung deposition and systemic availability of fluticasone diskus and budesonide turbuhaler in children. Am J Respir Crit Care Med 168:779–782 19. Gross G, Chervinsky P, Ramsdell R, Vanden Burgt J (1997) Half the daily dose of new CFCfree formulation steroid achieves equivalent pulmonary function in moderate asthma. Am J Respir Crit Care Med 155:A666 20. Anderson PB, Langley SJ, Mooney P, et al. (2002) Equivalent efficacy and safety of a new HFA-134a formulation of BDP compared with the conventional CFC in adult asthmatics. J Investig Allergol Clin Immunol 12:107–113 21. Pedersen S, O’Byrne P (1997) A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 52 (suppl 39):1–34 22. Simons FER (1998) Benefits and risks of inhaled glucocorticoids in children with persistent asthma. J Allergy Clin Immunol 102:S77–84 23. Pedersen S, Hansen OR (1995) Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol 95:29–33 24. Van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF, et al. (1992) Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Rev Respir Dis 146:574–554 25. Verberne AAPH, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF, and the Dutch Paediatric Asthma Study Group (1997) One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 156:688–695 26. Waalkens HJ, Van Essen-Zandvliet EE, Hughes MD, Gerritsen J, Duiverman EJ, Knol K, et al. (1993) Cessation of long-term treatment with inhaled corticosteroids (budesonied) in children with asthma results in deterioration. Am Rev Respir Dis 148:1252–1257 27. Guilbert TW, Morgan WJ, Zeiger RS, et al. (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354:1985–97. 28. Caroll CL, Bhandari A, Schramm CM, Zucker AR (2006) Chronic inhaled corticosteroids do not affect the course of acute severe asthma exacerbations in children. Pediatr Pulmonol 41:1213–1217 29. Edmonds MH, Camargo CA Jr, Pollack CV Jr, Rowe BH (2003) Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev 3:CD002308 30. Smith M, Iqbal S, Elliott TM, Everard M, Rowe BH (2003) Corticosteroids for hospitalised children with acute asthma. Cochrane Database Syst Rev 2003:CD002886 31. Rodrigo GJ (2006) Rapid effects of inhaled corticosteroids in acute asthma: an evidencebased evaluation. Chest 130:1301–1311 32. Volovitz B (2007) Inhaled budesonide in the management of acute worsenings and exacerbations of asthma: a review of the evidence. Respir Med 101:685–695 33. Schuh S, Reisman J, Alshehri M, Dupuis A, Corey M, Arseneault R, Alothman G, Tennis O, Canny G (2000) A comparison of inhaled fluticasone and oral prednisone for children with severe acute asthma. N Engl J Med 343:689–694 34. Schuh S, Dick PT, Hartley M, Khaikin S, Rodrigues L, Coates AL (2006) High-dose inhaled fluticasone does not replace oral prednisolone in children with mild to moderate acute asthma. Pediatrics 118:644–650

588

H.P. Van Bever et al.

35. Nakanishi AK, Klasner AK, Rubin BK (2003) A randomized controlled trial of inhaled flunisolide in the management of acute asthma in children. Chest 124:790–794 36. Agertoft L, Pedersen S (1994) Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 88:373–381 37. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, Ullman A, Lamm CJ, O’Byrne PM, and the START Investigators Group (2003) Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 361:1071–1076 38. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ (1995) Asthma and wheezing in the first six years of life. N Engl J Med 332:133–138 39. Van Bever HP, Desager KN, Hagendorens M (2002) Critical evaluation of prognostic factors in childhood asthma. Pediatr Allergy Immunol 12:1–9 40. Illi S, von Mutius E, Lau S, Niggeman B, Gruber C, Wahn U, and the Multicentre Allergy Study (MAS) group (2003) Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet 368:763–770 41. Bender B, Milgrom H, Rand C (1997) Nonadherence in asthmatic patients: is there a solution to the problem? Ann Allergy Asthma Immunol 79:177–186 42. Stern L, Berman J, Lumry W, Katz L, Wang L, Rosenblatt L, Doyle JJ (2006) Medication compliance and disease exacerbation in patients with asthma: a retrospective study of managed care data. Ann Allergy Asthma Immunol 97:402–408 43. Landwehr LP, Spahn JD, Szefler SJ, Leung DYM (1995) Management of steroid-resistant asthma. Clin Immunother 4:124–137 44. Allen DB (1996) Growth suppression by glucocorticoid therapy. In: Rosenfield RL, editor. Growth and growth disorders. WB Saunders, Philadelphia, pp. 699–718 45. Ferguson AC, Murray AB, Tze W-J (1982) Short stature and delayed skeletal maturation in children with allergic diseases. J Allergy Clin Immunol 69:461–466 46. Wolthers OD (1996) Long-, intermediate- and long-term growth studies in asthmatic children treated with inhaled corticosteroids. Eur Respir J 9:821–827 47. The Childhood Asthma Management Program Research Group (CAMP) (2000) Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 343:1054–1063 48. Wolthers OD, Hansen M, Juul A, Nielsen HK, Pedersen S (1997) Knemometry, urine cortisol excretion, and measures of the insulin-like growth factor axis and collagen turnover in children treated with inhaled glucocorticoids. Pediatr Res 41:44–50 49. Tinkelman DG, Reed CE, Nelson HS, Offord KP (1993) Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 92:64–77 50. Simons FER, and the Canadian Beclomethasone Dipropionate-Salmeterol Xinofoate Study Group (1997) A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 337:1659–1665 51. Wales JKH, Barnes ND, Swift PGF (1991) Growth retardation in children on steroids for asthma. Lancet 338:1535 52. Thomas BC, Stanhope R, Grant DB (1994) Impaired growth in children with asthma during treatment with conventional doses of inhaled corticosteroids. Acta Paediatr 83:196–199 53. Littelwood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. Lancet 1:115–116 54. Saha M-T, Laippala P, Lenko HL (1997) Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids. Acta Paediatr 86:138–142 55. Hunt GJJ, Edmunds ATE, Kelnar CJH (1994) Height velocity standard deviation scores in 162 prepubertal children receiving beclomethasone dipropionate, budesonide, or sodium cromoglycate. Thorax 49:399P 56. Inoue T, Soi S, Takamatsu I, Murayama N, Kameda M, Hayashida M, et al. (1995) Effects of inhaled beclomethasone on height growth and bone metabolism in children with asthma. Arerugi 44:678–684 57. Crowley S, Hindmarsh PC, Matthews DR, Brook CGD (1995) Growth and the growth hormone axis in prepubertal children with asthma. J Pediatr 126:297–303

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

589

58. Doull IJM, Freezer NJ, Holgate ST (1995) Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 151:1715–1719 59. Le Bourgeois M, Benoist MR, de Blic J, Allaire JM, Scheinmann P (1993) One year treatment with two doses of inhaled flunisolide (250 and 500 mcg bid): effects on growth of asthmatic children. Am Rev Respir Dis 147:A265 60. Allen DB, Bronsky EA, LaForce CF, Nathan RA, Tinkelman DG, Vandewalker ML, et al. (1998) Growth in asthmatic children treated with fluticasone propionate. J Pediatr 132:472–477 61. Price JF, Russell G, Hindmarsh PC, Weller P, Heaf DP, Williams J (1997) Growth during one year of treatment with fluticasone propionate or sodium cromoglycate in children with asthma. Pediatr Pulmonol 24:178–186 62. Anhoj J, Bisgaard AM, Bisgaard H (2002) Systemic activity of inhaled steroids in 1- to 3-year-old children with asthma. Pediatrics, 109:40. 63. Bisgaard H, Allen D, Miles EA, et al. (2004) Long-term safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years old with recurrent wheezing. Pediatrics, 113:e87–94 64. Allen DB, Mullen M, Mullen B (1994) A meta-analysis of the effcet of oral and inhaled corticosteroids on growth. J Allergy Clin Immunol 93:967–976 65. Godfrey S, König P (1974) Treatment of childhood asthma for 13 months and longer with beclomethasone dipropionate aerosol. Arch Dis Child 49:591–596 66. Balfour-Lynn L (1986) Growth and childhood asthma. Arch Dis Child 61:1049–1055 67. Volovitz B, Amir J, Malik H, Kauschansky A, Varsano I (1993) Growth and pituitary-adrenal function in children severe asthma treated with inhaled budesonide. N Engl J Med 329:1703–1708 68. Merkus PJFM, van Essen-Zandvliet EEM, Duiverman EJ, van Houwelingen HC, Kerrebijn KF, Quanjer PH (1993) Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma. Pediatrics 91:1121–1226 69. Silverstein MD, Yunginger JW, Reed CE, Petterson T, Zimmerman D, Li JTC, et al. (1997) Attained adult height after childhood asthma: effect of glucocorticoid therapy. J Allergy Clin Immunol 99:466–474 70. Agertoft L, Pedersen S (2000) Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 343:1064–1069 71. Van Bever HP, Desager KN, Lijssen N, Weyler JJ, Du Caju MV (1999) Does treatment of asthmatic children with inhaled corticosteroids affect their adult height? Pediatr Pulmonol 27:369–375 72. Allen DB (2005) Inhaled steroids for children: effects on growth, bone, and adrenal function. Endocrinol Metab Clin N Am 34:555–564 73. Birkebaek NH, Esberg G, Andersen K, Wolthers O, Hassager C (1995) Bone and collagen turnover during treatment with inhaled dry powder budesonide and beclomethasone dipropionate. Arch Dis Child 73:524–527 74. Rao R, Gregson RK, Jones AC, Murrils AJ, Warner JA, Warner JO (1997) Inhaled steroids in standard dose do not affect bone architecture or turnover with long term use in childhood asthma. Am J Respir Crit Care Med 155:A267 75. Agertoft L, Pedersen S (1998) Bone mineral density in children with asthma receiving longterm treatment with inhaled budesonide. Am J Respir Crit Care Med 157:178–183 76. Konig P, Hillman L, Cervantes C, et al. (1993) Bone metabolism in children with asthma treated with inhaled beclomethasone dipropionate. J Pediatr 122:219–226 77. Kelly HW, Strunk RC, Donithan M, et al. (2003) Growth and bone density in children with mild-moderate asthma: a cross-sectional study in children entering the Childhood Asthma Management Program (CAMP). J Pediatr 142:286–291 78. Roux C, Kolta S, Desfougeres JL, et al. (2003) Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma. J Pediatr 142:286–291 79. van Staa TP, Cooper C, Leufkens HG, et al. (2003) Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18:913–918

590

H.P. Van Bever et al.

80. Bisgaard H, Nielsen MDD, Andersen B, Andersen P, Foged N, Fuglsang G, et al. (1988) Adrenal function in children with bronchial asthma treated with beclomethasone or budesonide. J Allergy Clin Immunol 81:1088–1095 81. Prahl P (1991) Adrenocortical suppression following treatment with beclomethasone dipropionate and budesonide. Clin Exp Allergy 21:145–146 82. Nicolaizik WH, Marchant JL, Preece MA, Warner JO (1994) Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Crit Care Med 150:624–628 83. Philip M, Aviram M, Lieberman E, Zadik Z, Giat Y, Levy J, et al. (1992) Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids. Ped Pulmonol 12:84–89 84. Todd GR, Acerini CL, Buck JJ, et al. (2002) Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate. Eur Respir J 19:1207–1209 85. Simons FER, Persaud MP, Gillespie CA, Cheang M, Shuckett EP (1993) Absence of posterior subcapsular cataracts in young patients treated with inhaled corticosteroids. Lancet 342:776–778 86. Geller DE (2007) Clinical side effects during aerosol therapy: cutaneous and ocular effects. J Aerosol Med 20 (suppl 1):S100-S109 87. Connett G, Lenney W. Inhaled budesonide and behavioural disturbances. Lancet 338:634–635 88. Choong K, Zwaigenbaum L, Onyett H (1995) Severe varicella after low dose inhaled corticosteroids. Pediatr Infect Dis J 14:809–811 89. Turpeinen M, Sorva R, Juntunen-Backman K (1991) Changes in carbohydrate and lipid metabolism in children with asthma inhaling budesonide. J Allergy Clin Immunol 88:384–389 90. de Vries TW, de Langen-Wouterse JJ, de Jong-Van den Berg LT, Duiverman EJ (2007) Hypertrichosis as a side effect of inhaled steroids in children. Pediatr Pulmonol 42:370–373 91. Bousquet J, Clark TJ, Hurd S, Khaltaey N, Lenfant C, O’byrne P, Sheffer A (2007) GINA guidelines on asthma and beyond. Allergy 62:102–112 92. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD (2003) Tucson Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol 111:661–675 93. Tan TN, Lim DLC, Chong YS, Lee BW, Van Bever HP (2005) Prevalence of allergy-related symptoms in the second year of life. Ped Allergy Immunol 16:151–156 94. Martinez FD (2002) What have we learned from the Tucson Children’s Respiratory Study? Paediatr Respir Rev 3:193–7 95. Chavasse RJ, Bastian-Lee Y, Seddon P (2002) How do we treat wheezing infants? Evidence or anecdote. Arch Dis Childh 87:546–7 96. Devulapalli CS, Haaland G, Pettersen M, Carlsen KH, Lodrup Carlsen KC (2004) Effect of inhaled steroids on lung function in young children: a cohort study. Eur Respir J 23:869–75 97. Chavasse RJ, Bastian-Lee Y, Richter H, et al. (2001) Persistent wheezing in infants with an atopic tendency responds to inhaled fluticasone. Arch Dis Childh 85:143–8 98. Van Bever HP, Schuddinck L, Wojciechowski M, Stevens WJ (1990) Aerosolized budesonide in asthmatic infants: a double blind study. Pediatr Pulmonol 9:177–180 99. Bisgaard H, Northman Hermansen B, Loland L, et al. (2006) Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 354:1998–2005 100. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A (2006) Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy Infants (IFWIN): doubleblind, randomised, controlled study. Lancet 368:754–762 101. Schokker S, Kooi EM, de Vries TW, Brand PL, Mulder PG, Duiverman EJ, van der Molen T (2007) Inhaled corticosteroids for recurrent respiratory symptoms in preschool children in general practice: randomized controlled trial. Pulm Pharmacol Ther Jan 23 (in press) 102. Blom D, Ermers M, Bont L, van Aalderen W, van Woensel J (2007) Inhaled corticosteroids during acute bronchiolitis in the prevention of post-bronchiolitic wheezing. Cochrane Database Syst Rev 24, CD004881.

Risk-Benefit of Asthma Therapy in Children: Topical Corticosteroids

591

103. Sorkness CA, Lemanske RF Jr, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, Strunk RC, Szefler SJ, Zeiger RS, Bacharier LB, Bloomberg GR, Covar RA, Guilbert TW, Heldt G, Larsen G, Mellon MH, Morgan WJ, Moss MH, Spahn JD, Taussig LM, and the Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute (2007) Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 119:64–72 104. Verberne AAPH, Frost C, Duiverman EJ, Grol MH, Kerribijn KF (1998) Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. Am J Respir Crit Care Med 158:213–219 105. Pohunek P, Kuna P, Jorup C, De Boeck K (2006) Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma. Pediatr Allergy Immunol 17:458–65 106. Bisgaard H (2003) Effect of long-acting b2 agonists on exacerbation rates of asthma in children. Pediatr Pulmonol 36:391–8 107. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ (2004) The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol 57:68–75 108. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group (2006) The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129:15–26 109. Martinez FD (2005) Safety of long-acting beta-agonists--an urgent need to clear the air. N Engl J Med 353:2637–9 110. Todd G, Dunlop K, McNaboe J, Ryan MF, Carson D, Shields MD (1996) Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate. Lancet 348:27–29

Risk-Benefit of Asthma Therapy in Children: Nonsteroidal Anti-Inflammatory Drugs James P. Kemp

Introduction Asthma is a chronic inflammatory disease of the airways, and anti-inflammatory treatment is an integral part of asthma treatment for both adults and children. Current international asthma management guidelines recommend low-dose inhaled corticosteroids (ICS) or a leukotriene modifier for children over age 5 and low-dose ICS for children age 5 and younger, who require a controller medication [1, 2]. While the guidelines list ICS as being the most effective controller medications [1, 2], for many children, nonsteroidal anti-inflammatory treatments are an effective alternative to or adjunctive therapy with ICS to achieve asthma control. Nonsteroidal anti-inflammatory treatments used in childhood asthma include the leukotriene modifiers, cromolyn, nedocromil, ketotifen, theophylline, and, for children age 12 and older, omalizumab. This chapter will cover the benefits and risks of these nonsteroidal anti-inflammatory drugs for treatment of asthma in children. Other than the leukotriene modifiers and omalizumab, most of these agents have been in use for longer than ICS. Nonetheless, their mechanisms of action are not fully understood, and their efficacy is not always well-defined, particularly for children.

General Principles The goals of asthma therapy are to enable each child to maintain normal activities of daily living (at school, at play) as well as physical activities (sports, outdoor games); to reduce or eliminate daytime symptoms (cough, wheeze) and nocturnal

J.P. Kemp () Department of Pediatrics, University of California School of Medicine, San Diego, Allergy and Asthma Medical Group and Research Center, 9610 Granite Ridge Drive, Suite B, San Diego, CA 92123, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_36, © Springer 2010

593

594

J.P. Kemp

disturbance from asthma (cough, awakenings); and to minimize or eliminate need for reliever medication as well as the occurrence of asthma exacerbations. These goals have been emphasized in the new guidelines as indicators of asthma control [1, 2]. Another important goal, particularly true in pediatric medicine, is to avoid any adverse effects of treatment. Evidence from surveys worldwide suggests that asthma treatment goals are often not met: parents and children frequently overestimate the control of disease, accepting activity limitations and the presence of asthma symptoms as being usual or normal [3, 4]. Selection of asthma treatment in previous years has been guided by four predefined levels of asthma severity (intermittent, mild persistent, moderate persistent, and severe persistent) as per the asthma management guidelines [5–8], and most of the information in this chapter refers to these categories. More recently, the 2006 Global Initiative for Asthma (GINA) guidelines propose treatment selection according to the classification by the level of asthma control, namely controlled, partly controlled, and uncontrolled (Table 1) [1, 2]. This classification accounts for the fact that responsiveness to treatment is also a measure of asthma severity [9]. Asthma control is thus a treatment goal as well as a measurement to guide treatment selection. Asthma control is a parameter that should be periodically assessed for each patient to serve as the basis for subsequent treatment decisions [9]. Therapy for asthma should be individualized for each child. Asthma is now understood to be a heterogeneous disorder, with different asthma phenotypes that each may respond differently to therapy [10]. Moreover, children can manifest asthma differently at different ages, for example, symptoms in preschool children are often episodic rather than persistent and may be precipitated by viral respiratory tract infection [11]. Finally, as risk factors for developing asthma are identi-

Table 1 Classification of asthma by level of control (From [2], with permission)

Characteristic Daytime symptoms Limitations of activities Nocturnal symptoms/ awakening Need for reliever/rescue treatment Lung function(PEF or FEV1)a Exacerbations a

Controlled (All of the following)

Partly controlled (Any measure present in any week)

None (twice or less/week) None None

More than twice/ week Any Any

None (twice or less/week) Normal

More than twice/week <80% predicted or personal best (if known) One or more/yearb

None

Uncontrolled Three or more features of partly controlled asthma present in any week

One in any weekc

Lung function testing is not reliable for children 5 years and younger Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate c By definition, an exacerbation in any week makes it an uncontrolled asthma week b

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

595

fied – including atopic dermatitis, a family history of asthma or allergy, and early allergic sensitization – primary prevention of asthma can be considered for highrisk children [12]. An important area identified for future research is to reach a better understanding of the mechanisms leading to airway inflammation, airway remodeling, altered pulmonary function, and bronchial hyper-responsiveness that characterize asthma [13]. A longer duration of asthma in children has been associated with lower lung function as well as more asthma symptoms and greater need for rescue b-agonist [14]. Thus, the question arises whether early intervention can change lung function outcomes: To treat or not to treat? Evidence thus far suggests that early treatment can reduce morbidity but does not change lung function outcomes [15, 16]. For 1-month-old infants with episodic wheezing, early introduction of 2-week courses of ICS with each wheezing episode did not halt the progression from episodic to persistent wheezing, nor was the proportion of symptom-free days over 3 years of treatment increased [15]. For children 2–3 years of age, regular ICS therapy for 2 years reduced symptoms and asthma exacerbations but did not alter lung function or development of asthma symptoms during a third year without treatment [16]. Studies using a mouse model of asthma have produced intriguing results with regard to airway remodeling [17, 18]. In this model, the typical changes of airway remodeling, including subepithelial fibrosis and smooth muscle cell layer thickening, are induced by allergen administration. Administration of montelukast, a type 1 cysteinyl leukotriene receptor antagonist (LTRA) reversed these structural changes, while administration of dexamethasone did not; both montelukast and dexamethasone reversed airway eosinophilia and goblet cell metaplasia [18]. How these findings translate to clinical practice will be of immense interest. But, currently, the findings indicate that multiple inflammatory processes are involved in asthma and not all patients respond equally well to the same treatment. The roles in childhood asthma therapy of nonsteroidal anti-inflammatory agents will continue to be shaped by the results of ongoing and future research. Dosages of these agents for children are summarized in Table 2.

Cromolyn Sodium and Nedocromil Mechanism of Action Cromolyn sodium and nedocromil are inhaled agents formerly known as mast cell stabilizers. Their effects in asthma include the modulation of inflammatory cell activity – suppression of inflammatory mediator release from mast cells and suppression of activation of inflammatory cells – as well as the reduced firing of sensory neurons [5, 19, 20]. These effects are thought to be mediated by regulation of chloride channels [19, 20].

600 mg tablets

Single-use, 5 mL vial containing 150 mg omalizumab upon reconstitution

Zileuton

Omalizumab

Dosage

³12 year old: 150–375 mg subcutaneously every 2 or 4 weeks (dose based on baseline IgE level and body weight)

³15 year old: 10 mg once daily; 6–14 year old: 5 mg once daily; 6 months to 5 years old: 4 mg once daily ³12 year old: 20 mg twice daily 5–11 year old: 10 mg twice daily ³12 year old: 600 mg four times daily

2 inhalations (each 0.8 mg) 4 times/day 1 ampule by nebulizer 4 times/day 2 inhalations (each 1.75 mg) 2–4 times/day ³3 year old: 1 mg 2 times/day 6 months to 3 years: 0.5 mg 2 times/day ³12 year old: <45 kg: start at 12–14 mg kg–1 once daily; >45 kg: start at 300–400 mg once daily ³1 year old: start at 5 mg kg–1/day divided 3–4 times/day; and slowly increase to 10 mg kg–1/day divided 3–4 times/day

Notes and comments

For children ³12 year old. Monitor hepatic transaminases before starting and periodically during therapy For children ³12 year old. Monitor for possible anaphylaxis. Store under refrigeration; maximum 150 mg per injection site

Take ³1 h before or ³2 h after meals

Monitor serum concentration at peak (goal 5–10 mg L–1); Many drug interactions

Use for ³4 week to evaluate effects; for children ³2 year old Use for ³1 week; for children ³6 year old Use for ³8 week to evaluate effects

Prescribers of theophylline are advised to read prescribing information for each specific product to guide on appropriate dose selection and administration intervals

a

10- and 20-mg tablets

Zafirlukast

Antileukotrienes Montelukast

Theophyllinea

4-mg granules; 4- and 5-mg chewable tablets; 10 mg tablets

Cromolyn sodium

Nedocromil sodium Ketotifen

Available formulations

Metered-dose inhaler: 8.1 and 14.2 g Nebulizer solution 20 mg/2 mL Metered-dose inhaler: 16.2 g 1 mg tablets; syrup: 1 mg/5 mL 400- and 600-mg controlled release tablets; 100-, 200-, 300-, 400-mg extended-release capsules 100- and 200-mg capsules; Elixir and solution: 80 mg/15 mL; Syrup: 80 mg/15 mL and 150 mg/15 mL

Agent

Table 2 Dosages of nonsteroidal anti-inflammatory agents used for treating childhood asthma

596 J.P. Kemp

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

597

Benefits and Place in Therapy Cromolyn and nedocromil have been used for many years in treating mild to moderate asthma in childhood [21]. The use of these agents for treating childhood asthma has gradually diminished since about 1990 with the widening use of ICS. In fact, the most recent GINA guidelines [1] for both children and adults characterize the role of cromolyn and nedocromil in long-term treatment of asthma as being “limited.” This conclusion is based on results of a recent systematic review of placebo-controlled trials indicating that there is insufficient evidence that sodium cromoglycate (cromolyn) has beneficial effects as maintenance therapy in childhood asthma [22]. Similarly, for nedocromil, a recent metaanalysis of placebo-controlled trials concludes that further study is warranted to establish the place of nedocromil in childhood asthma therapy [23]. Despite these data, the clinical experience of the author indicates that these agents are effective for some children who take them regularly. Other reported uses for cromolyn and nedocromil are as add-on therapy with ICS and for preventing exercise-induced bronchoconstriction (EIB). When taken by inhalation before exercise, nedocromil reduces the severity and duration of EIB and is associated with minimal to no side effects (Fig. 1) [24]. The efficacy and tolerability of cromolyn are similar to those of nedocromil when used for preventing EIB [25]. On average, the effects of these agents are less than those of short-acting b-agonists for preventing EIB; however, owing to individual variation in response and their good safety profile, cromolyn and nedocromil may be alternatives for some patients with EIB [26].

Fig. 1 Results of six studies evaluating nedocromil to prevent exercise-induced bronchoconstriction: treatment effects of nedocromil and placebo on the time course of exercise-induced asthma. Data are mean maximum fall in forced expiratory volume in 1 s (FEV1) and 95% confidence interval. Squares, placebo; diamonds, nedocromil (From [24], with permission)

598

J.P. Kemp

Cromolyn and nedocromil have an excellent safety profile. The minimal incidence of side effects associated with these agents may be perhaps due to the maintenance of a normal resting physiological state by their preventing chloride channel activation [20].

Risks and Drawbacks Both cromolyn and nedocromil are administered by inhalation, and both may produce a cough upon inhalation. Moreover, the bitter taste of nedocromil, noted by 25–30% of patients, may be objectionable to some children. The route (inhalation) and frequency of administration (three to four times daily with cromolyn) may be associated with reduced compliance with therapy [27, 28].

Ketotifen Mechanism of Action Ketotifen is an orally administered antiallergic compound that has been used for many years in some countries for managing allergy, asthma, and atopic dermatitis. The effects of ketotifen are not fully elucidated but include histamine H1-receptor antagonism and inhibition of the release of proinflammatory mediators from mast cells and neutrophils [29]. In addition, ketotifen stimulates nitric oxide synthase activity, which suggests that its antiallergic effect may be in part mediated through the formation of nitric oxide [29].

Benefits and Place in Therapy Ketotifen is not included in the 2006 GINA Workshop Report or pediatric Pocket Guide [1, 2]. The following statement appears in the 2005 report: “The evidence on the effects of ketotifen in children is insufficient to warrant its use.” [5] Nonetheless, a recent Cochrane review of placebo-controlled trials of ketotifen therapy for asthma or wheezing in children (aged 4 months to 18 years) concludes that ketotifen used as sole or add-on therapy improves the control of asthma and wheezing for children with mild and moderate asthma [30]. The authors note that many children in the trials had atopy and thus the results cannot be extrapolated to all children with asthma. In one small placebo-controlled study, ketotifen was administered long term to infants considered to be at high risk of developing asthma [31]. After 3 years of therapy, 9% of those receiving ketotifen (4/45) and 35% of those receiving placebo

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

599

(14/40) had developed asthma, suggesting that ketotifen may affect the onset of asthma in some preasthmatic children [31].

Risks and Drawbacks Ketotifen may be more efficacious for children with a history of atopy. Transient sedation and weight gain are reported side effects of ketotifen [30]. This agent has a long onset of activity that can make the evaluation of clinical benefits difficult.

Theophylline Mechanism of Action The best-understood effect in asthma of the methylxanthines is bronchodilation via relaxation of bronchial smooth muscle secondary to phosphodiesterase inhibition with resulting increases in cAMP. Results of recent studies indicate that theophylline also has modest anti-inflammatory properties in asthma [32–34]. Interestingly, it appears that the anti-inflammatory effects are evident at lower plasma concentrations (5–10 mg L–1) than the bronchodilatory effects, which first appear at 10 mg L–1 [33]. Mechanisms of the anti-inflammatory effects are currently being elucidated and include the induction of histone deacetylase (HDAC) activity by theophylline [32]. This effect appears to be synergistic with the effects of corticosteroids, which recruit HDAC to the site of active inflammatory gene transcription, where HDAC inhibits inflammatory gene transcription by inhibiting the acetylation of core histones [32]. This activation of HDAC by theophylline may possibly overcome a form of steroid resistance that occurs when oxidative stress reduces HDAC activity [32, 33].

Benefits and Place in Therapy Oral theophylline is the methylxanthine in most common clinical use and has been prescribed for decades for childhood asthma. Theophylline reduces asthma symptoms and the need for rescue medication in children as young as 18 months [1, 35]. In the most recent GINA guidelines [1], the recommendations for theophylline administration are as monotherapy or as add-on therapy with inhaled or oral corticosteroids [1]. The guidelines note that the efficacy of theophylline is less than that of low-dose ICS, similar to the findings of a recent Cochrane review, which suggest that xanthines are suitable as first-line controller therapy only when ICS are not available [35]. The results of this meta-analysis found insufficient evidence to

600

J.P. Kemp

support the use of theophylline as add-on therapy and called for further studies in this area [35]. In developed countries, where its use has fallen substantially since the introduction of ICS, theophylline is often reserved for use as add-on therapy for patients with moderate to severe asthma not controlled adequately with ICS [36]. In developing countries where ICS are difficult or too expensive to obtain, theophylline is often still used as first-line asthma therapy for children. Theophylline is orally administered, inexpensive, and widely available. As discussed above, its bronchodilating effects are now thought to be accompanied also by anti-inflammatory effects, which may or may not be clinically relevant.

Risks and Drawbacks The therapeutic index of theophylline is relatively narrow. Therapeutic plasma concentrations in children are 5–10 mg L–1, while symptoms of toxicity may appear at plasma concentrations of ³20 mg L–1 [33]. The most common side effects are anorexia, nausea, vomiting, and headache [37]. At high concentrations, central nervous system toxicity can manifest as seizures. Absorption and clearance of theophylline may be variable [35]; both are affected by genetic and environmental factors, including febrile illness [1]. Theophylline is metabolized by hepatic cytochrome CYP1A2 [33, 38]. Thus, the clearance of theophylline decreases with concurrent administration of macrolide (e.g., erythromycin) and quinolone antibiotics, resulting in increased plasma concentrations. Conversely, the clearance increases with concurrent administration of hepatic microsomal enzyme inducers, including phenobarbital and phenytoin. Plasma theophylline concentrations should be monitored for children receiving doses higher than 10 mg kg–1/day and those receiving other medications that may affect theophylline clearance.

Leukotriene Modifiers Mechanism of Action Included in this class are the LTRA, antagonists of the type 1 cysteinyl leukotriene (cysLT1) receptor – montelukast, zafirlukast, and pranlukast – as well as the 5-lipoxygenase inhibitor zileuton, which inhibits leukotriene synthesis. Known also as the antileukotrienes, the leukotriene modifiers exert their effects through interference with the action of the cysteinyl leukotrienes or their synthesis. The cysteinyl leukotrienes are a group of compounds, formerly called the slowreacting substance of anaphylaxis (SRS-A), that have many effects in asthma and allergic inflammation. These effects, which are thought to be mediated primarily

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

601

through the cysLT1 receptor, include airway smooth muscle contraction and bronchoconstriction, mucus secretion, increased vascular permeability, edema, recruitment of inflammatory cells, and promotion and maintenance of the inflammatory response in both upper and lower airways [39, 40]. In addition, recent data suggest that cysteinyl leukotrienes contribute not only to promoting but also to maintaining airway remodeling in asthma [17, 18, 39]. The synthesis and effects of cysteinyl leukotrienes appear to be relatively independent of regulation by exogenous corticosteroids [39]. This fact suggests that leukotriene modifiers could provide alternative or additive benefit to that provided by ICS.

Benefits and Place in Therapy The most recent GINA guidelines list leukotriene modifiers as providing clinical benefit, although usually less than that obtained with low-dose ICS, for children ³5 years old at all levels of asthma severity [1]. The listed indications of antileukotrienes for children with asthma in the guidelines include it as controller therapy, to prevent EIB (approved for 15–18 years olds in the US), as add-on therapy for children with asthma inadequately controlled by low-dose corticosteroids, and to reduce viral-induced exacerbations for children aged 2–5 years [1]. In addition, montelukast relieves the symptoms of allergic rhinitis (AR) and thus can be administered for children as young as 2 years with concomitant asthma and AR, common comorbidities [40]. The LTRA montelukast and zafirlukast are used most commonly worldwide; pranlukast is used most commonly in Japan; and zileuton is available only in the United States [41, 42]. There are no comparative trials of the leukotriene modifiers. Of these agents, montelukast has been studied most extensively for its role in treating childhood asthma, while zileuton has not been studied and is not approved for children <12 years old. In published clinical trials, montelukast monotherapy has shown efficacy in children as young as 2 years [43–46] and is approved for use in some countries down to 6 months and in the USA down to 1 year, while zafirlukast is approved for use in children as young as 5 years [47]. Clinical benefits of these agents included significant improvements in FEV1, rescue b-agonist use, days with asthma exacerbations, quality-of-life assessments, and peripheral eosinophil levels. Of note, these clinical trials enrolled mostly children with mild to moderate asthma. Adding a leukotriene modifier to ICS is an alternative to increasing the dose of ICS [1, 43]. In one study of children with corticosteroid-dependent asthma [48], the addition of montelukast to therapy produced a small additive effect on lung function and a 23% reduction in asthma exacerbation days. The anti-inflammatory effect of montelukast appears to be additive to that of ICS, as measured by improvements in measures of airway inflammation recorded with the addition of montelukast therapy for children with corticosteroid-dependent asthma [49, 50].

602

J.P. Kemp 5 Montelukast FEV1 % Change (Mean ± SE)

0 Placebo

–5 –10 –15 –20 –25 –30 0

5 10 15 30 45 Time After Exercise (Minutes)

60

Fig. 2 Mean percent change in FEV1 from pre-exercise FEV1 at time points from 0 to 60 min after exercise (From [51], with permission)

Relief of EIB in childhood is important to enable planned as well as spontaneous physical activity. Both montelukast and zafirlukast are effective in preventing EIB in children from 6–14 years of age, and the effect of montelukast is maintained throughout the 24 h dosing interval (Fig. 2) [51–53]. Montelukast also reduces the symptoms and inflammatory mediators of AR in children with concomitant asthma and AR [54–56]. Observational studies show reduced use and cost of asthma rescue and allergy medication for children with concomitant AR who receive montelukast [54, 57]. For very young children (10–26 months) with early childhood asthma, montelukast has a positive effect on lung function, airway inflammation, and symptom scores [58]. Moreover, montelukast therapy in one study was shown to reduce viral-induced asthma exacerbations in preschool children with intermittent asthma [59]. Short-term studies comparing montelukast with ICS for children with mild to moderate asthma have tended to favor ICS [60–64], although for children with mild persistent asthma the clinical benefits of montelukast and ICS are relatively similar [63, 65]. Moreover, the results of observational studies suggest that the “real world” effectiveness of montelukast may be similar to that of ICS for children with mild persistent asthma [54, 57, 66]. This could result, in part, from improved compliance with the oral dose relative to the inhaled route of administration of ICS [66, 67]. Responsiveness of individual patients to ICS or montelukast therapy is variable (Fig. 3) [60, 61]. For children aged 6–17 years with mild to moderate persistent asthma and those who are younger and have a shorter disease course tend to respond favorably to montelukast. Instead, those with lower pulmonary function and higher levels of markers of allergic inflammation respond more favorably to ICS [61]. Variability in responsiveness to montelukast therapy appears at least in part to be influenced by genetic variations, which are currently being characterized [68, 69].

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

603

Fig. 3 Difference in asthma control days between fluticasone propionate and montelukast (fluticasone minus montelukast) for individual participants. Each line designates a single participant (From [60], with permission)

Finally, slowing of growth is not an issue for children receiving leukotriene modifiers whereas it remains an issue for those receiving ICS [16, 64, 65].

Risks and Drawbacks The LTRA have a good safety and tolerability profile [70]. Churg-Strauss syndrome is very rare in children, and causality has not been established [71]. The bioavailability of zafirlukast is affected by food intake and thus, this LTRA must be taken at least 1 h before or 2 h after food; administration is twice daily. Drawbacks to the use of zileuton include frequent administration (two to four times daily) and its metabolism by hepatic cytochrome P450 enzymes; thus, monitoring of hepatic transaminases is recommended monthly during the first 3 months and then for every 2–3 months for the first year of therapy, and periodically thereafter [72].

604

J.P. Kemp

Omalizumab Mechanism of Action Asthma symptoms during childhood are often associated with elevations in total serum IgE levels [73]. Omalizumab is a monoclonal anti-immunoglobulin E (antiIgE) that reduces circulating IgE levels and has multiple anti-inflammatory effects at the tissue level, including decreased airway eosinophilia and downregulation of IgE receptor expression on basophils and mast cells [74].

Benefits and Place in Therapy The role of omalizumab in childhood asthma therapy is currently being defined, as most of the clinical trials to date have enrolled adult and adolescent patients [1]. Omalizumab therapy has the greatest beneficial effect for patients with severe asthma; it also shows efficacy in clinical studies for treating moderate to severe allergic asthma and allergic rhinitis [74, 75]. Omalizumab is approved in many countries for use in patients ³12 years old with moderate to severe or severe allergic asthma that is not controlled with ICS. In a preliminary trial enrolling children 6–12 years old with moderate to severe allergic asthma requiring ICS [76], omalizumab therapy was effective in reducing asthma exacerbations and the need for ICS. Moreover, levels of fractional exhaled nitric oxide, a marker of airway inflammation, did not rise during ICS dose reduction among children receiving omalizumab in a small substudy [77], indicative of an anti-inflammatory effect of omalizumab in this age group.

Risks and Drawbacks The drawbacks of therapy with omalizumab are the high cost, the need for refrigeration, and the injectable route of administration. Moreover, at least 0.2% of patients receiving omalizumab have experienced an anaphylactic reaction, and thus the US Food and Drug Administration has recently added a Black Box warning about the risk of anaphylaxis to the prescribing information. Omalizumab is administered as a subcutaneous injection every 2 or 4 weeks. During 1 year of administration to children aged 6–12 years with allergic asthma, other than severe injection site reactions, adverse effects of omalizumab occurred with no greater frequency than with placebo, and no serious adverse effects were recorded [78].

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

605

Conclusions While ICS remain the first-line choice for treating childhood asthma, nonsteroidal anti-inflammatory agents are an attractive alternative for some patients due to the drawbacks of ICS use – particularly the inhaled route of administration (difficult for some patients) and parental and patient fears of side effects. Moreover, the use of nonsteroidal anti-inflammatory agents as add-on or alternative therapy may address the limitations of ICS with regard to efficacy and compliance in some patients. Results of ongoing research will guide future recommendations for childhood asthma therapy. Issues and questions of particular interest with regard to the positioning of nonsteroidal anti-inflammatory agents in childhood asthma therapy include the following: • • • • •

How to best identify children who will develop persistent asthma How to halt the progression to persistent asthma over time How to best treat intermittent wheezing in infants and preschool children How to best treat children with asthma and concomitant rhinitis How to best treat patients showing poor responsiveness or lack of compliance to ICS and • How to promote compliance with asthma therapies in the teenage years. A better understanding of the genetic mechanisms and environmental-gene interactions influencing the pathophysiology of asthma will help to better define optimal therapies for different phenotypes of childhood asthma. Equally important, a better understanding of how airway remodeling develops will help to identify the means of reversing this process and improving lung function for pediatric patients. Acknowledgments Writing support was provided by Elizabeth V. Hillyer, with funding support from Merck and Co., Inc., Whitehouse Station, NJ, USA. The views expressed are solely those of the author, and the author had full control over the content and the preparation of the manuscript.

References 1. Global Initiative for Asthma. GINA report, Global Strategy for Asthma Management and Prevention 2006; Available at http://www.ginasthma.com/ 2. Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention in Children 2006; Available at http://www.ginasthma.com/ 3. Fuhlbrigge AL, Guilbert T, Spahn J, Peden D, Davis K (2006) The influence of variation in type and pattern of symptoms on assessment in pediatric asthma. Pediatrics 118:619–625 4. Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, Weiss ST (2004) Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol 114:40–47

606

J.P. Kemp

5. Global Initiative for Asthma. 2005 Update: Workshop Report, Global Strategy for Asthma Management and Prevention; Available at http://www.ginasthma.com/ 6. British Thoracic Society, Scottish Intercollegiate Guidelines Network. 2005 update to the British Guideline on the Management of Asthma. Available at http://www.sign.ac.uk/guidelines/ fulltext/63/index.html 7. Canadian Consensus Asthma Guidelines Dissemination and Implementation Committee. Canadian Asthma Consensus Report, 1999; Available at http://www.asthmaguidelines.com/ 8. Becker A, Berube D, Chad Z, Dolovich M, Ducharme F, D’Urzo T, Ernst P, Ferguson A, Gillespie C, Kapur S, Kovesi T, Lyttle B, Mazer B, Montgomery M, Pedersen S, Pianosi P, Reisman JJ, Sears M, Simons E, Spier S, Thivierge R, Watson W, Zimmerman B (2005) Canadian Pediatric Asthma Consensus guidelines, 2003 (updated to December 2004): introduction. CMAJ 173:S12–S14 9. Humbert M, Holgate S, Boulet LP, Bousquet J (2007) Asthma control or severity: that is the question. Allergy 62:95–101 10. Martinez FD (2002) Development of wheezing disorders and asthma in preschool children. Pediatrics 109:362–367 11. Kaditis AG, Gourgoulianis K, Winnie G (2003) Anti-inflammatory treatment for recurrent wheezing in the first five years of life. Pediatr Pulmonol 35:241–252 12. de Longueville M (2000) What are the candidate groups for pharmacotherapeutic intervention to prevent asthma? Pediatr Allergy Immunol 11 Suppl 13:41–44 13. Busse W, Banks-Schlegel S, Noel P, Ortega H, Taggart V, Elias J (2004) Future research directions in asthma: an NHLBI Working Group report. Am J Respir Crit Care Med 170:683–690 14. Zeiger RS, Dawson C, Weiss S (1999) Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 103:376–387 15. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F (2006) Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 354:1998–2005 16. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF, Jr., Strunk RC, Allen DB, Bloomberg GR, Heldt G, Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354:1985–1997 17. Henderson WR, Jr., Tang LO, Chu SJ, Tsao SM, Chiang GK, Jones F, Jonas M, Pae C, Wang H, Chi EY (2002) A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med 165:108–116 18. Henderson WR, Jr., Chiang GK, Tien YT, Chi EY (2006) Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med 173:718–728 19. Alton EW, Norris AA (1996) Chloride transport and the actions of nedocromil sodium and cromolyn sodium in asthma. J Allergy Clin Immunol 98:S102–S105 20. Norris AA (1996) Pharmacology of sodium cromoglycate. Clin Exp Allergy 26 Suppl 4:5–7 21. National Asthma Education and Prevention Program (2002) Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics--2002. J Allergy Clin Immunol 110:S141–S219 22. Tasche MJ, Uijen JH, Bernsen RM, de Jongste JC, van der Wouden JC (2000) Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 55:913–920 23. Sridhar AV, McKean M (2006) Nedocromil sodium for chronic asthma in children. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD004108. DOI: 10.1002/14651858. CD004108.pub2 24. Spooner C, Rowe BH, Saunders LD (2000) Nedocromil sodium in the treatment of exerciseinduced asthma: a meta-analysis. Eur Respir J 16:30–37 25. Kelly KD, Spooner CH, Rowe BH (2001) Nedocromil sodium versus sodium cromoglycate in treatment of exercise-induced bronchoconstriction: a systematic review. Eur Respir J 17:39–45

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

607

26. Spooner CH, Spooner GR, Rowe BH (2003) Mast-cell stabilising agents to prevent exerciseinduced bronchoconstriction. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD002307. DOI: 10.1002/14651858.CD002307 27. Bukstein DA, Bratton DL, Firriolo KM, Estojak J, Bird SR, Hustad CM, Edelman JM (2003) Evaluation of parental preference for the treatment of asthmatic children aged 6 to 11 years with oral montelukast or inhaled cromolyn: a randomized, open-label, crossover study. J Asthma 40:475–485 28. Kelloway JS, Wyatt RA, Adlis SA (1994) Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 154:1349–1352 29. Heyman SN, Karmeli F, Brezis M, Rachmilewitz D (1997) The effect of ketotifen on nitric oxide synthase activity. Br J Pharmacol 120:1545–1551 30. Bassler D, Mitra A, Ducharme FM, Forster J, Schwarzer G (2004) Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD001384. DOI: 10.1002/14651858.CD001384.pub2 31. Bustos GJ, Bustos D, Bustos GJ, Romero O (1995) Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 25:568–573 32. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002) A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 99:8921–8926 33. Barnes PJ (2003) Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med 167:813–818 34. Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25:552–563 35. Seddon P, Bara A, Ducharme FM, Lasserson TJ (2006) Oral xanthines as maintenance treatment for asthma in children. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD002885. DOI: 10.1002/14651858.CD002885.pub2 36. Kemp JP, Kemp JA (2001) Management of asthma in children. Am Fam Physician 63:1341–1348, 1353–1344 37. Ellis EF (1985) Theophylline toxicity. J Allergy Clin Immunol 76:297–301 38. Zhang ZY, Kaminsky LS (1995) Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol 50:205–211 39. Ogawa Y, Calhoun WJ (2006) The role of leukotrienes in airway inflammation. J Allergy Clin Immunol 118:789–798 40. Busse W, Kraft M (2005) Cysteinyl leukotrienes in allergic inflammation: strategic target for therapy. Chest 127:1312–1326 41. Kemp JP (2000) Leukotriene receptor antagonists for the treatment of asthma. IDrugs 3:430–441 42. Kemp JP (2003) Recent advances in the management of asthma using leukotriene modifiers. Am J Respir Med 2:139–156 43. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, Becker A (1998) Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 279:1181–1186 44. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL (2001) Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 108:E48 45. Meyer KA, Arduino JM, Santanello NC, Knorr BA, Bisgaard H (2003) Response to montelukast among subgroups of children aged 2 to 14 years with asthma. J Allergy Clin Immunol 111:757–762 46. Becker A, Swern A, Tozzi CA, Yu Q, Reiss T, Knorr B (2004) Montelukast in asthmatic patients 6 years-14 years old with an FEV1 > 75%. Curr Med Res Opin 20:1651–1659 47. Pearlman DS, Lampl KL, Dowling PJ, Jr., Miller CJ, Bonuccelli CM (2000) Effectiveness and tolerability of zafirlukast for the treatment of asthma in children. Clin Ther 22:732–747 48. Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, Laessig W, Schuster A, Perez-Frias J, Sekerel BE, Menten J, Leff JA (2001) Montelukast added to budesonide in

608

49.

50.

51.

52.

53.

54.

55. 56.

57.

58.

59.

60.

61.

62.

63.

64.

J.P. Kemp children with persistent asthma: a randomized, double-blind, crossover study. J Pediatr 138:694–698 Strauch E, Moske O, Thoma S, Storm Van’s Gravesande K, Ihorst G, Brandis M, Kuehr J (2003) A randomized controlled trial on the effect of montelukast on sputum eosinophil cationic protein in children with corticosteroid-dependent asthma. Pediatr Res 54:198–203 Ghiro L, Zanconato S, Rampon O, Piovan V, Pasquale MF, Baraldi E (2002) Effect of montelukast added to inhaled corticosteroids on fractional exhaled nitric oxide in asthmatic children. Eur Respir J 20:630–634 Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, Knorr B (1998) Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 133:424–428 Pearlman DS, Ostrom NK, Bronsky EA, Bonuccelli CM, Hanby LA (1999) The leukotriene D4-receptor antagonist zafirlukast attenuates exercise-induced bronchoconstriction in children. J Pediatr 134:273–279 de Benedictis FM, del Giudice MM, Forenza N, Decimo F, de Benedictis D, Capristo A (2006) Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children. Eur Respir J 28:291–295 Luskin A, Bukstein D, Kocevar VS, Yin DD (2005) Asthma rescue and allergy medication use among asthmatic children with prior allergy prescriptions who initiated asthma controller therapy. Ann Allergy Asthma Immunol 95:129–136 Nayak A (2004) A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opin Pharmacother 5:679–686 Ciprandi G, Frati F, Marcucci F, Sensi L, Tosca MA, Milanese M, Ricca V (2003) Nasal cytokine modulation by montelukast in allergic children: a pilot study. Allerg Immunol (Paris) 35:295–299 Sazonov-Kocevar V, Laforest L, Travier N, Yin DD, Ganse EV (2006) Asthma and allergy medication use and costs among pediatric primary care patients on asthma controller therapy. Pediatr Allergy Immunol 17:620–628 Straub DA, Moeller A, Minocchieri S, Hamacher J, Sennhauser FH, Hall GL, Wildhaber JH (2005) The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma. Eur Respir J 25:289–294 Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P (2005) Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 171:315–322 Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM, Lemanske RF, Jr., Strunk RC, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM (2006) Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 117:45–52 Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, Zeiger RS, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM (2005) Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 115:233–242 Ostrom NK, Decotiis BA, Lincourt WR, Edwards LD, Hanson KM, Carranza Rosenzweig JR, Crim C (2005) Comparative efficacy and safety of low-dose fluticasone propionate and montelukast in children with persistent asthma. J Pediatr 147:213–220 Garcia Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P (2005) Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study. Pediatrics 116:360–369 Sorkness CA, Lemanske RF, Jr., Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, Strunk RC, Szefler SJ, Zeiger RS, Bacharier LB, Bloomberg GR, Covar RA, Guilbert TW, Heldt G, Larsen G, Mellon MH, Morgan WJ, Moss MH, Spahn JD, Taussig LM (2007) Longterm comparison of 3 controller regimens for mild-moderate persistent childhood asthma: The Pediatric Asthma Controller Trial. J Allergy Clin Immunol 119:64–72

Risk-Benefit of Nonsteroidal Anti-inflammatory Drugs

609

65. Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, Dass SB, Knorr BA (2006) Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Ann Allergy Asthma Immunol 96:800–807 66. Bukstein DA, Luskin AT, Bernstein A (2003) “Real-world” effectiveness of daily controller medicine in children with mild persistent asthma. Ann Allergy Asthma Immunol 90:543–549 67. Weinberg EG, Naya I (2000) Treatment preferences of adolescent patients with asthma. Pediatr Allergy Immunol 11:49–55 68. Whelan GJ, Blake K, Kissoon N, Duckworth LJ, Wang J, Sylvester JE, Lima JJ (2003) Effect of montelukast on time-course of exhaled nitric oxide in asthma: influence of LTC4 synthase A(-444)C polymorphism. Pediatr Pulmonol 36:413–420 69. Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, Wang J, Sylvester J, Holbrook J, Wise R, Weiss ST, Barnes K (2006) Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med 173:379–385 70. Bisgaard H (2001) Leukotriene modifiers in pediatric asthma management. Pediatrics 107:381–390 71. Boyer D, Vargas SO, Slattery D, Rivera-Sanchez YM, Colin AA (2006) Churg-Strauss syndrome in children: a clinical and pathologic review. Pediatrics 118:e914–e920 72. Critical Therapeutics Inc (2005) Zyflo (zileuton tablets) Prescribing Information; Available at http://www.criticaltherapeutics.com/pat_pi.html 73. Sherrill DL, Stein R, Halonen M, Holberg CJ, Wright A, Martinez FD (1999) Total serum IgE and its association with asthma symptoms and allergic sensitization among children. J Allergy Clin Immunol 104:28–36 74. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C (2005) The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol 115:459–465 75. Holgate ST, Djukanovic R, Casale T, Bousquet J (2005) Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy 35:408–416 76. Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, Taylor AF, Rohane P (2001) Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics 108:E36 77. Silkoff PE, Romero FA, Gupta N, Townley RG, Milgrom H (2004) Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody. Pediatrics 113:e308–e312 78. Berger W, Gupta N, McAlary M, Fowler-Taylor A (2003) Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Ann Allergy Asthma Immunol 91:182–188

The Role of Influenza Vaccination in Asthmatic Children Herman J. Bueving and Johannes C. van der Wouden

Introduction Asthma is the most occurring chronic disease in children. Asthma related genes and environmental factors play a role in the etiology. Nowadays, asthma is regarded as a chronic inflammatory disease of the airways instead of solely a reversible airway obstruction. Asthma is often diagnosed on specific symptoms such as chest tightness, wheezing, dyspnea, and coughing. It is likely that, rather than a single disease entity, asthma consists of related, partially overlapping syndromes. The first symptoms often are experienced before the age of 5. Children with the highest risk have a family history of atopy and/or asthma. Viral infections with symptoms of wheezing acquired in the first year of life may be associated with the risk of developing asthma later on [1]. However, making the diagnosis with a reasonable certainty that is supported by spirometry is only possible from the age of 6 onward. More than 50% of children with a period of wheezing earlier on in life are not diagnosed as having asthma at the age of 6 [2]. The use of rescue and anti-inflammatory medication has largely altered the prospects of asthma patients and has improved their quality of life. Thus, nowadays, most asthma patients lead a normal life without restrictions. Disease control achieved by the asthmatics is an important predictor of the likelihood of complications of the disease [3]. However, asthma exacerbations neither respond to inhaled steroids nor can they substantially be prevented in this way [4, 5]. Only the use of oral corticosteroids seems to be unmistakably effective in case of exacerbations [6, 7]. Children with asthma are believed to be prone to more severe respiratory illness than healthy children when infected with airway pathogens. Influenza is the only (lower) respiratory tract infection in humans for which a vaccine has existed for decades. The guidelines of most Western and developing countries advise to vaccinate patients with asthma, including children [8].

H.J. Bueving () and J.C. van der Wouden Department of General Practice, Erasmus MC, University Medical Center Rotterdam, Burg. s’Jacobsplein 51 3015 CA Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_37, © Springer 2010

611

612

H.J. Bueving and J.C. van der Wouden

So, administering influenza vaccination to children may prevent the development of asthma and when having asthma may prevent subsequent morbidity, health use, and complications. In this contribution, we will address the current state of affairs regarding the effect of influenza infection in children and the effectiveness of influenza vaccination in children with asthma.

Influenza: Incidence and Clinical Impact Viral infections, including influenza, have long been associated with asthma exacerbations. The influenza viruses are classified in three genera, labeled A, B, and C. Only types A and B cause considerable epidemics. Every year influenza viruses change their genome partially, which is called antigenic drift. Because of different subtypes and antigenic drift, formerly built-up natural immunity or vaccine-initiated immunity will not provide protection throughout subsequent seasons. Three types of influenza A viruses are known to infect humans and transmit from human to human: H1N1, H2N2, and H3N2. Estimates for the seasonal incidence of influenza vary, depending on the methods used. To reliably assess influenza, the presence of influenza virus should coincide with symptomatic disease. However, in reports on the impact of influenza outbreaks, proxy measures are often used, such as isolated serologic incidence rates, rates of influenza like illness, and complications. Seasonal incidence measured in that way varies from 0–48% [9]. But for discussing the overall impact of influenza and protective measures such as vaccination, one should obviously use an average incidence. The best estimates for an average incidence come from two prospective long-term open population studies. Reported incidences are 4.6% (children aged 0–19 years) respectively 9.5% (children aged 0–5 years) [9–11]. The overall picture is that in healthy children in the majority of cases influenza can be characterized as a self-limiting disease. The mechanism by which influenza causes asthma exacerbations is not yet known precisely. Postulations vary from direct infection to indirect induction of inflammatory responses [12]. Influenza primarily infects the lower respiratory tract, but also causes systemic symptoms (fever and malaise) and upper respiratory tract (URT) symptoms. Studies in asthmatic children report varying incidences, suggesting that between 30 and 80% of exacerbations are due to a virus [13–15]. Viruses found are rhinovirus, coronavirus, respiratory syncytial virus (RSV), influenza virus, and an assortment of other viruses. Rhinovirus is most frequently associated with exacerbations of asthma. We found three studies that assessed the incidence of influenza-related respiratory illness in asthmatic children while confirming the presence of influenza by culture. This “hard” incidence was found to be 11.5% for both influenza A and B in 48 unvaccinated children (aged 2–14 years) under the surveillance of an asthma

Influenza Vaccination in Asthmatic Children

613

clinic in Japan [16]. Three children (6%) were hospitalized for pneumonia. In another, community-based, study 18% of schoolchildren (aged 9–11 years) had influenza-related asthma exacerbations but no serious complications occurred [14]. Asthma exacerbations as well as episodes of URT symptoms lasted for about 7 days and did not differ between viruses detected. In the placebo arm of a trial in asthmatic children over two seasons, the incidence of laboratory-confirmed influenza-related asthma exacerbations was found to be 5%, again no serious complications occurred [17]. Influenza-related URT episodes lasted 8 days whereas influenza-related asthma exacerbations lasted 11 days. Incidences in children with asthma as reported here are between 5 and 18%. Although the one small study, with children under the surveillance of an asthma clinic, found a hospitalization rate of 6%, no complications were found in the above mentioned community-based study on asthmatic children not in the placebo arm of the study that recruited patients in general practice. Of all viral induced exacerbations, influenza accounted for 3.6% respectively 2% of lower respiratory tract (asthma) episodes [14, 15]. In conclusion, the incidence of influenza-related asthma exacerbations in children and its complications have not been extensively investigated. However, an observational study in children of 1–14 years over several seasons did not find excess morbidity diagnosed as asthma exacerbations [18]. The consequences of influenza infection in asthmatic children can be a rise in morbidity (e.g., exacerbations), more physician visits, the use of medication and hospitalizations or death. As some of these consequences are rare, data are only available from large observational studies [19]. Furthermore, quality of life may also be affected [15]. Because influenza can cause all kinds of illness in children, whether healthy or not, only part of the consequences of infection will be associated with asthma.

Availability and Immunogenicity of Vaccines Two main types of influenza vaccine are available for the prevention of influenza: the trivalent inactivated vaccine (TIV) for parenteral use and the trivalent cold adapted live attenuated vaccine (CAIV) for intranasal administration. Both vaccines are highly immunogenic and induce adequate immune response with a high level of seroprotection. Inactivated vaccine has been licensed for children with asthma, while cold adapted vaccine has not yet been licensed for asthmatic patients. Unlike vaccination, natural infections with influenza provide an immune response on several levels, i.e., secretory antibodies (IgA) present at the mucosal surface, serum antibodies (IgG) and stimulate T-cells directed at the influenza virus. Immune resistance is a lifelong one against the specific strain and provides partial protection against antigenic drifts. Inactivated vaccine only produces serum protection while live attenuated vaccine mimics natural infection better by also providing mucosal antibodies. There is limited evidence that live attenuated vaccines also give some protection against antigenic drifts of the influenza virus [20].

614

H.J. Bueving and J.C. van der Wouden

Although efforts are being made to develop an influenza vaccine with a broader spectrum and long-lasting immune response, research has only recently started, and success is not guaranteed [21].

Adverse Effects of Influenza Vaccination Safety and tolerability of inactivated vaccine in children with asthma, especially regarding exacerbations of asthma, are nowadays well established [22–24]. Cold adapted live attenuated vaccine also is generally well tolerated in children and adolescents with asthma [25, 26]; nevertheless, an increased risk of asthma/reactive airway disease in children younger than 36 months of age is of potential concern [27]. Even egg allergy should no longer be an absolute contraindication for influenza vaccination [28].

Effectiveness The effect of inactivated influenza vaccination in preventing clinical symptoms is a much-debated item [29]. Over the past years, live attenuated vaccines have been developed, tested, and used for intranasal administration. The less invasive route, of course, is a benefit in administering the vaccine. Besides, there is hope that the induced mucosal IgA immune response will provide a better protection against infection. In a large multicenter trial, a direct comparison between intramuscular inactivated and intranasal live attenuated vaccine in children with asthma [26] was made in which the live attenuated vaccine was 53% more efficacious in preventing influenza infection. However, as the authors correctly state, because there was no placebo group, the absolute efficacy cannot be calculated. A systematic review indicates that vaccines can have an efficacy of 65% for TIV and 79% for CAIV in reducing serologically confirmed cases of influenza in healthy children, i.e., by comparing pre and postseason antibody titers. However, when using symptombased outcomes, i.e., influenza-related disease, the vaccines showed an efficacy of only 28% for inactivated and 38% for live attenuated vaccine [30]. Moreover, in case of a mismatch between the vaccine composition and the natural virus, efficacy probably will be much lower or absent. In asthmatics, few studies shed light on the clinical effect of inactivated influenza vaccine (Table 1). Observational studies report varying and sometimes even contradictory outcomes. In a retrospective cohort study, effectiveness was only reached for severe asthmatics in a separate analysis, whereas analysis of the whole group revealed an increase of asthma exacerbations [31]. In another study, effectiveness on physician diagnosed acute respiratory disease episodes including otitis media was only significant in asthmatic children under 6 years of age and no effectiveness was found on any children [32]. A third retrospective cohort study showed

1–12

0–12

6–18

6–18

[31]

[32]

[17, 23]

[15]

NS = Not Significant

a

1–6

[30]

Randomized controlled trial

Randomized controlled trial

Children with asthma exacerbations,influenza confirmed by culture or PCR Minimal important difference in quality of life compared with baseline in influenza positive weeks,influenza confirmed by culture or PCR

Retrospective cohort Combined endpoint: influenza like illness, pneumonia, bronchitis, bronchiolitis, asthma exacerbations, otitis media Retrospective cohort Clinic visits, emergency department (ED) visits, hospitalizations for asthma

Retrospective cohort Asthma exacerbations evaluated in emergency department or hospital

Peculiarities No differences in the severity or frequency of asthma attacks found, three hospitalizations in control and two in vaccine group Adjusted incidence rate ratio results Results total vaccine group significant increase in severe asthmatics only exacerbations in all seasons 1993–1994 0.78 (NS)a 1994–1995 0.59 1995–1996 0.65 Subgroup analysis 1–6 years Results all children showed no 1995–1996 significant effect 1996–1997 OR 0.45 1996–1997 OR clinic visits 2.9 OR ED visits 2.0 OR hospitalizations 1.9 (NS)a 1999–2000 2000–2001 OR 1.24 (NS)a Some distinct effects on the 1999–2000 quality of life 2000–2001 OR 0.43 (NS)a

Table 1 Clinical effectiveness of inactivated influenza vaccine in asthmatic children Age in Season(s) and key results vaccine/ Article years Study type Main outcome placebo [16] 2–14 Non-randomized Febrile episodes,influenza Vaccine effectiveness clinical trial confirmed by culture 1992–1993 0.49

Influenza Vaccination in Asthmatic Children 615

616

H.J. Bueving and J.C. van der Wouden

that children in the vaccine group unexpectedly had a significantly increased risk of asthma related clinic visits and ED visits [33]. Although in one small prospective non-randomized study in a tertiary asthma clinic center a positive effect was found on febrile episodes, clinical efficacy for asthmatics has not been established yet at the highest level of evidence [23]. For asthmatic children in a prospective randomized controlled study, no positive clinical effect of vaccination on asthma exacerbations was found [17]. However, a distinct effect on the quality of life in influenza-related episodes in asthmatic children was reported [15]. In conclusion, of the few studies in this area, most show a suboptimal design, and uncertainty remains about the degree of protection vaccination offers against influenza-related symptoms such as asthma exacerbations.

Vaccine Uptake in Children with Asthma According to most national and international guidelines, people with moderate or severe asthma should be vaccinated [8]. However, definitions of asthma vary because of differences in the standardization of severity subcategories and because of differences in the views of physicians and patients on the severity of the disease. Besides, asthma in individual patients varies in degree of severity over the years, so when asthma patients have been vaccinated once, it does not mean that they will always need to be vaccinated. Asthma is a disease with an increasing incidence and is, both in absolute and relative numbers, one of the major disease categories to receive influenza vaccination, especially in children [34]. Despite the proven absence of serious side effects, vaccination uptake in asthmatic children, though differing worldwide, is far from optimal [35, 36]. Fear that vaccination causes illness and doubts about the benefits and effectiveness of influenza vaccination, are still, despite of vast opposite evidence, important reasons for patients and physicians to refrain from vaccination [37].

Cost Effectiveness of Influenza Vaccination When determining cost effectiveness of influenza vaccination, several seasons should be considered and included in the analysis of cost-effectiveness. However, an overall incidence of influenza-related illness between 4.6 and 9.5% in children [9–11] as found before or 5% [17] or even 18% [14] as found in asthmatic children is a difficult starting point. Using these figures, disregarding clinical relevance and assuming protective effectiveness of vaccination to be 100%, 22 children (0–19 years), 11 children (0–5 years),or 20 children (6–18 years) respectively six children (9–11 years) with asthma would have to be vaccinated in order to prevent influenzarelated illness in one child. Because the effectiveness of influenza vaccination is of

Influenza Vaccination in Asthmatic Children

617

course lower than 100% and clinical relevance has to be taken into account, the numbers needed to treat will be higher than calculated here. For instance, in healthy subjects, a clinical effectiveness of the vaccine of just 28% for TIV and 38% for CAIV was found [30]. When extrapolating, this fact alone at least triples the above mentioned numbers needed to treat. In asthmatics, there is no evidence about the degree of protection vaccination provides against influenza-related asthma exacerbations [23]. When assuming a 5% incidence and taking into account the upper boundary of the confidence interval in this study, a maximum protection rate of 34% can be derived [17]. Thus, vaccinating 59 children with asthma could prevent only one influenza-related asthma exacerbation.

Conclusion Although intuitively the best option for preventing influenza and subsequent clinical deterioration in children with asthma seems to be vaccination, no unequivocal evidence for its effectiveness is present. CAIV could prove to be a better alternative than the current TIV, when it is released for asthmatic children. Although from a pathophysiological point of view influenza is believed to be a threat for asthmatic children, very few data are available about this subject. Future research should first of all focus on a long-term observational research, spanning multiple seasons, to determine the real impact of influenza in children with (and without) asthma. Regarding vaccination, CAIV seems to be an improvement, although it still has to be delivered yearly, a huge logistic operation. Future research into influenza vaccination will understandably be focussed on broad-spectrum and long-lasting vaccines. If this goal is ever reached, it will make preventing influenza infections much easier.

References 1. Kiley J, Smith R, Noel P (2007) Asthma phenotypes. Curr Opin Pulm Med. 13:19–23 2. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ (1995) Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 332:133–138 3. Johnston NW, Sears MR (2006). Asthma exacerbations. 1: epidemiology. Thorax 61:722–728 4. McKean M, Ducharme F (2000) Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev. CD001107 5. Edmonds ML, Camargo CA, Jr., Pollack CV, Jr., Rowe BH (2003) Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev. CD002308 6. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW (2001) Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev. CD002178

618

H.J. Bueving and J.C. van der Wouden

7. Weinberger M (2003) Treatment strategies for viral respiratory infection-induced asthma. J Pediatr. 142:S34–S38 8. van Essen GA, Palache AM, Forleo E, Fedson DS (2003) Influenza vaccination in 2000: recommendations and vaccine use in 50 developed and rapidly developing countries. Vaccine 21:1780–1785 9. Bueving HJ, van der Wouden JC, Berger MY, Thomas S (2005) Incidence of influenza and associated illness in children aged 0–19 years: a systematic review. Rev Med Virol. 15:383–391 10. Monto AS, Koopman JS, Longini IM, Jr. (1985) Tecumseh study of illness. XIII. Influenza infection and disease, 1976–1981. Am J Epidemiol. 121:811–822 11. Neuzil KM, Zhu Y, Griffin MR, Edwards KM, Thompson JM, Tollefson SJ, Wright PF (2002). Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis. 185:147–152 12. Tan WC (2005). Viruses in asthma exacerbations. Curr Opin Pulm Med. 11:21–26 13. Minor TE, Dick EC, DeMeo AN, Ouellette JJ, Cohen M, Reed CE (1974) Viruses as precipitants of asthmatic attacks in children. JAMA 227:292–298 14. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O’Toole S, Myint SH, Tyrrell DA, et al. (1995) Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ 310:1225–1229 15. Bueving HJ, van der Wouden JC, Raat H, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, Osterhaus AD, Rimmelzwaan GF, Molken MR, Thomas S (2004) Influenza vaccination in asthmatic children: effects on quality of life and symptoms. Eur Respir J. 24:925–931 16. Sugaya N, Nerome K, Ishida M, Matsumoto M, Mitamura K, Nirasawa M (1994) Efficacy of inactivated vaccine in preventing antigenically drifted influenza type A and well-matched type B. JAMA 272:1122–1126 17. Bueving HJ, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, Rimmelzwaan GF, Osterhaus AD, Rutten-van Molken MP, Thomas S, van der Wouden JC (2004) Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial. Am J Respir Crit Care Med. 169:488–493 18. Fleming DM, Pannell RS, Elliot AJ, Cross KW (2005) Respiratory illness associated with influenza and respiratory syncytial virus infection. Arch Dis Child. 90:741–746 19. Belshe R, Lee MS, Walker RE, Stoddard J, Mendelman PM (2004) Safety, immunogenicity and efficacy of intranasal, live attenuated influenza vaccine. Expert Rev Vaccines. 3:643–654 20. Hampson AW, Osterhaus AD, Pervikov Y, Kieny MP (2006) Report of the second meeting on the development of influenza vaccines that induce broad-spectrum and long-lasting immune responses, World Health Organization, Geneva, Switzerland, 6–7 December 2005. Vaccine 24:4897–4900 21. The American Lung Association Asthma Clinical Centers (2001) The safety of inactivated influenza vaccine in adults and children with asthma. N Engl J Med. 345:1529–1536 22. Cates CJ, Jefferson TO, Bara AI, Rowe BH (2004) Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev. CD000364 23. Bueving HJ, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, Rimmelzwaan GF, Osterhaus AD, Rutten-van Molken MP, Thomas S, van der Wouden JC (2004) Does influenza vaccination exacerbate asthma in children? Vaccine 23:91–96 24. Redding G, Walker RE, Hessel C, Virant FS, Ayars GH, Bensch G, Cordova J, Holmes SJ, Mendelman PM (2002) Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 21:44–48 25. Fleming DM, Crovari P, Wahn U, Klemola T, Schlesinger Y, Langussis A, Oymar K, Garcia ML, Krygier A, Costa H, Heininger U, Pregaldien JL, Cheng SM, Skinner J, Razmpour A, Saville M, Gruber WC, Forrest B (2006) Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 25:860–869

Influenza Vaccination in Asthmatic Children

619

26. Bergen R, Black S, Shinefield H, Lewis E, Ray P, Hansen J, Walker R, Hessel C, Cordova J, Mendelman PM (2004) Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J. 23:138–144 27. Zeiger RS (2002) Current issues with influenza vaccination in egg allergy. J Allergy Clin Immunol. 110:834–840 28. Jefferson T (2006) Influenza vaccination: policy versus evidence. BMJ 333:912–915 29. Jefferson T, Smith S, Demicheli V, Harnden A, Rivetti A, Di Pietrantonj C (2005) Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review. Lancet 365:773–780 30. Kramarz P, Destefano F, Gargiullo PM, Chen RT, Lieu TA, Davis RL, Mullooly JP, Black SB, Shinefield HR, Bohlke K, Ward JI, Marcy SM (2001) Does influenza vaccination prevent asthma exacerbations in children? J Pediatr. 138:306–310 31. Smits AJ, Hak E, Stalman WA, van Essen GA, Hoes AW, Verheij TJ (2002) Clinical effectiveness of conventional influenza vaccination in asthmatic children. Epidemiol Infect. 128:205–211 32. Christy C, Aligne CA, Auinger P, Pulcino T, Weitzman M (2004) Effectiveness of influenza vaccine for the prevention of asthma exacerbations. Arch Dis Child. 89:734–735 33. Erhart LM, Rangel MC, Lu PJ, Singleton JA (2004) Prevalence and characteristics of children at increased risk for complications from influenza, United States, 2000. J Pediatr. 144:191–195 34. Daley MF, Beaty BL, Barrow J, Pearson K, Crane LA, Berman S, Kempe A (2005) Missed opportunities for influenza vaccination in children with chronic medical conditions. Arch Pediatr Adolesc Med. 159:986–991 35. Gnanasekaran SK, Finkelstein JA, Hohman K, O’Brien M, Kruskal B, Lieu T (2006) Parental perspectives on influenza vaccination among children with asthma. Public Health Rep. 121:181–188 36. Lin CJ, Nowalk MP, Zimmerman RK, Ko FS, Zoffel L, Hoberman A, Kearney DH (2006) Beliefs and attitudes about influenza immunization among parents of children with chronic medical conditions over a two-year period. J Urban Health. 83:874–883 37. Neuzil KM, Wright PF, Mitchel EF, Jr., Griffin MR (2000) The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr. 137:856–864

Treatment of Infants with Atopic Dermatitis Ulrich Wahn

Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disease that affects a large number of children in industrialized countries [1]. The 12 month prevalence in 11-year-old children, as studied in the Global International Study of Asthma and Allergies in Childhood trial, ranged from 1 to 20%, with the highest prevalence typically found in Northern Europe [1, 2]. In 45% of children, the onset of AD occurs during the first 6 months of life, during the first year of life in 60%, and before the age of 5 years in at least 85% of the affected individuals. In those children with onset before the age of 2 years, 20% will have persisting manifestations of the disease, and an additional 17% will have intermittent symptoms by the age of 7 years (Fig. 1). A risk factor for persistent AD symptoms is the severity of disease in infancy [3]. The clinical pattern of AD varies with age. Infants typically present with erythematous papules and vesicles on the cheeks, forehead, or scalp, which are intensely pruritic. The childhood phase typically occurs from 2 years of age to puberty. Children are less likely to have the exudative lesions of infancy and instead exhibit more lichenified papules and plaques representing the more chronic disease and involving the hands, feet, wrists, ankles, and antecubital and popliteal regions.

Genetic and Other Risk Factors for AD Parental atopy, in particular AD, is significantly associated with the manifestation and severity of early AD in children [4]. It has been estimated that over half of the overall disease risk can be accounted for by genetic determinants. During the last years, several AD suceptibility genes have been identified. They encode proteins of different functional classes underlining the complexity of the AD pathogenesis [5–7]

U. Wahn () Department for Pediatric Pneumology and Immunology, Charite, Berlin, Germany e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_38, © Springer 2010

621

622

U. Wahn

Fig. 1 The natural history of AD from infancy to childhood obtained from the prospective birth cohort study Multicenter Atopy Study [3]

Environmental factors also play a role in the development of AD. Exposure to aeroallergens (pets, mites, and pollen) has been clearly shown to increase the risk factors for AD and AD severity. Sensitization to food allergens (cow’s milk and hen’s eggs) is associated with infantile AD and is related to disease severity. Food allergen sensitization is also predictive for persistence of symptoms throughout childhood. Only in a minority of those with food sensitization (up to 33% of patients with moderate-to-severe disease of all age groups) are food allergens of clinical relevance, as demonstrated by food challenge studies. Children with AD are at high risk of allergic asthma and allergic rhinitis. Of those with AD during the first 2 years of life, 50% will have asthma during subsequent years. The severity of AD, including early sensitization to food, increases the risk of asthma and allergic rhinitis. The exact mechanism for the progression of the disease in children with AD is unknown; however, it appears to be a complex interaction of genetics, environmental exposure, and sensitization. For children with a family history of atopy, early AD, and sensitization, almost all are expected to have asthma.

Pathophysiology The pathophysiology of AD is the product of a complex interaction between various susceptibility genes, host environments, infectious agents, defects in skin barrier function, and immunologic responses. Activation of T lymphocytes, dendritic cells (DCs), macrophages, keratinocytes, mast cells, and eosinophils is characteristic of AD skin inflammatory responses [8, 9].

Treatment of Infants with Atopic Dermatitis

623

In about 80% of adult patients with AD, the disease is associated with increased serum IgE levels (>150 kU L–1), sensitization against aeroallergens and food allergens, and/or concomitant allergic rhinitis and asthma. AD is characterized by dry skin, even involving nonlesional skin and increased transepidermal water loss. In particular, ceramides serve as the major water-retaining molecules in the extracellular space of the cornified envelope, and the barrier function of these complex structures is provided by a matrix of structural proteins, which are bound to ceramides. A reduced content of ceramides has been reported in the cornified envelope of both lesional and nonlesional skin in patients with AD. Changes in stratum corneum pH levels have been found in patients with AD and might impair lipid metabolism in the skin [10]. Overexpression of stratum corneum chymotryptic enzyme is also likely to contribute to the breakdown of the AD epidermal barrier. This would allow penetration of irritants and allergens, which trigger an inflammatory response, thus contributing to the cutaneous hyperreactivity characteristic of AD. The increased susceptibility to irritants in patients with AD might therefore represent a primary defect of epidermal differentiation compounded by the presence of inflammation-induced skin damage [11].

Triggers of AD Allergens Placebo-controlled food challenge studies have demonstrated that food allergens can induce eczematoid skin rashes in a subset of infants and children with AD. In some patients, urticarial reactions can trigger the itch-scratch cycle that flares this skin condition. Children with food allergy have positive immediate skin test responses or serum IgE directed to various foods, particularly egg, milk, wheat, soy, and peanut. Food allergen-specific T cells have been cloned from the skin lesions of patients with AD, providing direct evidence that foods can contribute to skin immune responses. In addition, it is well established that food can exacerbate AD both through allergic and nonallergic hypersensitivity reactions [12, 13]. Furthermore, direct contact with the skin (e.g., in the preparation of meals or when feeding infants) might be an important factor for the aggravation of eczema. Beyond the age of 3 years, food allergy is frequently outgrown, but sensitization to inhalant allergens is common [14].

Microorganisms Most patients with AD are colonized with S. aureus and experience exacerbation of their skin disease after infection with this organism [15–19]. In patients with AD with bacterial infection, treatment with antistaphylococcal antibiotics can result in

624

U. Wahn

reduction of skin disease. An important strategy by which S. aureus exacerbates AD is by secreting toxins called superantigens, which stimulate activation of T cells and macrophages. Most patients with AD make specific IgE antibodies directed against staphylococcal superantigens, which correlate with skin disease severity [20, 21]. Superantigens also induce corticosteroid resistance, thereby complicating their response to therapy.

Irritant Factors Frequently, rough or woolly clothing leads to mechanical irritation and exacerbation of AD and eczema. Chemical irritants like skin-cleansing agents should also be considered but can only be satisfactorily identified by means of avoidance.

Diagnostic Work-Up The investigation of exacerbating factors in AD involves a patient history, specific skin and blood tests, and challenge tests, depending on the degree of the disease severity and on the suspected factors involved.

Food Both SPTs and measurement of specific IgE can be used to assess sensitization to a food. Diagnostic sensitivity and specificity vary considerably among different foods, reading systems, and age groups. A decision point discriminating between clinical relevance of sensitization (with challenge as the gold standard) has been developed with regard to specific IgE and SPTs to egg, milk, peanut, and others foods in children. Decision points can be helpful in making the decision to perform oral challenges. However, the need for challenges has to be decided on an individual basis [22–26]. Other invalidated tests, such as lymphocyte cytotoxicity tests, the basophil degranulation test, or measurement of serum IgG (or subclasses) should not be used. APT is primarily a tool to investigate the mechanisms of eczema in the skin. However, APT can also reveal sensitization in patients with AD and might identify a subgroup of such patients. An elimination diet should not be recommended for a patient solely on the basis of a positive APT response to a food [27]. All the above mentioned tests require specialist knowledge in their performance and interpretation. Standardized, physician-supervised food challenges provide the most accurate diagnostic tool. However, it should be noted that patients can present with reactions at least 24 h after a food challenge, and the challenge settings and protocol should

Treatment of Infants with Atopic Dermatitis

625

be appropriately designed; for example, in case of a negative challenge response, the skin of the patient should be examined the following day [28, 29].

Treatment The long-term management of AD presents a clinical challenge and includes basic and topical treatment [30] as well as in subgroups of infants, systemic treatment as well as specific allergen avoidance. For optimal disease management, regular medical supervision, together with education of the patient or care providers and appropriate psychosocial support, is needed. In selected patients, hospitalization might be of great benefit, especially in centers with a multidisciplinary team approach [31, 32].

Basic Treatment Basic therapy of AD should comprise optimal skin care, addressing the skin barrier defect with regular use of emollients and skin hydration, along with identification and avoidance of specific and nonspecific trigger factors. Nonspecific irritants include contactants, such as clothing made from occluding or irritating synthetic or wool material. Further irritating factors are soaps and hot water temperature during showering or bathing. Contacts with water should be minimized, moderately heated water should be used, and mild syndets with an adjusted pH value (acidified to pH 5.5–6.0 in order to protect the acid mantle of the skin) should be used for cleansing [33, 34]. Further treatment, on the basis of disease severity, includes the addition of multiple therapeutic agents in a step-wise fashion (Fig. 2). A combination of different

Fig. 2 Stepwise management of patients with atopic dermatitis (AD). TCS, topical corticosteroides; TCI, topical calcineurin inhibitors; CyA cyclosporine A. * Over the age of 2 years[8]

626

U. Wahn

topical agents might be indicated. In cases of severe AD that cannot be controlled with topical treatment, systemic treatment options might need to be considered.

Topical Treatment Emollients A key feature of AD is severe dryness of the skin caused by a dysfunction of the skin barrier with increased transepidermal water loss. This is typically accompanied by intense pruritus and inflammation. The regular use of emollients is important for addressing this problem, and together with skin hydration, it represents the mainstay of the general management of AD. Emollients should be applied continuously, even if no actual inflammatory skin lesions are obvious. Because different emollients are available, selection criteria, such as the individual skin status, seasonal and climatic conditions, and the time of day, should be considered for optimizing the patients’ basic treatment. ‘‘Water-in-oil’’ or ‘‘oil-in-water’’ emulsions might be substituted to support the skin barrier function. Emollients containing polidocanol are effective in reducing pruritic symptoms. Adjuvant application of topical preparations with urea allows for intensive hydration of the skin, whereas salicyl acid can be added to an emollient for the treatment of chronic hyperkeratotic lesions.

Topical Glucocorticosteroids Topical glucocorticosteroids are still an important tool for the treatment of acute flare-ups. Over recent years, the risk of adverse effects induced by topical steroids could effectively be reduced by optimizing application protocols and using new steroid preparations with improved risk/benefit ratios and lower atrophogenic potential, such as prednicarbate, mometasone furoate, fluticasone, and methylprednisolone aceponate [35, 36]. For the topical use of glucocorticosteroids, different therapeutic schemes have been established: intermittent use might be as effective as an initial therapy with a high potent steroid followed by a time-dependent dose reduction or change over to a lower potent preparation [37]. The choice of an adequate vehicle is important to achieve the optimal therapeutic effect. Recent data indicate that in children and adults, an application of corticosteroids (fluticasone) on unaffected skin twice weekly prevents further flare-ups of AD [38]. Aside from an anti-inflammatory effect, treatment with topical steroids contributes to a reduction of skin colonization with S. aureus and therefore might affect a further trigger factor of AD [39, 40]. The side effects of uncontrolled topical steroid use, particularly on delicate skin areas, are well documented, and therefore topical steroid preparations should be applied not more than twice daily as short-term therapy for acute eczematous lesions.

Treatment of Infants with Atopic Dermatitis

627

In children, only mild to moderately potent steroid preparations should be used. In general, during acute flares, steroids should be used in combination with baseline emollient skin care to avoid steroid overuse and steroid-related side effects.

Topical Calcineurin Inhibitors (TCIs) The TCIs pimecrolimus and tacrolimus allow a steroid-free, anti-inflammatory topical therapy of AD [41, 42]. In both animal and human studies, both molecules demonstrated an immunomodulatory activity. Currently, in the United States and Europe, pimecrolimus cream (1%) [43] and tacrolimus ointment (0.03%) [44] are only approved for the treatment of AD in children aged 2 years and older. Tacrolimus ointment (0.1%) is only approved for use in adults. The anti-inflammatory potency of 0.1% tacrolimus ointment is similar to a corticosteroid with moderate potency, whereas 1% pimecrolimus cream is less active [45]. Thus far, no trials have been published comparing pimecrolimus 1% with a mild corticosteroid. Both agents proved to be effective, with a good safety profile for a treatment period of up to 2 years with pimecrolimus and up to 4 years with tacrolimus [46–48]. An occasionally observed side effect with TCIs is a transient burning sensation of the skin. In a comparative study of the local side effects of 0.03% tacrolimus ointment vs. 1% pimecrolimus cream in children, pimecrolimus achieved better local tolerability than tacrolimus [49]. Preliminary studies indicate that treatment with TCIs is not associated with a risk of skin atrophy. Therefore, they are a useful alternative for the treatment of sensitive skin areas, such as the face and intertriginous regions [50]. Generalized viral infections, such as eczema herpeticum or eczema molluscatum, have been observed during TCI treatment. It is unclear whether a trend for increased frequency of viral superinfections with use of TCIs really exists. Although there is no evidence of a causal link of cancer and the use of TCIs, the United States Food and Drug Administration has issued a black-box warning for pimecrolimus (Elidel; Novartis, Basel, Switzerland) and tacrolimus (Protopic; Astellas, Deerfield, Ill) because of a lack of long-term safety data. Furthermore, the new labeling states that these drugs are recommended as second-line treatments and that their use in children younger than 2 years of age is currently not recommended. Longterm safety studies with TCIs in patients with AD, including infants and children, are ongoing.

Wet-Wrap Therapy A wet layer of cotton dressing, which is then covered with tubular bandages applied over emollients in combination with antiseptics or topical steroids, has been shown to be beneficial in cases of exacerbated AD skin lesions. A more practical alternative approach using clothing rather than bandages has also been described in detail [51–53].

628

U. Wahn

Topical Antimicrobial Therapy The skin of patients with AD is heavily colonized with S. aureus, even at uninvolved sites. Toxins secreted by the majority of S. aureus on the skin behave as superantigens and, as discussed in the pathophysiology section, can directly influence the disease activity, although clinical signs of bacterial superinfection might be absent. Topical antiseptics, such as triclosan (2,4,4’-trichloro-2’-hydroxydiphenyl ether) or chlorhexidine, offer the advantage of a low sensitizing potential and low resistance rate [54]. They can be used in emollients or as part of an additional wet-wrap dressing therapy. The topical use of triclosan has been shown to be effective in significantly reducing skin colonization with S. aureus and skin symptoms. An irritative, photoallergenic, phototoxic, mutagenic, or carcinogenic potential of triclosan has not been observed. The use of silvercoated textiles and silk fabric with a durable antimicrobial finish can reduce S. aureus colonization and eczema severity. These new options are still under investigation [55]. The addition of a topical antimicrobial agent to a topical steroid preparation has been shown to result in greater clinical improvement than a topical steroid alone. Interestingly, AD seems not to be associated with a higher risk of sensitization against topical antimicrobials. Because of deficient skin barrier function, patients with AD are exposed to a higher risk of recurrent bacterial superinfections of the skin. For the treatment of mild and localized forms of this secondary infection, a topical antibiotic treatment might be beneficial. Although erythromycin and fusidic acid have been widely used in Europe, high resistance rates of S. aureus to erythromycin have resulted in a preferential use of fusidic acid [56]. Topical fusidic acid has proved to be very effective against S. aureus because of its low minimal inhibitory concentration and good tissue penetration. However, long-term therapy with fusidic acid is suspected to be responsible for increasing resistance. Therefore, a restricted topical application for only short periods of about 2 weeks is advisable. For intranasal eradication of methicillin-resistant S. aureus, topical mupirocin has been shown to be effective.

Systemic Treatment Antimicrobial Treatment Systemic antibiotic treatment is indicated for widespread bacterial secondary infection, (primarily S. aureus) [57]. First- or second-generation cephalosporins or semisynthetic penicillins for 7–10 days are usually effective. Erythromycinresistant organisms are fairly common, making macrolides less useful alternatives [58, 59]. In cases of penicillin or cephalosporin allergy, clindamycin or oral fusidic acid are possible alternatives. Unfortunately, recolonization after a course of anti-

Treatment of Infants with Atopic Dermatitis

629

staphylococcal therapy occurs rapidly. Maintenance antibiotic therapy, however, should be avoided because it might result in colonization by methicillin-resistant organisms. Infection of the skin with the herpes simplex virus in the form of an eczema herpeticum (Kaposi’s varicelliform eruption) represents a severe and possibly lifethreatening complication of AD, requiring a systemic antiviral treatment with acyclovir or other antiviral agents (e.g., valacyclovir) [60]. Recent findings underline the pathogenetic importance of a fungal colonization as a trigger factor. Contradictory data have been published about the efficacy of a systemic treatment of AD with ketoconazole, and although it is assumed that selected patients with AD might benefit from a topical or systemic antimycotic therapy, the effect of a therapeutic intervention needs to be better defined by further studies [61].

Systemic Corticosteroids Although oral corticosteroids are commonly used for many different skin diseases, few randomized clinical trials have been performed in patients with AD thus far. It is well known that relapse after the discontinuation of oral steroids is often observed. Corticosteroids in the form of a long-term oral therapy are associated with a series of well-documented side effects (e.g., disturbance of growth, cataracts, and development of lymphopenia). In cases of acute flare-up, patients might benefit from a short course of systemic therapy with corticosteroids, but long-term use in infants and children should be avoided [62, 63].

Cyclosporin A As with TCIs, cyclosporin A (CyA) inhibits calcineurin-dependent pathways, resulting in reduced levels of proinflammatory cytokines, such as IL-2 and IFN-g. Multiple clinical trials have shown CyA to be an effective treatment for adult and childhood AD, and although relapse after discontinuation of therapy is often observed, posttreatment disease severity often does not return to baseline levels [64–66]. Despite the effectiveness of oral CyA in the treatment of AD, because of the possible side effects, particularly renal toxicity, the use of CyA should be limited to patients with severe refractory disease, contraindications must be excluded, and blood pressure and laboratory parameters must be monitored closely. The treatment can be performed in the form of a short- or long-term therapy with high-dose (3–5 mg/kg/d) or low-dose (2.5 mg/kg/d) administration, depending on the patients’ individual medical conditions. The principle of treatment should be to aim for the lowest effective dose and the shortest treatment period because toxicity is related to

630

U. Wahn

both of these factors. In children, it should be considered that vaccinations might not be effective during immunosuppression.

Antihistamines The therapeutic value of antihistamines seems to reside principally in their sedative properties, and they are useful as a short-term adjuvant to topical treatment during relapses associated with severe pruritus. Although there are no large controlled studies to date, newer nonsedating antihistamines seem to have little or no value in atopic eczema [67–69].

Diet There is no universally recommended diet for infants with AD. Dietary restrictions should only be recommended in cases of an established diagnosis of food hypersensitivity. International guidelines for the diagnosis of food hypersensitivity have been published. As regards food-induced eczema, it is important to note that the predictive value of a positive case history is lower than that of food-induced immediate reactions.

Education The goal of the patients’ education should be living with atopic dermatitis by means of an empowered patient or, in the case of infants and young children, a caregiver who can work as a partner with the doctor in selfmanaging their own or their children’s disease. Education to enhance disease knowledge, psychologic improvement in disease perception, and scratch control behavior modification, together with regular daily treatment, will lead to better skin care. This improvement in disease control will restore family dynamics, and the patient and family will cope better and have an overall improvement in quality of life. Additionally, education should be aimed at reducing doctor shopping, facilitating a better partnership between the doctor and the patient-parent, and decreasing the long-termcosts of chronic disease treatment. From the recent controlled studies, there is the general impression that positive outcomes are dependent on the time spent with parents and the qualification of the trainer. Sharing personal experiences in managing AD was helpful in 80% of those parents who attended the program conducted by Staab et al. [70]. A 12-lesson educational program described positive outcomes after 1 year, including diminished fear of topical corticosteroid cream use. In a recent German

Treatment of Infants with Atopic Dermatitis

631

multicenter study, 820 children with AD were randomized into an intervention group (n = 443) and a control group (n = 377). The intervention group underwent a 12 h education program on an outpatient basis. After 1 year, the overall Severity Score for Atopic Dermatitis (SCORAD) measure, quality of life, scratching index, and adherence to treatment showed statistically significant improvement. Fundamentally, each patient with AD should be educated on various aspects of the disease. For economic and practical reasons, structured education will target patients with moderate and severe chronic AD and their parents. Structured patient education should enable both patient and parent to have realistic short-term goals, enter a process of problem solving, accept living with their disease, appropriately use available social support, and enhance their own motivation for therapy.

References 1. Anonymous. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351:1225–1232 2. Kay J, Gawkrodger DJ, Mortimer MJ, Jaron AG. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol 1994;30:35–39 3. Illi S, von Mutius E, Lau S, Nickel R, Gruber C, Niggemann B, et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004;113:925–931 4. Purvis DJ, Thompson JM, Clark PM, Robinson E, Black PN, Wild CJ, et al. Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age. Br J Dermatol 2005;152:742–749 5. Hoffjan S, Epplen JT. The genetics of atopic dermatitis: recent findings and future options. J Mol Med 2005;83:682–692 6. Lee YA, Wahn U, Kehrt R, Tarani L, Businco L, Gustafsson D, et al. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet 2000;26:470–473 7. Morar N, Willis-Owen S, Moffatt M, Cookson W. The genetics of atopic dermatitis. J. Allergy Clin Immunol 2006;118:24 8. Akdis CA, Akdis M, Bieber T, et al.Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol 2006;118:152–169 9. Novak N, Bieber T, Leung DY. Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol 2003;112(Suppl):S128–S39 10. Seidenari S, Giusti G. Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin. Acta Derm Venereol 1996;75:429–433 11. Sator PG, Schmidt JB, Honigsmann H. Comparison of epidermal hydration and skin surface lipids in healthy individuals and in patients with atopic dermatitis. J Am Acad Dermatol 2003;48:352–358 12. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgEmediated food allergy among children with atopic dermatitis. Pediatrics 1998;101:e8 13. Werfel T, Breuer K. Role of food allergy in atopic dermatitis. Curr Opin Allergy Clin Immunol 2004;4:379–385 14. Schafer T, Heinrich J, Wjst M, Adam H, Ring J, Wichmann HE. Association between severity of atopic eczema and degree of sensitization to aeroallergens in schoolchildren. J Allergy Clin Immunol 1999;104:1280–1284

632

U. Wahn

15. Abeck D, Mempel M. Staphylococcus aureus colonisation in atopic dermatitis and its therapeutic implications. Br J Dermatol 1998;139:13–16 16. Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 2002;119:433–439 17. Breuer K, Kapp A, Werfel T. Bacterial infections and atopic dermatitis. Allergy 2001;56:1034–1041 18. Leung DY. Infection in atopic dermatitis. Curr Opin Pediatr 2003;15:399–404 19. Rippke F, Schreiner V, Doering T, Maibach HI. Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus aureus. Am J Clin Dermatol 2004;5:217–223 20. Leung DYM, Harbeck H, Bina P, Reiser RF, Yang E, Norris AD, et al. Presence of IgE antibodies to staphylococcal enterotoxins on the skin of patients with atopic dermatitis: evidence for a new group of allergens. J Clin Invest 1993;92:1374–1380 21. Novak N, Allam JP, Bieber T. Allergic hyperreactivity to microbial components: a trigger factor of ‘‘intrinsic’’ atopic dermatitis? J Allergy Clin Immunol 2003;112:215–216 22. Celik-Bilgili S, Mehl A, Verstege A, Staden U, Nocon M, Beyer K, et al. The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges. Clin Exp Allergy 2005;35:268–273 23. Osterballe M, Bindslev-Jensen C. Threshold levels in food challenge and specific IgE in patients with egg allergy: is there a relationship? J Allergy Clin Immunol 2003;112:196–201 24. Sampson HA. Food allergy – accurately identifying clinical reactivity. Allergy 2005;60(Suppl 79):19–24 25. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113:805–819 26. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891–896 27. Darsow U, Laifaoui J, Kerschenlohr K, Wollenberg A, Przybilla B, Wuthrich B, et al. The prevalence of positive reactions in the atopy patch test with aeroallergens and food allergens in subjects with atopic eczema: a European multicenter study. Allergy 2004;59:1318–1325 28. Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U, Blanco C, Ebner C, Hourihane J, et al. Standardization of food challenges in patients with immediate reactions to foods – position paper from the European Academy of Allergology and Clinical Immunology. Allergy 2004;59:690–697 29. Breuer K, Heratizadeh A, Wulf A, Baumann U, Constien A, Tetau D, et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy 2004;34:817–824 30. Ainley-Walker PF, Patel L, David TJ. Side to side comparison of topical treatment in atopic dermatitis. Arch Dis Child 1998;79:149–152 31. Boguniewicz M, Nicol N. Conventional therapy. Immunol Allergy Clinics N Am 2002;22:107–124 32. Darsow U, Lubbe J, Taieb A, Seidenari S, Wollenberg A, Calza AM, et al. Position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol 2005;19:286–295 33. Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol 2003;4:771–788 34. Subramanyan K. Role of mild cleansing in the management of patient skin. Dermatol Ther 2004;17:26–34 35. Kerscher MJ, Hart H, Korting HC, Stalleicken D. In vivo assessment of the atrophogenic potency of mometasone furoate, a newly developed chlorinated potent topical glucocorticoid as compared to other topical glucocorticoids old and new. Int J Clin Pharmacol Ther 1995;33:187–189 36. Korting HC, Kerscher MJ, Schafer-Korting M. Topical glucocorticoids with improved benefit/ risk ratio: do they exist? J Am Acad Dermatol 1992;27:87–92

Treatment of Infants with Atopic Dermatitis

633

37. Thomas KS, Armstrong S, Avery A, Po AL, O’Neill C, Young S, et al. Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema. BMJ 2003;30:768 38. Berth-Jones J, Damstra RJ, Golsch S, Livden JK, Van Hooteghem O, Allegra F, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. BMJ 2003;326:1367 39. Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and Staphylococcus aureus in atopic dermatitis. J Am Acad Dermatol 1992;27:29–34 40. Stalder JF, Fleury M, Sourisse M, Rostin M, Pheline F, Litoux P. Local steroid therapy and bacterial skin flora in atopic dermatitis. Br J Dermatol 1994;131:536–540 41. Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ 2005;330:516 42. Breuer K, Werfel T, Kapp A. Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis. Am J Clin Dermatol 2005;6:65–77 43. Elidel [package insert]. Basel, Switzerland : Novartis Pharmaceuticals Corp.; 2006 44. Protopic [package insert]. Deerfield, IL: Astellas Pharma Manufacturing Inc.; 2006 45. Harper J, Green A, Scott G, Gruendl E, Dorobek B, Cardno B, et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol 2001;144:781–787 46. Hultsch T, Kapp A, Spergel J. Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Dermatology 2005;211:174–187 47. Paul C, Cork M, Rossi AB, Papp KA, Barbier N, de Prost Y. Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years. Pediatrics 2006;117:118–128 48. Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002;110:e2 49. Kempers S, Boguniewicz M, Carter E, Jarratt M, Pariser D, Stewart D, et al. A randomized inverstigator-blinded study comparing pimecrolimus cream 1% with tacrolimus 0.03% in the treatment of pediatric patients with moderate atopic dermatitis. J Am Acad Dermatol 2004;51:515–525 50. Queille-Roussel C, Paul C, Duteil L, Lefebvre MC, Rapatz G, Zagula M, et al. The new topical ascomycin derivate SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001;144:507–513 51. Foelster-Holst R, Nagel F, Zoellner P, Spaeth D. Efficacy of crisis intervention treatment with topical corticosteroid prednicarbat with and without partial wet-wrap dressing in atopic dermatitis. Dermatology 2006;212:66–69 52. Mallon E, Powell S, Bridgman A. ‘‘Wet-wrap’’ dressings for the treatment of atopic eczema in the community. J Dermatolog Treat 1994;5:97–98 53. Ricci G, Patrizi A, Bendandi B, Menna G, Varotti E, Masi M. Clinical effectiveness of a silk fabric in the treatment of atopic dermatitis. Br J Dermatol 2004;150:127–131 54. Sporik R, Kemp AS. Topical triclosan treatment of atopic dermatitis. J Allergy Clin Immunol 1997;99:861 55. Gauger A, Mempel M, Schekatz A, Schafer T, Ring J, Abeck D. Silver-coated textiles reduce Staphylococcus aureus colonization in patients with atopic eczema. Dermatology 2003;207:15–21 56. Verbist I. The antimicrobial activity of fucidic acid. J Antimicrob Chemother 1990;25(Suppl B):1–5 57. Boguniewicz M, Sampson H, Harbeck R, Leung DYM. Effects of cefuroxime axetil on S. aureus colonization and superantigen production in atopic dermatitis. J Allergy Clin Immunol 2001;108:651–652

634

U. Wahn

58. Hoeger PH. Antimicrobial susceptibility of skin-colonizing S. aureus strains in children with atopic dermatitis. Pediatr Allergy Immunol 2004;15:474–477 59. Ravenscroft JC, Layton A, Barnham M. Observations on high levels of fusidic acid resistant Staphylococcus aureus in Harrogate, North Yorkshire, UK. Clin Exp Dermatol 2000;25:327–330 60. Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B. Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. J Am Acad Dermatol 2003;49:198–205 61. Lintu P, Savolainen J, Kortekangas-Savolainen O, Kalimo K. Systemic ketoconazole is an effective treatment of atopic dermatitis with IgE-mediated hypersensitivity to yeasts. Allergy 2001;56:512–517 62. Aylett SE, Atherton DJ, Preece MA. The treatment of difficult atopic dermatitis in childhood with oral beclomethasone dipropionate. Acta Derm Venereol Suppl 1992;176:123–125 63. Anonymous. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351:1225–1232 64. Berth-Jones J, Finlay AY, Zaki I, Tan B, Goodyear H, Lewis-Jones S, et al. Cyclosporine in severe childhood atopic dermatitis: a multicenter study. J Am Acad Dermatol 1996;34:1016–1021 65. Hauk PJ, Leung DYM. Tacrolimus (FK506): new treatment approach in superantigenassociated diseases like atopic dermatitis? J Allergy Clin Immunol 2001;107:391–392 66. Zaki I, Emerson R, Allen BR. Treatment of severe atopic dermatitis in childhood with cyclosporin. Br J Dermatol 1996;135(Suppl 48):21–24 67. Diepgen TL. Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 2002;13:278–286 68. Wahlgren C-F, Hagermark O, Bergstrom R. The antipruritic effect of a sedative and a nonsedative antihistamine in atopic dermatitis. Br J Dermatol 1990;122:545–551 69. Warner JO. ETAC Study Group. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up. J Allergy Clin Immunol 2001;108:929–937 70. Staab D, Diepgen T, Fartasch M, Kupfer J, Lob-Corzilius T, Ring J, et al. Age-related, structured education programmes improve the management of atopic dermatitis in children and adolescents: results of the German Atopic Dermatitis Intervention Study (GADIS). BMJ 2006;332:933–938

Diagnosing Food Allergy in Children Dan Atkins

Introduction One of the most basic and satisfying roles of a parent is to feed their child. As a result, feeding behaviors and responses to food ingestion are among the most scrutinized aspects of a child’s life. Because of this careful monitoring, in addition to the frequency with which children eat throughout the day, it is not surprising that parents frequently attribute their child’s symptoms to food ingestion. As a result, clinicians who provide medical care for children are routinely called upon to provide advice and accurately distinguish an adverse reaction to a food from some other cause of symptoms. The consequences of inaccurately labeling a food as a cause of symptoms include delaying appropriate treatment for another disorder or needlessly removing a food from the diet which could have adverse nutritional and social consequences. In those situations where symptoms are triggered by food ingestion, determining which type of an adverse reaction to a food is responsible is important because of the implications regarding the mechanism involved, the likelihood of reproducibility, and the prognosis.

Features of IgE-Mediated Food Allergy Although IgE-mediated reactions have been reported to a wide variety of foods, milk, egg, peanut, wheat, and soy account for the majority of reactions in young children, whereas peanuts, tree nuts, fish, and shellfish are the most common food allergens in older children, adolescents and adults [1]. A history of food allergy or other allergic disease in immediate family members, as well as a personal history

D. Atkins () Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_39, © Springer 2010

635

636

D. Atkins

Table 1 Symptoms and signs often associated with IgE-mediated reactions to foods by organ system Skin Flushing, pruritus, urticaria, angioedema, eczema Gastrointestinal tract Oropharyngeal pruritus and edema, abdominal cramping, nausea, vomiting, diarrhea Respiratory tract Nasal congestion, nasal pruritus, rhinorrhea, repetitive sneezing, laryngeal edema, wheezing, coughing, shortness of breath Cardiovascular system Hypotension, tachycardia, palpitations, chest pain Neurological system Changes in level of consciousness Behavioral Irritability (preceding or in combination with other symptoms)

of eczema, asthma, allergic rhinitis or animal dander sensitivity, increases the likelihood of IgE-mediated food allergy. Symptoms involving the skin, gastrointestinal tract, respiratory tract and, less frequently, the cardiovascular system, either individually or in combination, typically begin during or within minutes to a couple of hours of food ingestion (see Table 1). The severity of symptoms varies from annoying to life threatening with individual reactions lasting from minutes to hours. Biphasic reactions, consisting of improvement after an initial reaction followed by a later resurgence of symptoms, and severe protracted reactions, although reported in children, are the exceptions rather than the rule. Depending upon the sensitivity of the patient and the route and extent of exposure, symptoms may gradually resolve without treatment or respond to the administration of epinephrine or an antihistamine, although more than one dose is occasionally required. Subsequent exposures to the offending food typically trigger reactions similar in onset and progression when a comparable dose of allergen is ingested. Inconsistencies in the timing and severity of allergic reactions to the same food may result from a difference in the route of exposure or amount consumed, denaturation of a food allergen during food preparation, cross-contact with other foods, factors that impact digestion or absorption such as vomiting, changes in the patient’s level of sensitivity or the ingestion of medications such as antihistamines that can mask symptoms. In rare instances, the ingestion of a food must be accompanied by another stimulus in order for an IgE-mediated reaction to occur. Food-dependent exercise-induced anaphylaxis is an interesting example where anaphylaxis is provoked by exercise within several hours of ingestion of a specific food [2–4]. Ingestion of the specific food not followed by exercise does not cause symptoms even though the patient usually has a positive skin test to the food. Alternatively, exercise not preceded by ingestion of the specific offending food is well tolerated, except in rare cases where the ingestion of any meal prior to exercise triggers symptoms. A wide variety of foods have been implicated in causing these reactions such as fish, shellfish, wheat, celery, mushrooms, and fruit [5, 6]. The typical age of patients with food-dependent exercise-induced anaphylaxis extends from adolescence through the late thirties

Diagnosing Food Allergy in Children

637

with women outnumbering men. The mechanism responsible for these reactions remains to be defined. This entity should be considered when reactions occur only following exercise preceded by food ingestion. Skin testing the patient to foods ingested shortly before the exercise preceding the reaction may aid in identification of the offending food [7, 8]. Another interesting IgE-mediated entity is the pollen-food allergy syndrome which is encountered in patients sensitized to pollens containing allergens that cross react with those found in fresh fruits and vegetables [9, 10]. Even though ingestion of the fresh food causes symptoms, cooking usually denatures these typically heat-labile allergens so that the same fruit or vegetable can be tolerated. Although the list of described pollen-food syndromes continues to grow, the more common clinically encountered examples include ragweed pollen sensitive patients who experience symptoms with the ingestion of melons or banana, birch pollen sensitive patients who experience symptoms when eating apple, hazelnut, celery, carrots, or raw potato, and mugwort pollen sensitive patients who react upon ingesting fresh apples, celery, peanuts or kiwi [11]. The syndrome was initially called the oral allergy syndrome with reference to the typical pattern of rapid onset pruritus and mild edema localized to oropharyngeal tissues. Because some patients experience significant laryngeal edema or symptoms extending beyond the oropharynx, including anaphylaxis, this name has been considered misleading and the pollen-food allergy syndrome has been proposed as a suitable alternative [12].

Features of NonIgE-Mediated Food Allergy The most commonly observed nonIgE-mediated food allergies in children present primarily with abdominal complaints that vary depending upon the location of the gastrointestinal tract involved. The family and personal history of other allergic diseases are often unrevealing. Typical presenting symptoms include abdominal pain, nausea, vomiting, diarrhea, bloody stools, early satiety, food refusal, and failure to thrive. The timing of symptom onset in relation to food ingestion is delayed in comparison to that observed in IgE-mediated reactions. As a result, identifying the culprit food is sometimes difficult, resulting in persistent symptoms until the offending food is identified and removed from the diet. Examples of these entities include allergic proctocolitis, food protein-induced enterocolitis syndrome (FPIES), and celiac disease. Allergic proctocolitis is a benign disorder encountered in formula and breast fed infants brought for evaluation because of stools streaked with blood [13]. Frequently implicated foods include milk and soy although occasionally other foods in the breast feeding mother’s diet are causative. Removal of the offending foods from the diet usually results in symptom resolution within 72 h and typically the food can be tolerated in the diet by a year of age. Infants with FPIES present with frequent vomiting, diarrhea, and failure to thrive while the culprit food remains in the diet.

638

D. Atkins

Although milk and soy are frequently causative, other foods such as cereals, vegetables, and meats have also been implicated [14, 15]. Children with this disorder may also present acutely with bouts of profuse vomiting and diarrhea beginning approximately 2 h after exposure to the offending food. Because of lethargy associated with these reactions in addition to hypovolemic shock observed in approximately 20%, the symptoms are often initially attributed to infection rather than food allergy until the reaction recurs upon subsequent food exposure. Treatment includes fluid resuscitation rather than epinephrine or antihistamines. The development of tolerance with age is the rule. Attempts at reintroduction of the food in the diet should be medically supervised with an intravenous line in place. Children with celiac disease classically present as infants or young children with recurrent vomiting, steatorrhea and failure to thrive as a result of chronic inflammation of the small bowel mucosa resulting from immunologic reactivity to gliadin peptides present in wheat, rye and barley [16]. The diagnosis is made using serologic screening tests along with typical findings on small intestinal biopsy and demonstration of improvement upon removal of gluten from the diet. Once the diagnosis is confirmed, lifelong dietary avoidance of gluten is indicated. Combined disorders that are both IgE- and nonIgE-mediated include primarily the allergic eosinophilic gastrointestinal disorders such as allergic eosinophilic gastroenteritis and eosinophilic esophagitis. Eosinophilic esophagitis can present from infancy through adulthood with difficulty feeding, failure to thrive, vomiting, epigastric pain, dysphagia, and food impaction [17]. The majority of patients have a positive family and personal history of other allergic disease along with positive skin tests to foods, although relatively few experience food-induced anaphylaxis. The diagnosis is made by the demonstration of 15 or more eosinophils per high power field on esophageal mucosal biopsies following an adequate period of high dose acid suppression. Favorable clinical responses have been observed in response to treatment with elimination diets and swallowed topical steroid preparations. The evaluation of nonIgE-mediated and combined food allergies is often best accomplished through the cooperative efforts of both an allergist and a gastroenterologist. In addition to efforts to identify the causative food, the accurate diagnosis and management of these disorders often requires upper endoscopy and/or colonoscopy to document the type and degree of inflammation present.

Evaluation of the Food Allergic Child History The goal of the history is to generate a list of suspected or potential culprit foods along with a thorough description of all symptoms considered to be food related and the timing of those symptoms in relation to food ingestion. Important aspects of the history are listed in Table 2. This information is then evaluated for features consistent with food allergy, some other type of adverse reaction to a food such as

Diagnosing Food Allergy in Children

639

Table 2 Important aspects of the food allergy history Suspected foods · List of suspected foods · Route of exposure Ingestion Contact Inhalation Injection · Amount ingested Estimated threshold dose · Manner of preparation Raw Cooked Added spices Mixed with other foods Preservatives · Simultaneously ingested foods · Illness in others ingesting the same foods · Review of current diet Ingested foods tolerated since the reaction Ingested foods not eaten since the reaction Description of reactions · Timing of symptom onset in relation to food ingestion · Associated factors Exercise Medication use · Symptoms · Severity · Duration Uniphasic Biphasic Protracted · Treatment provided · Response to treatment provided · Reproducibility of reaction on subsequent exposure · Timing of last reaction Other aspects · Psychological impact of reaction Anxiety level · Level of preparedness for future reactions

a toxic, metabolic or pharmacologic reaction, or another etiology unrelated to food ingestion. If food allergy is suspected, the next step is to decide whether the described reactions are consistent with IgE-mediated or nonIgE-mediated reactions or a combination of the two. This decision impacts further evaluation because skin testing and/or the measurement of serum food-specific IgE aids in identifying the causative food or documenting sensitization to a suspected food only when an IgEmediated reaction is involved.

640

D. Atkins

Review of the child’s diet should focus on identifying foods the child refuses to eat in addition to those that are tolerated. Although specific or multiple food refusal in young children with limited verbal ability is often attributed to behavior, careful questioning and a thorough physical examination is indicated to rule out other potential causes. Infants and toddlers often refuse foods to which they are allergic because of oropharyngeal tingling and burning, a metallic taste, abdominal pain or nausea triggered by the ingestion of these foods. Children with active esophagitis or dysphagia may avoid solid foods swallowed as a bolus because of pain associated with esophageal distention or spasm. Other potential causes of food refusal in children include chronic or intermittent aspiration resulting from swallowing disorders or oral tactile defensiveness in which certain food textures are not tolerated. Ongoing weight loss or failure to thrive, and not responding to dietary intervention to provide adequate caloric intake should prompt further evaluation to rule out other disease.

Physical Examination The focus of the physical examination varies depending upon the acuity of the patient’s presenting symptoms. In the less acute setting, the physical examination involves a search for findings suggestive of other allergic disease such as allergic shiners, conjunctival injection, clear rhinorrhea, nasal congestion with a pale, edematous nasal mucosa, a transverse nasal crease, wheezing or patches of eczema as their presence increases the likelihood of coexistent IgE-mediated sensitivity to foods. Careful monitoring of growth parameters at the initial visit and over time is indicated for food-allergic children. Weight loss or failure to thrive is rarely encountered in children with IgE-mediated sensitivity to only a few foods or those less pervasive in the diet. However, children with nonIgE mediated or mixed gastrointestinal allergy, young children with food refusal or those on severely restricted diets because of suspected or documented multiple food allergy may present with failure to thrive. When children present for evaluation in the midst of an acute allergic reaction to a food the upper and lower airway should be assessed immediately for the presence of airway obstruction due to laryngeal edema or bronchospasm as severe laryngeal edema and bronchospasm refractory to treatment are common causes of death in food-induced anaphylaxis [18, 19]. Continuous monitoring of the oxygen saturation during these reactions is advised. Other airway findings such as marked nasal congestion, repetitive sneezing, profuse clear rhinorrhea, hoarseness, stridor, coughing, accessory muscle use, nasal flaring, and wheezing should be noted. Close monitoring of the vital signs and physical examination for changes suggestive of impending shock such as delayed capillary refill or changes in mental status is indicated as refractory shock is the other major cause of death from these reactions [20]. Cutaneous changes including flushing, generalized pruritus, angioedema, urticaria, and flaring of eczema are often encountered along with gastrointestinal findings of oropharyngeal edema, increased or decreased bowel sounds, abdominal tenderness, vomiting and/or diarrhea. However, the absence of

Diagnosing Food Allergy in Children

641

cutaneous symptoms does not rule out the possibility of food-induced anaphylaxis. In addition, FPIES should be considered in children presenting with hyopovolemic shock caused by persistent vomiting and diarrhea beginning several hours after exposure to the offending food.

Skin Testing When findings on the history and physical examination suggest an IgE-mediated reaction, skin testing is indicated. Skin testing to foods is performed using commercial food extracts, freshly prepared food extracts or the “prick to prick” technique where the fresh food is initially pricked with the skin test device followed immediately by pricking the child’s skin [21, 22]. The latter two techniques are most often used when testing for sensitivity to fruits or vegetables that contain labile allergens susceptible to degradation during the extraction process, when a commercial extract of the suspected food is available, or when the skin test to a commercial extract is negative in contrast to a highly suggestive history. Skin testing with fresh extracts prepared from different portions of a meal eaten immediately prior to a reaction can help identify foods or ingredients worthy of further investigation. Reactions to a freshly prepared extract caused solely by irritation of the skin are ruled out by testing others not sensitive to the food with the same extract. Prick-skin testing to foods is safe as systemic symptoms resulting from prick-skin testing are exceedingly rare, even in subjects with a history of anaphylaxis. In contrast, intradermal skin testing to foods is discouraged because the results are less reliable and intradermal testing carries a greater risk of systemic reactions [23]. In most situations skin test selection is based on foods implicated by the history or limited to common food allergens or those that might cross react with the suspected food. Barriers to skin testing are few, but include widespread skin disease or the inability to discontinue medications such as antihistamines that interfere with skin reactivity. Even in these situations, skin testing can usually be postponed until treatment results in adequate clearing of the skin or medications can be withheld long enough to enable testing. The definition of a food skin test as positive when a wheal 3 mm in diameter larger than the negative saline control is observed and is based on initial studies in children by Bock in the late 1970s [24]. Using these criteria, the positive predictive accuracy of a properly performed food-skin test is considered less than 40%, suggesting that many children with a positive skin test to a food can ingest the food without ill effects [24]. Sporik et al., evaluating a large cohort of children with a median age of 3 years with skin testing followed by food challenges calculated skin-test diameters to peanut (>8 mm), cow’s milk (>8 mm) and egg (>7 mm) with positive predictive accuracies approaching 95% [25]. Extrapolation of their findings to other populations is discouraged because of potential differences in age, extracts, and techniques used, but their results demonstrate that as the mean wheal diameter used to define a positive skin test increases, although a decrease in sensitivity in encountered, an increase in specificity

642

D. Atkins

is observed. Like other investigators, they found no correlation between skin test size and reaction severity. Thus, skin test size does not predict the severity of the reaction. Because of the poor positive predictive accuracy of skin testing, removing a previously tolerated food from the diet based on skin test results alone is rarely recommended. However, a positive skin test can pinpoint foods worthy of further investigation and is highly suggestive of a diagnosis when accompanied by an appropriate history as exemplified by the child who experiences a significant reaction shortly after the ingestion of an isolated food, particularly if a similar reaction has recurred with subsequent exposures. Alternatively, the negative predictive accuracy of a properly performed skin test is greater than 95% [26]. When the history is highly suggestive but the skin test to the suspected food is negative, further evaluation such as repeating the skin test with the same extract, verifying the potency of the extract used, skin testing with a freshly prepared extract of the suspected food, testing for the presence of serum IgE specific for the food, and reviewing the history for other potential causes is required. Thus, skin testing is a quick, efficient method of documenting or ruling out IgE-mediated sensitivity to a food when quality extracts are applied using proper technique and the child has not taken medications known to interfere with testing.

Atopy Patch Testing Skin testing and the measurement of serum food-specific IgE antibodies are not beneficial in the evaluation of children with nonIgE mediated reactions where nonIgE-mediated immune mechanisms are involved. In recent years, the utility of the atopy patch test (APT) has been explored for the evaluation of children with atopic dermatitis [27], eosinophilic esophagitis [28], FPIES [29] and others with gastrointestinal symptoms suspected of being food-related, but not IgE-mediated [30]. Milk, egg, soy, and wheat are the foods most commonly evaluated for testing with the APT. The APT consists of applying the intact food allergen to noninflamed skin on the back under occlusion in a small aluminum cup. The patch test is removed after 48 h and any reaction at the site is assessed and recorded 20 min later and again 24 h after patch test removal. Reactions are graded based on the degree of erythema and the presence of papules or vesicles. Although usually well tolerated, irritant reactions and contact urticaria have been reported [31]. The utility of the APT in the evaluation of food allergic patients remains a topic of debate [32–35]. At this point the interest lies in the potential utility of this test in identifying the responsible foods in patients with nonIgE mediated gastrointestinal disorders such as FPIES or mixed reactions involving both IgE- and nonIgE-mediated mechanisms as seen in eosinophilic esophagitis and atopic dermatitis. Aspects that hinder wider use of the APT include the lack of standardization of the procedure including the lack of standardized reagents or how best to prepare them in addition to the time and expertise required for the accurate performance of the test [31].

Diagnosing Food Allergy in Children

643

Laboratory Testing Laboratory assays to measure the amount of unbound food allergen-specific IgE circulating in the serum are beneficial for the evaluation of the child suspected of IgE-mediated food allergy and who have extensive skin disease, when medications that interfere with skin testing cannot be withheld, or in a variety of other circumstances, such as the unavailability of an extract or in situations involving a highly suggestive history but a negative skin test. Another primary use of these assays is to help determine whether a food challenge is indicated. Although the sensitivity of skin testing and selected immunoassays is comparable [36], the performance of a skin test is advised before food challenge in the child with a highly suggestive history and a negative immunoassay. Levels of food allergen-specific IgE in an individual child are obtained longitudinally to monitor for potential changes in sensitization. As with skin tests, food allergen-specific IgE levels are helpful in predicting the likelihood of a reaction, but do not predict reaction severity. One of the most widely used and evaluated immunoassays for the measurement of food-specific IgE is the CAP-RAST system (CAP-FEIA [Pharmacia, Uppsala, Sweden]), which measures the amount circulating allergen-specific IgE in the serum in kilounits of allergen-specific IgE per liter (kUA/L). In 1997, in a retrospective study analyzing the sera of food allergic children in light of highly suggestive histories or the results of food challenges, Sampson and colleagues reported predictive threshold levels for several of the commonly allergenic foods including milk, egg, peanut, and fish [37]. Patients with values higher than the calculated threshold values had a 95% likelihood of reacting upon ingestion of the food. In a subsequent prospective study Sampson evaluated 100 children by history, oral food challenges and measuring allergen-specific IgE levels to egg, milk, peanut, soy, wheat and fish [38]. This study was undertaken to determine if the 95% predictive decision points for egg, milk, peanut, and fish determined in the previous study were accurate. Using the previously defined predictive decision points, more than 95% of the food allergies to these foods in this population of children were correctly identified. These diagnostic decision points have been further investigated and refined and their use in clinical settings has significantly reduced the need for food challenges [39]. CAP-RAST levels above which 95% or more of children would be expected to react have been reported for several of the major food allergens. Children less than 2 years of age with a CAP-RAST to egg greater than 2 kUA/L or a CAP RAST to milk greater than 5 kUA/L have a greater than 95% chance of reacting on challenges. For older children, the decision points for foods commonly causing allergic reactions are as follows: egg 7 kUA/L, milk 15 kUA/L, peanut 14 kUA/L, tree nuts ~15 kUA/L, and fish 20 kUA/L. However, individual patient CAP-RAST results often fall in an indeterminate zone below the diagnostic threshold, but above the value predicting tolerance. In addition, since these decision points have been determined for relatively few foods, threshold values for a given suspected food may not have been established. As a result of these and other nuances, food challenges remain an important tool for documenting the link between the ingestion of a suspected food and the onset of symptoms.

644

D. Atkins

Elimination Diets Elimination diets vary significantly depending upon the number of foods removed from the diet and become more difficult to construct as more foods or those pervasive in the diet come under suspicion. Limited elimination diets, removing only a few highly suspected foods are the simplest to prepare, particularly when foods not widely distributed throughout the diet are implicated. Oligoantigenic diets are constructed by limiting the diet to only a few foods rarely reported to cause reactions. Elemental formulas are the mainstay of elemental diets. Oligoantigenic and elemental diets are used when uncertainty about which foods cause symptoms exists or when a large number of foods are suspected. Elemental diets are useful in infants, but adherence to these diets is often difficult to maintain beyond infancy. When oligoantigenic and elemental diets are used, foods are added back to the diet individually at selected intervals accompanied by symptom monitoring. Tolerated foods are left in the diet, while those associated with a return of symptoms are removed. One food-associated disorder in which the use of elemental diets has been shown to be of particular benefit is eosinophilic esophagitis where improvement in 98% of children placed on elemental diets has been reported [40]. Lack of improvement on a diet free of suspected foods suggests either nonadherence, the need to consider other foods, or a cause other than food allergy. However, once the diagnosis of food allergy is firmly established, constructing an appropriate palatable elimination diet that meets the child’s nutritional requirements is an integral aspect of current treatment. Overzealous elimination of foods from the diet has been associated with adverse physical and psychological consequences in children [41, 42]. For example, children on dairy-free diets have been shown to have difficulty meeting their requirements for calcium, vitamin D and phosphorous [42]. As a result, consultation with a registered dietician to provide a complete nutritional assessment and patient education regarding label reading, food preparation, hidden sources of food allergens, and alternative nutrient sources is preferred.

Food Challenges Oral food challenges are performed to document the presence or lack of clinical reactivity to a specific food and are categorized into open, single-blind, or double-blind depending upon who is aware of the contents of each dose given during the challenge. Placebo controls are often added during the performance of singleblind and double-blind challenges. The oral food challenge selected and whether placebos are used depends upon the need to control for patient and/or observer bias. The DBPCFC, where neither the child, the child’s family nor the medical team is aware of the contents of the challenge, remains the challenge of choice in the research setting as it best controls for both patient and observer bias. Single-

Diagnosing Food Allergy in Children

645

blind placebo-controlled food challenges (SBPCFC), where only the medical staff knows the contents of challenge doses, are performed to eliminate bias on the part of the child and/or the child’s family. In an open food challenge (OFC), because the food is offered as it is usually eaten, both the child and medical staff know which and how much food is being given. A significant benefit of the OFC is the relative ease of performance as masking the challenge food is unnecessary, thereby significantly reducing preparation time. In most clinical situations an OFC suffices when objective symptoms are used to determine whether the challenge is positive. Oral food challenges provide the answers to a variety of clinical questions. If the culprit food is not obvious after a thorough history and attempts to document sensitization or when more than one food is implicated based on the history and test results, food challenges are indicated to determine which, if any, of the suspected foods cause symptoms. Accurately identifying the causative food prevents future reactions and avoids the needless elimination of foods from the diet. Food challenges are also performed to prove that a food can be safely returned to the diet. The majority of children, who as infants and toddlers were allergic to milk, egg, soy or wheat, develop tolerance to these foods as they age. In addition, about 20% of children with allergic reactions to peanut in the first years of life outgrow their sensitivity [43]. Toddlers found to be allergic to a specific food at an early age and during the course of their initial evaluation have evidence of sensitization to other foods they have not eaten are often kept on diets eliminating these foods through the first years of life. A thorough exposure history combined with information obtained from skin testing and an immunoassay for the level of food allergen-specific IgE is used to determine if and when to challenge children to these foods. When immune mechanisms other than IgE-mediated sensitivity are suspected, as exemplified by the FPIES, a food challenge may be the only accurate means of verifying the diagnosis [15]. In this situation, the challenge should be performed with an intravenous line in place. There are relatively few contraindications to the performance of a food challenge. They are not advised in a child with a history of a previous life threatening reaction without sufficient evidence to document a significant decrease in the level of sensitivity. Challenging a child with unstable asthma is ill advised and those with severe eczema should have their eczema appropriately controlled before being challenged. With a previous severe reaction to a food rarely encountered in the diet or if the child dislikes the food and would chose to continue avoidance, the potential benefit is unlikely to outweigh the risks of challenge. Children frightened by the consideration of a food challenge often benefit from working with a psychosocial clinician before a food challenge is performed. Decisions about who should be challenged are finalized only after a thorough discussion with the child and the child’s family regarding the rationale for challenge along with a review of the potential benefits and risks. A retrospective analysis of 253 failed food challenges performed in a tertiary care center to the common food allergens milk, egg, peanut, soy, or wheat in addition to the experience of other centers routinely performing these challenges provides evidence of safety when performed in a medical setting with the necessary

646

D. Atkins

medications and equipment available along with personnel experienced in the treatment of anaphylaxis [44]. In preparation for a challenge the history of previous suspected reactions to the food is reviewed and an interim history and physical examination is performed to document that the child is medically stable. Food challenges are performed by feeding gradually increasing doses of the suspected food at predetermined time intervals until objective symptoms occur or a normal portion of the food ingested openly is tolerated. In blinded studies the challenge food is disguised in another food the child will ingest. Typical total doses are the normal age adjusted single serving amounts or 8–10 g when freeze-dried or powdered foods are utilized. When freeze-dried or concentrated foods are used, the potential for alteration of labile allergens must be taken into consideration. Standardized recipes for DBPCFC to milk, soy, cooked egg, raw whole egg, peanut, hazelnut, and wheat in their usual edible form and validated by professional panelists in a food laboratory have been published [45]. Although the dosing and interval between doses are often established based upon the child’s history, different formats have been used successfully in different centers [46, 47]. If subjective symptoms are encountered after a dose, reasonable options include a longer wait before administering the next dose, repeating the previous dose or halting the challenge. A food challenge is completed when the child has an observable reaction or a normal portion of the food ingested openly is tolerated. The observation period following completion of the challenge depends upon several factors including the immune mechanism involved, the timing, severity and duration of previous reactions, whether the child reacted and the severity of the reaction plus the level of concern regarding biphasic anaphylaxis. Usually children are observed until they have been asymptomatic for a couple of hours after a reaction or for about 2 h after the last dose if the food was tolerated. Children with nonIgE mediated reactions such as the food-protein induced enterocolitis syndrome or other delayed reactions are observed longer. The implications of the challenge results should be thoroughly reviewed with the child and the child’s family and all questions thoroughly answered. If the challenge is negative including the challenged food regularly in the diet is encouraged.

Management of the Food Allergic Child Current management of the food-allergic child consists of the dietary avoidance of culprit foods and developing a plan for the prompt treatment of reactions resulting from accidental exposure. An individualized approach taking into consideration the immunologic mechanism involved, the age of the child, the severity of previous reactions, the current suspected degree of sensitivity, and the number of implicated foods is required. Dietary avoidance is accomplished by providing a palatable, nutritionally adequate elimination diet, along with education regarding label read-

Diagnosing Food Allergy in Children

647

ing, and a review of potential sources of accidental exposure. Diets eliminating foods pervasive to the diet or multiple foods are best constructed by a skilled dietician experienced in working with children with food allergies. Reliable resources for obtaining further information, such as the Food Allergy and Anaphylaxis Network (www.foodallergy.org), are invaluable. Wearing a medical information bracelet or necklace or carrying a card that identifies the child as food allergic and lists the child’s food allergies helps prevent reactions and can save precious time if the child is found unconscious or incommunicative. A Food Allergy Action Plan that lists the steps to take in case of a reaction including the order and doses of all medications to be administered as well as contact information for family members and health care providers should be provided. This plan should be developed and thoroughly reviewed with the children, their family members, and all other caretakers. The delayed administration of epinephrine has been associated with fatal allergic reactions to foods [18, 19]. As a result, an epinephrine auto-injector along with thorough instruction regarding when and how to use it should be provided to the families of children considered to be at risk for food-induced anaphylaxis. Features of the history that prompt providing an epinephrine autoinjector include a previous severe reaction or one involving the respiratory or cardiovascular system; generalized urticaria or angioedema during previous reactions; coexistent asthma; allergy to peanuts, nuts, fish, or shellfish; or a history of other family members with severe allergic reactions to foods [48]. Injection of the epinephrine dose intramuscularly into the lateral thigh is advised based upon studies demonstrating improved absorption by this route over subcutaneous administration [49]. Epinephrine auto-injectors are currently available in doses of 0.15 and 0.30 mg with the 0.15 mg dose suggested by the manufacturer for children weighing 15–30 kg and 0.30 mg recommended for those over 30 kg; however, physician discretion regarding dosing is advised based upon the history. Auto-injector use is preferred over the use of an epinephrine ampule and syringe to avoid delay in administering the dose and reduce the potential for significant dosing errors [50]. Providing more than one auto-injector is generally recommended, particularly in situations where access to medical care is limited or could be delayed. Once an epinephrine auto-injector is used, emergency medical services should be notified for the transport of the patient to the appropriate medical facility. Other medications commonly available to patients for use in the immediate treatment of allergic reactions to foods include oral antihistamines and inhaled bronchodilators. Antihistamines carried for the first aid treatment of allergic reactions should be chewable or liquid preparations to reduce the time required for absorption. Appropriate doses of these medications and when to use them should be reviewed. The first aid treatment of food-induced anaphylaxis including the rationale for epinephrine administration has been reviewed by Simon [51]. Although epinephrine is the drug of choice for the treatment of anaphylactic reactions to foods, it does not reverse the symptoms of nonIgE-mediated reactions such as food protein-induced enterocolitis where the mainstay of therapy is fluid replacement.

648

D. Atkins

Upon arrival at a medical facility for treatment of an allergic reaction to a food, the patient should be rapidly assessed and supportive care provided as indicated. Oxygen should be rapidly provided for any evidence of respiratory distress. If 10–15 min has elapsed since the initial dose and if the reaction persists or is progressing, another dose of epinephrine should be given. Patients presenting with hypotension should receive intravenous fluids with consideration for instituting vasopressor therapy. If antihistamines have not been given or symptoms persist, an additional dose of antihistamine should be administered and the use of an H2 blocker considered. Other supportive care such as bronchodilator therapy for patients with bronchospasm should be provided as indicated. Consideration of factors that inhibit response to therapy, such as beta blocker use, is encouraged in patients unresponsive to standard treatment. Intravenous glucagon may effectively treat hypotension in patients on beta blocker therapy who are not responding to the vasopressor effects of epinephrine [51]. Before the patient with food-induced anaphylaxis is released from medical care, the means for obtaining an epinephrine auto-injector should be provided along with appropriate teaching and arrangement for follow-up with an allergist. Long-term management of the food allergic child involves at least annual monitoring for evidence of newly developed tolerance or the acquisition of new food allergies through focused interim histories and evaluation of the results of immunoassays for food-specific IgE or skin testing when indicated. Other important aspects of long term follow-up include analyzing the diet for nutritional adequacy, monitoring growth parameters, reviewing the first aid treatment of allergic reactions to foods, and discussing the burden of illness while providing psychological support. The psychological impact on children and their families is a frequently ignored aspect of food allergy often successfully managed with appropriate psychosocial intervention, resulting in a significant improvement in quality of life.

Future Directions Promising results observed in recent studies suggest that improved diagnostic methods and treatments other than merely avoiding the offending food are forthcoming. For example, examination of specific epitopes or the number of epitopes on specific food allergens recognized by a patient’s food-specific IgE may improve the ability to predict the likelihood of the eventual development of tolerance or the potential for severe reactions [52–55]. In addition, a variety of immunotherapeutic approaches including oral immunotherapy [56–58], sublingual immunotherapy [59] and immunotherapy using altered allergens administered with specific adjuvants [60] are under investigation as are novel therapies including treatment with humanized monoclonal anti-IgE antibodies [61] and a modified Chinese herbal therapy [62]. The findings of these and other studies underway to better define the immune mechanisms involved in the development of oral tolerance as well as food allergy suggest that viable therapies will become available within the next decade.

Diagnosing Food Allergy in Children

649

References 1. Sampson HA (1999) Food allergy. Part 1: immunopathogenesis and clinical disorders. J Allergy Clin Immunol 103:717–28 2. Maulitz RM, Pratt DS, Schocket AL (1979) Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol 63:433–4 3. Roman A, Di Fonso M, Giuffreda F, Papa G, Artesani MC, Viola M, Palmieri V, Zeppilli P (2001) Food-dependent exercise-induced anaphylaxis: clinical and laboratory findings in 54 subjects. Int Arch Allergy Immunol 125:264–72 4. Tewari A, Du Tiot G, Lack G (2006) The difficulties of diagnosing food-dependent exerciseinduced anaphylaxis in childhood – a case study and review. Pediatr Allergy Immunol 17:157–60 5. Palosuo K, Varnonen E, Nurkkala J, Kalkkinen N, Harvima R, Reunala T, Alenius H (2003) Transglutaminase-mediated cross-linking of a peptic fraction of ω-5 gliadin enhances IgE reactivity in wheat-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol 111:1386–92 6. Shimamoto SR, Bock SA (2002) Update on the clinical features of food-induced anaphylaxis. Curr Opin Allergy Clin Immunol 2:211–16 7. Romano A, Di Fonso M, Giureda F, Quaratino D, Papa G, Palmeiri V, Zeppilli P, Venuti A (1995) Diagnostic work-up for food-dependent, exercise-induced anaphylaxis. Allergy 50:817–24 8. Guinnepain MT, Eloit C, Raard M, Brunet-Moret MJ, Rassemont F, Laurent J (1996) Exercise-induced anaphylaxis: useful screening of food sensitization. Ann Allergy Asthma Immunol 77:491–96 9. Amlot PL, Kemeny DM, Sachary C, Parkes P, Lessof MH (1987) Oral allergy syndrome (OAS): symptoms of IgE-mediated hypersensitivity to foods. Clin Allergy 17:33–42 10. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R (1988) The oral allergy syndrome. Ann Allergy 61:47–52 11. Egger M, Mutschlechner S, Wopfner N, Gadermaier G, Briza P, Ferreira F (2006) Pollen-food syndromes associated with weed pollinosis: an update from the molecular point of view. Allergy 61:461–76 12. Ma S, Sicherer SH, Nowak-Wegryzyn A (2003) A survey on the management of pollen-food allergy syndrome in allergy practices. J Allergy Clin Immunol 112:784–8 13. Maloney J, Nowak-Wegrzyn A (2007) Educational clinical case series for pediatric allergy and immunology: allergic proctocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic esophagitis with protein-losing gastroenteropathy as manifestations of non-IgE-mediated cow’s milk allergy. Pediatr Allergy Immunol 18:360–7 14. Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH (2003) Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics 111:829–35 15. Sicherer SH (2005) Food protein-induced enterocolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol 115:149–56 16. James SP (2005) Prototypic disorders of gastrointestinal mucosal immune function: celiac disease and Crohn’s disease. J Allergy Clin Immunol 115:25–30 17. Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P, Hassall E, Straumann A, Rothenber ME (2007) Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 133:1342–63 18. Bock SA, Munoz-Furlong A, Sampson HA (2001) Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 107:191–3 19. Sampson HA, Mendelson LM, Rosen JP (1992) Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 327:380–4 20. Simons FES (2004) First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol 113:837–44

650

D. Atkins

21. Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC (1989) Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 83:683–90 22. Dreborg S, Coucard T (1983) Allergy to apple, carrot and potato in children with birch pollen allergy. Allergy 38:167–72 23. Simons FE, Frew AJ, Ansotegui IJ, Bochner BS, Golden DB, Finkelman FD, Leung DY, Lotvall J, Marone G, Metcalfe DD, Muller U, Rosenwasser LJ, Sampson HA, Schwartz LB, van Hage M, Walls AF (2007) Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol 120:S2–24 24. Bock SA, Buckley J, Holst A, May CD (1978) Proper use of skin tests with food extracts in diagnosis of food hypersensitivity. Clin Allergy 7:375–83 25. Sporik R, Hill DJ, Hosking CS (2000) Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin Exp Allergy 30:1540–46 26. Sampson HA (1988) Comparative study of commercial food antigen extracts for the diagnosis of food hypersensitivity. J Allergy Clin Immunol 82:718–36 27. Kerschenlohr K, Darsow U, Burgdorf WHC, Ring J, Wollenberg A (2004) Lessons from atopy patch testing in atopic dermatitis. Curr Allergy Asthma Rep 4:285–89 28. Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA (2002) The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 109:363–68 29. Fogg MI, Brown-Whitehorn TA, Pawloski NA, Spergel JM (2006) Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol 17:351–55 30. Mehl A, Rolinck-Werninghaus C, Staden U, Verstege A, Wahn U, Beyer K, Niggemann B (2006) The atopy patch test in the diagnostic workup of suspected food-related symptoms in children. J Allergy Clin Immunol 118:923–9 31. Spergel JM, Brown-Whitehorn T (2005) The use of patch testing in the diagnosis of food allergy. Curr Allergy Asthma Rep 5:86–90 32. Isolauri E, Turjamaa K (1996) Combined skin prick and patch testing enhances identification of food allergy in infants with atopic dermatitis. J Allergy Clin Immunol 97:9–15 33. Roehr C, Reibel S, Ziegert M, Sommerfeld C, Wahn U, Niggemann B (2001) Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol 107:548–53 34. Osterballe M, Andersen KE, Bindslev-Jensen C (2004) The diagnostic accuracy of the atopy patch test in diagnosing hypersensitivity to cow’s milk and hen’s egg in unselected children with and without atopic dermatitis. J Am Acad Dermatol 51:556–62 35. Canini RB, Ruotolo S, Auricchio L, Caldore M, Porcaro F, Manguso F, Terrin G, Troncone R (2007) Diagnostic accuracy of the atopy patch test in children with food-related gastrointestinal symptoms. Allergy 62:738–43 36. Sampson HA, Albergo R (1984) Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol 74:26–33 37. Sampson HA, Ho DG (1997) Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 100:444–51 38. Sampson HA (2001) Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 107:891–6 39. Sampson HA (2004) Update on food allergy. J Allergy Clin Immunol 113:805–19 40. Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, Flick J, Kelly J, Brown-Whitehorn T, Mamula P, Markowitz JE (2005) Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol 3:1198–206 41. Salman S, Christie L, Burks A, McCabe-Sellers B (2002) Dietary intakes of children with food allergies: comparison of the Food Guide Pyramid and the Recommended Dietary Allowances. J Allergy Clin Immunol 109:S214

Diagnosing Food Allergy in Children

651

42. Christie L, Hine RJ, Parker JG, Burks W (2002) Food allergies in children affect nutrient intake and growth. J Am Diet Assoc 102:1648–51 43. Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA (2001) The natural history of peanut allergy. J Allergy Clin Immunol 107:367–74 44. Perry TT, Matsui E, Conover-Walker MK, Wood RA (2004) Risk of oral food challenges. J Allergy Clin Immunol 114:1164–8 45. Vlieg-Boestra BJ, Bijleveld CMA, van der Heide S, Beusekamp BJ, Wolt-Plompen SAA, Kulder J, Brinkman J, Duiverman EJ, Dubois AEJ (2004) Development and validation of challenge materials for double-blind, placebo-controlled food challenges in children. J Allergy Clin Immunol 113:341–6 46. Bock SA, Sampson HA, Atkins FM, Zeiger RS, Lehrer S, Sachs S, Bush RK, Metcalfe DD (1988) Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol 82:986–97 47. Bendslev-Jensen C, Ballmer-Weber BK, Bengtsson U, Blanco C, Ebner C, Hourihane J, Knulst AC, Moneret-Vautrin DA, Nekam K, Niggemann B, Osterballe M, Ortolani C, Ring J, Schnopp C, Werfel T(2004) Standardization of food challenges in patients with immediate reactions to foods-position paper from the European Academy of Allergology and Clinical Immunology. Allergy 59:690–97 48. Sicherer SH, Teuber ST (2004) Current approach to the diagnosis and management of adverse reactions to foods. J Allergy Clin Immunol 114:1146–50 49. Simons FER, Roberts JR, Gu X, Simons KJ (1998) Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 101:33–7 50. Simons FER, Chan ES, Gu X, Simons KJ (2001) Epinephrine for out-of-hospital (first aid) treatment of anaphylaxis in infants: is the ampule/syringe/needle method practical? J Allergy Clin Immunol 108:1040–4 51. Simons FES (2004) First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol 113:837–44 52. Jarvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ, Sampson HA (2002) B-cell epitopes as a screening instrument for persistent cow’s milk allergy. J Allergy Clin Immunol 110:293–7 53. Cooke SK, Sampson HA (1997) Allergenic properties of ovomucoid in man. J Immunol 159:2026–32 54. Beyer K, Ellman-Grunther L, Jarniene KM, Wood RA, Hourihane J, Sampson HA (2003) Measurement of peptide-specific IgE as an additional tool in identifying patients with clinical reactivity to peanuts. J Allergy Clin Immunol 112:202–7 55. Shreffler WG, Beyer K, Chu TT, Burks AW, Sampson HA (2004) Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes. J Allergy Clin Immunol 113:776–82 56. Patriarca G, Bucera E, Roncallo C, Pollastrini E, Bartolozzi F, De Pasquale T, Buonomo A, Gasbarrini G, Campli CD, Schiavino D (2003) Oral desensitizing treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther 17:459–65 57. Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro P (2004) A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy. Allergy 59:980–87 58. Buchanan AD, Green TD, Jones SM, Scurlock AM, Christie L, Althage KA, Steele PH, Pons L, Helm RM, Lee LA, Burks AW(2007) Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol 119:199–205 59. Enrique E, Pineda F, Malek T, Nartra J, Basagana M, Tella R, Castello JV, Alonso R, de Mateo JA, Cerda-Trias T, Miguel-Moncin MDMS, Monzon S, Garcia M, Palacios R, Cistero-Bahima A (2005) Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 116:1073–9 60. Nowak-Wegrzyn A (2007) New perspectives for use of native and engineered recombinant food proteins in treatment of food allergy. Immunol Allergy Clin N Am 27:105–27

652

D. Atkins

61. Leung DY, Sampson HA, Yunginger JW, Burks AWJ, Schneider LC, Wortel CH (2003) Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 348:986–93 62. Srivastava KD, Kattan JD, Zou ZM, Li JH, Zhang L, Wallenstein S, Goldfarb J, Sampson HA, Li XM (2005) The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol 115:171–8

Diagnosis and Treatment of Latex Allergy Kevin J. Kelly and Brian T. Kelly

Introduction The diagnosis and treatment of latex allergy is one of the most challenging problems confronting the clinician. Because natural rubber latex is a plant derived product of Hevea brasiliensis, variations in allergen total content, quantity of specific allergens in finished products, and variations in the individual allergens may occur during collection, storage and manufacture of finished rubber products. Thus, not all rubber products will result in sensitization or clinical reactions in patients. Because the human immune system is highly variable, an individual will not always react in the same manner when encountering an allergen such as latex. For example, a cluster of anaphylactic reactions in patients with spina bifida characterized in the early 1990s, resulted in one out of every eight individuals undergoing surgery over a single year for spina bifida developed intra-operative anaphylaxis. However, many latex allergic individuals in this cohort had multiple surgeries during a period when latex precautions were not known to be necessary. Despite this lack of precaution, some surgeries resulted in severe anaphylaxis while other surgeries were performed without incident in the same individual using latex products [1, 2]. Having a complete understanding of the clinical manifestations of latex allergy is necessary to make a correct diagnosis and plan of treatment. This chapter builds on the presentation in a chapter from volume 3[132] that outlines a comprehensive review about the clinical manifestations of latex allergy. To obtain complete knowledge of the subject, a review of latex allergens, available tests, and therapy will be outlined.

K.J. Kelly () Department of Pediatrics, Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA e-mail: [email protected] B.T. Kelly Medical College of Wisconsin, 8700 W. Wisconsin Avenue Milwaukee, WI, 53226, USA

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_40, © Springer 2010

653

654

K.J. Kelly and B.T. Kelly

Latex Allergens Over 2000 lactiferous (latex producing) plants are known to exist in the world. Natural rubber latex (NRL) is produced by the tropical tree H. brasiliensis from the plant family- Euphorbiaceae. Multiple flowering lactifer plants come from this family and are well recognized by the general public (Table 1). One of the most common examples is Euphorbia pulcherrima or poinsettia. Cis-1,4-polyisoprene, is the reason that the latex of H. brasiliensis is harvested and is contained in an estimated 40,000 finished products. Figure 1–d depicts the harvesting, collection and method of production of dipped latex products. Field latex, which usually contains about 1–2% protein, varies its protein content by clonal origin of the rubber plants, climatic factors, soil types, fertilizers, and yield enhancers used for the rubber cultivation [3–5]. The trees grow optimally in a tropical humid environment where the temperature remains 20–28°C resulting in a variety of microorganisms, especially fungi, and insects that invade and can injure and kill the tree. The latex itself may act in self defense against both the invading organisms and the damage inflicted during tapping by unique wound sealing property [3–5]. Beneath the surface of the cambium layer of the bark, the specialized lactifer cells form a tube-like or capillary circulation network throughout the rubber tree. The cytoplasm of the lactifer cells is secreted (the latex) when the cell is injured. It contains numerous defense related proteins and enzymes that are integral in the protection of the plant, biosynthesis of polyisoprene, and coagulation of latex. As might be predicted from other plants, defense proteins and enzymes are frequent causes of allergic sensitization and clinical reactions especially with foods [3]. The proteins present in latex may induce IgE mediated immune responses in latex allergic patients and, due to the cross-reactivity of some of these latex allergens, in fruit allergic and some vegetable and pollen sensitized patients [3–5]. Over 200 proteins have been identified in latex with hevein (50%) and hevamine (30%) making up the majority of these proteins [6, 7]. However, only hevein is recognized as a significant allergen that causes disease in humans. The latex also contains lipids, carbohydrate and inorganic salt or metal ions such as potassium, manganese, calcium, sodium, zinc, copper and iron [8]. The majority of the proteins present in freshly harvested latex are detected in finished latex products either in their natural configuration or an altered configuration which may lead to

Table 1 Common plants of the Euphorbiaceae family Genus/species Common name Acalypha hispida Chenile plant Acalypha wilkesiana Jacobs coat Euphorbia splendens Crown of thorns Manikot esculenta Tapioca Ricinus communis Castor bean Euphorbia pulcherrima Poinsettia Hevea brasiliensis Rubber tree

Diagnosis and Treatment of Latex Allergy

655

b

a

c

d

Fig. 1 (a) A worker precisely cuts the bark of the Hevea brasiliensis tree, injuring the lactifer cells. The cells and circulation of the latex secrete a milky white latex rich in cis-1,4 polyisoprene. (Reproduced with permission from [4].) (b) Latex is collected from the H. brasiliensis tree by injuring the lactifer circulation. The latex is secreted and collected in a pail with ammonia and thiuram to prevent coagulation. (Reproduced with permission from [4].) (c) Latex is harvested and then brought to a collection station for transport and storage. (Reproduced with permission from [4].) (d) Latex gloves are made by a dipping method with insertion of a porcelain former crated with a coagulant on the surface. The latex forms a thin film, which is then cross worked by sulfur heat vulcanization (Reproduced with permission from [4])

the formation of neo-antigens [8–10]. Treatment of latex with chemicals such as ammonia will increase the formation of protein fragments. In two-dimensional gel electrophoresis of nonammoniated latex, over 240 separate proteins or peptide fragments have been identified. However, the sera from latex allergic patients recognize and bind to only 25% of these proteins with IgE antibody [9]. The analysis of latex proteins by SDS PAGE demonstrated a wide range of peptides with molecular masses of 5–200 kDa [10]. The allergens of molecular weight in ranges of 11, 14, 18, 24, 27, 35, 66 and 100 kDa, have been found to be the most significant allergens affecting patients [11, 12]. Interestingly, multiple proteins of different molecular sizes exhibited binding specificity for either health care worker sera, spina bifida patient sera or both in IgE immunoblot [13, 14]. With the modern advancement in protein purification and molecular biology techniques, a number of latex proteins have been isolated, cloned and purified to

656

K.J. Kelly and B.T. Kelly

Table 2 Immunological characterization of Hevea brasiliensis latex allergens Molecular Accession Allergens Allergen name weight (kDa) number Function Hev b 1 Elongation 14.6 X56535 Rubber factor biosynthesis 58 Tetramer Hev b 2 1,3-glucanase 34/36 U22147 Defense protein Hev b 3 Elongation factor 23 AF 051317 Rubber biosynthesis AJ223388 Hev b 4 Microhelix 50–57 n.a Defense protein complex 100–115 Dimer Hev b 5 16 U51361 U42640 Hev b 6.01 Prohevein 20 M36986 Defense protein Hev b 6.02 Hevein 4.7 M36986 Defense protein Hev b 6.03 C-terminal 14 M36986 Defense protein hevein Hev b 7 Patatin 42.9 AJ220388 Defense protein homologue Inhibit rubber biosynthesis Hev b 8 Latex profiling 14 Y15402 Structural protein Hev b 9 Latex enolase 51 AJ132580 Hev b 10 Mn superoxide 26 L11707 dismutase AJ249148 Hev b 11 Class 1 chitinase 33 AJ238579 Defense protein Hev b 12 Lipid transfer 9.3 AY057860 Defense protein protein Hev b 13 Latex esterase 42 P83269 -

Significance as allergens Major

Major Major

Major

Major Major Major Major Minor

Minor Minor Minor

Minor Major Major

homogeneity [15]. This is critical in developing sensitive and specific immunodiagnostic tests. Based on their IgE binding properties, the Allergen Nomenclature Subcommittee of IUIS has accepted thirteen proteins as latex allergens (ftp:// biobase.dk/pub/who-iuis/allergen. list) (Table 2).

Functional Properties of Latex Allergens Biological Properties The characterized proteins in Hevea latex have four basic functions: polyisoprene elongation, plant defense, enzyme function, or service as structural proteins. As is the case with other plant allergens, many of the Hevea allergens have enzyme functions or defense functions. The biologic functions of the latex allergens will be reviewed first.

Diagnosis and Treatment of Latex Allergy

657

Polyisoprene Elongation Hev b 1, also known as rubber elongation factor (REF), facilitates the enzyme prenyltransferase in the adding of several thousands of isoprene subunits to the polyisoprene chains [16, 17]. In the process of centrifugation of latex, three layers are formed. The upper layer contains rubber particles of large and small size. The middle layer is an aqueous layer that contains many proteins. The bottom layer contains lutoids and organic and inorganic materials. Hev b 1 is tightly bound to large rubber particles (>350 nm in diameter) in the interface between the insoluble upper layer consisting of polyisoprene molecules and the aqueous layer. Hev b 3 is another REF homolog. In contrast to Hev b 1, which is on the surface of large particles, it is present on the surface of the small rubber particles (<70 nm in diameter) and participates in the synthesis of long chain polyisoprene [18]. Hevein (Hev b 6.02) is the most abundant protein of Hevea latex and is found in the lutoid fraction after centrifugation [19]. Released from the cells when the plant is damaged, hevein interacts with glycoprotein receptors on the sacs around the rubber particles resulting in the coagulation of latex [20]. Hev b 7, a cytosolic protein with esterase activity, acts by inhibiting rubber biosynthesis through restriction of isoprenyl diphosphate incorporation [21]. Plant Defense Functions Defense related proteins are a series of protective proteins produced by higher plants to guard themselves against various stresses including invading organisms such as fungi. The proteins include families of cross-reactive plant allergens that are responsible for inducing primary allergic reactions and secondary reactions as is seen in the latex-fruit syndrome. The defense proteins identified as allergens in latex include 1,3-glucanase, microhelix complex, prohevein, patatin homolog, class 1 chitinase, and lipid transfer protein. The latex allergen, Hev b 2 with b-1,3-glucanase property, catalyzes the hydrolytic cleavage of polymers of b-1,3-glucans. These glucan polymers are part of the essential cell wall component of most of the fungi. Hence, this cleavage protein appears to involve in plant protection against the fungal infection by degrading the cell walls of fungal pathogens [22, 23]. Another major structural component of the cell wall of many fungi and of the exoskeleton of insects is chitin. Multiple plants produce chitinases, which are proteins common in a wide variety of seed producing plants, and are involved in hydrolytic cleavage of chitin. A more recently characterized latex allergen, Hev b 11 shows endochitinase activity and is likely involved in hydrolytic cleavage of chitin in either fungi or insects. The cross-reactivity among the class 1 endochitinases from avocado, banana, chestnut and latex has been associated with latex-fruit syndrome but may also be due to a hevein domains within the protein [23–25.] Hevamine, a basic protein from the lutoid fraction of latex and not accepted as an official allergen, is classified as a defense-related enzyme with both chitinase and lysozyme activity [26]. Hevamine catalyzes cleavage of b-1,4-glycosidic bonds

658

K.J. Kelly and B.T. Kelly

in chitin as well as sugar moieties within the cell surface peptidoglycans, but may not have lysozyme activity as once identified [27].

Common Enzymes and Structural Proteins Hev b 5 is proline-rich protein with a 46% amino acid sequence homology to an acidic protein from kiwi [28, 29.] Latex profilin, Hev b 8, is an actin binding protein that is likely to be involved in organization of an actin network of Hevea latex plant’s cytoskeleton [30.] The latex enolase, Hev b 9 is a necessary enzyme within the glycolytic pathway while Hev b 10 with MnSOD activity protects the plant against highly toxic oxygen radical produced during the phagocytic processing of foreign organisms [15].

Immunologic Properties The immunologic properties of individual latex allergens have been evaluated by immune responses in either health care workers or patients with spina bifida since those individuals make up the majority of subjects found to have clinical disease. Most importantly, the immune responses have been evaluated using purified recombinant allergens in these groups. The allergens that the general population reacts to are likely to parallel these current observations. The results of these studies confirm the specificity and reliability of purified allergens in the immuno-diagnosis of latex allergy. The identified Hevea allergens have been classified as minor and major allergens depending on their reactivity with sera from various groups of latex allergic patients (Table 2).

Immune Responses to Rubber Biosynthesis Proteins The three allergens most involved in rubber biosynthesis include Hev b1, Hev b 3, and Hev b 7. What is most interesting is the dichotomy of reactions seen between health care workers (HCW) and spina bifida (SB) patients to this particular group of allergens. Spina bifida patients tend to react frequently to Hev b 1 and Hev b 3 while other at risk groups do not seem to react as frequently. Whether this is due to genetic differences, surgical exposure timing, or route of exposure to the allergens is unclear. Hev b 1 (Rubber elongation factor): REF appears in a native configuration as a tetramer of molecular mass of 58 kDa on large rubber particles. The monomer has been cloned and purified as a 137 amino acid long protein. Hev b 1 is a major allergen reacting with 81% of latex sensitized SB patients and 50% of health care workers (HCW) [31]. In a multicenter study using RAST and ELISA assays, 13–32% of HCW and 52–100% of SB patients with latex allergy showed strong IgE binding

Diagnosis and Treatment of Latex Allergy

659

with Hev b 1 [32]. Regardless, this is a very important allergen in patients with spina bifida and must be in sufficient quantity for diagnosis in this group of subjects. Hev b 3 (small rubber particle protein): This protein with strong IgE binding reactivity in patients with SB and latex allergy is associated with the small rubber particles (<75 nm) in latex [33–36]. Clinical and immunological reactivity of Hev b 3 with serum IgE in HCW is less frequent and weaker than in SB patients [34, 36]. The amino acid sequence homology is 47% when compared to another major allergen for SB patients (Hev b 1) [34]. More importantly, preincubated latex allergic sera with Hev b 1 showed more than 80% ELISA inhibition to solid phase Hev b 3. This clearly indicates the presence of similar conformational allergens in these proteins [36]. In addition, a recombinant form of Hev b 3 expressed in bacterial system exhibits specific binding to antilatex IgE from SB patients [37]. Hev b 7 (patatin like protein): Patatin is an important potato allergen (Sol t 1) and is a major storage protein in potatoes. Hev b 7 is a 46 kDa protein with patatin homology and has IgE binding reactivity with 23% HCW with latex allergy but has not been demonstrated to be a major allergen for patients with SB [38–41]. Although both HCW and SB patients exhibited IgE binding with Hev b 7, this allergen recognized only a small group of patients, for whom IgE antibody against other major latex allergens could not be detected [40]. Hev b 7 has two biologic functions. It inhibits rubber biosynthesis but also has hydrolase and esterase activity which inhibits the growth of invertebrate pests. Thus, it may also be classified as a defense-related protein. Although Hev b 6.01–6.03 has latex coagulation activity, it will be presented under defense-related proteins.

Immune Responses to Defense-Related proteins Higher plants have a defense system of proteins that are compared frequently to the immune system of animals, but in reality are significantly different. In fact, a number of these proteins can be induced by different techniques outlined in Table 3 which could increase the allergen content of harvested latex. Static defense proteins (e.g., storage proteins) may exert antifungal activity or (e.g., lectins) antimicrobial activity. Pathogenesis-related proteins (PR-proteins) are encoded by the host plant but are Table 3 Harvesting and manufacturing procedures that may affect latex allergen content in finished natural rubber products Latex allergen enhancement Latex allergen reduction Frequent tapping of rubber tree Reduced tapping frequency Hormone treatment (e.g., ethepon) High temperature vulcanization Defense protein induction Prolonged vulcanization time Low temperature vulcanization No powder Dipping process Pre and Post vulcanization leaching Storage time shortened Acid coagulation Cornstarch donning powder Halogenation

660

K.J. Kelly and B.T. Kelly

Table 4 Pathogenesis Related proteins that may cross-react with Hevea latex proteins Family Class Source Protein name PR-2 Latex, banana Hev b 2 B-1-3-Glucanases PR-3 Class I Chitinase Latex, avocado, banana, Cas s 5, Hev b 11, Pers a 1 chestnut PR-4 Chitinases Latex Hev b 6 PR-8 Class III Chitinases Latex Hevamine PR-14 Lipid transfer proteins Latex, apple, apricot, Amb a 6, Cas s 8, Cor a 8, Hev b cherry, chestnut, 12, Mal d 3, Pru ar 3, Pru av hazelnut, peach, 3, Pru d 1, Pru p 3, plum, ragweed

induced only in pathological situations (e.g., tapping of a latex tree). There are 14 identified families of PR-proteins with defense function and many are associated with food allergy, cross-reactions in pollen induced food allergy and the latex-fruit syndrome. Thus, it is important to understand the type of defense protein that are allergens in NRL, in order to predict which fruit and environmental allergens will cause clinical cross-reactivity. A list of the PR-families and the relevant latex allergen that belongs to these families of proteins is presented in Table 4. The Hevea latex allergens that have defense-related functions include Hev b 2, Hev b 4, Hev b 6.01-6.03, Hev b 7 (see above), Hev b 11, Hev b 12, and Hev b 13 [42–54]. Most latex allergic patients recognize one or more of these allergens and their potential cross-reactions with fruit proteins account for the multiple patients who have serious allergic reactions after ingestion of a food with such proteins. In addition, hevamine, a common protein that is not officially accepted as an allergen, is also a defense-related protein that some individuals develop IgE antibody against. Hev b 2: This basic b-1,3-glucanase can be isolated from B serum containing lutoids of Hevea latex. The native protein exhibits significant IgE binding with latex sensitized patients including both SB and HCW [42, 43]. Depending on the method used, the IgE reactivity may range from 20–61% of patients with clinical symptoms from latex allergen content [32]. The recombinant Hev b 2 over expressed in prokaryotic expression system, failed to react with IgE from sera of latex allergic patients [15]. The reason for the nonreactivity of recombinant Hev b2 may be due to the lack of glycosylation and posttranslational modifications comparable to the native protein. Foods such as banana, potato and tomato may contain b-1,3-glucanase activity but it is not clear if this is truly the protein resulting in cross-reactions [18]. Peptide sequencing shows similarity to tobacco and tomato endo-b-1,3-glucanase. Hev b 4: The microhelix component of latex or Hev b 4 has been identified in the bottom fraction lutoids; it was purified and discovered to be a major latex allergen reported by Sunderasen [33]. It is an acidic protein and under reducing condition appeared as a broad band in the range of 50–57 kDa. Although 65% of HCW were found to have significant IgE against this component, only 14% of these patients showed PBMC stimulation to Hev b 4 [32, 40]. Unfortunately, it has not been cloned and expressed and its function is likely to be a defense protein but further work must be done to prove this.

Diagnosis and Treatment of Latex Allergy

661

Hev b 5: Two independent investigator groups cloned and expressed Hev b 5, an acidic protein with a molecular mass of 16 kDa [28, 29]. It has 46% homology with an 18.9 kD protein from kiwi and is presumed to be partially responsible for clinical reactions to this fruit in latex allergic patients. This protein is a major allergen with strong IgE binding reactivity with both HCW and SB patients. In serologic assays, as many as 92% of HCW and 56% patients with SB showed IgE binding with the recombinant form of Hev b 5. In addition, the strong IgE binding property of Hev b 5 is witnessed by significant histamine release from basophils among latex allergic patients [28, 40]. Hev b 6 (prohevein): Hev b 6.01 is one of the most abundant proteins in the lutoid bodies of Hevea latex. It has two distinct domains, a 4.7 kD C-terminal domain (Hev b 6.02) and an N-terminal 14 kD peptide (Hev b 6.03). Prohevein has strong reactivity with IgE from HCW and SB patients with latex allergy [32]. In immunoblot and ELISA, the 43 amino acid long N-domain exhibits IgE binding with significantly higher number of latex sensitized patients when compared to the 144 amino acid long C-domain of Hev b 6. The results of skin test reactions correlated well with the in vitro IgE to latex allergens [14, 44, 45]. Epitope mapping of the prohevein molecule revealed more IgE binding regions near the N-terminal end of the protein [45].

Hev b 8 (Profilin) Prolifin, an actin binding protein, is involved in the formation of actin network of plant exoskeleton. The purified latex profilin when used in skin prick testing showed positive reactions in all the 24 SB patients and 6 of 17 HCW with latex allergy. Interestingly, latex derived profilin showed cross-reactivity with IgE among 36 patients with ragweed allergy, but the clinical relevance of this is unclear [30].

Hev b 9 (Enolase) Hev b 9 is most abundant in the aqueous layer of latex [7, 15]. A high degree of cross-reactivity can be expected because of the homology of enolases present in different organisms. However, unpublished work from our laboratory on sera from 26 HCW with latex allergy failed to demonstrate any IgE binding with the recombinant latex Hev b 9 and fungal enolases.

Hev b 10 (Manganese Superoxide Dismutase) This highly conserved enzyme (MnSOD) has been reported from a number of fungi, bacteria and human beings as well [7, 15]. Although MnSOD from the fungus Aspergillus fumigatus demonstrated significant IgE binding with sera from allergic aspergillosis,

662

K.J. Kelly and B.T. Kelly

one out of 26 latex allergic patients demonstrated IgE antibody binding with latex MnSOD (unpublished results). The limited study also indicates that in spite of the sequence similarities with MnSOD from other sources, the latex derived MnSOD showed only low levels of cross allergenicity with the corresponding mold enzyme.

Hev b 11 (Endochitinase) Chitinases and lysozymes constitute about 25% of the proteins in the lutoid fraction of NRL. The class 1 chitinase shares homology with N-terminal hevein domain, and also shares epitopes with chitinases from avocado and banana [24, 25]. As of now, the cross-reactivity and immune responses of Hev b 11 in latex allergic patients are minor contributors to disease.

Hev b 12 (Lipid Transfer Protein) Lipid transfer proteins with antifungal and antibacterial activity are named for their ability to transfer phospholipids from liposomes to mitochondria and are widely distributed in the plant kingdom. This class of proteins is the most important allergen in the Prunoideae fruits such as peach, cherry, apricot, and plum. This may help explain the cross-reactivity seen in stone fruits in latex allergic health care workers [54].

Hev b 13 (Latex Esterase) The biologic role of this protein is not as well defined but it is one of the major allergens found in natural and finished latex products that HCW react to [55]. This important allergen correlates well with the allergenic content of finished latex gloves and has been proposed to be one of four allergens used in a standard to measure immunological allergenic content of manufactured products [56].

Diagnosis of Latex Allergy The diagnosis of latex allergy in an individual patient requires a trained medical provider to take a complete medical history, perform a physical examination, and then supplement the clinical conclusions with appropriate testing. An algorithm that outlines one method of approaching a diagnosis of latex allergy is included in Fig. 2. It should be noted that epicutaneous skin testing or serologic testing for antilatex IgE in the absence of a clinical history and physical exam are not adequate for an accurate

Diagnosis and Treatment of Latex Allergy

663

An Algorithm for the Diagnosis of Latex Allergy Latex Allergy Evaluation Medical History Physical Examination

Immediate symptom Dermatitis, urticaria, angioedema, rhinitis, asthma, anaphylaxis

Asymptomatic *

Testing Indicated Anti-latex IgE by serology Patch test (dermatitis)

Testing Negative Do Further testing

Acute or Chronic Dermatitis

Testing indicated Patch test

Patch

Serology SPT

STOP No latex allergy Testing not indicated

Delayed symptom

STOP - Testing Positive No further testing** Latex allergy confirmed

Testing Positive Contact Dermatitis

Testing Negative Irritant Dermatitis***

Skin Prick Test Dilute extract of latex glove Testing Negative

Testing Positive No further testing Latex allergy confirmed

Further testing

Use Challenge Test Testing Negative No latex allergy

Testing Positive No further testing Latex allergy confirmed

Fig. 2 An algorithm for the diagnosis of latex allergy. This figure illustrates a diagnostic algorithm for the diagnosis of latex allergy in the United States where no diagnostic skin test reagent is cleared for use by the food and drug administration. (Reproduced with permission from [4].) *Spina bifida patients should be cared for in a latex safe environment from birth. **If occupation worker – pulmonary function testing and methacholine challenge. In other countries outside the US, a licensed skin test reagent has been used as the procedure of choice for initial diagnostic testing. ***Some reports in the medical literature implicate latex proteins as a cause of contact dermatitis. No standardized reagent is available for such testing that does not include potential contamination from additive chemicals

664

K.J. Kelly and B.T. Kelly

diagnosis of latex allergy since each of those tests has variable sensitivity, specificity, positive predictive value, and negative predictive values. Testing for latex allergy has been hindered in the US by the lack of a standard reagent clearance through USFDA. Despite a multicenter skin test study that confirmed one nonammoniated reagent to be reliable and safe, no licensed product has been forthcoming [57, 58]. Skin Testing: Skin testing has been the most sensitive and predictive test for confirming a diagnosis of latex allergy. Achieving the highest sensitivity has required the use of more than one source material for latex (e.g., natural latex nonammoniated and a latex glove extract) [57–65]. In one series, the sensitivity of using two source materials was 100%, specificity of 99%, and a negative test having 100% predictive value in concluding that a patient was not allergic to latex [63]. The reason for failure of a skin test reagent to be approved in the US may relate to the frequency of adverse reactions to epicutaneous testing with latex allergen. Early information demonstrated that skin testing resulted in a high rate of systemic reactions not seen with other allergens approved for skin testing [64, 65]. More importantly, this high rate of reaction was confirmed in a comparative retrospective study from the Mayo Clinic where the rate of systemic reactions to latex was 228/100,000 latex skin tests while reactions of this nature to other allergens was 72/100,000 penicillin skin tests and 23/100,000 aeroallergen tests [66]. This represents a 10-fold elevated risk of systemic reactions to latex skin testing compared to aeroallergen tests. Even the multicenter skin test study with clone 600 latex resulted in 16% of subjects having a systemic, albeit mild, reactions to skin testing [57, 58]. Standardized extracts were not used in any of the studies associated with anaphylactic events except the multicenter skin test study [58]. Comparisons of latex extracts, made using different techniques, indicated that the protein content obtained from a single glove can vary over 2-fold, depending on the extraction method. Other factors, such as temperature, salt concentration and detergent activity can also affect extraction efficiency [67]. In addition, the stability of the different latex antigens is variable. Since the antigen content of gloves can vary several 100-fold, unstandardized extracts may contain vastly different amounts of latex protein. Furthermore, the measurable content of specific allergens is likely to be even more unpredictable. Therefore, a significant portion of the risk associated with latex skin tests can be attributed to the use of uncharacterized extracts. One further approach to this problem is the use of recombinant latex allergens for skin testing, which may be nearly as sensitive and specific as crude uncharacterized latex [68]. Although the algorithm in Fig. 2, recommends skin testing, it may be safest to perform with a commercial latex standardized reagent such as the Stallergenes S.A. (Marseilles, France) used in Europe.

In Vitro Testing for Latex Allergy The vast majority of in vitro testing for latex allergy has used methods for detecting antilatex specific IgE antibody circulating in the serum of patients. These range from the use of research laboratory prepared enzyme linked immunosorbent assays

Diagnosis and Treatment of Latex Allergy

665

Table 5 Performance of specific IgE serology tests

Method Hycor HyTECH DPC AlaSTAT Pharmacia CAP a b

Sensitivity (%) 91.6 73.3b 76.3b

Specificity (%) 73.3 97.2 96.7

Positive predictive value (%) 71.4a 95.0 94.3

Negative predictive value (%) 92.3 83.4 85.0

The HyTECH test will result in an approximate 27% false positive rate Both the AlaSTAT and CAP methods will result in a 24–27% false negative rate

(ELISA) to commercial methods as seen in the Pharmacia UniCAP FEIA (Pharmaceia, Peapack, NJ), AlaSTAT (Diagnostic Products Corporation, Los Angeles, Ca), and Hycor HYTECH (Hycor Biomedical, Inc., Garden Grove, Ca) systems [58–60, 69–87]. As predicted, these systems all have their benefits and problems associated with them. Early use of the CAP system from Pharmacia resulted in lower sensitivity and false negative results in patients [59, 60, 69–71]. Modification of the allergen and even using allergen extracted from a Baxter Triflex glove enhanced the sensitivity to 82% [71]. A second approach to improve the performance of the commercial assay is to add recombinant allergens as may be done with the skin test reagents [77]. One of the most important studies compared the performance of the three commercially available serologic assays for latex specific IgE in 117 clinically allergic individuals and 195 clinically nonallergic controls [82]. When compared to skin test, both the Pharmacia CAP and AlaSTAT had similar sensitivity of 76% and 73% respectively with 97% specificity. Unfortunately, 25% of the latex-sensitized cases had false negative results. HyTECH had a significantly lower specificity of 73% which indicates that 27% of the positive results are erroneous (Table 5). Using this information, screening studies for latex allergy in a population with a low prevalence of latex allergy, these tests may cause a significant number of false positive reactions which makes these tests undesirable for this activity without a follow-up definitive test. Other in vitro methods of diagnosing latex allergy have included basophil histamine release, CD 63 activation of basophils, and lymphocyte proliferation methods [40, 45, 79, 88–95]. These assays are more specific but lack sensitivity. Their most useful activity has been to identify specific IgE epitopes and T-cell epitopes as noted in Table 6 [91–98]. These tests have not become useful clinical tools although genetic altering of strongly allergenic epitopes may be useful in down regulating and inducing tolerance by immunotherapy in latex allergic subjects.

In Vivo Provocation Testing In addition to using serologic testing or skin prick testing in diagnosing latex allergy, it is sometimes necessary to understand whether a specific allergen or latex product reported by clinical history is truly responsible for the symptoms or clarify discordant serum and skin test results. There have been many versions of provocation tests

666

K.J. Kelly and B.T. Kelly

Table 6 Epitopes of latex allergens Allergens IgE Epitopes/Source Hev b 1137 aa 30-49, 46-64, 121-137/HCW 2-11,16-25,36-55, 61-70 65-74,90-108/HCW & SB

T cell epitopes/source

31-49, 91-109/ PBMC 10-24,13-27,48-59,55-69, 100-114, 103-114, 147169 160-171,178-189 / Spina Bifida T cell clones

Hev b 3 208 aa

2-17, 29-38,41-50,60-69, 85-94, 103-112,118-127, 138-147,159-168,179-188/ HCW & SB Hev b 5

Hev b 6

95 96

40

46-65,109-128/ HCW T cell clones 15-22, 28-32, 50-56, 76-81 90-95,132-139 /HCW N-domain 13-24,29-36 C domain 62-69,74-81 134-139, 164-171/HCW N-domain 19-24,25-37 C-domain 60-66,76-79, 79-82, 82-96, 98-103,164-172/HCW & SB

References 95 40

97 100 101 102

49

for diagnosing latex allergy. These have included glove use tests using standardized gloves used in the multicenter latex skin test study [57]. In addition, multiple investigations have used a “latex glove wearing” test with or without a coupled inhalation test [99, 100]. The critical value of the provocation test is making certain that objective measurable or observable reactions are measured. These may include such things as urticaria, angioedema, or pulmonary function changes. Some investigators have chosen to use inhalation challenges alone or mucous membrane contact. These have been progressive, graded challenges and are currently only standardized in research settings. Trouble with blinding the challenge is difficult but has been accomplished using a hooded exposure chamber [101, 102].

Prevention and Treatment of the Patient with Latex Allergy Numerous scientists, clinicians, and industry experts have spent the last 15–20 years on prevention of latex allergy by reducing sensitization i in patients who are at highest risk of developing this devastating problem. Thus, the focus has been on prevention strategies for children who have spina bifida, individuals who require multiple surgeries, as well as health care workers and other occupations that require contact with natural rubber latex gloves. Some general principals of prevention and care of the latex allergic patient are listed in Table 7.

Diagnosis and Treatment of Latex Allergy

667

Table 7 Latex safe precautions in a hospital and clinical setting in documented or suspected latex allergy Only nonlatex glove use Allergy alert band for the patient “Latex safe precautions” on door to patient room Check all medical devices for latex content No latex contact to skin or mucosal surfaces of patient (no source for inhalation) No intravenous valves inline Inject medication via stopcock devices instead of injector ports on tubing Operating room – schedule as the first case of the day if powdered gloves in prior use in O.R. Multiple dose vials – take top off or change needle after drawing up medication Premedication – not necessary when strict latex safe precautions used Ideal – latex gloves used should be powder free and low in allergen for nonlatex allergic patients Ban powdered latex products manufactured by dipping process from building (e.g., balloons) Tables 1, 2, 3, and 7 (Reproduced with permission from [4]

The prototype patient for prevention of latex allergy is the infant born with spina bifida. As early as 1993, experts suggested guidelines modeled after the prevention program implemented by the author of this article at the Children’s Hospital of Wisconsin [103]. These measures included such things as complete abstinence of latex materials used in the care of these patients from birth. This especially meant no latex gloves, catheters, dressings, tape or other medical devices that contained latex in the hospital and home setting. Given the level of disability and the vast number of surgeries in these subjects, it was quite a daunting task that is now considered routine care. Because these recommendations were so far from the normal care of at risk subjects, an opinion article to vastly change care and prevent latex allergy was published in 1996 [104]. Given that over 40,000 devices and materials contained natural rubber latex as a component, stopping all use of latex containing materials became impractical. Information about latex allergen content of these materials as well as analysis of the devices reported to cause allergic reactions to latex, reported to the USFDA center for devices and radiologic health, seemed to be the best approach to prevention. Avoiding the use of latex materials that were made by a dipping process with short vulcanization times and low heat was the most likely strategy to prevent allergic reactions. Indeed, the concept of “latex safe” environments vs. “latex-free” environments turned out to be safe, practical and ideal for patients with latex allergy [105]. Further observations in Canada, Europe and USA noted that airborne latex was created by cornstarch donning powder from latex gloves which continued to sensitize and cause allergic reactions not only in patients but health care workers [106–127]. In fact, sensitization in health care workers may not only occur from direct wearing of latex gloves but through inhalation of airborne particles that carry latex allergen [110, 112–120]. This became such an emotional and critical issue, one author suggested that prevention of latex allergy was an exercise in “principled medical center leadership” [117]. A number of investigators in the above referenced articles noted a high content of latex allergen from the source materials. In fact, the allergen content in dipped products has been reduced according to the industry by

668

K.J. Kelly and B.T. Kelly

as much as 1000-fold since the early 1990s (Personal communication: Mr. Milt Hinsch, SSL Medical, Atlanta, Georgia). This has led to a marked reduction is the prevalence of latex allergy in health care workers and reduction in the use of products that emit airborne latex [127]. The care of the patient with latex allergy requires that individual to avoid personal contact of the skin and mucous membranes with latex materials. In addition, they should only enter areas where airborne latex allergen is controlled by use of nonpowdered latex products. If they are a health care worker, they should use nonlatex gloves and only work in areas where either powder-free latex gloves are used routinely or nonlatex gloves are used. Rarely, immunotherapy is a consideration for cure of latex allergy. However, the side effects of such therapy, length of time to achieve tolerance, and lack of a standard reagent make this therapy relatively futile [128–130]. Promise of modified allergens to make immunotherapy safer and more effective is on the horizon [131].

Summary The diagnosis and treatment of latex allergy requires astute clinical skills, recognition of patterns of latex induced reactions and cross-reactions, and clinical judgment when interpreting test results. Ultimately, confirmation of a diagnosis of latex allergy lies with the clinician.

References 1. Kelly KJ, Setlock M, Davis JP. Anaphylactic reactions during general anesthesia among pediatric patients. MMWR 1991; 40(26):437 2. Kelly KJ, Pearson ML, Kurup VP et al. Anaphylactic reactions in patients with spina bifida during general anesthesia: epidemiologic features, risk factors, and latex hypersensitivity. J Allergy Clin Immunol 1994; 94(1):53–61 3. Yagami T. defense-related proteins as families of cross-reactive plant allergens. Recent Res Dev Allergy Clin Immunol 2000; 1:41–64 4. Kelly KJ. Latex Allergy. In: Atlas of Allergies and Clinical Immunology (3rd edition); Fireman P (Ed). Mosby Elsevier: Philadelphia 2006; 16(2): 259–270. 5. Sanchez-Monge R, Blanco C, Diaz-Perales A, et al. Isolation and characterization of major banana allergens: identification as fruit class I chitinases. Clin Exp Allergy 1999; 29:673–680 6. Kurup VP, Alenius H, Kelly KJ, et al. A two-dimensional electrophoretic analysis of latex particles reacting with IgE and IgG antibodies from patients with latex allergy. Int Arch Allergy Immunol 1996; 109:58–67 7. Posch A, Chen Z, Wheeler C, et al. Characterization and identification of latex allergens by two-dimensional electrophoresis and protein microsequencing. J Allergy Clin Immunol 1997; 99:385–395 8. Subramaniam A. The chemistry of natural rubber latex. In: Fink JN (Ed). Immunology and Allergy Clinics of North America. Philadelphia: W.B. Saunders Company, 1995; 1–20

Diagnosis and Treatment of Latex Allergy

669

9. Alenius H, Kurup V, Kelly K, Palosuo T, Turjanmaa K, Fink J. Latex allergy: frequent occurrence of IgE antibodies to a cluster of 11 latex proteins in patients with spina bifida and histories of anaphylaxis. J Lab Clin Med 1994; 123:712–720 10. Makinen-Kiljunen S, Turjanmaa K, Palosuo T, et al. Characterization of latex antigens and allergens in surgical gloves and natural rubber by immunoelectrophoretic methods. J Allergy Clin Immunol 1992; 90:230–235 11. Chambeyron C, Dry J, Leynadier F, et al. Study of the allergic fractions of latex. Allergy 1992; 47:92–97 12. Lu L-J, Kurup VP, Fink JN, Kelly KJ. Comparison of latex antigens from surgical gloves, ammoniated and nonammoniated latex: effect of ammonia treatment on natural rubber latex proteins. J Lab Clin Med 1995; 126:161–168 13. Lu L-J, Kurup VP, Hoffman DR, Kelly KJ, Murali PS, Fink JN. Characterization of a major latex allergen associated with hypersensitivity in spina bifida patients. J Immunol 1995; 155:2721–2728 14. Alenius H, Reunala T, Turjanmaa K, et al. Surgical glove latex glove allergy: Characterization of rubber protein allergens by immunoblotting. Int Arch Allergy Appl Immunol 1991; 96:376–380 15. Breiteneder H. The allergens of Hevea brasiliensis. ACI International 1998;10:101–109 16. Dennis MS, Light DR. Rubber elongation factor from Hevea brasiliensis. Identification, characterization, and role in rubber biosynthesis. J Biol Chem 1989; 264:18608–18617 17. Dennis MS, Henzel WJ, Bell J, et al. Amino acid sequence of rubber elongation factor protein associated with rubber particles in Hevea latex. J Biol Chem 1989; 264:18618–18626 18. Oh SK, Kang H, Shin DH, et al. Isolation, characterization, and functional analysis of a novel cDNA clone encoding a small rubber particle protein from Hevea brasiliensis. J Biol Chem 1999; 274:17132–17138 19. Broekaert W, Lee HI, Kush A, et al. Wound-induced accumulation of mRNA containing a hevein sequence in laticifers of rubber tree (Hevea brasiliensis). Proc Natl Acad Sci USA 1990; 87:7633–7637 20. Gidrol X, Chrestin H, Tan H-L, Kush A. Hevein, a lectin-like protein from Hevea brasiliensis (rubber tree) is involved in the coagulation of latex. J Biol Chem 1994; 269:9278–9283 21. Yusof F, Audley BG, Ward MA, Walker JM. Purification and characterization of an inhibitor of rubber biosynthesis from C-serum of Hevea brasiliensis latex. J Rubber Res 1998; 1:95–110 22. Breton F, Coupé M, Sanier C, d’Auzac JD. Demonstration of beta-1,3-glucanase activities in lutoids of Hevea brasiliensis latex. J Nat Rubb Res 1995; 10:37–45 23. Yagami T, Sato M, Nakamura A, Komiyama T, Kitagawa K, Akasawa A, et al. Plant defenserelated enzymes as latex antigens. J Allergy Clin Immunol 1998; 101:379–385 24. Graham LS, Sticklen MB. Plant chitinases. Can J Bot 1994; 72:1057–1083 25. Posch A, Wheeler CH, Chen Z, et al. Class I endochitinase containing a hevein domain is the causative allergen in latex-associated avocado allergy. Clin Exp Allergy 1999; 29:667–672 26. Terwisscha van Scheltinga T, Kalk, AC, Beintema, JJ, Dijkstra BW. Crystal structures of hevamine, a plant defense protein with chitinase and lysozyme activity, and its complex with an inhibitor. Structure 1994; 2:1181–1189 27. Bokma E, van Koningsveld GA, Jeronimus-Stratingh M, et al. Hevamine, a chitinase from the rubber tree Hevea brasiliensis, cleaves peptidoglycan between the C-1 of N-acetylglucosamine and C-4 of N-acetylmuramic acid and therefore is not a lysozyme. FEBS Lett 1997; 411:161–163 28. Slater JE, Vedvick T, Arthur-Smith A, et al. Identification, cloning, and sequence of a major allergen (Hev b 5) from natural rubber latex (Hevea brasiliensis). J Biol Chem 1996; 271:25394–2539 29. Akasawa A, Hsieh LS, Martin BM, et al. A novel acidic allergen, Hev b 5, in latex. Purification, cloning and characterization. J Biol Chem 1996; 271:25389–25393 30. Vallier P, Balland S, Harf R, et al. Identification of profilin as an IgE-binding component in latex from Hevea brasiliensis: clinical implications. Clin Exp Allergy 1995; 25:332–339 31. Chen ZP, Cremer R, Posch A, et al. On the allergenicity of Hev b 1 among health care workers and patients with spina bifida allergic to natural rubber latex. J Allergy Clin Immunol 1997; 100:684–693

670

K.J. Kelly and B.T. Kelly

32. Kurup VP, Yeang HY, Sussman GL, Bansal NK, Beezhold DH, Kelly KJ, Hoffman DR, Williams B, Fink JN. Detection of immunoglobulin antibodies in the sera of patients using purified latex allergens. Clin Exp Allergy 1999; 30:359–369 33. Yeang HY, Cheong KF, Sunderasan E, et al. The 14.6 kd rubber elongation factor (Hev b 1) and 24 kd (Hev b 3) rubber particle proteins are recognized by IgE from patients with spina bifida and latex allergy. J Allergy Clin Immunol 1996; 98:6 34. Alenius H, Kalkkinen N, Lukka M, et al. Purification and partial amino acid sequencing of a 27-kD natural rubber allergen recognized by latex-allergic children with spina bifida. Int Arch Allergy Immunol 1995; 106:258–262 35. Alenius H, Palosuo T, Kelly K, Kurup V, Reunala T, Makinen-Kiljunen S, Turjanmaa K, Fink J. IgE reactivity to 14-kD and 27-kD natural rubber proteins in latex-allergic children with spina bifida and other congential anomalies. Int Arch Allergy Immunol 1993; 102:61–66 36. Banerjee B, Kanitpong K, Fink JN, Zussman M, Sussman GL, Kelly KJ, Kurup VP. Unique and shared IgE epitopes of Hev b 1 and Hev v 3 in latex allergy. Mol Immunol 2000; 37:789–798 37. Wagner B, Krebitz M, Buck D, Niggemann B, Yeang HY, Han KH, Scheiner O, Breiteneder H. Cloning, expression, and characterization of recombinant Hev b 3, a Hevea brasiliensis protein associated with latex allergy in patients with spina bifida. J Allergy Clin Immunol 1999; 104:1084–1092 38. Kostyal DA, Hickey V, Noti JD, et al. Cloning and characterization of a latex allergen (Hev b 7): homology to patatin, a plant PLA2. Clin Exp Immunol 1998; 112:355–362 39. Beezhold DH, Sussman GL, Kostyal DA, Chang N. Identification of a 46-kD latex protein allergen in health care workers. Clin Exp Immunol 1994; 98:408–413 40. Johnson BD, Kurup VP, Sussman GL, Arif SAM, Kelly KJ, Beezhold DH, Fink JN. Purified and recombinant latex proteins stimulate peripheral blood lymphocytes of latex allergic patients. Int Arch Allergy Immunol 1999; 120:270–279 41. Sowka S, Wagner S, Krebitz M, et al. cDNA cloning of the 43-kDa latex allergen Hev b 7 with sequence similarity to patatins and its expression in the yeast Pichia pastoris. Eur J Biochem 1998; 255:213–219 42. Sunderasan E, Hamzah S, Hamid S, et al. Latex B-serum beta-1,3-glucanase (Hev b 2) and a component of the microhelix (Hev b 4) are major latex allergens. J Nat Rubb Res 1996; 10:82–99 43. Chye ML, Cheung KY. Beta-1,3-glucanase is highly-expressed in lactifers of Hevea brasiliensis. Plant Mol Biol 1995; 29:397–402 44. Alenius H, Kalkkinen N, Reunala T, et al. The main IgE binding epitopes of a major latex allergen, prohevein is present in its 43 amino acid fragment hevein. J Immunol 1996; 156:1618–1625 45. Banerjee B, Wang X, Kelly KJ, Fink JN, Sussman GL, Kurup VP. IgE from latex-allergic patients binds to cloned and expressed B cell epitopes of prohevein. J Immunol 1997; 159:5724–5732 46. Brehler R, Theissen U, Mohr C, Luger T. “Latex-fruit syndrome.” Frequency of cross-reacting IgE antibodies. Allergy 1997; 52:404–410 47. Blanco C, Carrillo T, Castillo R, et al. Latex allergy: clinical features and cross reactivity with fruits. Ann Allergy 1994; 73:309–314 48. Beezhold DH, Sussman GL, Liss GM, Chang NS. Latex allergy can induce clinical reactions to specific foods. Clin Exp Immunol 1996; 26:416–422 49. Lavaud F, Prevost A, Cossart C, et al. Allergy to latex avocado, pear, and banana: evidence for a 30 kd antigen in immunoblotting. J Allergy Clin Immunol 1996; 95:557–564 50. Alroth M, Alenius H, Turjanmaa K, et al. Cross-reacting allergens in natural rubber latex and avocado. J Allergy Clin Immunol 1995; 96:167–173 51. Alenius H, Mäkinen-Kiljunen S, Alroth M, Turjanmaa K, Reunala T, Palosuo T. Crossreactivity between allergens in natural rubber latex and banana studied by immunoblot inhibition. Clin Exp Allergy 1996; 26:341–348 52. Akasawa A, Hsieh L, Tanaka K, Lin Y, Iikura Y. Identification and characterization of avocado chitinase with cross-reactivity to a latex protein. J Allergy Clin Immunol 1996; 97:321

Diagnosis and Treatment of Latex Allergy

671

53. Mahler V, Diepgen TL, Kubeta O, Leakakos T, Truscott W, Schuler G, Kraft D, Valenta R. Mutual boosting effects of sensitization with timothy grass pollen and latex glove extract on IgE antibody responses in a mouse model. J Invest Dermatol 2000; 114: 1039–1043 54. Breiteneder H, Ebner C. Molecular and biochemical classification of plant-derived food allergens. J Allergy Clin Immun 2000; 106:27–36 55. Bernstein DI, Biagini RE, Kamani R, Hamilton R, Murphy K, Bernstein C. et al. In vivo sensitization to purified to purified Hevea brasiliensis proteins in health care workers sensitized to natural rubber latex. J Allergy Clin Immunol 2003; 111:610–6 56. Yeang H, Arif SAM, Raoulf-Heimsouth M, Loke Y, Sander I, Sulong SH, Lau C, Hamilton RG. Hev b 5 and Hev b 13 as allergen markers to estimate the allergenic potency of latex gloves. J Allergy Clin Immunol 2004; 114:593–8 57. Hamilton RG, Adkinson F, and the Multicenter Latex Skin Testing Study Task Force. Diagnosis of natural rubber latex allergy: multicenter latex skin testing efficacy study. J Allergy Clin Immunol 1998; 102:482–490 58. Hamilton RG, Biagini RE, Krieg EF, Multi-Center Latex Skin Testing Study Task Force. Diagnostic performance of FDA-cleared serological assays for natural rubber latex-specific IgE antibody. J Allergy Clin Immunol 1999; 103:925–30 59. Wrangsjo K, Wahlberg JE, Axelsson IGK: IgE-mediated allergy to natural rubber in 30 patients with contact urticaria. Contact Derm 1988; 19:264–271 60. Turjanmaa K, Reunala T, Rasanen L. Comparison of diagnostic methods in latex surgical contact urticaria. Contact Derm 1988; 19:241–247 61. Turjanmaa K, Reunala T. Condoms as a source of latex allergen and cause of contact urticaria. Contact Derm 1989; 20:360–364 62. Pecquet C, Leynadier F, Dry J. Contact urticaria and anaphylaxis to natural latex. J Am Acad Dermatol 1990; 22:631–633 63. Moneret-Vautrin DA, Laxenaire MC. Routine testing for latex allergy in patients with spina bifida is not recommended [reply]. Anesthesiology 1991; 74:391–392 64. Kelly KJ, Kurup V, Zacharisen M, et al. Skin and serologic testing in the diagnosis of latex allergy. J Allergy Clin Immunol 1993; 91:1140–1145 65. Bonnekoh B, Merk HF. Safety of latex prick skin testing in allergic patients [letter]. JAMA 1992; 267:2603 66. Valyasevi MA, Maddox DE, Li JT. Systemic reactions to allergy skin tests. Ann Allergy Asthma Immunol 1999; 83(2):132–6 67. Fink JN, Kelly KJ, Elms N, Kurup VP. Comparative studies of latex extracts used in skin testing. Ann Allergy Asthma Immunol 1996; 76(2):149–152 68. Yip L, Hickey V, Wagner B, Liss G, Slater J, Breiteneder H, Sussman G, Beezhold D. Skin prick test reactivity to recombinant latex allergens. Int Arch Allergy Immunol 2000; 121:292–299 69. Gerber AC, Jorg W, Zbinden S. et al. Severe intraoperative anaphylaxis to surgical gloves: latex allergy, an unfamiliar condition. Anesthesiology 1989; 71:800–802 70. Moneret-Vautrin DA, Laxenaire MC, Bavoux F. Allergic shock to latex and ethylene oxide during surgery for spina bifida. Anesthesiology 1990; 73:556–558 71. Hamilton RG, Charous BL, Yunginger JW. Evaluation of crude and end-product latex as allergens for IgE anti-latex assays. J Allergy Clin Immunol 1993; 91:241. Abstract 72. Biagini R, Krieg E, Pinkerton L, Hamilton R. Receiver operating characteristics analyses of food and drug administration-cleared serological assays for natural rubber latex-specific immunoglobulin E antibody. Clin Diagn Lab Immunol 2001; 8(6):1145–1149 73. Ebo G, Stevens W, Bridts C, DeClerck L. Clinical laboratory assessment of IgE. J Allergy Clin Immunol 2003; 111(6):1414–1416 74. Hamilton R, Peterson E, Ownby D. Clinical and laboratory-based methods in the diagnosis of natural rubber latex allergy. J Allergy Clin Immunol 2002; 110(2):S47–S56 75. Ownby D, McCullough J. Testing for Latex Allergy. J Clin Immunoassay 1993; 16(2):109–113

672

K.J. Kelly and B.T. Kelly

76. Ownby D, Magera B, Williams P. A blinded, multi-center evaluation of two commercial in vitro tests for latex-specific IgE antibodies. Ann Allergy Asthma Immunol 2000; 84:193–196 77. Lundberg M, Chen Z, Rihs HP, Wrangsjo K. Recombinant spiked allergen extracts. Allergy 2001; 56:794–795 78. Kelly K, Kurup V, Reijula K, Fink J. The diagnosis of natural rubber latex allergy. J Allergy Clin Immunol 1994; 93(5):813–816 79. Ebo D, Stevens W, Bridts C, Clerck L. Latex-specific IgE, skin testing, and lymphocyte transformation to latex in latex allergy. J Allergy Clin Immunol 1997; 100(5):618–623 80. Hamilton R, Adkinson N. Validation of the latex glove provocation procedure in latex-allergic subjects. Ann Allergy Asthma Immunol 1997; 79:266–272 81. Biagini R, Krieg E, Pinkerton L, Hamilton R. receiver operating characteristics analyses of food and drug administration-cleared serological assays for natural rubber latex-specific immunoglobulin E antibody. Clin Diagn Lab Immunol 2001; 8(6):1145–1149 82. Hamilton R, Biagini R, Krieg E, Multi-Center Latex Skin Testing Study Task Force. Diagnostic performance of Food and Drug Administration-cleared serologic assays for natural rubber latex-specific IgE antibody. J Allergy Clin Immunol 1999; 103(5, Part 1):925–930 83. Beezhold D. LEAP: latex ELISA for antigenic proteins ©* preliminary report. Guthrie J 1992; 61(2):77–81 84. Ebo G, Stevens W, Bridts C, DeClerck L. Clinical laboratory assessment of IgE. J Allergy Clin Immunol 2003; 111(6):1414–1416 85. Hamilton R, Peterson E, Ownby D. Clinical and laboratory-based methods in the diagnosis of natural rubber latex allergy. J Allergy Clin Immunol 2002; 110(2):S47–S56 86. Ownby D, McCullough J. Testing for latex allergy. J Clin Immunoassay 1993; 16(2):109–113 87. Ownby D, Magera B, Williams P. A blinded, multi-center evaluation of two commercial in vitro tests for latex-specific IgE antibodies. Ann Allergy Asthma Immunol 2000; 84:193–196 88. Turjanmaa K, Räsänen L, Lehto M, Mäkinen-Kiljunen S, Reunala T. Basophil histamine release and lymphocyte proliferation tests in latex contact urticaria. Allergy 1989; 44:181–186 89. Ebo D, Lechkar B, Schuerwegh A, Bridts C, DeClerck L, Stevens W. Validaton of a two-color flow cytometric assay detecting in vitro basophil activation for the diagnosis of IgE-mediated natural rubber latex allergy. Allergy 2002; 57:706–712 90. Murali P, Kelly K, Fink J, Kurup V. Investigations into the cellular immune responses in latex allergy. J Lab Clin Med 1994; 124(5):638–643 91. Raulf-Heismoth M, Chen Z, Libers V, et al. Lymphocyte proliferation response to extracts from different latex materials and to the purified latex allergen Hev b 1 (rubber elongation factor). J Allergy Clin Immunol 1996; 98:640–651 92. Bohle B, Wagner B, Vollmann U, et al. Characterization of T cell responses to Hev b 3, an allergen associated with latex allergy in spina bifida patients. J Immunol 2000; 164: 4393–4398 93. de Silva HD, Sutherland MF, Suphioglu C, McLellan SC, Slater JE, Rolland JM, O’hehir RE. Human T-cell epitopes of the latex allergen Hev b 5 in health care workers. J Allergy Clin Immunol 2000; 105:1017–1024 94. Chen Z, van Kampen V, Raulf-Heimsoth M, Baur X. Allergenic and antigenic determinants of latex allergen Hev b 1: peptide mapping of epitopes recognized by human, murine and rabbit antibodies. Clin Exp Allergy 1996; 26:406–415 95. Raulf-Heimsoth M, Chen Z, Liebers V, Allmers H, Baur X. Lymphocyte proliferation response to extracts from different latex materials and to the purified latex allergen Hev b 1 (rubber elongation factor). J Allergy Clin Immunol 1996; 98:640–651 96. Beezhold DH, Hickey VL, Slater JE, Sussman GL. Human IgE-binding epitopes of the latex allergen Hev b 5. J Allergy Clin Immunol 1999; 103:1166–1172 97. Slater JE, Paupore EJ, O’Hehir RE. Murine B-cell and T-cell epitopes of the allergen Hev b 5 from natural rubber latex. Mol Immunol 1999; 36:135–143 98. Beezhold DH, Kostyal DA, Sussman GL. IgE epitope analysis of the hevein preprotein; a major latex allergen. Clin Exp Immunol 1997; 108:114–121

Diagnosis and Treatment of Latex Allergy

673

99. Heese A, van Hintzenstern J, Peters KP, Koch HU, Hornstein OP. Allergic and irritant reactions to rubber gloves in medical health services. Spectrum, diagnostic approach, and therapy. J Am Acad Dermatol 1991; 25:831–839 100. Niggemann B, Buck D, Michael T, Wahn U. Latex provocation tests in patients with spina bifida: who is at risk of becoming symptomatic? J Allergy Clin Immunol 1998; 102:665–670 101. Laoprasert N, Swanson MC, Jones RT, Schroeder DR, Yunginger JW. Inhalation challenge testing of latex-sensitive health care workers and the effectiveness of laminar flow HEPA filtered helmets in reducing rhinoconjunctival and asthmatic reactions. J Allergy Clin Immunol 1998; 102:998–1004 102. Kurtz KM, Hamilton RG, Schaefer JA, Adkinson NF. A hooded exposure chamber method for semi-quantitative latex aeroallergen challenge. J Allergy Clin Immunol 2001; 107:178–184 103. Committee Report. Task Force on Allergic Reactions to Latex. J Allergy Clin Immunol 1993; 92(1, Part 1):16–18. (Committee Members: Slater J, Abramson S, Graft D, Honsinger R, Kelly K, Kwittken P, Ownby D, Virant F.) 104. Kelly KJ, Sussman G, Fink JN: Stop the Sensitization. J Allergy Clin Immunol 1996; 98(1):857–858 105. Swanson M, Bubak M, Hunt L, Yunginger J, Warner M, Reed C. Quantification of occupational latex aeroallergens in a medical center. J Allergy Clin Immunol 1994; 94 (3, Part 1):445–451 106. Baur X, Ammon J, Chen Z, Beckmann U, Czuppon A. Health risk in hospitals through airborne allergens for patients presensitised to latex. Lancet 1993; 342:1148–1149 107. Tarlo S, Sussman G, Contala A, Swanson M: Control of airborne latex by use of powder-free latex gloves. J Allergy Clin Immunol 1994; 93(6):985–9. 108. Kelly KJ. Management of the Latex Allergy Patient. In: Immunology and Allergy Clinics of North America. Fink JN (Ed). W.B. Saunders: Philadelphia 1995; 139–157 109. Swanson M, Bubak M, Hunt L, Yunginger J, Warner M, Reed C. Quantification of occupational latex aeroallergens in a medical center. J Allergy Clin Immunol 1994; 94(3, Part 1):445–451 110. Tarlo S, Sussman G, Contala A, Swanson M. Control of airborne latex by use of powder-free latex gloves. J Allergy Clin Immunol 1994; 93(6):985–989 111. Nieto A, Mazón A, Pamies R, Lanuza A, Muñoz A, Estornell F, García-Ibarra F. Efficacy of latex avoidance for primary prevention of latex sensitization in children with spina bifida. J Pediatr 2002; 140(3):370–372 112. Hunt L, Fransway A, Reed C, Miller L, Jones R, Swanson M, Yunginger J. An epidemic of occupational allergy to latex involving health care workers. JOEM 1995; 37(10):1204–1209 113. Newsom S, Shaw P. Airborne Particles from Latex Gloves in the Hospital Environment. Eur J Surg 1997; Suppl 579:31–33 114. Allmers H, Brehler R, Chen Z, Raulf-Heimsoth M, Fels H, Baur X. Reduction of latex aeroallergens and latex-specific IgE antibodies in sensitized workers after removal of powdered natural rubber latex gloves in a hospital. J Allergy Clin Immunol 1998; 102(5):841–846 115. Baur X, Chen Z, Allmers H. Can a threshold limit value for natural rubber latex airborne allergens be defined? J Allergy Clin Immunol 1998; 101(1, Part 1):24–27 116. Allmers H, Schmengler J, Skudlik C. Primary prevention of natural rubber latex allergy in the German health care system through education and intervention. J Allergy Clin Immunol 2002; 110(2):318–323 117. Jackson E, Arnette J, Martin M, Tahir W, Frost-Arner L, Edlich R. A global inventory of hospitals using powder-free gloves: a search for principled medical leadership. J Emerg Med 2000; 18(2):241–246 118. Hamilton R, Brown R. Impact of personal avoidance practices on health care workers sensitized to natural rubber latex. J Allergy Clin Immunol 2000; 105(4):839–841 119. Kelly K. Latex allergy: where do we go from here? Can J Allergy Clin Immunol 2000; 5(8):337–340 120. Charous B, Blanco C, Tarlo S, Hamilton R, Baur X, Beezhold D, Sussman G, Yunginger J. Natural rubber latex allergy after 12 years: recommendations and perspectives. J Allergy Clin Immunol 2002; 109(1):31–34

674

K.J. Kelly and B.T. Kelly

121. Vandenplas O, Binard-Van Cangh F, Brumagne A, Caroyer J, Thimpont J, Sohy C, Larbanois A, Jamart J. Occupational asthma in symptomatic workers exposed to natural rubber latex: evaluation of diagnostic procedures. J Allergy Clin Immunol 2001; 107(3):542–547 122. Saary M, Kanani A, Alghadeer H, Holness D, Tarlo S. Changes in rates of natural rubber latex sensitivity among dental school students and staff members after changes in latex gloves. J Allergy Clin Immunol 2002; 109(1):131–135. 123. Sussman G. The effects of interventions and glove changes in health care workers with latex allergy. Ann Allergy Asthma Immunol 2003; 90:179–180. 124. Tarlo S, Easty A, Eubanks K, Parsons C, Min F, Jurvet S, Liss G. Outcomes of a natural rubber latex control program in an Ontario teaching hospital. J Allergy Clin Immunol 2001; 108(4):628–633 125. Ebo D, Stevens W. IgE-mediated natural rubber latex allergy: practical considerations for health care workers. Ann Allergy Asthma Immunol 2002; 88:568–575 126. Bernstein D, Karnani R, Biagini R, Bernstein C, Murphy K, Berendts B, Bernstein J, Bernstein I. Clinical and occupational outcomes in health care workers with natural rubber latex allergy. Ann Allergy Asthma Immunol 2003; 90:209–213 127. Zeiss C, Gomaa A, Murphy F, Weissman D, Hodgson M, Foster D, Dejativongse S, Colella K, Kestenberg K, Kurup V, Bush R, Chiu A, Kelly K, Fink J. Latex hypersensitivity in Department of Veterans Affairs health care workers: glove use, symptoms, and sensitization. Ann Allergy Asthma Immunol 2003; 91:539–545 128. Czuppon AB, Chen Z, Rennert S, et al. The rubber elongation factor of rubber trees (Hevea brasiliensis) is the major allergen in latex. J Allergy Clin Immunol 1993; 92:690–697 129. Alenius H, Kalkkinen N, Yip E, et al. Significance of rubber elongation factor as a latex allergen. Int Arch Allergy Immunol 1996, 109:362–368 130. Tomazic VJ, Withrow TJ, Hamilton RG. Characterization of the allergen(s) in latex protein extracts. J Allergy Clin Immunol 1995; 96:635–642 131. Attanyaka DP, Kekwick RG, Franklin FC. Molecular cloning and nucleotide sequencing of the rubber elongation factor gene from Hevea brasiliensis. Plant Mol Biol 1991; 16:1079–1081 132. Kelly KJ, Kelly Brian: Latex Allergy: Clinical Manifestations. In: Allergy Frontiers: From Epigenetics to Future Perspectives; Clinical manifestation of allergic diseases. Pawankar R, Holgate S, Rosenwasser L (eds). Springer Japan KK, 2009; 3:487–508, March 2009

New Aspects of Peanut and Tree Nut Allergy Corinne A. Keet and Robert A. Wood

Introduction In recent years, as our understanding of peanut and tree nut allergy has increased, the potential for real therapies has expanded greatly. Hope for a cure for peanut and other food allergies is on the horizon. At the same time, the rates of peanut and tree nut allergy have continued to increase, and much remains to be learned about these potentially deadly allergies. Recent news headlines have been filled with talk of a peanut allergy “epidemic.” Schools and airplanes have become battlegrounds over what measures need to be taken to ensure safety for peanut allergic patients. A 2005 news story about a peanut allergic Canadian teenager who died after kissing her boyfriend only amplified these concerns [1]. Behind these headlines, the data do point to an increase in peanut and tree nut allergy, along with other allergies. In the UK, admissions for anaphylaxis from food allergy have increased by 500% since 1990 [2]. In the US, a survey conducted in 1997 and again in 2002 showed a doubling of the rate of peanut and tree nut allergy in children from 0.6 to 1.2%, mostly as a result of increases in peanut allergy, while the rates of peanut and tree nut allergy in adults did not change significantly. This suggests that overall rates will further increase in the coming years as these children become adults [3, 4]. At present, approximately 1% of the US population is estimated to be allergic to peanuts or tree nuts [3]. Based on data from a large registry, the median age of first reaction to peanut is 18 months and to tree nuts is 36 months. For 74% with peanut allergy and 68% with tree nut allergy, the first allergic reaction was also the first known exposure to the nut [5]. Peanut and tree nut allergies tend to be more severe than other food allergies, and more than half of the participants in that registry

C.A. Keet and R.A. Wood () Department of Pediatrics, Division of Pediatric Allergy and Immunology, Johns Hopkins University School of Medicine; Johns Hopkins Hospital, CMSC 1102, 600 North Wolfe Street, Baltimore, MD, 21287, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_41, © Springer 2010

675

676

C.A. Keet and R.A. Wood

reported anaphylactic reactions. Food allergy has a significantly negative impact on the life of a child and his or her family. In one survey, food allergy’s effects on quality of life were similar to chronic diseases such as juvenile diabetes [6]. Peanut and tree nuts are responsible for the majority of food related anaphylaxis fatalities in the US and UK, with 50–60% of fatalities caused by peanuts and 15–30% caused by tree nuts [7–10]. Threshold studies have demonstrated that peanut allergic patients can react to as little as 100 mg of peanut orally, a quantity that can easily be accidentally ingested even by those attempting to strictly avoid peanuts [11]. Avoidance and, when it fails, prompt treatment with epinephrine and other medications are currently the only available means to deal with peanut and tree nut allergy. This situation, however, is changing. In this chapter, we review some of the current developments in our understanding of risk factors for peanut and tree nut allergy, epitope specificity and cross-reactivity, diagnosis, natural history, and emerging treatments.

Environmental and Genetic Factors At this time, the reasons for the increase in peanut and tree nut allergy remain unclear. On one hand, peanut and tree nut consumption is increasing as their nutritional benefits become more widely known. More pregnant and nursing women are thought to eat nuts than in the past, exposing the developing immune system to these allergens [12]. On the other hand, overall rates of allergy have increased in the past 2–3 decades, outpacing changes in consumption patterns. Moreover, certain populations eat peanuts at high rates but do not seem to suffer from significant peanut allergy. One theory that has received much attention is the so called “hygiene hypothesis,” postulating that the developing immune system requires infectious stimuli in order to develop into a nonallergenic phenotype. Supporting this theory, children who grow up on a farm, have older siblings, and are enrolled in daycare at young ages have lower rates of allergic disease [13, 14]. In experimental mice, allergy is induced in a germ-free environment, because the presence of normal intestinal microflora seems to promote tolerance [15]. Endotoxins, or lipopolysaccharides, found in certain gram negative bacteria, are potent stimulators of the immune system and are hypothesized to direct the immune system in a Th1, or nonallergic, direction [16]. Although many details about the allergic response remain to be elucidated, it is generally thought that the allergic response is characterized by so-called Th2 helper T cells that produce the inflammatory cytokines Il-4, Il-5, Il-13, which in turn promote eosinophilia and IgE production [17]. In contrast, tolerance occurs in a Th1 dominated milieu. At birth, the infant’s immune system is immature, and is characterized by Th2 predominance. High-dose allergen and endotoxin exposure are thought to assist in the redirection to Th1 responses as the infant grows [18]. Although evidence has continued to accumulate to support the hygiene hypothesis, more and more gaps in this theory emerge, making it clear that other factors must also be in play.

New Aspects of Peanut and Tree Nut Allergy

677

Genetics Although environmental factors are important in the development of food allergy, it is also clear that genetic factors play a key role in determining who is affected by peanut and tree nut allergy. These factors, however, cannot explain the recent rapid increase in allergy since the gene pool changes over generations, not decades. Siblings of peanut allergic patients are more likely to develop peanut allergy themselves, as are children of atopic mothers [12, 19, 20]. In an attempt to quantify the genetic contribution to the risk of peanut allergy, Sicherer et al. identified 58 twin pairs in which at least one member was peanut allergic. Among the 14 monozygotic pairs, 9 were concordant for peanut allergy, compared to 3 of 44 dizygotic pairs. From these numbers, they estimated the heritability of peanut allergy to be 82% [21]. Given these data, it appears that genetic factors were important but not sufficient for allergy development, and that certain environmental conditions must have contributed to the development of the peanut allergy. Identifying which genes are responsible for the level of heritability is an ongoing project. Work on the genetic basis of food allergy has proceeded along several lines. Linkage analyses have identified chromosomal areas on which candidate genes lie, while our current understanding of pathophysiology and extreme phenotypes has provided other avenues of study.

Linkage Analyses Starting with an Amish population in the early 1990s, chromosome 5q31 was linked to total IgE levels [22]. In further studies, this area was found to be linked to bronchial hyperresponsiveness in a Dutch population [23], asthma and atopy in a Japanese population [24], circulating eosinophils in a US population [25], total IgE and eosinophil numbers in an Australian population [26], mite-sensitive asthma in a Japanese population [27], atopic dermatitis in a Swedish population [28], and atopic symptoms in Dutch [29] and various US populations [30]. Although these findings failed to be replicated in a variety of African American, European and Australian populations [31–35], chromosome 5q31 has received particular interest because it contains genes for IL4, IL5, and IL13, all of which are cytokines involved in the Th2 driven allergic response, as well as CD14. The CD14 receptor is a membrane-bound and soluble receptor found on the surface of immune cells, which interacts with one of the toll like receptors (TLR4) and binds to lipopolysacchiride (endotoxin) and other infectious antigens. CD14 is thought to play a role in modulating the Th1/Th2 balance, and genetic variations have been linked to asthma, total IgE levels, and atopy [36]. For development of asthma, the risk conferred by specific polymorphisms of this gene may be related to environmental conditions [37]. Woo et al. tested the CD14 gene for an association with food allergy in a US population, and found an association between one polymorphism

678

C.A. Keet and R.A. Wood

and food allergy, especially in Caucasian subjects [38]. In contrast, a recent study in Japan found no association between polymorphisms in this area and food allergy [39]. Detailed analyses of environment/genotype interactions have not been done for food allergy. Chromosome 12q has also been linked with total serum IgE and atopy in several populations [28, 30, 40]. One gene that is found in this area, Signal Transducer and Activator of Transcription – 6 (STAT-6), is involved in the signaling pathway that involves Il-4 and Il-13 in the upregulation of Th2 cytokines and antibody class switching to IgE. A polymorphism in this gene was associated with nut allergy when a group of nut allergic patients in the UK were compared to blood donor controls. Moreover, homozygosity for this polymorphism was associated with increased risk of severe nut reactions [41]. Other candidate areas are 2q, 6p, 7q, 11q, 17q, and 22q, although the data are very preliminary [30, 42, 43].

HLA The major histocompatibility complex (MHC) received early and sustained attention as an area possibly involved in the genetic risk for food allergy because of its centrality to the immune response. The genes for the Human Leukocyte Antigens (HLA), the human version of the MHC, code for two classes of HLA receptor, Class I and II. Class I genes are expressed by most cells, while class II gene expression is usually limited to antigen presenting cells, including B cells, macrophages, and dendritic cells. Certain HLA alleles put individuals at higher risk of specific autoimmune diseases. For example, the presence of the B27 allele is associated with a high risk of ankylosing spondylitis, while the DR3 allele is associated with a variety of autoimmune connective tissue and endocrine disorders, with relative risks varying from 2.5 to 12 [44]. The mechanism of this association is thought to be related to the differential affinity of certain HLA chains for self-peptides. Theoretically, a similar mechanism could be at work in food allergy; certain HLA alleles could code for chains that have high affinity for the nut epitopes that are known to be allergenic. Lack of those alleles would mean that the allergenic epitopes are not presented to T cells, and the proteins escape immune detection. Several authors compared patients with various food allergies to healthy controls, and found an association with specific HLA alleles and the food allergy in question. However, it was not clear whether the HLA alleles were associated with underlying atopy or cross-reactive pollen allergy, or whether they were truly associated with the food allergy in question [45]. Three other recent studies looking at peanut allergy in particular failed to find a strong association with any HLA allele and peanut allergy, although the data suggest some tentative links [45–47]. The studies done so far used serologic type to classify HLA alleles; an alternative approach would be to look at the actual peptide-binding groove. This approach was successful in finding an HLA association with the latex-fruit syndrome in

New Aspects of Peanut and Tree Nut Allergy

679

one study. For nut allergy, it would be more difficult because of the broader sensitization patterns [48].

SPINK5 Another way to approach the genetic study of allergy is to take an extreme phenotype with a known genetic cause and then look at that gene to see if polymorphisms might be responsible for milder phenotypes. Such an approach was used for the SPINK5 gene (serine protease inhibitor Karzal type 5). Mutations in this gene cause Netherton syndrome, which is a rare recessive disease consisting of congenital ichthyosis with defective cornification, hair abnormalities, and atopic disease. Immunologically, this syndrome is characterized by Th2 skewed responses. Proceeding from this knowledge, researchers have linked this gene to atopic dermatitis and asthma. A study of Japanese children linked a specific polymorphism in this gene to food allergy. The link could be due to problems with mucosal or skin integrity, or, alternatively, could relate to problems with the immune system which originate in the thymus [49]. The SPINK5 gene is located on chromosome 5q32, close to several genes for interleukins and other immunoregulatory proteins [50].

Peanut and Tree Nut Allergens Identification of the major peanut and tree nut allergens is important in the design of new treatments and diagnostic tests for peanut and tree nut allergy, assists in the monitoring for contamination, and forwards our understanding of cross-reactivity. As the case of the Brazil nut allergen Ber e 1 shows, lack of knowledge of nut allergens can lead to dangerous choices when it comes to modifying foods [51]. Like so many aspects of food allergy, our knowledge is partial, and the coming years will likely see major advances in this area. Most peanut and tree nut allergens are seed storage proteins. As a rule, they are broadly resistant to denaturation by the type of enzymatic reactions normally found in the GI tract. Typically, they serve in defense roles for the plant. Several major families of nut allergens include vicilins, legumins, and 2S albumins. The vicilin and legumin proteins share a beta-barrel conformation and are part of the cupin superfamily. Lipid-transfer proteins (LPS), profillins and heveins are panallergens broadly found in pollens, nuts, seeds, fruits, and vegetables, and are responsible for some of the IgE mediated cross-reactivity between these disparate substances [52, 53]. In the US and Europe, the most common tree nuts to which patients report allergy are walnut, cashew, almond, pecan, Brazil nut, hazelnut, macadamia nut, pistachio, and pine nut, although only walnut, cashew, almond, Brazil nut and hazelnut have been well studied [3, 54]. A more detailed review of the proteins responsible for tree nut allergy was published in 2003 [52]; here we will focus on the common nuts

680

C.A. Keet and R.A. Wood

and their major allergens (defined as proteins that show IgE binding with more than 50% of allergic patients).

Peanut The peanut, or arachis hypogaea, is native to South America. Remnants from tombs in Peru dating from as early as 1200 bc show evidence of cultivation of peanuts, and by the time the Conquistadors arrived in the Americas, cultivation of peanuts was widespread throughout Central and South America [55]. The peanut is a legume related botanically to beans and peas but not to tree nuts. The important peanut allergens are named Ara h 1–8, and peanut oleosin has also been identified as a peanut allergen. Over 90% of peanut allergic patient’s sera bind intensely to either Ara h 1 or 2 [56]. Of these proteins, purified Ara h 2 has been shown in various experiments to bind to more sera of patients with peanut allergy, to be a more potent stimulator of basophils, to have greater ability to crosslink IgE in peanut allergic patients’ sera, and to cause more reaction on skin testing of peanut allergic patients compared to Ara h 1 [56, 57]. In addition, anti-Ara h 2 accounts for a larger percentage of total antipeanut IgE than anti-Ara h 1 in peanut allergic patients [56]. Thus, Ara h 2 appears to be more important in the allergic response to peanut than Ara h 1. An important caveat is that a recent study found that Ara h 1 is actually found as an oligomeric structure rather than a trimeric protein, as was previously thought [53]. Because most of these studies used Ara h 2 that was purified as a trimeric protein, further studies using the oligomeric protein may show different results. Although severity of peanut allergy has not been shown to be related to binding to any specific peanut protein, it has been linked to the diversity of epitope binding of a patient’s serum [58, 59].

Hazelnut The hazelnut tree is native to Europe and Asia, and allergy to hazelnut seems to be more common in Europe than in the US, where hazelnut products, although increasing in popularity, are not the staple that they are in parts of Europe. There are several different types of hazelnut allergy. In areas where birch and other trees of the family Betulaceae (alder, hazel and hornbean) are endemic, such as northern Europe, a pollen-associated food allergy wherein patients are initially sensitized to the tree pollen is common. Cor a 1, a hazelnut allergen, shares significant homology with Bet v 1, the birch pollen allergen [52]. This hazelnut allergy is frequently characterized by the oral allergy syndrome; patients with systemic allergy are less likely to be birch allergic [60]. Subcutaneous immunotherapy (SCIT) for pollen allergy reduces the hazelnut allergy in patients with both allergies [61, 62].

New Aspects of Peanut and Tree Nut Allergy

681

Mugwort pollen is also thought to be cross-reactive with hazelnut, likely related to distinct allergenic proteins [52]. The allergens responsible for nonpollen-related allergy to hazelnut have not been as well characterized. Among the proteins that have been shown to be important, an 11S globulin named Cor a 9 that reacted with sera from 86% of nonpollen allergic hazelnut allergic patients in the US. This protein has homology with the cashew nut allergen Ana o 2, the peanut allergen Ara h 3, and soybean glycein [63]. Another allergen is a LPS named Cor a 8, which reacted with 62–77% of Spanish patients’ sera in another study [64]. Several other proteins may also be important for allergy, but they have not yet been analyzed in such depth.

Walnut Trees in the walnut family are found throughout the world. The so-called English walnut is actually native to the area that spans Southeast Europe, Southwest and central Asia, and southern China, and is much more widely consumed in the US than the native black walnut. In the US, walnut is the most common tree nut allergy [3]. Several proteins have been identified as important allergens. In one study, 75% of walnut allergic patients reacted with a recombinant 2S albumin precursor named rJug r 1. This protein is similar to allergens in Brazil nut, castor bean, cottonseed, and mustard seed. Another allergen, Jug r 2, reacted with 60% of walnut allergic patients’ sera in a separate study. This vicilin protein has 75% homology with the peanut allergen Ara h 1. Yet another protein, Jug r 4, a legumin, reacted with 57–65% of sera from walnut allergic patients [52, 65]. In a study of Italian patients with confirmed walnut allergy, the major allergen was a lipid-transfer protein, now called Jug r 3, which bound 78% of the patients’ sera. These patients generally had severe allergy, and were also often allergic to other fruits with LTPs, including stone fruits, apple, grape, corn, and hazelnut [66].

Almond, Cashew and Brazil Nut The almond was domesticated at least 4,000 years ago in the Near East; Tutankhamen’s tomb in Egypt, which dates from 1325 bc, contained almonds [67]. Almonds are the most commonly eaten tree nut in the United States, with a per capita consumption of more than ½ lb per year [68]. The most fully described almond allergen is amandin, a legumin which forms 65–70% of the extractable proteins in almonds. In one unpublished study, more than 50% of almond allergic patients’ sera are bound to this protein [52]. The cashew tree is native to Brazil, and is now grown widely throughout tropical regions. Two major allergens have been identified. Ana o 1 is a vicilin to which about 50% of cashew allergic patients react. It forms a relatively small part of the

682

C.A. Keet and R.A. Wood

extractable protein, only about 5%. Ana o 2, also called anacardein, accounts for 50% of the extractable protein in the cashew, and is a legumin-like seed storage protein. About 62% of allergic patients react to the recombinant form of the protein, rAna o 2 [52, 69]. Finally, Brazil nut, although not a commonly consumed nut in the United States, is thought to be a major allergen in the UK [54]. A 2S albumin, Ber e 1, has been identified as an allergen for this nut. The protein is rich in methionine and was cloned and introduced to soybean in order to increase the nutritional value of the soybean. Eight of nine tested Brazil nut allergic patients reacted to the genetically modified bean, none to soybeans themselves, causing serious concerns about this genetically modified crop [51]. The Ber e 1 augmented soybean project was stopped for concerns about food allergy. Further work on identifying other allergens is ongoing.

Cross-Reactivity Whether in practice- or population-based prevalence studies, 20–50% of peanut allergic patients are also allergic to tree nuts [3, 54]. As with other food allergies, more patients are sensitized than are actually allergic; Clark and colleagues reported in a large series of nut allergic patients that by age ten, 86% were sensitized to multiple nuts, while 47% were actually multi-allergic clinically. In that study, as time went on, more subjects developed multiple allergies and sensitizations. Unfortunately, they did not separate out peanut allergy from other nut allergies, so specific cross-reactivity patterns could not be assessed [70]. In Sicherer et al.’s survey study in the US, 45% of tree nut allergic patients were allergic to more than one nut [3]. There are several mechanisms that might account for simultaneous allergy to peanuts and tree nuts. Since peanut and tree nuts are botanically unrelated, it had been thought that this was simply a manifestation of an underlying allergic phenotype reacting to multiple potent allergens. However, there is now emerging data that the cross-reactivity is more likely the result of homologous epitopes between peanut and tree nuts. At present, the data on cross-reactivity between peanut and tree nuts are not entirely clear. Goetz et al. found limited cross-reactivity between pistachio and walnut with peanut, but not between peanut and other tree nuts [71]. In contrast, de Leon and others in Australia found that preincubation of sera from peanut allergic patients with extracts from almond, Brazil nut, and hazelnut inhibited binding to peanut, and that basophils coated with peanut-specific antibodies were activated by contact with almond and Brazil nut extracts [72]. Moreover, they found that IgE specific for recombinant Ara h 2 are bound to almond and Brazil nut extracts, indicating that this protein may be responsible for some of the cross-reactivity previously described [73].

New Aspects of Peanut and Tree Nut Allergy

683

In some series, over 25% of children with peanut allergy have a history of allergy to other, nonnut foods, most commonly milk and egg. This phenomenon is likely attributable to underlying atopy rather than cross-reactivity [54]. Peanuts are botanically closely related to other legumes, and extensive cross-reactivity has been found on serologic and skin testing. Nonetheless, clinical cross-reactivity is uncommon [74, 75].

Tree Nut Allergy Tree nuts appear to have more significant epitope homology. Using ELISA inhibition assays, Goetz et al. defined two groups of cross-reactive tree nuts. Walnut, pecan, and hazelnut were strongly cross-reactive, while hazelnut, cashew, Brazil nut, pistachio, and almond were moderately cross-reactive. These cross-reactivities followed botanical classification. Walnut, pecan, and hazelnut are members of the same botanical subclass, and walnut and pecan, which showed the strongest cross-reactivity, are members of the same family, Juglandaceae. Among the other group, cashew and pistachio, which are both members of the botanical family Anacardiaceae, showed the strongest cross-reactivity [71]. Clinical cross-reactivities have not been established at this level of detail; most nut allergic patients are counseled to avoid all nuts, and systemic oral food challenges have not generally been conducted.

Diagnosis Diagnosis of peanut and tree nut allergy is generally done through diagnostic testing guided by history. Allergen specific IgE levels and skin testing are the most important tests, but because they lack specificity, they must be taken in context of the patient’s exposure and reaction history. Food challenges, while the gold standard, are not usually necessary to establish the clinical diagnosis of a nut allergy since the clinical reactions tend to be so dramatic.

Skin Testing For skin testing, although a wheal size of greater than 3 mm is generally considered positive, this cutoff has a low positive predictive value in an unscreened population. For example, Clark and Ewan analyzed 1,000 patients with allergy to at least one tree nut or peanut. They found that of the 660 patients with skin prick tests between 3–7 mm, 54% were allergic and 46% were tolerant to that tree nut or peanut by clinical history [76]. In order to try to avoid the need for food challenges in patients who have an unclear history by making skin testing more specific, several researchers

684

C.A. Keet and R.A. Wood

have investigated whether using an increased diameter size helps diagnosis. Wheal diameters above 8 mm were found to be over 95% accurate for predicting a positive food challenge to walnut, peanut, Brazil nut, and almond [76–78]. Others report even higher cutoffs [79]. Ho et al. reported that for children younger than 2 years old being tested for peanut allergy, a wheal diameter of 4 mm was 95% predictive. Commercial extracts can vary widely in concentration of the major allergic proteins [80]. Finally, anaphylaxis to skin testing, although extremely rare, has been reported [81, 82]. Recently, recombinant peanut proteins have been developed for use in skin testing. Preliminary study shows some promise of a product with more consistent properties. With recombinant proteins, it may also be possible to predict the degree of severity of reaction based on the number of peanut proteins to which a patient reacts. Thus far, linking severity of clinical reactivity with diagnostic parameters has proved difficult. Larger scale testing of the recombinant peanut proteins for skin testing is still needed to determine their clinical utility [83].

IgE Levels Serum assays of allergen specific IgE are also more sensitive than specific. Peanut has been most extensively studied; for children undergoing food challenge, Perry et al. found that 50% pass when the level was <2 kUa/L [84], while Fleischer et al. found that 58% of patients with TN-IgE level of 5 kUa/L or less and 63% with TN-IgE levels of 2 kUa/L or less passed food challenges [85]. Sampson and Ho reported a level of 15 kUa/L for 95% of subjects to have a positive food challenge [86, 87]. Clark and Ewan confirmed Sampson’s results for peanut and extended it to tree nuts as well [76].

Possibilities for Remission Recent data have revised our thinking about whether peanut and tree nut allergy can be outgrown. In several studies, approximately 20% of patients with peanut allergy do outgrow their allergy, including some who had initially had severe allergy. Patients who initially had PN specific IgE levels below 10 kUa/L were more likely to eventually outgrow the allergy. In addition, patients who had strictly avoided peanuts, who had initial reactions involving only the skin, and who did not have a history of eczema were more likely to outgrow their allergies, although these factors were not sufficient to predict which patients would outgrow their allergies [88, 89]. Current PN-IgE levels were predictive of an outgrown allergy. Fifty five percent of patients passed food challenges when their PN-IgE levels fell below 5 kUa/L, although 63% passed with PN-IgE below 2, and only 35% of those between 2 and 5 passed.

New Aspects of Peanut and Tree Nut Allergy

685

Optimal results from food challenges can thus be expected with PN-IgE levels below 2 [89]. Fleischer et al. continued to follow the patients who had passed food challenges showing that they had outgrown their peanut allergy for a median of 2 years. They found that 7.9% of 38 patients had recurrence of reactions to peanut. All reactions occurred in patients who consumed peanut infrequently or in limited amounts, and thus the authors recommend that patients who have outgrown their peanut allergy eat peanut frequently, but also carry epinephrine indefinitely. For tree nut allergy, 8.9% of 101 patients aged greater than 4 with a history of prior reactions outgrew the allergy. Fifty eight percent of those with tree nut specific IgE levels of 5 kUa/L or less passed the food challenges, compared to 63% of those with tree nut IgE levels of 2 kUa/L or less [85]. Interestingly, resolution of allergy did not occur in any patients who had reacted to more than two different nuts in the past [90].

Avoidance In the absence of effective therapies to cure peanut and tree nut allergy, avoidance of the allergen remains vitally important. Peanuts and tree nuts are frequently hidden ingredients in baked goods, candy, and snack foods, and restaurants are also common sites of accidental exposure [7, 9]. A new labeling law, the food allergen labeling and consumer protection act (FALCPA), requires that common allergenic foods be identified in ingredient lists for commercial foods. This law, which was implemented in 2006, defines the common allergenic foods as milk, eggs, fish, crustacean shellfish, soybeans, wheat, peanuts, and tree nuts [91]. Accidental inclusion of allergenic ingredients is not covered by the law, nor is the use of precautionary labels.

Treatments Recent years have seen the initial development of several promising strategies for treatment of food allergy. Because there is no space to discuss all of the avenues of current research here, we focus on a few treatments that have shown the most promise thus far.

Immunotherapy For almost 100 years, since well before IgE was identified, allergy has been treated with immunotherapy. The injection of increasing quantities of purified allergen, an

686

C.A. Keet and R.A. Wood

example of specific immunotherapy, has been most successful for inhaled allergens. Although the precise mechanisms of immunotherapy remain incompletely known, there are some consistent findings and promising avenues for further research. SCIT has been studied the most. In multiple studies, it has been shown to elicit IgG (mostly IgG1 and IgG4), and sometimes IgA antibodies, with less consistent effects on IgE. Regulatory T cells have been a topic of more recent interest. These cells include CD4+CD25+ cells from the thymus, as well as Tr1 cells, Th3 cells, and CD3+ cells, which are induced in the periphery. These cells are thought to down regulate both Th1 and Th2 responses by both direct cell contact and immunosuppressive cytokines such as Il-10 and TGF-b. Dendritic cells seem to play a critical role in inducing these cells. There is some evidence that these cells are important in the induction of tolerance by immunotherapy, but the data remain incomplete [92, 93]. For food allergy, injected immunotherapy has been much less successful. Although there have been case reports of successful treatment of peanut allergy with injected immunotherapy [94], in a placebo-controlled trial of SCIT for peanut allergy, most patients had repeated systemic reactions to the treatment, some severe [95]. In recent years, sublingual and oral immunotherapy have emerged as promising alternatives. When used for respiratory allergy, sublingual immunotherapy is better tolerated, with fewer systemic reactions than with oral immunotherapy [96]. However, both strategies have been tested with some foods, with promising preliminary results. For egg allergy, Buchanan et al. conducted an open trial of oral immunotherapy in egg allergic patients who had not had anaphylactic reactions. Over 2 years of treatment, all subjects tolerated significantly higher doses of eggs, and four of seven passed a full oral food challenge to egg. However, after 3–4 months of an egg restricted diet, only two maintained full tolerance to egg [97]. For cow’s milk, an Italian study found that 71% of 21 patients were successfully desensitized to cow’s milk, while another 14% tolerated lower maintenance doses; [98] and in a French study, 4 of 8 patients with milk allergy originally enrolled were able to reintroduce dairy into their diets following 6 months of immunotherapy. Adverse reactions, while common in these studies, were not severe [99]. Enrique et al. conducted a placebo-controlled trial of sublingual immunotherapy in 23 hazelnut allergic patients. After 8–12 weeks of therapy, the mean quantity of hazelnut required to provoke symptoms increased from 2.29 to 11.56 g after 8–12 weeks of treatment, and 50% reached the highest dose of hazelnut (20 g). Systemic reactions occurred in 0.2% of subjects during the build up phase of the study [100]. There have been several case reports of successful oral desensitization to peanut [101, 102], and interim results of an ongoing trial are promising [103]. Duration of therapy, optimal dosages, route, and selection of patients who have most potential to benefit are all variables that are yet to be determined. In another attempt to create a safer kind of immunotherapy, researchers are modifying allergenic proteins so that they stimulate T cells without crosslinking IgE and causing mast cell and basophil degranulation. Both peptide fragments and mutated proteins that lack affinity for IgE are being used. Mutated proteins have had some effectiveness in a mouse model, while peptide

New Aspects of Peanut and Tree Nut Allergy

687

fragments were effective when used in cat-allergic patients [104]. Human trials of modified peanut will be starting soon.

Anti-IgE Another area of active interest is the use of anti-IgE monoclonal antibodies. These antibodies form complexes with membrane-bound and free IgE without allowing cross-linking, and thus prevent the IgE on B cells from interacting with mast cells and basophils. This, in turn, prevents the release of the mediators of immediate allergy. One such antibody, omalizumab, was approved by the US FDA in 2003 for treatment of allergic asthma, but has not yet been studied for food allergy. A similar drug, however, TNX-901, was studied for peanut allergy. In this study, Leung et al. randomized peanut allergic volunteers to different doses of the medication. TNX901 or placebo was given subcutaneously every 4 weeks for 4 months. Oral-foodchallenge threshold doses of peanut increased in a dose-dependent manner, and at the highest dose, the threshold for reaction to peanut increased from approximately one half peanut to almost nine peanuts [105]. TNX-901 is no longer in development, but trials of omalizumab for peanut allergy will hopefully be done. In addition, trials are underway to see if treating patients with omalizumab prior to immunotherapy for respiratory allergies will result in fewer side effects and greater efficacy [106]. If successful, this method could extend to food immunotherapy. Despite the positive results of studies thus far, there are limitations to the potential of this medication for treatment of peanut and nut allergy. First, some subjects even on the highest dose of TNX-901 did not develop any protection. Second, continued treatment would be needed since protection from anaphylaxis would disappear once treatment is stopped. Third, although the threshold for anaphylaxis was increased so that most patients would likely not be at risk for accidental exposure, they would still have to avoid peanuts. Finally, monoclonal antibodies are very expensive, and for a medication that would have to be used for life, the cost could be prohibitive. In addition, there have been recent reports on post-marketing data of anaphylaxis from omalizumab [107].

Herbal Treatments Herbal remedies have been used to control allergic symptoms for centuries in Asia. Although the Traditional Chinese literature does not describe food allergy or treatments for it, researchers, encouraged by suppression of other allergic responses by Chinese herbs, have developed a mixture of Traditional Chinese herbs for treatment of peanut allergy. In initial murine trials of this combination, food allergy herbal formula–1 (FAHF-1), peanut-induced anaphylaxis was blocked. In these animals, IgE levels, peanut-induced lymphocyte proliferation, and synthesis of

688

C.A. Keet and R.A. Wood

the inflammatory cytokines IL-4, IL-5, and IL-13 were all reduced [108]. Because of regulatory concerns about two of the herbal components of FAHF-1, they modified the compound, and tested the new mixture, FAHF-2, again in the same murine peanut allergy model. In the treated peanut allergic mice, there were no signs of anaphylaxis after challenge with peanut for at least 5 weeks post therapy. Newer, unpublished, results have found protection for as long as 6 months in mice with established peanut allergy [109]. The clinical findings were associated with significantly reduced splenocyte production of Il-4, Il-5, and Il-13 and enhancement of IFN-gamma upon peanut stimulation in vitro, consistent with a suppression of Th2 and increase in Th1 responses. The herbal compound appeared to have no adverse effects on the mouse, even at the highest dose that they could feed the animal, and did not appear to cause overall immune suppression, although other aspects of the immune response of treated animals have yet to be studied. The mechanism by which this compound works is not known. Animal studies of this herbal compound have been very promising, and research is ongoing [110].

Conclusions In recent years, we have learned many things about peanut and tree nut allergy. Several potential genetic risk factors for food allergy have been identified, many peanut and tree nut allergic epitopes have been classified, helping our understanding of cross-reactivity, and the best use of skin testing and specific IgE for diagnosis has been clarified. We have learned that peanut and tree nut allergy can be outgrown, and now have guidelines for testing patients who might have outgrown their allergies. Most promising, several potential therapies for food allergy are now undergoing study, and the prospects for effective treatment in the coming years is very real.

References 1. Times NY. Kiss Kills Teenager With Peanut Allergy. Nov 2005; webpage. Available at: http:// query.nytimes.com/gst/fullpage.html?res=9C07EFD91431F93AA15752C1A9639C8B63. Accessed June 16, 2007. 2. Gupta R, Sheikh A, Strachan DP, Anderson HR. Time trends in allergic disorders in the UK. Thorax. Jan 2007;62(1):91–96. 3. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. Dec 2003;112(6):1203–1207. 4. Grundy J, Matthews S, Bateman B, Dean T, Arshad SH. Rising prevalence of allergy to peanut in children: data from 2 sequential cohorts. J Allergy Clin Immunol. Nov 2002;110(5): 784–789. 5. Sicherer SH, Furlong TJ, DeSimone J, Sampson HA. The US peanut and tree nut allergy registry: characteristics of reactions in schools and day care. J Pediatr. Apr 2001;138(4): 560–565.

New Aspects of Peanut and Tree Nut Allergy

689

6. Sicherer SH, Noone SA, Munoz-Furlong A. The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol. Dec 2001;87(6):461–464. 7. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. Jan 2001;107(1):191–193. 8. Yunginger JW, Squillace DL, Jones RT, Helm RM. Fatal anaphylactic reactions induced by peanuts. Allergy Proc. Jul–Aug 1989;10(4):249–253. 9. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. Aug 1992;327(6):380–384. 10. Pumphrey RS, Roberts IS. Postmortem findings after fatal anaphylactic reactions. J Clin Pathol. Apr 2000;53(4):273–276. 11. Wensing M, Penninks AH, Hefle SL, Koppelman SJ, Bruijnzeel-Koomen CA, Knulst AC. The distribution of individual threshold doses eliciting allergic reactions in a population with peanut allergy. J Allergy Clin Immunol. Dec 2002;110(6):915–920. 12. Hourihane JO, Dean TP, Warner JO. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. Bmj. Aug 1996;313(7056):518–521. 13. Strachan DP. Hay fever, hygiene, and household size. Bmj. Nov 1989;299(6710): 1259–1260. 14. McKeever TM, Lewis SA, Smith C, et al. Siblings, multiple births, and the incidence of allergic disease: a birth cohort study using the West Midlands general practice research database. Thorax. Oct 2001;56(10):758–762. 15. Sudo N, Aiba Y, Oyama N, et al. Dietary nucleic acid and intestinal microbiota synergistically promote a shift in the Th1/Th2 balance toward Th1-skewed immunity. Int Arch Allergy Immunol. Oct 2004;135(2):132–135. 16. Eder W, von Mutius E. Hygiene hypothesis and endotoxin: what is the evidence? Curr Opin Allergy Clin Immunol. Apr 2004;4(2):113–117. 17. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergenspecific T-cell memory in atopic and normal children. Lancet. Jan 1999;353(9148):196–200. 18. Woodfolk JA. T-cell responses to allergens. J Allergy Clin Immunol. Feb 2007;119(2):280– 294; quiz 295–286. 19. Rasanen M, Laitinen T, Kaprio J, Koskenvuo M, Laitinen LA. Hay fever–a Finnish nationwide study of adolescent twins and their parents. Allergy. Sep 1998;53(9):885–890. 20. Lichtenstein P, Svartengren M. Genes, environments, and sex: factors of importance in atopic diseases in 7-9-year-old Swedish twins. Allergy. Nov 1997;52(11):1079–1086. 21. Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol. Jul 2000;106(1 Pt 1):53–56. 22. Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. May 1994;264(5162):1152–1156. 23. Postma DS, Bleecker ER, Amelung PJ, et al. Genetic susceptibility to asthma–bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med. Oct 1995;333(14):894–900. 24. Noguchi E, Shibasaki M, Arinami T, et al. Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population. Am J Respir Crit Care Med. Nov 1997;156(5):1390–1393. 25. Martinez FD, Solomon S, Holberg CJ, Graves PE, Baldini M, Erickson RP. Linkage of circulating eosinophils to markers on chromosome 5q. Am J Respir Crit Care Med. Dec 1998;158(6):1739–1744. 26. Palmer LJ, Daniels SE, Rye PJ, et al. Linkage of chromosome 5q and 11q gene markers to asthma-associated quantitative traits in Australian children. Am J Respir Crit Care Med. Dec 1998;158(6):1825–1830. 27. Yokouchi Y, Nukaga Y, Shibasaki M, et al. Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics. Jun 2000;66(2):152–160.

690

C.A. Keet and R.A. Wood

28. Beyer K, Nickel R, Freidhoff L, et al. Association and linkage of atopic dermatitis with chromosome 13q12-14 and 5q31-33 markers. J Invest Dermatol. Nov 2000;115(5):906–908. 29. Koppelman GH, Reijmerink NE, Colin Stine O, et al. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med. Mar 2001;163(4):965–969. 30. Xu J, Meyers DA, Ober C, et al. Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am J Hum Genet. Jun 2001;68(6):1437–1446. 31. Jacobs KB, Burton PR, Iyengar SK, Elston RC, Palmer LJ. Pooling data and linkage analysis in the chromosome 5q candidate region for asthma. Genet Epidemiol. 2001;21 Suppl 1:S103–108. 32. Holloway JW, Lonjou C, Beghe B, et al. Linkage analysis of the 5q31-33 candidate region for asthma in 240 UK families. Genes Immun. Feb 2001;2(1):20–24. 33. Mansur AH, Bishop DT, Markham AF, Britton J, Morrison JF. Association study of asthma and atopy traits and chromosome 5q cytokine cluster markers. Clin Exp Allergy. Feb 1998;28(2):141–150. 34. Kamitani A, Wong ZY, Dickson P, et al. Absence of genetic linkage of chromosome 5q31 with asthma and atopy in the general population. Thorax. Sep 1997;52(9):816–817. 35. Laitinen T, Kauppi P, Ignatius J, et al. Genetic control of serum IgE levels and asthma: linkage and linkage disequilibrium studies in an isolated population. Hum Mol Genet. Nov 1997;6(12):2069–2076. 36. Yang IA, Fong KM, Holgate ST, Holloway JW. The role of toll-like receptors and related receptors of the innate immune system in asthma. Curr Opin Allergy Clin Immunol. Feb 2006;6(1):23–28. 37. Yang IA, Savarimuthu S, Kim ST, Holloway JW, Bell SC, Fong KM. Gene-environmental interaction in asthma. Curr Opin Allergy Clin Immunol. Feb 2007;7(1):75–82. 38. Woo JG, Assa’ad A, Heizer AB, Bernstein JA, Hershey GK. The -159 C-->T polymorphism of CD14 is associated with nonatopic asthma and food allergy. J Allergy Clin Immunol. Aug 2003;112(2):438–444. 39. Campos E, Shimojo N, Inoue Y, et al. No association of polymorphisms in the 5¢ region of the CD14 gene and food allergy in a Japanese population. Allergol Int. Mar 2007;56(1): 23–27. 40. Nickel R, Beyer K, Huang SK, Barnes KC, Wahn U. Genetic markers of atopy in infancy: results from the German multicenter allergy study. Clin Exp Allergy. Dec 1999;29 Suppl 4:23–25. 41. Amoli MM, Hand S, Hajeer AH, et al. Polymorphism in the STAT6 gene encodes risk for nut allergy. Genes Immun. Jun 2002;3(4):220–224. 42. Dreskin SC. Genetics of food allergy. Curr Allergy Asthma Rep. Feb 2006;6(1):58–64. 43. Koppelman GH, Stine OC, Xu J, et al. Genome-wide search for atopy susceptibility genes in Dutch families with asthma. J Allergy Clin Immunol. Mar 2002;109(3):498–506. 44. Klein J, Sato A. The HLA system. Second of two parts. N Engl J Med. Sep 2000;343(11): 782–786. 45. Shreffler WG, Charlop-Powers Z, Sicherer SH. Lack of association of HLA class II alleles with peanut allergy. Ann Allergy Asthma Immunol. Jun 2006;96(6):865–869. 46. Howell WM, Turner SJ, Hourihane JO, Dean TP, Warner JO. HLA class II DRB1, DQB1 and DPB1 genotypic associations with peanut allergy: evidence from a family-based and casecontrol study. Clin Exp Allergy. Feb 1998;28(2):156–162. 47. Hand S, Darke C, Thompson J, et al. Human leucocyte antigen polymorphisms in nut-allergic patients in South Wales. Clin Exp Allergy. May 2004;34(5):720–724. 48. Dreskin SC. Do HLA genes play a role in the genetics of peanut allergy? Ann Allergy Asthma Immunol. Jun 2006;96(6):766–768. 49. Kusunoki T, Okafuji I, Yoshioka T, et al. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol. Mar 2005;115(3):636–638.

New Aspects of Peanut and Tree Nut Allergy

691

50. Magert HJ, Standker L, Kreutzmann P, et al. LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J Biol Chem. Jul 1999;274(31):21499–21502. 51. Nordlee JA, Taylor SL, Townsend JA, Thomas LA, Bush RK. Identification of a Brazil-nut allergen in transgenic soybeans. N Engl J Med. Mar 1996;334(11):688–692. 52. Roux KH, Teuber SS, Sathe SK. Tree nut allergens. Int Arch Allergy Immunol. Aug 2003;131(4):234–244. 53. van Boxtel EL, van Beers MM, Koppelman SJ, van den Broek LA, Gruppen H. Allergen Ara h 1 occurs in peanuts as a large oligomer rather than as a trimer. J Agric Food Chem. Sep 2006;54(19):7180–7186. 54. Ewan PW. Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations. Bmj. Apr 1996;312(7038):1074–1078. 55. Kochert G, Stalker HT, Gimenes M, Galgaro L, Lopes CR, Moore K. - RFLP and cytogenetic evidence on the origin and evolution of allotetraploid domesticated peanut, arachis hypogaea (Leguminosae).- 83(- 10):- 1291. 56. Palmer GW, Dibbern DA, Jr., Burks AW, et al. Comparative potency of Ara h 1 and Ara h 2 in immunochemical and functional assays of allergenicity. Clin Immunol. Jun 2005;115(3):302–312. 57. Koppelman SJ, Wensing M, Ertmann M, Knulst AC, Knol EF. Relevance of Ara h1, Ara h2 and Ara h3 in peanut-allergic patients, as determined by immunoglobulin E Western blotting, basophil-histamine release and intracutaneous testing: Ara h2 is the most important peanut allergen. Clin Exp Allergy. Apr 2004;34(4):583–590. 58. Lewis SA, Grimshaw KE, Warner JO, Hourihane JO. The promiscuity of immunoglobulin E binding to peanut allergens, as determined by Western blotting, correlates with the severity of clinical symptoms. Clin Exp Allergy. Jun 2005;35(6):767–773. 59. Shreffler WG, Beyer K, Chu TH, Burks AW, Sampson HA. Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes. J Allergy Clin Immunol. Apr 2004;113(4):776–782. 60. Flinterman AE, Hoekstra MO, Meijer Y, et al. Clinical reactivity to hazelnut in children: association with sensitization to birch pollen or nuts? J Allergy Clin Immunol. Nov 2006;118(5):1186–1189. 61. Alonso R, Enrique E, Pineda F, et al. An observational study on outgrowing food allergy during non-birch pollen-specific, subcutaneous immunotherapy. Int Arch Allergy Immunol. Feb 2007;143(3):185–189. 62. Bucher X, Pichler WJ, Dahinden CA, Helbling A. Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy. Dec 2004;59(12):1272–1276. 63. Beyer K, Grishina G, Bardina L, Grishin A, Sampson HA. Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions. J Allergy Clin Immunol. Sep 2002;110(3):517–523. 64. Schocker F, Luttkopf D, Scheurer S, et al. Recombinant lipid transfer protein Cor a 8 from hazelnut: a new tool for in vitro diagnosis of potentially severe hazelnut allergy. J Allergy Clin Immunol. Jan 2004;113(1):141–147. 65. Wallowitz M, Peterson WR, Uratsu S, Comstock SS, Dandekar AM, Teuber SS. Jug r 4, a legumin group food allergen from walnut (Juglans regia Cv. Chandler). J Agric Food Chem. Oct 2006;54(21):8369–8375. 66. Pastorello EA, Farioli L, Pravettoni V, et al. Lipid transfer protein and vicilin are important walnut allergens in patients not allergic to pollen. J Allergy Clin Immunol. Oct 2004;114(4): 908–914. 67. Zohary DaH, Maria. Domestication of plants in the old world. Oxford, United Kingdom: Oxford University Press; 2000. 68. ERS (Economic Research Service) USDoA. Fruit and tree nut yearbook spreadsheet files. [Web Page]. October, 2006; http://usda.mannlib.cornell.edu/usda/ers/89022/TAB-A01.xls. Accessed June 16, 2007.

692

C.A. Keet and R.A. Wood

69. Wang F, Robotham JM, Teuber SS, Sathe SK, Roux KH. Ana o 2, a major cashew (Anacardium occidentale L.) nut allergen of the legumin family. Int Arch Allergy Immunol. Sep 2003;132(1):27–39. 70. Clark AT, Ewan PW. The development and progression of allergy to multiple nuts at different ages. Pediatr Allergy Immunol. Sep 2005;16(6):507–511. 71. Goetz DW, Whisman BA, Goetz AD. Cross-reactivity among edible nuts: double immunodiffusion, crossed immunoelectrophoresis, and human specific igE serologic surveys. Ann Allergy Asthma Immunol. Jul 2005;95(1):45–52. 72. de Leon MP, Drew AC, Glaspole IN, Suphioglu C, Rolland JM, O’Hehir RE. Functional analysis of cross-reactive immunoglobulin E antibodies: peanut-specific immunoglobulin E sensitizes basophils to tree nut allergens. Clin Exp Allergy. Aug 2005;35(8):1056–1064. 73. de Leon MP, Drew AC, Glaspole IN, Suphioglu C, O’Hehir RE, Rolland JM. IgE crossreactivity between the major peanut allergen Ara h 2 and tree nut allergens. Mol Immunol. Jan 2007;44(4):463–471. 74. Bernhisel-Broadbent J, Taylor S, Sampson HA. Cross-allergenicity in the legume botanical family in children with food hypersensitivity. II. Laboratory correlates. J Allergy Clin Immunol. Nov 1989;84(5 Pt 1):701–709. 75. Bernhisel-Broadbent J, Sampson HA. Cross-allergenicity in the legume botanical family in children with food hypersensitivity. J Allergy Clin Immunol. Feb 1989;83(2 Pt 1):435–440. 76. Clark AT, Ewan PW. Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clin Exp Allergy. Aug 2003;33(8):1041–1045. 77. Ho MH, Heine RG, Wong W, Hill DJ. Diagnostic accuracy of skin prick testing in children with tree nut allergy. J Allergy Clin Immunol. Jun 2006;117(6):1506–1508. 78. Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin Exp Allergy. Nov 2000;30(11): 1540–1546. 79. Wainstein BK, Yee A, Jelley D, Ziegler M, Ziegler JB. Combining skin prick, immediate skin application and specific-IgE testing in the diagnosis of peanut allergy in children. Pediatr Allergy Immunol. May 2007;18(3):231–239. 80. Akkerdaas JH, Wensing M, Knulst AC, et al. How accurate and safe is the diagnosis of hazelnut allergy by means of commercial skin prick test reagents? Int Arch Allergy Immunol. Oct 2003;132(2):132–140. 81. Senna G, Bonadonna P, Crivellaro M, Schiappoli M, Passalacqua G. Anaphylaxis due to Brazil nut skin testing in a walnut-allergic subject. J Investig Allergol Clin Immunol. 2005;15(3):225–227. 82. Bernstein DI, Wanner M, Borish L, Liss GM. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990–2001. J Allergy Clin Immunol. Jun 2004;113(6):1129–1136. 83. Astier C, Morisset M, Roitel O, et al. Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy. J Allergy Clin Immunol. Jul 2006;118(1):250–256. 84. Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. Jul 2004;114(1): 144–149. 85. Fleischer DM, Conover-Walker MK, Matsui EC, Wood RA. The natural history of tree nut allergy. J Allergy Clin Immunol. 2005;116(5):1087–1093. 86. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. May 2001;107(5):891–896. 87. Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol. Oct 1997;100(4):444–451. 88. Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The natural history of peanut allergy. J Allergy Clin Immunol. Feb 2001;107(2):367–374. 89. Fleischer DM, Conover-Walker MK, Christie L, Burks AW, Wood RA. The natural progression of peanut allergy: resolution and the possibility of recurrence. J Allergy Clin Immunol. Jul 2003;112(1):183–189.

New Aspects of Peanut and Tree Nut Allergy

693

90. Fleischer DM, Conover-Walker MK, Christie L, Burks AW, Wood RA. Peanut allergy: recurrence and its management. J Allergy Clin Immunol. Nov 2004;114(5):1195–1201. 91. Taylor SL, Hefle SL. Food allergen labeling in the USA and Europe. Curr Opin Allergy Clin Immunol. Jun 2006;6(3):186–190. 92. Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van Overtvelt L. Immune mechanisms of allergen-specific sublingual immunotherapy. Allergy. Feb 2006;61(2):151–165. 93. Larche M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol. Oct 2006;6(10):761–771. 94. Bullock RJ, Barnett D, Howden ME. Immunologic and clinical responses to parenteral immunotherapy in peanut anaphylaxis–a study using IgE and IgG4 immunoblot monitoring. Allergol Immunopathol (Madr). Sep–Oct 2005;33(5):250–256. 95. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol. Jun 1997;99(6 Pt 1):744–751. 96. Gidaro GB, Marcucci F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingualswallow immunotherapy: an analysis of published studies. Clin Exp Allergy. May 2005;35(5):565–571. 97. Buchanan AD, Green TD, Jones SM, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol. Jan 2007;119(1):199–205. 98. Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG. A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy. Allergy. Sep 2004;59(9): 980–987. 99. de Boissieu D, Dupont C. Sublingual immunotherapy for cow’s milk protein allergy: a preliminary report. Allergy. Oct 2006;61(10):1238–1239. 100. Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. Nov 2005;116(5):1073–1079. 101. Mansfield L. Successful oral desensitization for systemic peanut allergy. Ann Allergy Asthma Immunol. Aug 2006;97(2):266–267. 102. Patriarca G, Nucera E, Pollastrini E, et al. Oral rush desensitization in peanut allergy: a case report. Dig Dis Sci. Mar 2006;51(3):471–473. 103. Scurlock AM, Steele, P.H., Andrzejewski, S.S., Pons, L.A., Althage, K.A., Christie, L., Carlisle, S.K., Buchanan, A.D., Jones, S.M., Burks, A.W. Safety of oral peanut immunotherapy for peanut allergic patients. J Allergy Clin Immunol. Feb 2005:S246 104. Pons L, Burks W. Novel treatments for food allergy. Expert Opin Investig Drugs. Jul 2005;14(7):829–834. 105. Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med. Mar 2003;348(11):986–993. 106. Novartis UoMMC. Safety and Efficacy Study of Omalizumab Given Prior to Immunotherapy. In: ClinicalTrials.gov [Internet]. http://www.clinicaltrials.gov/ct/show/NCT00329381 NLM Identifier: NCT00329381, 2000-[cited 2007 Jun 16]. 107. Administration USFaD. Omalizumab (marked as Xolair) Information. [Web Page]. Feb 2007; http://www.fda.gov/cder/drug/infopage/omalizumab/Accessed June 16, 2007. 108. Li XM, Zhang TF, Huang CK, et al. Food Allergy Herbal Formula-1 (FAHF-1) blocks peanut-induced anaphylaxis in a murine model. J Allergy Clin Immunol. Oct 2001;108(4): 639–646. 109. Li XM, Srivastava K. Traditional Chinese medicine for the therapy of allergic disorders. Curr Opin Otolaryngol Head Neck Surg. Jun 2006;14(3):191–196. 110. Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol. Jan 2005;115(1):171–178.

Allergic Fungal Sinusitis: Controversy and Evolution of Understanding with Therapeutic Implications Berrylin J. Ferguson and Arpita Mehta

Introduction Fungal rhinosinusitis can be categorized into distinct forms on the basis of histopathology. The invasive manifestations are fulminant or rapidly progressing, chronic or indolent, and granulomatous. The noninvasive manifestations are fungus balls and allergic fungal sinusitis (AFS). A noninvasive and controversial category introduced within the last decade resembles AFS; however, patients are not allergic and are termed nonallergic eosinophilic fungal rhinosinusitis (NA-EFRS). AFS or NA-EFRS is the subject of this chapter and will be contrasted to eosinophilic sinus disease in which fungi are absent. Classically, AFS is defined as the histopathologic presence of eosinophilic mucin containing fungal hyphae retrieved from the nose or paranasal sinuses from patients who demonstrate IgE mediated allergy to the fungus. Patients with AFS often have asthma, peripheral eosinophilia, nasal polyps, and allergic rhinitis. The nose and sinus contents contain green, sticky or tan mucin plugs, which when examined pathologically reveal eosinophilic mucin, Charcot Leyden crystals, degenerating inflammatory cells, and sparse hyphae (Fig. 1). The presence of hyphae is considered to be important in making the diagnosis; however, hyphal presence is often sparse and the diagnosis of AFS may be missed due to sampling error [1]. The absence of fungus histopathologically or of allergy has lead to two additional categorizations: (1) Nonfungal eosinophilic mucin rhinosinusitis (NF-EMRS) in which fungi are not seen or cultured and are NOT considered to be of etiologic importance [2] (Fig. 2) and (2) Nonallergic eosinophilic fungal rhinosinusitis (NA-EFRS) in which fungi are present and believed to be causal in the pathophysiology through nonallergic mechanisms [3].

B.J. Ferguson () and A. Mehta Division of Sino-Nasal Disorders and Allergy, Department of Otolaryngology, University of Pittsburgh School of Medicine, The Eye and Ear Institute Building, 200 Lothrop Street, Suite 500, Pittsburgh, PA 15213, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_42, © Springer 2010

695

696

B.J. Ferguson and A. Mehta

Fig. 1 High power photomicrograph of AFS demonstrating hyphae in eosinophilic mucin and a conidia in hematoxylin and eosin (H&E) (original magnification × 100). Frequently, special fungal stains are required to identify hyphae. It is unusual to see conidia

Fig. 2 Low power photomicrograph of nonfungal eosinophilic mucin rhinosinusitis (NF-EMRS) showing eosinophilic mucin. Special stains for fungus (not shown) were negative. (25×)

The therapy for AFS includes surgery as well as topical and systemic steroids. Topical and systemic antifungals, leukotriene modulators, immunotherapy following surgical extirpation, and anti-IgE may be useful in individual patients. Recidivism and recurrence are frequent in the absence of medical therapy.

Allergic Fungal Sinusitis

697

Historical Aspects AFS was initially recognized clinically in 1976 by Safirstein as an inflammatory condition of the nose and sinuses associated with thick, sticky, eosinophilic mucin which grew out of aspergillus [4]. In 1981, Miller, in abstract form, noted the histopathologic similarity of the sinus manifestation to the already well-recognized pulmonary pathology of Allergic Bronchopulmonary Aspergillosis (ABPA) [5]. Independently, 2 years later, Katzenstein described this association in a series of six cases. None of these early reports had fungal culture data and based their terminology of allergic aspergillus sinusitis on the histologic appearance of the fungus and its resemblance to aspergillus [1]. We now appreciate that many fungi, in addition to Aspergillus species, are associated with AFS and that histologically it may be impossible to differentiate between fungal species [6]. The term allergic fungal sinusitis was coined in 1989 [7]. In 1998, Manning showed, in a case control study, that all the patients with AFS associated with Bipolaris displayed elevated IgE to Bipolaris, in contrast to controls in which this was present in only a minority of patients [8].

Confusion and Controversy over the Diagnosis of AFS Categorization The confusion over the role of fungus in the etiology of chronic rhinosinusitis (CRS) was heightened by the assertion of Ponikau and colleagues in the late 1990s that fungi were responsible for most cases of CRS. They reported that 93% of patients undergoing sinus surgery had both eosinophilic mucin and fungus present by nasal lavage sampling. Ponikau based his conclusion of a nonallergic etiology of eosinophilic fungal sinusitis on the fact that less than half of his sample of almost 100 patients with eosinophilic mucin and fungal presence were allergic. In this same report, Ponikau also noted that fungus could be grown from the nasal washings of 100% of normal controls [3]. They proposed that cell mediated responses provoked by fungus in susceptible host was responsible for eosinophilic fungal rhinosinusitis (EFRS). In order to highlight the nonallergic nature of Ponikau’s proposed categorization, we refer to this as nonallergic eosinophilic fungal rhinosinusitis (NA-EFRS). Since the proposal of Ponikau that fungus was causal in nearly all cases of CRS, there have been three large studies that compare the demographics of eosinophilic sinus disease relative to presence or absence of fungus with conflicting findings. In 2000, Ferguson reported that the eosinophilic mucin rhinosinusitis without fungus differed significantly in clinical characteristics of patients with AFS, although overlap existed [2]. Ferguson’s database was a comprehensive literature review of AFS and NF-EMRS combined with a database of patients from northeastern United States. The review compared 69 NF-EMRS patients with 431 patients with AFS and found

698

B.J. Ferguson and A. Mehta

that AFS patients were significantly younger (30.7 years compared with 48.0 years), less likely to have asthma (41% compared with 93%), less likely to have aspirin sensitivity (13% compared with 54%), less likely to have bilateral disease (55% versus 100%), and had significantly higher total IgE levels (mean 1,941 mg/dL with a range of 12–13,084 mg/ dL) compared with NF-EMRS patients (mean, 267 mg/ dL with a range of 14–1,162 mg/dL). Over 90% of this database was drawn from North America [2]. In 2006, Saravanan prospectively categorized 70 patients in northern India undergoing sinus surgery and found that 36 of 70 (51%) patients had AFS, 12 of 70 (17%) had NF-EMRS, 4 (6%) had fungus balls, and the remaining 18 had noneosinophilic CRS from other causes. Similar to the report by Ferguson, the mean age of the AFS patients was younger than the NF-EMRS (28 ± 13 years versus 41 ± 10 years) and bilateral disease was less common in the AFS group (75% versus 100%), but these findings did not achieve statistical significance. Bony erosion (100% versus 40%) and heterogeneity of densities on CT scan (97% versus 67%) were significantly more common in the AFS group compared to the NF-EMRS [9]. In Adelaide, Australia, a prospective evaluation of 188 patients with EMRS found that patients with classic AFS were significantly younger than patients with other forms of EMRS; however, there was no difference in the subgroups in any other parameters examined including presence of aspirin sensitivity, bilaterality of disease, immunoglobulin levels, or asthma. Virtually 100% of all AFS patients have bilateral disease in southern Australia [10]. Possible explanations for the differences between these three large series include the impact of differences introduced by climate, genetic susceptibility, and socioeconomic factors. In the Ferguson literature and retrospective review, 93% of the patients were from North America, while the two large prospective series were from a single location. Saravanan’s study represented patients from central northern India, and Pant’s study was of patients from Adelaide, Australia. It is possible that in northern India and southern Australia conditions could exist that lead to a higher mold inoculum and more frequent bilateral disease.

Epidemiology and Geography Allergic fungal sinusitis incidence varies geographically [11]. Endemic areas include areas of high humidity in the United States along the Mississippi River and in the South, in Northern India (51% undergoing sinus surgery), Adelaide Australia (8.6% undergoing sinus surgery) [2, 9, 12], and areas of the Persian Gulf. In 1998, the highest reported rate in the United States was in Memphis, Tennessee, where 20% of surgical endoscopic sinus cases were for AFS. Memphis lies on the other side of the Mississippi River, a few hundred miles downstream from St. Louis, Missouri, where in 1983 Katzenstein was the first to report on the incidence of AFS, 6.2% of all surgical sinus cases. Most telling is the absence of AFS in certain regions such as the Northwestern part of United States where there is a

Allergic Fungal Sinusitis

699

cooler climate. The presence of mold spores is necessary for AFS to occur. The geographic variation in incidence of AFS could be secondary to differences in mold counts. Outdoor mold spore counts vary widely geographically and seasonally. Other sources of mold exposure include damp basements, bathrooms, humidifiers, and possibly air conditioning units. Air conditioning is more common and more utilized in the southern United States and in the Persian Gulf where there is high incidences of AFS.

Pathophysiology Similarities and Differences of AFS to ABPFD AFS is thought to be the pathophysiological nasal/sinus equivalent of allergic bronchopulmonary aspergillosis (ABPA), yet differences exist between these two entities which have a similar histopathologic appearance. ABPA is more precisely called allergic bronchopulmonary fungal disease (ABPFD), since fungi in addition to Aspergillus can cause this disease. Both ABPA and AFS require an individual genetically predisposed to mold allergy that is exposed by inhalation to the mold spore. The spore must elude mucociliary clearance or expulsion by sneezing or coughing for a time period which is long enough to allow germination. It is estimated that an average person inhales 5.7 × 107 spores of various species within a 24-h period [13]. Occasionally, due to the maxillary transport disruption, dryness, or a large inoculum, the mold spore may not be cleared. In a susceptible and allergic individual, germination increases the antigenicity of the fungus [14], leading to increased production of allergic mucin in which the fungus continues to grow. This leads to a “positive feed-back loop” in which growth of the antigenic fungus induces the production of more allergic mucin, which leads to increased growth of antigenic fungus (Fig. 3). The sticky allergic mucin resists clearance by normal mucociliary action, and the inflammatory cytokine milleaux promotes the growth of nasal polyps. If the mold spore randomly gets lodged in just one side of the nose, unilateral AFS will develop. The fungi most frequently associated with AFS are those with rapid germination rates. Antigenicity for most of the fungi associated with AFS increases with germination. At body temperature, Alternaria may germinate within as little as 2 h [15]. Pant found that fungal IgE levels were similar in patients with NF-EMRS and fungal allergy compared to patients with AFS [16]. This implies that presence of fungal allergy alone is not sufficient for the development of AFS. Patients also have fungal allergy without EMRS. Thus, IgE to fungal antigens in patients with NF-EMRS may represent cases in which fungi have not become entrapped in the nose or sinuses. In other words, the mucociliary/host defenses have been adequate to prevent entrapment of fungal spores or a co-factor such as superantigen may be absent. Recently, the controversy involving the definition of AFS has been intensified by reports of mucosal invasion as indicated by granulomatous inflammation and branching septate fungal hyphae in the submucosal tissues in patients with presumed extensive AFS [17, 18].

700

B.J. Ferguson and A. Mehta

AFS

+ feed back loop Germinates quickly in mucous, Possible superantigen producing bacteria cofactor

Inhaled spore, Not cleared By MCT More mucous stimulated

↑ Hyphal Growth

+

↑ Antigenic stimulation

antigenicity increases More mucous stimulated

Fig. 3 Diagram of positive feedback cycle in which an inhaled spore becomes trapped in the nose or sinus of a susceptible host. Allergic mucin is secreted. The spore germinates and grows in the mucin, increasing the antigenic stimulation, resulting in an increased production of mucin

Proteases and Fungal Sinus Disease Gibson proposed that the pathophysiology of ABPA is not only one of IgE mediated reactions to fungal antigens, which stimulates the Th2 pathway leading to eosinophilic infiltrate, but that the presence of aspergillus proteases promote epithelial activation and a potent chemokine response that induces neutrophilic airway inflammation [19]. The effect of fungal proteases on sinus mucosa is largely unexplored but may be an additional mechanism in which fungi can stimulate inflammation independent of an IgE mediated/allergic pathway. Kita has shown that fungus can cause eosinophil degranulation independent of IgE mediated mechanisms [20]. In addition, the same investigators have shown that peripheral blood monocytes (PBMC’s) from patients with CRS respond to the supernatant of Alternaria with the production of IL-5 independent of an IgE mediated mechanism. This does not occur in patients without CRS [21]. It is possible that this is not an immunologically mediated reaction but is caused by fungal proteases, which could lead to nonallergic fungal ECRS. Proteases in fungi interact with nasal epithelial cells and enhance the production of inflammatory cytokines in vitro. These cytokines induce the migration of eosinophils and neutrophils. Shin reported that nasal polyp cells produce inflammatory cytokines in vitro on fungal exposure which is associated with the increased expression of protease activated receptors [22].

Allergic Fungal Sinusitis

701

Superantigen and Genetic Predisposition In 2001, Schubert proposed that the presence of superantigens might be a condition which would lead to the cytokine mileaux, which would predispose to the generation of IgE against fungal presence leading to AFS. It is known that staph superantigens are important in perpetuating atopic dermatitis. Subsequently, several investigators have shown that staph superantigens are present in at least some of the patients with nasal polyposis [23–25]. Not only do superantigens upregulate susceptible T-cells but may be responsible for B-cell activation. Superantigens enhance the TH2 response which leads to the isotype class switching of immunoglobulin synthesis favoring the production of IgE not only to the superantigens but also potentially to other foreign proteins, which may be present incidentally, such as fungus [26]. Wormald’s laboratory in Australia recently demonstrated that peripheral blood lymphocytes (PBL) from patients with CRS, both with and without nasal polyps as well as with normal controls, expressed significantly more interferon gamma (INF-g) and a more modest increase in IL-5 when exposed to staphylococcal exotoxin (superantigen) Type B (SEB). This was enhanced by the addition of fungal extracts (Aspergillus and Alternaria). Unlike Shin’s study, no significant increase in IL-5 was seen upon exposure to just fungal extracts in Wormald’s study. They concluded that SEB exerted a proinflammatory effect on PBLs and fungal extracts may act synergistically to promote this action [27]. In AFS, the currently proposed mechanisms would involve Th2 associated cytokine such as IL-5, and not necessarily a Th1 cytokine such as INF-g. Whether AFS patients’ PBLs respond differently than CRS patients would be of interest. PBLs on exposure in vitro to SEB or fungal extracts have not been studied. Both ABPA and AFS are associated with certain class II genes of the major histocompatibility complex (HLA-DR2 and HLA-DR5, respectively). Not all patients with AFS have this genotype nor do all patients with this genotype develop either ABPA or AFS. Schubert reported that HLA-DQB1*03 was significantly a more frequent finding in patients with AFS than in chronic sinusitis without fungus; both were elevated compared to normal controls [28]. Such a finding is compatible with a role for bacterial superantigen exposure to genetically susceptible patients leading to the nonspecific upregulation activation of T-cells, which can set the stage for a TH2 mediated reaction to fungus that may be present incidentally [29] (Table 1).

Table 1 Pathogenesis of allergic fungal sinusitis Currently required elements Probably or possibly required Noninvasive fungal growth Superantigen from bacterial coinvestigation Eosinophilic mucin HLA subtype susceptible to superantigen stimulation Type I allergy to fungus cultured

702

B.J. Ferguson and A. Mehta

Fig. 4 Photomicrograph of eosinophilic mucin with nests of bacteria and hyphae. (hematoxylin and eosin) (original magnification × 100). In inset, hyphae are demonstrated by silver stain, the most sensitive stain for detection of fungi. (original magnification × 40)

Recently, Ferguson reported statistically significant association of bacteria with fungus in eosinophilic mucin compared to the presence of fungus without associated bacteria (Fig. 4). This may be evidence for a co-pathogenic role for bacteria, which presumably could produce superantigen required for AFS to occur or it may represent an incidental association [30]. A recent report by Orlandi and colleagues showed differences in genes present or activated in AFS compared to NF-EMRS. This is a preliminary study of a small number of cases that offers a potentially attractive method of categorizing EMRS, which might overcome current confusion generated by overlapping clinical characteristics and potentially lead to selective therapeutic interventions [31].

IgE Levels and Associated Fungal Findings In both AFS and ABPA, high levels of serum IgE are usually seen, and these levels fluctuate with disease activity. It is possible to encounter low levels of IgE, particularly in patients with quiescent disease [32]. Kuhn found that total IgE was both more specific and sensitive than fungal specific IgE for predicting persistence or recurrence of AFS [33]. The most common fungi associated with AFS vary geographically. In the southern United States, AFS is commonly associated with Bipolaris species. This antigen is not available commercially, and most clinicians substitute Helminthosporium during allergy antigen testing owing to its cross reactivity [34]. The most common

Allergic Fungal Sinusitis

703

fungi associated with AFS, for which commercial assays for serological screening exist, are species of Helminthosporium, Aspergillus, Alternaria, and Curvularia. Elevated IgE and IgGs to the fungus are common in ABPFD. The precipitating antibodies (IgG) that are integral to a Gell and Coombs Type III reaction can be found in over 90% of ABPFD patients. Interestingly, there has been no similar demonstration of immune complexes and the development of AFS. Another difference between ABPFD and AFS is the absence of AFS in patients with cystic fibrosis. Between 6 and 25% of patients with cystic fibrosis are reported to have ABPFD [35], while ABPFD as a whole afflicts only 1% of all asthmatics.

Fungal Culture In order to determine the fungal cause of AFS, a culture must be obtained. Over homogenization of the specimen will prevent fungal growth. Nasal washes resulted in fungal recovery from nearly everyone’s nose, and whether the fungus is causative or incidental is impossible to determine [3]. Therefore, most investigators rely on cultures obtained from the eosinophilic or allergic mucin. Associated fungal causes vary geographically. In North America, most cases of AFS are caused by dematiaceous or pigment producing species such as Bipolaris, Exserohilum robatum, Curvularia lunata, and Alternaria. In northern India, the majority of AFS cases are caused by Aspergillus flavus, and in the Persian Gulf countries, Aspergillus species predominate.

Clinical Presentation Associated clinical findings include a male predominance, nasal polyps, unilateral presence in half of the cases in North America, and asthma (40–61%). Sinus CT findings which are characteristic of AFS do not exclude other causes of eosinophilic sinus disease. This is discussed more fully under the radiographic subsection. In children with growing faces, remodeling of the facial skeleton to develop proptosis is common. Patients may relate blowing out the mucin plugs and complain of unilateral or bilateral nasal obstruction. Visual loss has been reported rarely in patients with sphenoid involvement. Dhiwakar et al. suggest that the combination of nasal polyposis, CT scan with heterogeneity and bone erosion, and specific elevated fungal IgE titer have high preoperative predictive value for AFS [36]. Most authors report nasal polyps in all forms of eosinophilic sinus disease, and therefore it may be sensitive but not specific for the diagnosis of AFS. AFS can occur or reoccur in the absence of nasal polyps. The five criteria described by Bent and Kuhn for the diagnosis of AFS include those which are part of the classic definition: Type I hypersensitivity to fungi and eosinophilic mucin with noninvasive hyphal presence as well as two additional clinical findings: A characteristic radiograph and nasal polyps. These two latter

704

B.J. Ferguson and A. Mehta

findings are usually present in patients with AFS, but AFS can occur in their absence [37]. Asthma, when present with AFS, is usually mild and not steroid dependent, although there are case reports of concomitant ABPA associated with AFS [38].

Radiological Findings Computed tomography (CT) imaging of the sinuses is the modality of choice to diagnose AFS. The most common finding is central areas of high attenuation, which represent the eosinophilic mucin surrounded by densities of lesser attenuation that represent mucosal thickening and nasal polyps (Fig. 5). Mukherjig et al. performed a retrospective study examining the CT scans of 45 patients with AFS. Areas of hyperattenuation were found in all patients, 51% had bilateral findings and 20% had bony erosion and local extension of disease. Nussenbaum et al. reviewed 142 AFS patients’ CT scans and also found a 20% incidence of bony erosion, most commonly involving the lamina papyracea.

Fig. 5 Coronal CT of AFS showing opacification of the right maxillary sinus and ethmoid. Note the heterogenicity of densities with the denser material representing the mucin plugs and the lighter density representing nasal polyp or mucosal thickening

Allergic Fungal Sinusitis

705

The ethmoid sinus was most commonly involved, although multiple sinuses were frequently involved and often expanded by the mucin. In northern India, both bony erosion and heterogeneous opacity with sinus expansion on CT scan were significantly more common in patients with AFS versus other forms of sinusitis. 100% of patients with AFS in this series demonstrated bony erosion. This high incidence of bony erosion may reflect the socioeconomic differences in which patients are not seen until they have developed advanced disease [9]. Magnetic resonance imaging of AFS frequently shows a hypointense central T1 signal, central T2 signal void, and increased peripheral T1/T2 enhancement. Thus, the diagnosis of a sinus abnormality could be missed due to the signal void if only an MRI scan is obtained. These findings are not specific for AFS and may be found in other eosinophilic sinus conditions. CT should be the primary mode of assessment for AFS to acquire important information regarding bony landmarks.

Treatment The initial treatment in AFS is usually surgical. This provides pathologic material in order to make the diagnosis as well as the material for culture. In the absence of medical therapy, recurrence rates as high as 100% have been reported. Therefore, medical adjunctive therapy such as steroid, antifungal, and immunotherapy are utilized to improve the prognosis [39] (Table 2). Systemic steroids given before surgical therapy may diminish the eosinophilic component of the disease, and the pathologist may erroneously report nothing more than a fungus ball. Once steroids are withdrawn, the eosinophilic nature returns and the histopathologic diagnosis of AFS can be made. Numerous fungi are responsible for AFS. The causative organism may be recovered from air samples of the residences of the affected patients [40]. The rate of re-inoculation after treatment accounts for some of the high recurrence rates.

Surgical Management Surgery is required to establish the diagnosis of AFS, remove the inciting fungal pathogen, reestablish physiological drainage, and preserve healthy mucosa. By fulfilling these goals, medical therapy can be optimized and control the disease.

Table 2 Therapy of allergic fungal sinusitis Definitely helpful Probably or possibly helpful Steroids, systemic, or topical Surgery Nasal lavage *demonstrated efficacy in ABPA

Immunotherapy Oral antifungals* anti IgE*

Not helpful or unclear Topical amphotericin B Leukotriene modulators Calcineurin inhibitors Antibiotics

706

B.J. Ferguson and A. Mehta

There are two surgical approaches toward the sinuses, external and endoscopic. Before the introduction of endoscopic techniques in the mid 1980s, AFS was approached externally through Caldwell-Lucs, external ethmoidectomies, and frontal sinus trephination or obliteration procedures. Endoscopic techniques are now primarily utilized [41]. This requires obtaining a preoperative CT scan within a few weeks of the operation to clearly demarcate any bony dehiscences and to identify the regions of disease. A microdebrider, which is a powered instrument with an oscillating blade attached to suction, facilitates the removal of the sticky tenacious mucin. The microdebrider’s trap allows easy collection of tissue for establishing diagnosis [42]. A microdebrider should not be used, or used only with great caution, in areas of bony dehiscence. Computer assisted navigational systems facilitate safe surgery in areas where landmarks have been obscured [43]. In refractory cases, stripping of nasal mucosa to remove presumed biofilm and irreversibly diseased tissue may prevent further recurrences. Aggressive and mutilating surgery should be avoided. Occasionally, frontal sinus obliteration is required.

Medical Management Steroid therapy is the mainstay of ABPA and AFS, but because systemic steroids carry risk therapy, use should be limited [44]. The usual starting dose is 60–40 mg a day, which is then tapered over weeks to months [45]. Kupferberg et al. report that postoperative systemic steroids significantly reduce the recurrence of AFS and that doses less than 15 mg every other day lead to recurrence [46]. Schubert and Goetz in a series of consecutive AFS patients found that oral steroids given within the first 2 years postoperatively significantly delayed revision surgery [34]. Systemic steroids have potential for significant problems short-term including insomnia, personality change, diabetes, psychosis, or exacerbation of a peptic ulcer. Long-term usage may lead to osteoporosis, avascular necrosis of the hip, cataract formation, glaucoma, and hypertension. The risks associated with systemic steroids in children are growth retardation and potential irreversible bone growth loss; therefore, lower doses of 0.5–1 mg/kg per day are recommended [46]. Topical corticosteroids have limited systemic bioavailability and are usually part of the long-term management of AFS patients. Intranasal steroid sprays are usually more beneficial after surgery, when there is greater access to the affected nasal mucosa [47].

Antifungal Therapy Early nonrandomized, noncontrolled studies reported 70% improvement in symptoms and CT scans after irrigation of the nose with 20 mL of amphoterocin B 20 twice a day for 4 months. Studies to assess the effect of intranasal antifungals have evolved. (Table 3) In the best designed study to date, Ebbens et al. reported no benefit from usage of amphotericin irrigation either objectively of subjectively [48].

NP without AFS CRS CRS, prior ESS, without AFS

Weschta – 2004 Ponikau – 2005 Ebbens – 2006

R,DB,PC N = 74 R,DB,PC N = 24 R,DB,PC,MC N = 116

NR,NB N = 74

Amp B dose

200 mL spray qid × 8 weeks 20 ml bid 100 mg/mL × 6 months 25 mL amphotericin B bid 100 mg/mL × 13 weeks

20 ml bid 100 mg/ mL × x > 3 months 20 ml bid 1:1,000 × 4 weeks

Resolution of polyps in 42–62% of mod & mild NP, 0% severe NS imp* 8% imp in CT NS difference, objectively, subjectively, or by QOL

Result Imp in 75%

NR = nonrandomized; NB = nonblinded; R = randomized; MC = multicenter DB = double blinded; PC = placebo controlled; QOL = quality of life; ESS = endoscopic sinus surgery; AFS = allergic fungal sinusitis; CRS = chronic rhinosinusitis; NP = nasal polyp Table 3 [48,55–58]

Nasal polyps

Ricchetti – 2002

Table 3 Studies of topical amphotericin B in CRS Entry criteria Design Ponikau – 2002 CRS NR,NB n = 51

Allergic Fungal Sinusitis 707

708

B.J. Ferguson and A. Mehta

In the pulmonary equivalent of the disease, ABPA, the antifungal intraconazole at a dose of 200 mg BID for 16 weeks, was shown to significantly improve the disease in a randomized placebo controlled multicenter study [49]. No benefit with high-dose oral terbinafine was shown in a randomized placebo controlled multicenter study of patients with CRS not restricted to AFS [50].

Immunotherapy Initially, immunotherapy was considered to be contraindicated in AFS due to its theoretical potential to worsen the disease through the formation of immune complexes. Goldstein was the first to suggest that immunotherapy may prevent recurrences [51]. Mabry and colleagues initially showed that fungal specific immunotherapy following endoscopic sinus surgery for AFS did not cause harm. Subsequently, they performed a retrospective review and found that patients who received 3 years of immunotherapy experienced a significant reduction in recurrence compared to patients who did not receive immunotherapy [52]. Marple et al. further expanded this study and followed AFS patients for at least 4–10 years and found that regardless of whether patients received immunotherapy or not, most patients were in remission [53].

Anti-IgE The humanized monoclonal antibody to the Fc portion of IgE, omalizumab, is currently approved for patients with severe allergic asthma. There are no reports of usage in patients with AFS, although the senior author has seen a case which responded within a week of initiating with omaluzimab. Recently, van der Ent et al. reported that a patient with ABPA responded dramatically and rapidly following a single dose of omalizumab [54].

Other Modalities Antibiotics have on occasion been reported to improve AFS, but there are no trials to support their use for this indication. If AFS does require the presence of a bacterial superantigen, then perhaps antibacterial therapies may have a role, but that role remains to be elucidated. If superantigen stimulation is important, the calcineurin inhibitors may have a role, as they do in atopic dermatitis, in which picrolimus and tacrolimus have proven efficacy. They have not been studied for this indication. Saline lavages remain unstudied for this condition, but have a prominent role in most physicians’ armamentarium, to be used before the application of a topical steroid. Saline irrigations are widely utilized in India for these conditions.

Allergic Fungal Sinusitis

709

Discussion In summary, our understanding of the pathophysiology of these various histopathologic forms of sinusitis characterized by eosinophilic mucin with presence or absence of fungus and IgE mediated hypersensitivity is incomplete and evolving. In 1999, noninvasive fungus was shown to be present in the majority of patients with ECRS, as well as by culture in most normals. Thus, fungal presence or fungal allergy alone is insufficient to make the diagnosis of AFS. It is the host’s eosinophilic response to these ubiquitous fungi, which leads to the clinical findings of AFS (nasal polyps, allergic mucin plugs, characteristic double densities radiographically). It is likely that the inflammatory cascade which leads to AFS is a multifactorial event, requiring IgE mediated sensitivity (atopy), specific T-cell HLA receptor expression, exposure to specific fungi, disruption of local mucosal defense mechanisms, and possibly co-stimulation with bacterial superantigens.

References 1. Katzenstein AL, Sale SR, Greenberger PA (1983) Allergic Aspergillus sinusitis: A newly recognized form of sinusitis. J Allergy Clin Immunol 72(1):89–93 2. Ferguson BJ (2000) Eosinophilic mucin rhinosinusitis: A distinct clinicopathological entity. Laryngoscope 110(5 Pt 1):799–813 3. Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA, Roberts GD (1999) The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 74(9):877–84 4. Safirstein BH (1976) Allergic bronchopulmonary aspergillosis with obstruction of the upper respiratory tract. Chest 70(6):788–90 5. Miller JW, Jhonston A, Lamb D (1981) Allergic aspergillosis of the maxillary sinuses. Thorax 710 6. Manning SC, Schaefer SD, Close LG, Vuitch F (1991) Culture-positive allergic fungal sinusitis. Arch Otolaryngol Head Neck Surg 117(2):174–8 7. Robson JM, Hogan PG, Benn RA, Gatenby PA (1989) Allergic fungal sinusitis presenting as a paranasal sinus tumour. Aust N Z J Med 19(4):351–3 8. Manning SC, Holman M (1998) Further evidence for allergic pathophysiology in allergic fungal sinusitis. Laryngoscope 108(10):1485–96 9. Saravanan K, Panda NK, Chakrabarti A, Das A, Bapuraj RJ (2006) Allergic fungal rhinosinusitis: An attempt to resolve the diagnostic dilemma. Arch Otolaryngol Head Neck Surg 132(2):173–8 10. Pant H, Kette FE, Smith WB, Macardle PJ, Wormald PJ (2006) Eosinophilic mucus chronic rhinosinusitis: Clinical subgroups or a homogeneous pathogenic entity? Laryngoscope 116(7):1241–7 11. Ferguson BJ, Barnes L, Bernstein JM, Brown D, Clark CE, 3rd, Cook PR, DeWitt WS, Graham SM, Gordon B, Javer AR, Krouse JH, Kuhn FA, Levine HL, Manning SC, Marple BF, Morgan AH, Osguthorpe JD, Skedros D, Rains BM, 3rd, Ramadan HH, Terrell JE, Yonkers AJ (2000) Geographic variation in allergic fungal rhinosinusitis. Otolaryngol Clin North Am 33(2):441–9 12. Collins MM, Nair SB, Wormald PJ (2003) Prevalence of noninvasive fungal sinusitis in South Australia. Am J Rhinol 17(3):127–32 13. Novey HS (1998) Epidemiology of allergic bronchopulmonary aspergillosis. Immunol Allergy Clin North Am 18(3):641–653

710

B.J. Ferguson and A. Mehta

14. Green BJ, Mitakakis TZ, Tovey ER (2003) Allergen detection from 11 fungal species before and after germination. J Allergy Clin Immunol 111(2):285–9 15. Mitakakis TZ, Barnes C, Tovey ER (2001) Spore germination increases allergen release from Alternaria. J Allergy Clin Immunol 107(2):388–90 16. Pant H, Kette FE, Smith WB, Wormald PJ, Macardle PJ (2005) Fungal-specific humoral response in eosinophilic mucus chronic rhinosinusitis. Laryngoscope 115(4):601–6 17. Thakar A, Sarkar C, Dhiwakar M, Bahadur S, Dahiya S (2004) Allergic fungal sinusitis: Expanding the clinicopathologic spectrum. Otolaryngol Head Neck Surg 130(2):209–16 18. Klapper SR, Lee AG, Patrinely JR, Stewart M, Alford EL (1997) Orbital involvement in allergic fungal sinusitis. Ophthalmology 104(12):2094–100 19. Gibson PG (2006) Allergic bronchopulmonary aspergillosis. Semin Respir Crit Care Med 27(2):185–91 20. Inoue Y, Matsuwaki Y, Shin SH, Ponikau JU, Kita H (2005) Nonpathogenic, environmental fungi induce activation and degranulation of human eosinophils. J Immunol 175(8):5439–47 21. Shin SH, Ponikau JU, Sherris DA, Congdon D, Frigas E, Homburger HA, Swanson MC, Gleich GJ, Kita H (2004) Chronic rhinosinusitis: An enhanced immune response to ubiquitous airborne fungi. J Allergy Clin Immunol 114(6):1369–75 22. Shin SH, Lee YH, Jeon CH (2006) Protease-dependent activation of nasal polyp epithelial cells by airborne fungi leads to migration of eosinophils and neutrophils. Acta Otolaryngol 126(12):1286–94 23. Bernstein JM, Kansal R (2005) Superantigen hypothesis for the early development of chronic hyperplastic sinusitis with massive nasal polyposis. Curr Opin Otolaryngol Head Neck Surg 13(1):39–44 24. Seiberling KA, Conley DB, Tripathi A, Grammer LC, Shuh L, Haines GK, 3rd, Schleimer R, Kern RC (2005) Superantigens and chronic rhinosinusitis: Detection of staphylococcal exotoxins in nasal polyps. Laryngoscope 115(9):1580–5 25. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P (2001) Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 107(4):607–14 26. Seiberling KA, Grammer L, Kern RC (2005) Chronic rhinosinusitis and superantigens. Otolaryngol Clin North Am 38(6):1215–36, ix 27. Douglas R, Bruhn M, Tan LW, Ooi E, Psaltis A, Wormald PJ (2007) Response of peripheral blood lymphocytes to fungal extracts and staphylococcal superantigen B in chronic rhinosinusitis. Laryngoscope 117(3):411–4 28. Schubert MS, Hutcheson PS, Graff RJ, Santiago L, Slavin RG (2004) HLA-DQB1*03 in allergic fungal sinusitis and other chronic hypertrophic rhinosinusitis disorders. J Allergy Clin Immunol 114(6):1376–83 29. Schubert MS (2006) Allergic fungal sinusitis. Clin Rev Allergy Immunol 30(3):205–16 30. Ferguson BJ, Seethala R, Wood WA (2007) Eosinophilic bacterial chronic rhinosinusitis. Laryngoscope 117(11):2036–40 31. Orlandi RR, Thibeault SL, Ferguson BJ (2007) Microarray analysis of allergic fungal sinusitis and eosinophilic mucin rhinosinusitis. Otolaryngol Head Neck Surg 136(5):707–13 32. Geha RS (1977) Circulating immune complexes and activation of the complement sequence in acute allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 60(6):357–9 33. Kuhn FA, Javer AR, Utilizing fungal specific IgE levels as a serological marker for allergic fungal sinusitis (AFS) activity., in American Rhinologic Society Spring Meeting. 1999. 34. Schubert MS, Goetz DW (1998) Evaluation and treatment of allergic fungal sinusitis. II. Treatment and follow-up. J Allergy Clin Immunol 102(3):395–402 35. de Almeida MB, Bussamra MH, Rodrigues JC (2006) Allergic bronchopulmonary aspergillosis in paediatric cystic fibrosis patients. Paediatr Respir Rev 7(1):67–72 36. Dhiwakar M, Thakar A, Bahadur S, Sarkar C, Banerji U, Handa KK, Chhabra SK (2003) Preoperative diagnosis of allergic fungal sinusitis. Laryngoscope 113(4):688–94 37. Bent JP, 3rd, Kuhn FA (1994) Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 111(5):580–8

Allergic Fungal Sinusitis

711

38. Shah A, Panchal N, Agarwal AK (2001) Concomitant allergic bronchopulmonary aspergillosis and allergic Aspergillus sinusitis: A review of an uncommon association*. Clin Exp Allergy 31(12):1896–905 39. Ferguson BJ (1998) What role do systemic corticosteroids, immunotherapy, and antifungal drugs play in the therapy of allergic fungal rhinosinusitis? Arch Otolaryngol Head Neck Surg 124(10):1174–8 40. Noble JA, Crow SA, Ahearn DG, Kuhn FA (1997) Allergic fungal sinusitis in the southeastern USA: Involvement of a new agent Epicoccum nigrum Ehrenb. ex Schlecht. 1824. J Med Vet Mycol 35(6):405–9 41. Quraishi HA, Ramadan HH (1997) Endoscopic treatment of allergic fungal sinusitis. Otolaryngol Head Neck Surg 117(1):29–34 42. Ferguson BJ, DiBiase PA, D’Amico F (1999) Quantitative analysis of microdebriders used in endoscopic sinus surgery. Am J Otolaryngol 20(5):294–7 43. Metson R, Gliklich RE, Cosenza M (1998) A comparison of image guidance systems for sinus surgery. Laryngoscope 108(8 Pt 1):1164–70 44. Schubert MS (2001) A superantigen hypothesis for the pathogenesis of chronic hypertrophic rhinosinusitis, allergic fungal sinusitis, and related disorders. Ann Allergy Asthma Immunol 87(3):181–8 45. Waxman JE, Spector JG, Sale SR, Katzenstein AL (1987) Allergic Aspergillus sinusitis: Concepts in diagnosis and treatment of a new clinical entity. Laryngoscope 97(3 Pt 1):261–6 46. Kupferberg SB, Bent JP (1996) Allergic fungal sinusitis in the pediatric population. Arch Otolaryngol Head Neck Surg 122(12):1381–4 47. Marple BF (2001) Allergic fungal rhinosinusitis: Current theories and management strategies. Laryngoscope 111(6):1006–19 48. Ebbens FA, Scadding GK, Badia L, Hellings PW, Jorissen M, Mullol J, Cardesin A, Bachert C, van Zele TP, Dijkgraaf MG, Lund V, Fokkens WJ (2006) Amphotericin B nasal lavages: Not a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol 118(5):1149–56 49. Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Catanzaro A, Bamberger DM, Weinmann AJ, Tuazon CU, Judson MA, Platts-Mills TA, DeGraff AC, Jr. (2000) A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 342(11):756–62 50. Kennedy DW, Kuhn FA, Hamilos DL, Zinreich SJ, Butler D, Warsi G, Pfister PJ, Tavakkol A (2005) Treatment of chronic rhinosinusitis with high-dose oral terbinafine: A double blind, placebo-controlled study. Laryngoscope 115(10):1793–9 51. Goldstein MF, Dunsky EH, Dvorin DJ, Lesser RW (1994) Allergic fungal sinsusitis: A review with four illustrated cases. Am J Rhinol 8:13–18 52. Mabry RL, Marple BF, Folker RJ, Mabry CS (1998) Immunotherapy for allergic fungal sinusitis: Three years’ experience. Otolaryngol Head Neck Surg 119(6):648–51 53. Marple B, Newcomer M, Schwade N, Mabry R (2002) Natural history of allergic fungal rhinosinusitis: A 4- to 10-year follow-up. Otolaryngol Head Neck Surg 127(5):361–6 54. van der Ent CK, Hoekstra H, Rijkers GT (2007) Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody. Thorax 62(3):276–7 55. Ponikau JU, Sherris DA, Kita H, Kern EB (2002) Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol 110(6):862–6 56. Ricchetti A, Landis BN, Maffioli A, Giger R, Zeng C, Lacroix JS (2002) Effect of anti-fungal nasal lavage with amphotericin B on nasal polyposis. J Laryngol Otol 116(4):261–3 57. Weschta M, Rimek D, Formanek M, Polzehl D, Podbielski A, Riechelmann H (2004) Topical antifungal treatment of chronic rhinosinusitis with nasal polyps: A randomized, double-blind clinical trial. J Allergy Clin Immunol 113(6):1122–8 58. Ponikau JU, Sherris DA, Weaver A, Kita H (2005) Treatment of chronic rhinosinusitis with intranasal amphotericin B: A randomized, placebo-controlled, double-blind pilot trial. J Allergy Clin Immunol 115(1):125–31

Immunomodulatory Role of Bacillus Calmette-Guérin in the Prevention and Therapy of Allergy and Asthma Toluwalope O. Makinde, Againdra K. Bewtra, and Devendra K. Agrawal

Abbreviations gd T-cell NKT cells TH1 Treg cells

Gamma-delta T-cell Natural killer T-cell Helper type-1 T-cell T-regulatory cell.

Introduction There has been an increased prevalence and severity of asthma in recent decades. This increase in episodes of allergic asthma has been more evident in westernized nations where most infectious diseases have been markedly reduced by early immunization programs and extensive use of antibiotics [1]. Better diagnosis and exposure to conventional allergens have not been able to sufficiently explain the increased incidence of asthma. A substantial shift in genome does not occur in the span of only a few decades, and so genetic predisposition has also been ruled out as a major factor contributing to the observed increase in atopic diseases [1]. Paradoxically, several investigators have observed an inverse relationship between

T.O. Makinde Department of Biomedical Sciences, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178, USA A.K. Bewtra Department of Internal Medicine, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178, USA D.K. Agrawal () Departments of Medical Microbiology and Immunology, Biomedical Sciences, and Internal Medicine, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE 68178, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_43, © Springer 2010

713

714

T.O. Makinde et al.

atopic diseases, such as asthma, and exposure to infectious pathogens including Mycobacterium bacilli [2]. Many immune cells and mediators contribute to the development and exacerbation of allergic response and asthma. It is, therefore, not surprising to see the development of numerous drugs to combat the disease. None of these therapies has a curative effect and there still remains a cohort of patients who are unresponsive to these treatments [3]. This warrants continued research in this area to develop more effective therapeutic approaches with minimal side effects to control this debilitating disease. In the following sections, we critically reviewed the role of BCG in preventing a T helper (TH) 2 response, its effect on immune cells, and its efficacy as a potential therapeutic agent to control allergy and asthma.

Hygiene Hypothesis According to the “hygiene hypothesis,” the relative lack of infections early in life could promote the development of allergic diseases in genetically predisposed individuals [4]. However, it is important to note that not all infectious diseases contribute to the observed decrease in atopic conditions. For instance, respiratory syncytial virus (RSV) infection in early childhood may increase the risk for subsequent allergen sensitization and asthma [5]. Microbial infections that stimulate cell-mediated immune response are likely candidates for the inhibitory effect in the development of allergy and asthma.

Bacillus Calmette-Guérin Bacillus Calmette-Guérin (BCG) is a live, genetically attenuated strain of Mycobacterium bovis (M. bovis), a bacterium that causes tuberculosis (TB)-like disease in cows. This vaccine was developed in the early part of the twentieth century and is still used as the primary means of immunization against TB. This vaccine is a strong inducer of TH1 immune response, and also activates cytotoxic T-cells and natural killer (NK) cells [2].

Therapeutic Effects of BCG BCG-vaccinated children experienced a significant decrease in overall mortality when compared to children that were not vaccinated with BCG. BCG vaccineinduced prevention of TB deaths is an insufficient explanation for this decrease in mortality [6]. Apart from its use as a TB vaccine, BCG also has proven therapeutic efficacy and applications in several other diseases such as HIV and cancer [7–9].

BCG and Immunomodulation

715

Of relevance to this chapter is the protective role of BCG against the development of allergic and asthmatic response.

BCG in Allergy and Asthma Analysis of the health records of children in Guinea-Bissau, West Africa, showed that early BCG vaccination of children in this region significantly reduced their susceptibility to atopic diseases [10]. However, this protective effect was most evident in children who were vaccinated during the first weeks of life, indicating the importance of an early intervention for inducing its protective effect [11]. This theory is not supported by an epidemiological study conducted in Denmark where no correlation was observed between the age of BCG vaccination and the risk of asthma development [12]. Neonatal vaccination with BCG induced a protective effect that lasted up to 14 years postvaccine administration, suggesting that the neonatal conditioning of the immune response may have a long term effect [13,14]. Consistent with several other findings in experimental animals, we have also shown that BCG and M. vaccae, both have a protective effect on ovalbumin (OVA)-induced bronchoconstriction, bronchoalveolar lavage eosinophilia, airway hyperresponsiveness, and IL-4 production in a murine model [15]. IL-12 level is increased after BCG vaccination. However, endogenous IL-12 may contribute to airway eosinophilia [16]. Thus, it is unclear whether the protective effect of Mycobacterium in allergy and asthma is indeed via increase in IL-12 levels and warrants further investigation. In our subsequent study, BCG administration reversed established late allergic response without affecting early allergic response, BAL fluid IL-4 levels, or antigen-specific IgE level [17]. Although a previous study showed that the systemic administration of BCG also lowered antigen-specific IgE level [18], others have observed results similar to ours [19]. These findings suggest that along with its preventive role BCG may also have a therapeutic effect in allergic asthma.

Factors Regulating Efficacy of BCG as an Anti-Asthma Therapy There is significant discrepancy in the observations, both in clinical and experimental models, on the efficacy and duration of the effect of BCG as an anti-allergic or anti-asthmatic vaccine [13,14]. Furthermore, the efficacy observed in many animal models has not been convincingly reproduced in humans. This could be due to many factors that might regulate the effect of BCG. The efficacy of BCG vaccineinduced tolerance was found to be most effective when administered very early in life [11–13]. Prior exposure of the child to mycobacterial antigens [20], genetic predisposition [21], BCG strain [8], dosage [22], and route of administration [23] all play significant roles in the efficacy of BCG therapy.

716

T.O. Makinde et al.

BCG-Induced Immunoregulation and Airway Remodeling Neonatal BCG vaccination attenuated inflammation and mucus production in a murine asthmatic model [24]. In our laboratory, although BCG suppressed AHR and inflammation, we did not observe a significant effect on subepithelial fibrosis [25]. It is, however, surprising that although there is proven efficacy for BCG-induced protective effect against allergy and asthma, a recent study found that BCG-induced apoptosis in BEAS-2B cells [26]. Another study found that BCG-induced human b-defensin-2 mRNA in airway epithelial cells [27]. The defensins are components of the innate immune system, and bridge innate and acquired immune responses by recruiting dendritic cells (DCs) and T-cells to the sites of microbial infection [27]. Thus, more studies are required to fully establish the role of BCG in chronic asthma.

TH1/TH2 Concept TH2 cells produce and secret cytokines such as IL-4, IL-5, IL-9, and IL-13 and these cytokines play a central role in the development of allergic reaction and airway hyperresponsiveness. On the other hand, TH1 cytokines, including IL-2, IFN-g, and TNF-b, support cell-mediated immunity [28]. A predisposition to a TH1 response would prevent the development of allergic response in the form of atopy that is associated with a TH2 response (Fig. 1) [2].

PLASMA MEMBRANE

PLASMA MEMBRANE

STAT3

IL-10 R Cytokines

IL-10 Secretion

NFκB

? TLR2/CD14

TH2 Cell TReg Cell

In IL-4 milieu

IL-10 IL-12

IL-4

In IL-10 milieu

BCG

IL-10 TCR

BCG antigen

MHC II

IFN-γ

TH1 Cell

In IL-12 milieu IL-12 Secretion

IFN-γ IL-12R IFN-γ Secretion

Inhibits IL-4 production IFN-γR

NAÏVE T CELL

Inhibits IL-4 production

DENDRITIC CELL OR MACROPHAGE

Fig. 1 Differentiation of naïve T-cell into TH1, Treg or TH2 depending on the cytokine milieu. IL-12 and IFN-g secretion from dendritic cells (DCs) or macrophages support a TH1 polarization. IL-10 secretion supports a Treg response, and IL-4 milieu supports a TH2 response. Both IL-10 and IFN-g would inhibit production of IL-4, hence block TH2 response

BCG and Immunomodulation

717

In Japan, children with positive TB bacilli skin test, induced by BCG vaccination at birth, had reduced incidence of allergy and asthma [29]. Also, children with a positive delayed hypersensitivity tuberculin skin test response had serum cytokine concentrations suggestive of a predominant TH1 response, in contrast to the TH2 cytokine profile seen in children with a negative tuberculin skin test [29]. In another study, BCG vaccination at birth induced a memory-like TH1 immune response [30].

Growing Skepticism on the TH1/TH2 Concept Although there is evidence supporting the TH1/TH2 concept in the pathogenesis of allergy and asthma, recent findings refute the hypothesis. Elevated levels of both TH1 and TH2 cytokines have been observed in the blood and airways of asthmatic subjects [31]. Airway hyperresponsiveness and airway inflammation (except eosinophil infiltration) enhanced by high-doses of lipopolysaccharide can be completely inhibited in the absence of TH1 cytokine [32]. Both TH1 and TH2 cytokines following antigen challenge recruit endothelial cell progenitor cells in the lung and are associated with increased angiogenesis in the lung [33]. Several studies have shown BCG-induced protective effect to an atopic reaction without a clear shift toward a TH1 response. In one of these studies, although the protective effect was accompanied by increased IFN-g levels, IL-5 remained elevated [34]. In a recent study BCG upregulated the mRNA expression of cytokines that support both TH1 and TH2 responses including TNF-a, iNOS, IL-6, and IL-12 from alveoli macrophages [35]. Also M. vaccae induced its protective effect against the development of a TH2 response through a mechanism independent of IFN-g [36]. This suggests that the TH1/TH2 balance in mycobacterial immunoregulation of atopic reaction may not stand alone [36]. There may be a potential role for other immune cells in the therapeutic effects of mycobacterial antigens. After BCG treatment, the percentage of CD4+ CD25+ (Treg) cells in the peripheral blood of asthmatic mice was significantly increased. IL-10 production was also increased [37]. Interestingly, increase in CD8+ cell population, in conjunction with TH1 cells, correlated with the protective effect of BCG [38]. The potential role of other immune cells in BCG vaccine-induced immunomodulation will be discussed in the following section.

Role of Other Immunoregulatory Cells Treg Cells A study in Malawian children found that apart from absence of cases of sepsis, children with BCG scar had a higher ratio of IL-10-producing to IL-4-producing T-cells, as well as a higher ratio of IL-10 producing to IL-6 producing monocytes

718

T.O. Makinde et al.

Table 1 Immunomodulatory role of cytokines in Bacillus Calmette-Guérin (BCG) vaccineinduced tolerance Cytokine Source Role in BCG protection + Suppress TH2 cytokine release IFN-g TH1cells, gd T-cells, and CD8 T-cells, NK, NKT Context-based immune activation or TGF-b Treg cells (CD4+ CD25+ cells) alteration Inhibits cytokine release to support IL-10 Treg cells (CD4+ CD25+ cells) both TH1 and TH2 response IL-12 APCs Enhances TH1 polarization

in their blood compared to children without BCG scarring [39]. A recent study found that BCG administration enhanced the generation of Treg cells and IL-10 production [40]. In another study, heat-killed M. vaccae administration induced the generation of Treg cells. Several studies, including studies in our laboratory have found that Treg have an immunomodulatory effect in preventing the overt inflammation that is associated with a TH2 response (Fig. 1) [41]. A study found that BCGtreated DCs enhanced the production of IL-12 and IL-10. However, it did not suppress the production of IL-5, a TH2 cytokine [42]. Another recent study found that DCs matured in the presence of BCG showed enhanced IL-10 and diminished IL-12 production. The same DCs primed naïve T-cells to develop into IL-10producing T-cells, with no TH1 or TH2 bias [43]. Tregs can suppress allergic TH2 response either by cell–cell contact or by secretion of mediators such as TGF-b and IL-10, both of which can function as anti-inflammatory cytokines [44] [Table 1]. TGF-b can activate or alter the immune system depending on experimental model and the micro-environment [45].

CD8+ T-Cells BCG vaccination of human newborns induced a specific, functional CD8+ T-cell response. Specific MHC class restricted CD8+ T-cells capable of producing IFN-g, TNF-a, and perforin have been found in the peripheral blood of BCG-vaccinated persons (Fig. 2) [46,47]. Although T-cells, NK cells, and macrophages produce IFN-g, CD4+ and CD8+ are considered to be the primary sources of IFN-g, with CD4+ T-cells being more important than CD8+ T-cells [48,49]. Nonetheless, CD8+ T-cell is still a significant player in mycobacterial immunoregulation. Deficiency in CD8+ T-cells results in decrease in host defense against mycobacterial infection [49–51]. Vaccination of human newborns with BCG induces a specific CD8+ T-cell response, although it was quantitatively smaller than the BCG-induced CD4+ T-cell response [52]. In this study, BCG increased production of IFN-g and cytotoxic proteins from CD8+ T-cells [52]. BCG can also induce the generation of memory CD8 T-cells that produced IFN-g [53].

BCG and Immunomodulation

719 BCG Vaccination

APC

IL-12, 1L-4, 1L-10, TGF-β Activates

CD8+

?

TRCD8+

?

THo

NKT

Promotes TH1 response

IL-10

TRNKT

?

THo

NK

γδ T cell

?

? IFN-γ

?

IFN-γ

IL-10

IFN-γ

IFN-γ

Promotes TReg response

Fig. 2 Bacillus Calmette-Guérin (BCG) vaccination leads to activation of antigen presenting cells (APC) and subsequent cytokine release with enhanced production of IL-10 and IFN-g from CD8+, TRCD8+, NKT, TRNKT, NK, gd-T cells. These cytokines promote either a TH1 or Treg response

gd-T Cells gd-T cells are important component of the innate and adaptive immune response. After exposure to pathogens, gd-T cells proliferate robustly, producing cytokines, and effector molecules important for inhibiting the proliferation of intracellular pathogens [54, 55]. gd-T cells can mediate both positive and negative immunoregulatory effects [56]. gd-T cells are enriched in epithelial surfaces and mount potent, early responses to invading pathogens. gd-T cells provide a nonredundant early source of IFN-g, which enhances IL-12 production by DCs, leading to conditioning of the immune system away from a TH2 response (Fig. 2). gd-T cells respond to antigen presented by antigen presenting cells (APCs) but are not restricted by conventional MHC class I or class II [57, 58]. Apart from secretion of IFN-g, gd-T cells also express several chemokines and chemokine receptors that enable them to migrate to epithelial surface to recruit other immune cells [54, 59,60]. BCG vaccination enhances human gd-T cell responsiveness to mycobacteria suggestive of a memory cell-like phenotype [20]. gd-T cells also provided helper function for Mycobacterium-specific CD4+ and CD8+ T-cells [20]. gd-T cells depletion inhibited CD4+ and CD8+ T-cell expansion, but did not prevent IFN-g production [20]. CD4+ T-cells provide important helper function for the expansion of gd-T cells induced by mycobacterial extract, suggesting interdependence between the two [55, 61]. In the absence of CD4+ T-cells, IL-2 was able to induce gd-T cell expansion. This suggests that IL-2 secretion from CD4+ T-cells may have been

720

T.O. Makinde et al.

responsible for gd-T cells expansion [61]. This may also suggest a link between TH1 cells that produce high amount of IL-2 and gd-T cells.

NKT Cells BCG vaccination induced IL-21 expression by human peripheral blood mononuclear cells (PBMCs) in, at least in part, NKT cell-dependent fashion [62]. BCG-activated PBMCs significantly reduced IgE production by human B cells [62]. Another study observed a change in the density of CD4+ NKT cells following BCG injection and shift in their cytokine production from IL-4 to IFN-g (Fig. 2) [63]. However, BCG induced an early expansion of Va14-NKT cells in the liver, lungs, and spleen in murine model. These NKT cells initially produced IFN-g but change in NK1.1 expression led to subsequent shift to IL-4 production [64]. Reports from another study suggest that while NKT cells contribute to IFN-g secretion, the expansion in IFN-g producing T-cells is essentially responsible for the increased level of IFN-g observed following BCG injection [65].

Antigen Presenting Cells DCs and macrophages both function in antigen presentation and contribute to the cytokine milieu after a mycobacterial infection [2]. Depletion of macrophage in OVA-sensitized mice led to decreased production of TH1 cytokines particularly IFN-g and increased production of TH2 cytokines including IL-4 and IL-5 [66]. DCs matured in the presence of BCG exhibited an increase in IL-10 production and diminished IL-12 production. These DCs further primed naïve CD4+ T-cells to develop into IL-10 producing T-cells [43]. The expression of CD80, CD86, CD40, IL-12, and IL10 was upregulated in BCG-treated DCs, although IL-5 production was not suppressed [42]. This is consistent with other findings according to which BCG interaction with DCs results in direct cell maturation and activation, with increased production of cytokines including IL-12 and IL-10 [67–69]. IL-12 induces TH0-cells for increased production of IFN-g and decreased production of IL-4 and IL-5 [70]. IL-10 is an anti-inflammatory cytokine and it inhibits the secretion of cytokines, including IL-12 [67,71].

Role of NRAMP and TLRs NRAMP1 Natural resistance-associated macrophage protein 1 gene (Nramp1) encodes antibacterial resistance and has been linked to increased risk of atopic reaction [72]. Nramp1-resistant mice had macrophages that were somewhat activated under resting

BCG and Immunomodulation

721

condition, and therefore showed a high resistance to intracellular pathogens. Nramp1 gene encodes a membrane protein involved in cation transport [73]. Nramp1 influences the efficacy of mycobacterial treatment in allergy and asthma [74]. NRAMP1 affects both T-cell-mediated responses and macrophage activation [74]. Nramp1 has been associated with IL-10 production, suggesting a link with Treg activity [73]. Following OVA sensitization and challenge, Nramp1 resistant mice showed lower levels of Th2 cytokines, IgE, and mast cell granules compared to congenic Nramp1 susceptible mice [73, 75].

Toll-Like Receptors Toll-like receptors (TLRs) are expressed both on T-cells and APCs [76, 77]. Leukocyte cells from a farmer’s children expressed significantly higher amount of mRNA encoding for TLR2 and CD14 than those from nonfarmers [78]. TLR2 activation leads to release of inhibitory IL-12 p40 dimers and IL-23. IL-23 promotes the proliferation of CD45RBlow T-cells, which might include Treg cells [79]. TLRs are involved specifically in the recognition of the bacteria. Mycobacteria tend to activate TLR2s, an interaction that is facilitated by CD14 [80]. Under in vitro conditions BCG can induce maturation of DCs by activating the TLRs present on DCs [81,82]. Additionally, BCG infection also enhanced migration of DCs via TLRs to mediastinal lymph nodes, where they can engage in a robust activation of naive T-cells [83]. Depending on the level of TLR activation, DCs can induce the production of IL-12 [84]. On the other hand, TLR-mediated signaling leads to the release of CC chemokines and eotaxin, which then recruit eosinophils [85].

Conclusion Experimental and clinical studies show significant efficacy of BCG in the prevention and therapeutic application in atopic diseases. BCG can activate various cells, leading to the secretion of several mediators including IL-12, IL-10, IFN-g, and under certain circumstances TH2 cytokines. The surrounding cytokine milieu is important in determining the direction of the allergen-specific immune response. Thus, depending on the type of cell first encountered and the micro-environment, the protective and the therapeutic effect of BCG could be modulated to induce TH1 and Treg cells. There is renewed effort in the development of recombinant BCG strains that promote the secretion of pro-TH1 cytokine like IL-12 and IL-18. Indeed, a recombinant BCG strain expressing human IL-12 protein was successfully constructed [86]. Also, recombinant BCG expressing mouse IL-18 showed a synergistic effect on BCG induction of IFN-g, GMCSF, and decreased production of IL-10 in splenocytes [87].

722

T.O. Makinde et al.

References 1. Cookson WO, Moffatt MF (1997) Asthma: an epidemic in the absence of infection? Science 275:41–42 2. Barlan IB, Bahceciler N, Akdis M, Akdis CA (2005) Role of bacillus Calmette-Guerin as an immunomodulator for the prevention and treatment of allergy and asthma. Current Opinion in Allergic and Clinical Immunology 5:552–557 3. Silverman R (2000) Treatment of acute asthma. A new look at the old and the new. Clinics in Chest Medicine 21:361–379 4. Strachan DP (2000) Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 1:S2–10 5. Eigen H (1999) The RSV-asthma link: the emerging story. Introduction. Journal of Pediatrics 135:1–5 6. Roth A, Gustafson P, Nhaga A, Djana Q, Poulsen A, Garly ML, Jensen H, Sodeman M, Rodrigues A, Aaby P (2005) BCG vaccination scar associated with better childhood survival in Guinea-Bissau. International Journal of Epidemiology 34:540–547 7. Alexandroff AB, Jackson AM, O’Donnell MA, James K (1999) BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689–1694 8. Aguirre-Blanco AM, Lukey PT, Cliff JM, Dockrell HM (2007) Strain dependent variation in Mycobacteria bovis BCG-induced human T-cell activation and gamma interferon production in vitro. Infection and Immunity 75:3197–3201 9. Aldovini A, Young RA (1991) Humoral and cell-mediated immune response to live recombinant BCG-HIV vaccine. Nature 351(6326):479–482 10. Aaby P, Shaheen SO, Heyes CB, Goudiaby A, Hall AJ, Shiell AW, Jensen H, Marchant A (2000) Early BCG vaccination and reduction in atopy in Guinea-Bissau. Clinical Experimental Allergy 30:644–650 11. Grüber C, Kulig M, Bergmann R, Guggenmoos-Holzmann I, Wahn U; MAS-90 study group(2001) Delayed hypersensitivity to tuberculin, total immunoglobulin E, specific sensitization, and atopic manifestation in longitudinally followed early bacilli Calmette-Guérinvaccinated and non-vaccinated children. Pediatrics 107:E36 12. Bager P, Rostgaard K, Nielsen NM, Melbye M, Westergaard T (2003) Age of bacilli CalmetteGuerin vaccination and risk of allergy and asthma. Clinical and Experimental Allergy 33:1512–1517 13. Townley RG, Barlan IB, Patino C, Vichyanond P, Minervini MC, Simasathien T, Nettagul R, Bahceciler NN, Basdemir D, Akkoc T, Pongprueksa S, Hopp RJ (2004) The effect of BCG vaccine at birth on the development of atopy or allergic disease in young children. Annals of Allergy, Asthma and Immunology 92:350–355 14. Marks GB, Ng K, Zhou J, Toelle BG, Xuan W, Belousova EG, Britton WJ (2003) The effect of neonatal BCG vaccination on atopy and asthma at age 7 to 14 years: a historical cohort study in a community with a very low prevalence of tuberculosis infection and a high prevalence of atopic disease. The Journal of Allergy Clinical Immunology 111:541–549 15. Hopfenspirger MT, Parr SK, Hopp RJ, Townley RG, Agrawal DK (2001) Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and brochoalveolar lavage eosinophilia in a mouse model of bronchial asthma. International Immunopharmacology 1:1743–1751 16. Wang S, Fan Y, Han X, Yang J, Bilenki L, Yang X (2001) IL-12-dependent vascular cell adhesion molecule-1 expression contributes to airway eosinophilic inflammation in a mouse model of asthma-like reaction. The Journal of Immunology 166:2741–2749 17. Hopfenspirger MT, Agrawal DK (2002) Airway hyperresponsiveness, late allergic response, and eosinophilia are reversed with mycobacterial antigens in ovalbumin-presensitized mice. The Journal of Immunology 168:2516–2522 18. Yang X, Wang S, Fan Y, Zhu L (1999) Systemic mycobacterial infection inhibits antigenspecific immunoglobulin E production, bronchial mucus production and eosinophilic inflammation induced by allergen. Immunology 98:329–337

BCG and Immunomodulation

723

19. Erb KJ, Holloway JW, Sobeck A, Moll H, Le Gros G (1998) Infection of mice with Mycobacterium bovis bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. The Journal of Experimental Medicine 187:561–569 20. Hoft DF, Brown RM, Roodman ST. (1998) Bacilli Calmette-Guérin vaccination enhances human gamma delta T cell responsiveness to mycobacteria suggestive of a memory-like phenotype. The Journal of Immunology 161:1045–1054 21. Hylkema MN, Timens W, Luinge M, Vander Der Werf N, Hoekstra MO (2002) The effect of bacillus Calmette-Guerin immunization depends on the genetic predisposition to Th2-type responsiveness. American Journal of Respiratory Cell and Molecular Biology 27:244–249 22. Shibata Y, Henriksen RA, Honda I, Nakamura RM, Myrvik ON (2005) Splenic PGE2releasing macrophage regulate Th1 and Th2 immune responses in mice treated with heatkilled BCG. Journal of Leukocyte Biology 78:1281–1290 23. Choi IS, Lin XH, Koh YA, Cui Y (2007) Inoculation route-dependent and allergen-specific suppressive effects of bacille Calmette-Guerin vaccination on asthmatic reactions in BALB/c mice. Lung 185:179–186 24. Zhang GS, Shen HH (2005) [The preventive effect of bacillus Calmette-Guerin vaccination in early life on airway inflammation and mucus production in murine model of asthma]. Zhonghua Jie He He Hu Xi Za Zhi 28:17–21 25. Hopfenspirger MT (2003) Mycobacterial antigens and immunomodulation in allergic asthma. Ph.D. (Biomedical Sciences) Dissertation, Creighton University, Omaha, Nebraska, USA 26. Lai Y, Mohammed KA, Nasreen N, Baumuratov AS, Bellew BF, Antony VB (2007) Induction of cell cycle arrest and apoptosis by BCG infection in cultured human bronchial airway epithelial cells. American Journal of Physiology Lung - Cellular and Molecular Physiology 293: L393–401 27. Mendez-Samperio P, Alba L, Trejo A. (2007) Mycobacterium bovis-mediated induction of human b-defensin-2 in epithelial cells is controlled by intracellular calcium and p38 MAPK. Journal of Infection 54:469–474 28. Romagnani S (1992) Induction of TH1 and TH2 responses: a key role for the ‘natural’ immune response? Immunology Today 13:379–381 29. Shirakawa T, Enomoto T, Shimazu S, Hopkin JM (1997) The inverse association between tuberculin responses and atopic disorder. Science 275:77–79 30. Marchant A, Goetghebuer T, Ota MO, Wolfe I, Ceesay SJ, De Groote D, Corrah T, Bennett S, Wheeler J, Huygen K, Aaby P, McAdam KP, Newport MJ (1999) Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination. The Journal of Immunology 163:2249–2255 31. Cho SH, Stanciu LA, Holgate ST, Johnston SL (2005) Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD4+ and CD8+ T cells in atopic asthma. American Journal of Respiratory and Critical Care Medicine 171:224–230 32. Kim YK, Oh SY, Jeon SG, Park HW, Lee SY, Chun EY, Bang B, Lee HS, Oh MH, Kim YS, Kim JH, Gho YS, Cho SH, Min KU, Kim YY, Zhu Z (2007) Airway exposure levels of lipopolysaccharide determine type 1 versus type 2 experimental asthma. The Journal of Immunology 178:5375–5382 33. Asosingh K, Swaidani S, Aronica M, Erzurum SC (2007) Th1- and Th2-dependent endothelial progenitor cell recruitment and angiogenic switch in asthma. The Journal of Immunology 178:6482–6494 34. Nahori MA, Lagranderie M, Lefort J, Thouron F, Joseph D, Winter N, Gicquel B, Lapa e Silva JR, Vargaftig BB (2001) Effect of Mycobacterium bovis BCG on the development of allergic inflammation and bronchial hyperresponsiveness in hyper-IgE BP2 mice vaccinated as newborn. Vaccine 19:1484–1495 35. Xu G, Li Y, Yang J, Zhou X, Yin X, Liu M, Zhao D (2007) Effect of recombinant Mce4A protein of Mycobacterium bovis on expression of TNF-alpha, iNOS, IL-6, and IL12 in bovine alveolar macrophages. Molecular and Cellular Biochemistry 302:1–7 36. Zuany-Amorim C, Manlius C, Trifilieff A, Brunet LR, Rook G, Bowen G, Pay G, Walker C (2002) Long term protective and antigen-specific effect of heat-killed Mycobacterium vaccae in a murine model of allergy pulmonary inflammation. The Journal of Immunology 169:1492–1499

724

T.O. Makinde et al.

37. Xia Y, Zhang JH, Ji ZH, Li XD, Yu ZW, Liu HY (2006) [Effect of bacillus Calmette-Guerin treatment on airway inflammation and T regulatory cells in mice with asthma]. Zhongguo Dang Dai Er Ke Za Zhi 8:413–416 38. Su Yc, Peng HJ, Wang SR, Han SH, Tsai JJ (2001) Effect of BCG on ovalbumin-induced bronchial hyperreactivity in a guinea pig model. The Journal of Microbiology, Immunology and Infections 34:25–34 39. Jason J, Archibald LK, Nwanyanwu OC, Kazembe PN, Chatt JA, Norton E, Dobbie H, Jarvis WR (2002) Clinical and immune impact of Mycobacterium bovis BCG vaccination scarring. Infection and Immunity 70:6188–6195 40. Xia Y, Zhang Jh, Ji ZH, Li XD, Yu ZW, Liu HY (2006) [Effect of bacillus Calmette-Guerin treatment on airway inflammation and T regulatory cells in mice with asthma]. Zhonqquo Dan Dai Er Ke Za Zhi 8:413–416 41. McGee HS, Agrawal DK (2009) Naturally occurring and inducible T regulatory cells modulating immune response in allergic asthma. American Journal of Respiratory and Critical Care Medicine 180:211–225 42. Koh YI, Choi IS, Lee JJ (2004) Effects of cytokine milieu secreted by BCG-treated dendritic cells on allergen-specific Th immune response. Journal of Korean Medical Science 19:640–646 43. Madura Larsen J, Stabell Benn C, Fillie Y, Van der Kleij D, Aaby P, Yazdanbakhsh M (2007) BCG stimulated dendritic cells induce an interleukin-10 producing T-cell population with no T helper 1 or T helper 2 bias in vitro. Immunology 121:276–282 44. McGee HS, Agrawal DK (2006) Th2 cells in the pathogenesis of airway remodeling: regulatory T cells a plausible panacea for asthma. Immunologic Research 35:219–232 45. Makinde T, Murphy RF, Agrawal DK (2007) The regulatory role of TGF-b in airway remodeling in asthma. Immunology and Cell Biology 85:348–356 46. Smith SM, Malin AS, Pauline T, Lukey, Atkinson SE, Content J, Huygen K, Dockrell HM (1999) Characterization of human Mycobacterium bovis bacille Calmette-Guerin-reactive CD8+ T cells. Infection and Immunity 67:5223–5230 47. Serbina NV, Liu CC, Scanga CA, Flynn JL (2000) CD8+ CTL from lungs of Mycobacterium tuberculosis-infected mice express perforin in vivo and lyse infected macrophages. The Journal of Immunology 165:353–363 48. Tascon RE, Stavropoulos E, Lukacs KV, Colston MJ (1998) Protection against Mycobacterium tuberculosis infection by CD8+ T cells requires the production of gamma interferon. Infection and Immunity 66:830–834 49. Ngai P, McCormick S, Small C, Zhang X, Zganiacz A, Aoki N, Xing Z (2007) Gamma interferon responses of CD4 and CD8 T-cell subsets are quantitatively different and independent of each other during pulmonary Mycobacterium bovis BCG infection. Infection and Immunity 75:2244–2252 50. Wang J, Santosuosso M, Ngai P, Zganiacz A, Xing Z (2004) Activation of CD8 T cells by mycobacterial vaccination protects against pulmonary tuberculosis in the absence of CD4 T cells. The Journal of Immunology 173:4590–4597 51. Ladel CH, Daugelat S, Kaufmann SH (1995) Immune response to Mycobacterium bovis bacille Calmette Guerin infection in major histocompatibility complex class І- and ІІ-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance. European Journal of Immunology 25:377–384 52. Murray RA, Mansoor N, Harbacheuski R, Soler J, Davids V, Soares A, Hawkridge A, Hussey GD, Maeker H, Kaplan G, Hanekom WA (2006) Bacillus Calmette Guerin vaccination of human newborns induces a specific, functional CD8+ T cell response. The Journal of Immunology 177:5647–5651 53. Hope JC, Kwong LS, Sopp P, Collins RA, Howard CJ (2000) Dendritic cells induce CD4+ and CD8+ T-cell responses to Mycobacterium bovis and M. avium antigens in bacille Calmette Guerin vaccinated and nonvaccinated cattle. Scandinavian Journal Immunology 52:285–291 54. Abate G, Eslick J, Newman FK, Frey SE, Belshe RB, Monath TP, Hoft DF (2005) Flowcytometric detection of vaccinia-induced memory effector CD4(+), CD8(+), and gamma delta

BCG and Immunomodulation

55.

56. 57.

58.

59.

60. 61.

62.

63.

64.

65.

66.

67. 68.

69.

70. 71.

725

TCR(+) T cells capable of antigen-specific expansion and effector functions. The Journal of Infectious Diseases 192:1362–1371 Vila LM, Haftel HM, Park HS, Lin MS, Romzek NC, Hanash SM, Holoshitz J (1995) Expansion of Mycobacterium-reactive gamma delta T cells by a subset of memory helper T cells. Infection and Immunity 63:1211–1217 Born W, Cady C, Jones-Carson J, Mukasa A, Lahn M, O’Brien R (1999). Immunoregulatory functions of gamma delta T cells. Advances in Immunology 71:77–144 Ravn P, Boesen H, Pedersen BK, Andersen P (1997) Human T cell responses induced by vaccination with Mycobacterium bovis bacillus Calmette-Guerin. Journal of Immunology 158:1949–1955 Caccamo N, Sireci G, Meraviglia S, Dieli F, Ivanyi J, Salerno A (2006) gammadelta T cells condition dendritic cells in vivo for priming pulmonary CD8 T cell responses against Mycobacterium tuberculosis. European Journal of Immunology 36:2681–1690 Boismenu R, Feng L, Xia YY, Chang JC, Havran WL (1996) Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. The Journal of Immunology 157:985–992 Kabelitz D, Wesch D (2003) Features and functions of gamma delta T lymphocytes: focus on chemokines and their receptors. Critical Review in Immunology 23:339–370 Pechhold K, Wesch D, Schondelmaier S, Kabelitz D (1994) Primary activation of Vgamma 9-expressing gamma delta T cells by Mycobacterium tuberculosis. Requirement for Th1-type CD4 T cell help and inhibition by IL-10. The Journal of Immunology 152:4984–4992 Harada M, Magara-Koyanagi K, Watarai H, Nagata Y, Ishii Y, Kojo S, Horiguchi S, Okamoto Y, Nakayama T, Suzuki N, Yeh WC, Akira S, Kitamura H, Ohara O, Seino K, Taniguchi M (2006) IL-12-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses. The Journal of Experimental Medicine 203:2929–2937 Emoto M, Emoto Y, Buchwalow IB, Kaufmann SH (1999) Induction of IFN-gammaproducing CD4+ natural killer T cells by Myobacterium bovis bacillus Calmette Guerin. European Journal of Immunology 29:650–659 Dieli F, Taniguchi M, Kronenberg M, Sidobre S, Ivanyi J, Fattorini L, Iona E, Orefici G, De Leo G, Russo D, Caccamo N, Sireci G, Di Sano C, Salerno A (2003) An anti-inflammatory role for V alpha14 NK T cells in Mycobacterium bovis bacillus Calmette-Guérin-infected mice. The Journal of Immunology 171:1961–1968 Saxena RK, Weissman D, Saxena QB, Simpson J, Lewis DM (2002) Kinetics of changes in lymphocyte subpopulations in mouse lungs after intrapulmonary infection with M. bovis (bacillus Calmette-Guerin) and identity of cells responsible for IFNgamma responses. Clinical and Experimental Immunology 128:405–410 Tang C, Inman MD, van Rooijen N, Yang P, Shen H, Matsumoto K, O’Byrne PM (2001). The type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-gamma-dependent mechanism. The Journal of Immunology 166:1471–1481 Henderson RA, Watkins SC, Flynn JL (1997) Activation of human dendritic cells following infection with Mycobacterium tuberculosis. The Journal of Immunology 159:635–643 Kim KD, Lee HG, Kim JK, Park SN, Choe IS, Choe YK, Kim SJ, Lee E, Lim JS (1999) Enhanced antigen-presenting activity and tumor necrosis factor-alpha-independent activation of dendritic cells following treatment with Mycobacterium bovis bacillus Calmette-Guerin. Immunology 97:626–633 O’Donnell MA, Luo Y, Chen X, Szilvasi A, Hunter SE, Clinton SK (1999) Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guerin. Journal of Immunology 163:4246–4252 Romagnani S (2000) T-cell subsets (Th1 versus Th2). Annals of Allergy, Asthma and Immunology 85:9–18 Borish L, Aaron A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S (1996) Interleukin-10 regulation in normal subjects and patients with asthma. Journal of Allergy and Clinical Immunology 97:1288–1296

726

T.O. Makinde et al.

72. Alm JS, Sanjeevi CB, Miller EN, Dabadghao P, Lilja G, Pershagen G, Blackwell JM, Scheynius A (2002) Atopy in children in relation to BCG vaccination and genetic polymorphisms at SLC11A1 (formerly NRAMP1) and D2S1471. Gene Immunology 3:71–77 73. Rook GA, Martinelli R, Brunet LR (2003) Innate immune response to mycobacteria and the downregulation of atopic responses. Current Opinion in Allergy and Clinical Immunology 3:337–342 74. Smitt JJ, Van Loveren H, Hoekstra MO, Karimi K, Folkerts G, Nijkamp FP (2003) The Slc11a1 (Nramp1) gene controls efficacy of mycobacterial treatment of allergic asthma. The Journal of Immunology 171:754–760 75. Smitt JJ, Van Loveren H, Hoekstra MO, Nijkamp FP, Bloksma N (2003) Influence of the macrophage bacterial resistance gene Nramp1 (Sic11a1) on the induction of allergic asthma in mouse. FASEB Journal 17:958–960 76. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. The Journal of Experimental Medicine 197:403–411 77. Pandey S, Agrawal DK (2006) Immunobiology of toll-like receptors: emerging trends. Immunology and Cell Biology 84:333–341 78. Lauener RP, Birchler T, Adamski J, Braun-Fahrlander C, Bufe A, Herz V, von Mutius E, Nowak D, Rieldler J, Waser M, Sennhauser FH; ALEX study group (2002) Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 360:465–466 79. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725 80. Bochud PY, Hawn TR, Aderem A (2003) Cutting edge: a toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. The Journal of Immunology 170:3451–3454 81. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of adaptive immune responses. Nature Immunology 5:987–995 82. Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S, Kawata T, Azuma I, Toyoshima K, Seya T (2003) Simultaneous blocking of human toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus CalmetteGuerin peptidoglycan. Infection and Immunity 71:4238–4249 83. Anis MM, Fulton SA, Reba SM, Harding CV, Boom WH (2007) Modulation of naïve CD4+ T-cell responses to an airway antigen during pulmonary mycobacterial infection. Infection and Immunity 75:2260–2268 84. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K (2002) Lipopolysaccharide-enhanced, toll-like receptor 4 dependent T helper cell type 2 responses to inhaled antigen. The Journal of Experimental Medicine 196:1645–1651 85. D’Avila H, Almeida PE, Roque NR, Castro-Faria-Neto HC, Bozza PT (2007) Toll-like receptor-2-mediated C-C chemokine receptor 3 and eotaxin-driven eosinophil influx induced by Mycobacterium bovis BCG pleurisy. Infection and Immunity 75:1507–1511 86. Hao M, Bao L, Gao L, Zhang HD (2007) [Construction and screen of recombinant BCG strain expressing and secreting human interleukin 12 protein]. Sischuan Da Xue Xue Bao Yi Xue Ban 38:186–189 87. Luo Y, Yamada H, Chen X, Ryan AA, Evanoff DP, Triccas JA, O’Donnell MA (2004) Recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity. Clinical and Experimental Immunology 137:24–34

Use of Theophylline and Sodium Cromoglycate in Pediatric Asthma Akihiro Morikawa

Introduction Theophylline and sodium cromoglycate are old drugs used in the treatment of asthma, but in some patients, they are still useful for maintenance therapy. Theophylline is not only a bronchodilator, but also has anti-inflammatory effects [1] due to multiple mechanisms including adenosine receptor antagonism and epigenetic influences over inflammatory gene expression both of which occur at lower concentrations (5–10 µm ml-1). In Japan, slow release theophylline is still used as a controller therapy except in infants with asthma [2]. Sodium cromoglycate produces only minimal side effects and is also used as a controller in persistent asthma, especially in infantile asthma.

Theophylline Pharmacological Properties Physiological Effects Theophylline was first introduced into asthma therapy as a bronchodilator, and an increasing acute bronchodilator response was shown in early dose–response studies. Theophylline directly relaxes human airways smooth muscle in vitro and, like b2-agonists, acts as a functional antagonist, preventing and reversing the effects of all bronchoconstrictor agonists [3]. Theophylline may also have an additional effect on mucociliary clearance through a stimulatory effect on ciliary beat frequency and

A. Morikawa () Kitakanto Allergy Institute, Kibounoie Hospital 22-4 ohmama, ohmama-machi, Midori, Gunma 376-0101, Japan e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_44, © Springer 2010

727

728

A. Morikawa

water transport across the airway epithelium [4]. Aminophylline, theophylline derivative, increases diaphragmatic contractility and reverses diaphragm fatigue, although an effect of theophylline on respiratory muscles remains unclear [5].

Anti-Inflammatory Effects There is an increasing evidence that theophylline has anti-inflammatory effects in asthma [6]. In patients with asthma, intravenous theophylline inhibits the late response to allergen challenge [7]. A reduced infiltration of eosinophils and CD4+ lymphocytes into the airways were observed after allergen challenge subsequent to theophylline, suggesting an inhibitory effect of theophylline on the chronic inflammatory response [8,9]. In patients with mild asthma, theophylline reduced the numbers of eosinophils in bronchial biopsies, bronchoalveolar lavage, and induced sputum [10]. These anti-inflammatory effects of theophylline in asthma are seen at concentrations around 5 mg ml-1, which is below the dose (10–20 mg ml-1) wherein significant clinically useful bronchodilatation is evident.

Molecular Mechanisms of Theophylline Effects PDE Inhibition The molecular mechanism of bronchodilatation is likely explained by phosphodiesterase (PDE) inhibition, resulting in an increase in cAMP by inhibition of PDE3, PDE4, and in cyclic guanosine 3’, 5’-monophosphate by inhibition of PDE5, but relatively high concentrations are needed for maximal relaxation [11]. Indeed, therapeutic concentrations of theophylline exhibit only 5–10% inhibition of total PDE activity in human lung extracts [12]. Theophylline has no selectivity for any particular isoenzyme, such as PDE4, which is the predominant PDE isoenzyme in inflammatory cells that mediates anti-inflammatory effects in the airways.

Adenosine Receptor Antagonism Theophylline is a potent inhibitor of adenosine receptors at therapeutic concentrations, with antagonism of A1- and A2-receptors [13]. In an in vitro study, adenosine constricts airway smooth muscle of patients with asthma via the release of histamine and leukotrienes, suggesting that adenosine releases mediators from sensitized mast cells [14]. Inhaled adenosine monophosphate causes bronchoconstriction in subjects with asthma, and this is prevented by therapeutic concentrations of theophylline [15]. However, this does not necessarily prove that adenosine receptor antagonism is important for its antiasthma effect.

Use of Theophylline and Sodium Cromoglycate in Pediatric Asthma

729

Other Effects Selective maxi-K channels inhibitor, charybdotoxin, reduces bronchodilator effect of theophylline in human airways, suggesting that theophylline opens these maxi-K channels via an increase in cAMP [16]. Several other effects of theophylline have been described, including an increase in circulating catecholamines, inhibition of calcium influx into inflammatory cells, inhibition of prostaglandin effects, promotion of apoptosis of T-lymphocytes, release of interleukin-10, antagonism of tumor necrosis factor-alpha, and prevention of the translocation of the proinflammatory transcription factor nuclear factor-kB into the nucleus [17]. These effects may be mediated via PDE inhibition, although this has not been seen at the low doses that are effective in asthma.

Therapeutic Use Although the efficacy of theophylline is less than that of inhaled glucocorticosteroids, theophylline has been shown to be effective as add-on treatment to inhaled glucocorticosteroids in children older than 5 years. It is significantly more effective than placebo at controlling day and night symptoms and improving lung function [18–20]. Add-on treatment with theophylline has been found to improve asthma control and reduce the maintenance glucocorticosteroid dose necessary in children with severe asthma treated with inhaled or oral glucocorticosteroids [21,22]. Maintenance treatment offers a marginal protective effect against exercise-induced bronchoconstriction [23]. A few studies in children of 5 years and younger also suggest some clinical benefit. Most clinical evidence regarding the use of theophylline in children has been obtained from studies in which plasma theophylline levels were maintained within the therapeutic range of 5–10 mg ml-1. Sustained-release products are preferable for maintenance therapy, since they enable twice-daily dosing. Plasma theophylline concentrations should be measured, when doses more than 10 mg kg-1/day are used. The Japanese Pediatric Guidelines (JPGL) 2005 guidelines for asthma recommend that slow-release theophylline can be used as an add-on therapy to patients not controlled by low doses of inhaled corticosteroids in children older than 5 years [24]. Several clinical studies have demonstrated that adding theophylline to inhaled corticosteroids in patients with mild to moderate asthma who are not controlled gives equivalent or better asthma control than doubling the dose of inhaled corticosteroids [25–27]. Although long-acting inhaled b2-agonists are more effective as an add-on therapy, theophylline is still useful in the management of severer patients at Steps 3 and 4 of the JPGL2005 guidelines [24]. Its benefits have been demonstrated by clinical improvement after addition of theophylline in patients not controlled even on high doses of inhaled corticosteroids [28].

730

A. Morikawa

In the management of acute severe asthma, intravenous aminophylline has been superseded by the use of high doses of short-acting b2-agonists delivered by nebulizer or metered dose inhaler with spacer, as this is more effective and safer. The JPGL 2005 guidelines recommend that drip infusion of intravenous aminophylline is usually reserved for children 2 years and older with severe exacerbations who do not respond adequately to b2-agonist therapy [24].

Epigenetics Acetylation of core histones is associated with activation and transcription of inflammatory genes and is regulated by coactivator molecules that have intrinsic histone acetytransferase activity [29]. Proinflammatory transcription factors, such as nuclear factor-kB and activator protein-1, bind to coactivator molecules and activate this enzyme. In asthmatic airways, there is an increase in nuclear factor-B activation and an increase in histone acetyltransferase activity. Histone acetylation is reversed by histone deacetylases (HDAC), and there is a reduction in HDAC activity in asthmatic airways [30]. Theophylline activates HDAC activity and therefore suppresses the expression of inflammatory genes [31]. This effect is seen at therapeutic concentrations of theophylline (10.6–10.5 M) but is lost at higher concentrations (10.4 M). The effect is blocked by the HDAC inhibitor trichostatin A. A significant increase in HDAC activity is seen in bronchial biopsies after treatment of patients with asthma with low doses of theophylline (mean plasma concentration – 5 mg ml-1). It is not yet certain whether HDAC are the direct target of theophylline as several other nuclear proteins are coprecipitated in these inflammatory gene complexes [32]. The mechanism whereby low concentrations of theophylline activate HDAC are not yet known, but it is not mediated by either PDE inhibition or adenosine receptor antagonism because PDE inhibitors (nonselective, PDE4 and PDE3 inhibitors) and adenosine A1- and A2-receptor antagonists do not mimic this action of theophylline. Low concentrations of theophylline markedly potentiate the anti-inflammatory effects of corticosteroids in vitro, with a potentiation of 100-fold to 1,000-fold [31], and this may underlie the benefit of low-dose theophylline added to low or high doses of inhaled corticosteroids seen in clinical studies of patients with asthma.

Sodium Cromoglycate Introduction A histamine antagonist is useful for controlling symptoms of immediate allergic reactions, but only partially effective in bronchial asthma, allergic rhinitis, and

Use of Theophylline and Sodium Cromoglycate in Pediatric Asthma

731

atopic dermatitis. The reasons why an inhibitor of histamine is only partially effective are that many kinds of chemical mediators contribute to the inflammatory processes underlying these diseases. An attractive and advantageous procedure to prophylaxis is to prevent production or release of many kinds of chemical mediators by inhibiting response of mast cells and basophils sensitized to specific antigen. The first anti-allergic drug is sodium cromoglycate. This agent mainly inhibits antigen-induced release of histamine from human pulmonary mast cells [33]. However, there is no report about sodium cromoglycate and nedocromil from the viewpoint of epigenetics.

Pharmacological Properties Sodium cromoglycate, the disodium salt of 1, 3-bis (2-carboxychromone -5-yloxy)2-hydroxy-propane, is the following structure shown in Fig. 1a. Sodium cromoglycate was synthesized first as the smooth muscle relaxant from a chromone benzopyrone of plant origin (Ammi visnaga). After some modification, it was revealed that sodium cromoglycate has a novel mechanism of action, namely, inhibition of release of histamine and other autacoids. Furthermore, it has been recently demonstrated that sodium cromoglycate inhibits the release of tumor necrosis factor a (TNF-a) from rat mast cells [34]. In addition, it also inhibits IL-5 and TNF-a production from human lung specimens, suggesting that it acts as an antiinflammatory drug [35]. Nedocromil, a compound with a similar chemical and

a

NaOOC

O

O

O

OCH2CHCH2O

COONa

O

OH CROMOLYN SODIUM

b

H3CCH2 NaOOC

CH2CH2CH3

N

O

O

O

NEDOCROMIL SODIUM

Fig. 1

Structure of cromolyn and nedocromil

COONa

732

A. Morikawa

biological property, became available and proved the efficacy [36]. Nedocromil sodium is the following structure shown in Fig. 1b. It is generally more effective than sodium cromoglycate in animal model and human beings.

Pharmacologic Effects Sodium cromoglycate inhibits the release of histamine and other autacoid, e.g., leukotriene, from sensitized human lung during IgE mediated allergic responses. This effect is not likely to be restricted to the antigen-antibody reaction. It can be observed when tested with other secretagogues such as compound 48/80, dextran, phospholipase A, and calcium ionophore A23187. Recently, several anti-allergic drugs including glucocorticosteroid, anti-leukotriene receptor antagonist, and sodium cromoglycate have been used for the treatment of asthma. The major mechanism of anti-inflammatory action of glucocorticosteroid is inhibition of cytokine production by T-lymphocytes. Whether sodium cromoglycate has the same mechanism as glococorticosteroid or not is unclear. Matsuse et al. reported the inhibitory effects of sodium cromoglycate on antigen-induced cytokine production by peripheral blood mononuclear cells from patients with atopic asthmatics in vitro. They concluded that sodium cromoglycate has antigen-specific anti-allergic inflammatory effects [37].

Absorption, Fate and Excretion Sodium cromoglycate is very poorly absorbed after oral administration and inhalation. By inhalation, only about 10% amount of sodium cromoglycate penetrates deep into the lungs and is absorbed into the blood, where its half-life is about 80 min. This drug is not metabolized and is exerted unchanged, about half in the urine and half in the bile [38].

Toxicity Sodium cromoglycate, generally, is well tolerated by patients, and adverse reactions are infrequent. Sometimes, dizziness, dysuria, joint swelling and pain, nausea, headache, and rash are encountered. Such reactions have been reported at a frequency of less than 1 in 10,000 patients. Very rare instances including laryngeal edema, angioedema, urticaria, and anaphylaxis also have been documented. The safety of sodium cromoglycate for use during pregnancy was established by Kaiser Study [38].

Use of Theophylline and Sodium Cromoglycate in Pediatric Asthma

733

Therapeutic Use The main use of sodium cromoglycate is in the prophylactic treatment of bronchial asthma. Clinical efficacy of sodium cromoglycate is well established in patients with mild to moderate asthma [39]. It is noted that although sodium cromoglycate is effective in all patients, younger patients tend to respond better than adult. Pediatric studies of sodium cromoglycate from 1970s to 1980s focused on comparison with theophylline, which at the time was the drug of first choice in USA for treating children with asthma [40]. Sodium cromoglycate inhibits both immediate and late asthmatic responses when challenged with antigen or exercise. Both sodium cromoglycate and nedocromil prevent exercise-induced bronchoconstriction in children and adult [41,42]. Furthermore, combination of nebulized sodium cromoglycate and beta-2 agonist twice-daily gave good control of symptoms in children with severe, intractable asthma [43]. In 1980s, it is revealed that the pathophysiology of bronchial asthma is the chronic inflammation of the airway [44]. Inhaled glucocorticosteroids are currently the most effective anti-inflammatory medications for the treatment of asthma. An anti-inflammatory effect of sodium cromoglycate and nedocromil is weak, and these drugs are less effective than a low dose of inhaled glucocorticosteroid in both adult and children [45]. For this reason, the role of these drugs in long-term treatment of asthma in adult and children is limited. Because of limited efficacy, sodium cromoglycate is not recommended for the treatment of asthma in the GINA guideline 2006 [46]. However, nedocromil may allow a reduction of steroids in patients receiving high doses of inhaled glucocorticosteroids. In addition, sodium cromoglycate is very safe and attenuate bronchospasm induced by exercise or cold air.

References 1. Barnes PJ, Pauwels RA. Theophylline in the management of asthma:time for reappraisal? Eur respire J. 1994; 7:579–591 2. Morikawa A, Nishima S. New Japanese pediatric guidelines for the treatment and management of bronchial asthma. Pediatr Int. 2007; 49:1023–1031 3. Finney MJB, Karlson JA, Persson CGA. Effects of bronchoconstriction and bronchodilation on a novel human small airway preparation. Br J Pharmacol. 1985; 85:29–33 4. Wanner A. Effects of methylxanthines on airway mucociliary function. Am J Med. 1985; 79:16–21 5. Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med. 1981; 305:249–252 6. Barnes PJ. Theophylline new perspectives for an old drug. Am J Respir Crit Care Med. 2003; 167:813–818 7. Pauwels R, van Revterghem D, van der Straeten M, Johanesson N, Persson CGA. The effect of theophylline and enprophylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol. 1985; 76:583–590

734

A. Morikawa

8. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Anti-inflammatory effects of lowdose oral theophylline in atopic asthma. Lancet 1994; 343:1006–1008 9. Jaffar ZH, Sullivan P, Page C, Costello J. Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J. 1996; 9:456–462 10. Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ. Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol. 1996; 97:1242–1246 11. Rabe KF, Magnussen H, Dent G. Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J. 1995; 8:637–642 12. Poolson JB, Kazanowski JJ, Goldman AL, Szentivanyi A. Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol. 1978; 5:535–539 13. Pauwels RA, Joos GF. Characterization of the adenosine receptors in the airways. Arch Int Pharmacodyn Ther. 1995; 329:151–156 14. Bjorck T, Gustafsson LE, Dahlen SE. Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am Rev Respir Dis. 1992; 145:1087–1091 15. Feoktistov I, Polosa R, Holgate ST, Biaggioni I. Adenosine A2B receptors: a novel therapeutic target in asthma? Trends Pharmacol Sci. 1998; 19:148–153 16. Miura M, Belvisi MG, Stretton CD, Yacoub MH, Barnes PJ. Role of potassium channels in bronchodilator responses in human airways. Am Rev Respir Dis. 1992; 146:132–136 17. Tomita K, Chikumi H, Tokuyasu H, Yajima H, Hitsuda Y, Matsumoto Y, Sasaki T. Functional assay of NF-kappaB translocation into nuclei by laser scanning cytometry: inhibitory effect by dexamethasone or theophylline. Naunyn Schmiedebergs Arch Pharmacol. 1999; 359:249–255 18. Katz RM, Rachelefsky GS, Siegel S. The effectiveness of the short- and long-term use of crystallized theophylline in asthmatic children. J Pediatr. 1978; 92(4):663–667 19. Bierman CW, Pierson WE, Shapiro GG, Furukawa CT. Is a uniform round-the-clock theophylline blood level necessary for optimal asthma therapy in the adolescent patient? Am J Med. 1988; 85(1B):17–20 20. Pedersen S. Treatment of nocturnal asthma in children with a single dose of sustained-release theophylline taken after supper. Clin Allergy. 1985; 15(1):79–85 21. Nassif EG, Weinberger M, Thompson R, Huntley W. The value of maintenance theophylline in steroid-dependent asthma. N Engl J Med. 1981; 304:71–75 22. Brenner M, Berkowitz R, Marshall N, Strunk RC. Need for theophylline in severe steroidrequiring asthmatics. Clin Allergy. 1988; 18(2):143–150 23. Magnussen H, Reuss G, Jorres R. Methylxanthines inhibit exercise-induced bronchoconstriction at low serum theophylline concentration and in a dose-dependent fashion. J Allergy Clin Immunol. 1988; 81(3):531–537 24. Morikawa A, Nishima S. Japanese Pediatric Allergology. The Japanese Pediatric Guidelines (JPGL) 2005. Kyowa Kikaku, Tokyo, 2005 25. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med. 1997; 337:1412–1418 26. Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A, Steinijans VW. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J. 1997; 10:2754–2760 27. Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. Comparison of highdose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 2000; 55:837–841 28. Rivington RN, Boulet LP, Cote J, Kreisman H, Small DI, Alexander M, Day A, Harsanyi Z, Darke AC. Efficacy of slow-release theophylline, inhaled salbutamol and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med. 1995; 151:325–332 29. Urnov FD, Wolffe AP. Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene 2001; 20:2991–3006

Use of Theophylline and Sodium Cromoglycate in Pediatric Asthma

735

30. Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity of histone deacetylases (HDACs) in human asthmatic airways. Am J Respir Crit Care Med. 2002; 166:392–396 31. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 2002; 99:8921–8926 32. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1b-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. 2000; 20:6891–6903 33. Altounyan, REt C. Inhibition of experimental asthma by new compound, disodium cromoglycate, “Intal”. Acta Allergol (Kbh), 1968; 51:677–693 34. Bissonette EY, Enciso JA, Befus AD. Inhibition of tumor necrosis factor-alpha (TNF-alpha) release from mast cells by the anti-inflammatory drugs, sodium cromoglycate and nedocromil sodium. Clin Exp Immunol. 1995; 105:78–84 35. Matsuo N, Shimoda T, Matsuse H, Obase Y, Asai S, Kohno S.Effects of sodium cromoglycate on cytokine production following antigen stmulation of a passively sensitized human lung model. Ann Allergy asthma Immunol. 2000; 84:72–78 36. Holgate ST. Clinical evaluation of nedocromil sodium in asthma. Eur J Respir Dis Suppl. 1986; 147:149–159 37. Matsuse H, Shimoda T, Matsuo N, Obase Y, Fukushima C, Asai S, Kohno S. Sodium cromoglycate inhibits antigen-induced cytokine production by peripheral blood mononuclear cells from atopic asthmatics in vitro. Ann Allergy Asthma immunol. 1999; 83:511–515 38. Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics sixth ed. Macmillan Inc., NY, 1980, 621 39. Shatz M, Zeiger KS, Berstein IL, Johson CL. Therapy with cromolyn sodium. Ann Intern Med. 1978; 89:228–233 40. Tasche MJ, Uijen JH, Bernsen RM, de Jongste JC, van den Wouden JC. Inhaled disodium cromoglycate(DSCG) as maintenance therapy in children with asthma:a systematic review. Thorax 2000; 55:913–920 41. Hambleton G,Weinberger M, taylor J, Cavanaugh M, Ginchansky E, Godfrey S, Tooley M, Bell T, Greenberg S. Comparison of cromoglycate (cromolyn) and theophylline in controlling symptomed of chronic asthma. A collaborative study. Lancet 1977; 19:381–385 42. Kelly K, Spooner CH, Rowe BH. Nedocromil sodium versus sodium cromoglycate for preventing exercise-induced bronchoconstriction in asthmatics. Cochrane Database Syst Rev. 2000; 4:CD002731 43. Spooner CH, Spooner GR, Rowe BH. Mast-cell stabilizing agents to prevent exercise-induced bronchoconstriction Cochrane Database Syst Rev. 2003; 4:CD002307 44. Furusho k, Nishikawa K, Sasaki S, Akasaka T, Arita M, Edwards A. The combination of nebulized sodium cromoglycate and salbutamol in the treatment of moderate-to-sevre asthma in children. Pediatric Allergy Immunol. 2002; 13:209–216 45. Guevara JP, Duchame FM, Keren R, Nihtianova S, Zorc J. Inhaled corticosteroids versus sodium cromoglycate in children and adult asthma. Cochrane Database Syst Rev. 2006; 19(2):CD003558 46. Busse WW, Lemanske RF, Jr. Asthma. N. Eng J Med. 2001; 344:350–362 47. Global Strategy for Asthma Management and Prevention 2006. National Institute of Health, National Heart, Lung, and Blood Institute

Antibody Deficiency Syndromes (Including Diagnosis and Treatment) Kenneth Paris, Lily Leiva, and Ricardo U. Sorensen

Introduction Antibody deficiency syndromes range from an absence of all immunoglobulins (agammaglobulinemia) to milder, but clinically relevant, deficiencies of specific antibodies in patients with normal immunoglobulin concentrations. In clinical practice, physicians encounter many forms of antibody deficiencies that do not fit the strict criteria for each syndrome that has been defined by several expert groups in primary immunodeficiencies [1, 2]. We recognize that antibody deficiencies are the most frequently reported immunodeficiencies in different areas of the world [3] and antibody deficiencies are the most frequently encountered immunodeficiencies in clinical immunology practice. The antibody deficiencies with the least clinical impact are found at the highest frequency in the population. For example, IgA deficiency, which can be observed in asymptomatic individuals, is the most frequently encountered immunodeficiency [4] while agammaglobulinemias are relatively rare. There may be a common misconception that the less frequent severe antibody deficiency syndromes are not relevant in clinical practice. However, early diagnosis of an antibody deficiency requires awareness and a thorough evaluation and may prevent permanent sequelae from the severe infections that can occur.

Antibody-Mediated Immunity Immunity to infection with pathogenic organisms is, in part, provided by the antibodies produced by B cells. In conjunction with the complement system, antibodies enhance the ability of polymorphonuclear cells (PMN’s) and macrophages to engulf and kill

K. Paris (), L. Leiva, and R.U. Sorensen Department of Pediatrics, Research Institute for Children 4th Floor, Louisiana State University Health Sciences Center, Children’s Hospital, 200 Henry Clay Avenue, New Orleans, LA, USA; Jeffrey Modell Diagnostic Center, Children’s Hospital, 200 Henry Clay Avenue, New Orleans, LA 70118, USA e-mail: [email protected]

R. Pawankar et al. (eds.), Allergy Frontiers: Therapy and Prevention, DOI 10.1007/978-4-431-99362-9_45, © Springer 2010

737

738

K. Paris et al.

these microorganisms. With regards to extracellular pathogens such as Streptococcus pneumoniae, Haemophilus influenza, Staphylococcus aureus, and viruses, these antibodies can protect the host prior to infection and clinical disease. More thorough protection against intracellular pathogens is provided by cell-mediated immunity. These pathogens include viruses, mycobacteria, salmonella, fungi such as Pneumocystis jirovicii and protozoa like Toxoplasma gondii. Cellular immune function should be evaluated when infections caused by these organisms are present. Immunity is provided by the three major immunoglobulins namely IgG, IgA, and IgM each having unique characteristics which convey protection. IgM is the first isotype synthesized by B cells in response to antigen stimulation. It is a pentamer with a large size and therefore remains within the vascular space. It is produced at highest concentrations during acute infections, and helps control blood borne disease. Its half life is approximately 5–6 days and therefore it does not confer long term protection against infection. IgG, in contrast to IgM, provides long term protection. IgG is also present in the greatest concentration within the intravascular and extravascular spaces. Four subclasses of IgG are recognized – each with its own structure, function and relative concentration within the circulation [5]. IgG1 and IgG3 are the subclasses produced predominantly in response to protein antigens, whereas anti-polysaccharide antibodies are predominantly found in IgG2. IgG4 is the subclass found in the least concentration. 60–65% of the total IgG is comprised of IgG1, 20–25% is IgG2, 5–10% is IgG3 and IgG4 is 3–6%. There is a wide range of normal values for both total IgG concentrations and for each subclass. Normal values vary widely according to patient age. IgA is the only immunoglobulin which is normally secreted into body secretions, mainly in the gastrointestinal and respiratory tracts. Production of IgA usually occurs in response to antigens encountered within the lumens of those organs. The main function of secretory immunoglobulin is to prevent microbial and foreign antigens (e.g., food) from penetrating the gut, respiratory and other mucosa. IgA is critical for mucosal immunity, although in its absence, other immunoglobulins also offer this protection. Discussion of antibody deficiencies requires a brief review of B cells and the development of humoral immunity. B cells mature in an antigen independent and antigen dependent manner. Development of the B cell is dependent on various enzymes and on the production of immunoglobulin chains within the B cell. For example, the enzyme B cell tyrosine kinase is essential for the progression of development from immature to mature B cells. The early stages of development can be identified by internal expression of various immunoglobulin chains and receptors [6]. These same receptors and immunoglobulin chains are later expressed on the cell surface, and are markers for later stages of B cell maturation. The ultimate development of B cells into plasma depends on exposure to antigen. These plasma cells then secrete large amounts of specific antibodies. Additionally, the complex interaction of the B cell with CD40L on T cells initiates the switch from IgM production to IgG and IgA. Various forms of the hyper-IgM syndrome have been described where this switch does not occur, leading to high

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

739

amounts of IgM and low IgG and IgA. Memory B cells are produced after antigen exposure as well, and the immunodeficiency known as CVID is associated with a defect in production of these cells. Immunoglobulin production changes throughout the lifetime. Immunoglobulin production is lowest immediately after birth, but increases during the first years of life. Active transport of IgG across the placenta during the third trimester of pregnancy causes high IgG concentrations immediately after birth. The half-life of this maternal IgG is approximately 20–30 days, and IgG levels decrease until synthesis of IgG by the infant surpasses catabolism. This occurs sometime after 3 months of age. Exposure to new antigens stimulates the production of specific IgM and subsequently IgG and IgA. Transient hypogammaglobulinemia of infancy is thought to be a defect in this normal “maturation” of the immune system with eventual normalization of IgG levels by 2 years of age. This maturation is reflected in the development of responses to protein and polysaccharide antigens. The ability to produce antibodies to protein antigens is present at birth, while the responses to polysaccharide antigens develop during the first 2 years of life.

Clinical Aspects of Antibody Deficiency The hallmark of antibody deficiency is recurrent infection with gram positive and encapsulated gram-negative organisms. These infections may be mild in nature, or consist of single severe infections such as pneumococcal sepsis, CNS infection or similar invasive infection. Recurrent otitis media may be the only clinical early manifestation of agammaglobulinemia, the most severe form of antibody deficiency [7]. Additionally, serious complications of routine infections such as mastoiditis (otitis media), empyema (pneumonia) or abscess (meningitis) may also signal an antibody deficiency [8]. In the congenital or transient deficiencies of infancy, it is usual for these infections to begin at approximately 4–6 months of age due to the loss of maternal IgG. Infections with specific bacteria are also a component of some antibody deficiencies. A life threatening meningoencephalitis is seen in children with x-linked agammaglobulinemia [9]. Mycoplasma infections have been described in patients with chronic pulmonary infections that were resistant to typical antibiotic therapy or who had concomitant arthritis [9]. IgA deficient patients may have recurrent Giardia lamblia infection. Autoimmunity and other blood dyscrasias are noninfectious manifestations of antibody deficiency syndromes. Both x-linked agammaglobulinemia and x-linked hyper-IgM syndrome are associated with neutropenia. Chronic thrombocytopenia has been described in some phenotypes of CVID as well. The idea that patients with antibody deficiencies appear ill is false. Most patients develop normally, likely because of long asymptomatic periods or mild disease. This is especially true of common variable immunodeficiency which may develop and become symptomatic later in life.

740

K. Paris et al.

At times, the clinical presentation of antibody deficient patients mimics allergic diseases such as asthma and allergic rhino-sinusitis. The sequelae of these diseases often provide an environment conducive for bacterial super infection, even in the immuno competent host. Therefore, patients with antibody deficiencies have been diagnosed as having allergic asthma and they have even been subjected to long periods of allergy immunotherapy because of wheezing associated with recurrent bronchitis. Antibody deficiencies may co-exist with allergies, aggravating the susceptibility to recurrent infections. In practical terms, this means that a high index of suspicion is necessary to detect the presence of antibody deficiency syndromes.

General Evaluation of Antibody-Mediated Immunity The evaluation of the immunological phenotype of antibody deficiency syndrome is based on the results of the following tests: • Quantitative immunoglobulins (IgG, IgA, IgM, and IgE) • IgG subclass concentrations • Specific antibody titers against protein antigens including tetanus and diphtheria toxoids (and possibly H. influenzae) • Antibody titers against pneumococcal polysaccharide antigens • Occasionally measurement of isohemagglutinins • Circulating B lymphocytes The measurement of IgG subclass concentrations is controversial since age plays an important role in defining the normal concentrations of all IgG subclasses and must always be considered in the interpretation of results. A minimum of two determinations obtained at an interval of at least 1 month is recommended before a diagnosis of IgG subclass deficiency can be confirmed. Also, the clinical relevance of an isolated IgG subclass deficiency is not well established. However, the finding of a subclass deficiency in association with either IgA deficiency or poor response to polysaccharide antigens may be indicative of the eventual development of a more serious deficiency such as CVID. Total circulating IgA is measured as part of an immunoglobulin panel including IgM, IgG, and IgA. Measuring IgA subclasses or secretory IgA is usually not necessary since it is seldom useful. Perhaps the most important part of the evaluation of humoral immunity is the determination of the ability to produce specific antibodies after natural infection with a microbial pathogen, or in response to vaccination. Diphtheria and tetanus toxoids, viral vaccines and multivalent S. pneumoniae conjugate and polysaccharide vaccines are part of the recommended immunization schedule for every child, making the response to these antigens a convenient marker for immunocompetence. Evaluation of specific antibody titers requires a careful immunization history. If antibody concentrations to one or more vaccine antigens are low and immunization

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

741

is incomplete or not recent, active immunization should be used to evaluate the antibody response. It is important to note that a “protective” antibody concentration is not the same as a normal immune response. For example, while the protective anti-tetanus antibody titer is ³ 0.1 IU ml–1, most normal children will generate titers at least tenfold higher. A review of the assessment and clinical interpretation of polysaccharide antibody responses has recently been published by the authors and is a guide to this component of the evaluation of antibody deficiencies [10]. In short, the evaluation of the response to polysaccharide vaccines requires a precise history of prior pneumococcal immunization with both the heptavalent conjugate pneumococcal vaccine (PCV-7) and or the 23-valent pneumococcal polysaccharide vaccine (PPV). The response to pure polysaccharides can be evaluated after 2 years of age by measuring antibodies against pneumococcal serotypes present only in the pure polysaccharide vaccine (Table 1). Pneumococcal immunization as an evaluation tool is favored

Table 1 Comparison of pneumococcal polysaccharide serotypes found in commercially available pneumococcal vaccines Serotypes Vaccines Danish # US # PPV PCV-7 1 1 X 2 2 X 3 3 X 4 4 X X 5 5 X 6B 26 X X 7F 51 X 8 8 X 9N 9 X 9V 68 X X 10A 34 X 11A 43 X 12F 12 X 14 14 X X 15B 54 X 17F 17 X 18C 56 X X 19A 57 X 19F 19 X X 20 20 X 22F 22 X 23F 23 X X 33F 70 X PPV = 23 Valent polysaccharide vaccine PCV-7 = Heptavalent conjugate vaccine Shaded Rows = Serotypes included in PPV and PCV-7

742

K. Paris et al.

because it combines the enhancement of specific immunity to these common respiratory pathogens with the evaluation for the syndrome of specific antibody deficiency. Protection against infection and even colonization has been associated with antibody concentrations ³ 1.3 µg ml–1 (or 200–300 ng of antibody N/ml) [11,12]. When patients have received gamma globulin or other plasma products, it is possible to test for antibody responses to the neoantigen bacteriophage Phi X174 which is available at specialized centers [13]. B cell enumeration is not performed unless an abnormality in immunoglobulin concentrations is already established. B cell percentages need to be determined by flow cytometry using monoclonal antibodies against specific B cell markers (CD19, CD20). Most patients fit within one of the deficiency phenotypes listed under classification of antibody deficiencies. The measurement of immunoglobulins and specific antibodies allows the inclusion of most patients in one of the deficiency phenotypes listed under classification of antibody deficiencies. For several immunoglobulin deficiencies, e.g., mild IgG deficiencies, selective IgA deficiencies and IgG subclass deficiencies, the clinical relevance is determined by the severity and frequency of infections and by the status of specific antibodies against protein and polysaccharide antigens. For patients who do not fit well into classic deficiency phenotypes, it is best to define both the immunoglobulin and the specific antibody status, e.g., selective IgA deficiency with or without specific antibody deficiency, when describing these patients.

Antibody Deficiency Syndromes Agammaglobulinemia Agammaglobulinemia occurs when there are significant decreases in all major classes of immunoglobulins. Agammaglobulinemia is diagnosed when there is serum IgG usually less than 200 mg dl–1 (2g L–1) and IgM and IgA are generally less than 20 mg dl–1 and CD19+ B cells are below 2% [2,7]. Cell mediated function is normal. These patients present with respiratory infections such as otitis media, sinusitis and pneumonia. The infections may be severe in approximately 20% of patients. The onset of infections usually corresponds with the decrease in IgG levels at approximately 3–6 months of age when catabolism of maternal IgG leaves affected infants hypogammaglobulinemic. In isolated agammaglobulinemia, there is usually no sign of a T cell deficiency, and infections with opportunistic infections are rare. X-linked agammaglobulinemia is an immune deficiency affecting males due to mutations in the B-cell tyrosine kinase (BTK) gene located on Xq 21.3-22 [14,15]. Mutations result in absent BTK mRNA in neutrophils or monocytes and absent BTK protein in monocytes or platelets. BTK mutation analysis confirms the diagnosis of XLA. The presence of male relatives with less than 2% B cells also suggests XLA as the diagnosis. It is the most common form of agammaglobulinemia.

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

743

There are cases of patients with higher concentrations of immunoglobulins than usual who have been diagnosed with BTK mutations later in life [16]. A history of male family members with recurrent infections is not always present since spontaneous mutations occur as well. S. pneumoniae and H. influenza cause the majority of infections in these patients. When present, central nervous system ECHO virus infections are characteristic of XLA, and are difficult to treat. A characteristic finding in patients with XLA is the absence of tonsils and lymph nodes. Patients who have had multiple infections are prone to the development of bronchiectasis [17]. This complication is seen despite treatment with gamma globulin and antibiotics. The autosomal recessive agammaglobulinemias are rare, but present with similar manifestations as XLA. There are several mutations within the genes involved in B cell maturation that cause ARA. Mutations in C mu heavy chain, signal-transducing molecule Ig-alpha, surrogate light chain Ig lambda-like peptide, or BLNK (the cytoplasmic adapter protein B cell linker protein) should be investigated when male patients are evaluated with a phenotype consistent with XLA but whose BTK is normal. These proteins are important in the maturation of B cells from the pro-B to pre-B cell stage. Additionally, female patients with agammaglobulinemia and affected patients with a family history of consanguinity should be evaluated for these mutations.

Hyper-IgM Syndrome In the hyper IgM syndrome, there is usually a striking increase in IgM, with absence of IgG and IgA, due to defects in class switching. Some forms of the hyper IgM syndrome are caused by mutations in enzymes present in B cells, and so are considered to be purely antibody deficiencies. These two enzymes, AICDA (activation induced cytidine deaminase) and UNG (uracil DNA glycosylase) are involved in class switch recombination after the interaction of CD40L with CD40 on the B cell. Infections seen in this syndrome are similar to those in patients with agammaglobulinemia. The most common form of the hyper-IgM syndrome is caused by absence of CD40 ligand (CD40L) on T cells, which is important in class switching from IgM production to IgG and IgA. There are other forms caused by mutations in NEMO (NF-KB essential modulator). These are combined T and B cell immunodeficiencies and will not be discussed here.

Common Variable Immunodeficiency Disease (CVID) CVID has an onset of above 2 years of age and affects both sexes. Patients have a hypogammaglobulinemia and variable T cell abnormalities, although infection with intracellular pathogens is unusual. CVID is diagnosed by a decrease of at least

744

K. Paris et al.

2 SD below the mean for age in two out of three of the major isotypes (IgM, IgG, and IgA), and by absent isohemagglutinins and/or poor response to protein and polysaccharide vaccines. B cells are normal, or only mildly decreased. Other defined primary and secondary causes of hypogammaglobulinemia need to be excluded [2]. Because the phenotype of CVID is variable, patients who have a decrease of at least 2 SD below the mean for age in only one of the major immunoglobulin isotypes but fulfill all other criteria may have CVID. In all patients with a persistently low IgG concentration and diarrhea (or the nephrotic syndrome), an IgG loss must first be ruled out. IgG-loss syndromes can be detected by evaluation of urine for proteinuria and IgG, determination of alpha 1-antitrypsin clearance in stool, by assessment of total protein and albumin concentrations and by calculating the half-life of IgG after an infusion of IgG [18]. Recurrent infections, cancer and autoimmune disease are common in patients with CVID [19,20]. The age of clinical onset of CVID is quite variable, with some patients diagnosed in childhood and others diagnosed at any time during adulthood. Its late onset causes it to be the most common primary immunodeficiency diagnosed in adults. Clinical presentation generally occurs in the first three decades of life and serum immunoglobulin concentrations may increase or decrease over time leading to changes from IgA deficiency to CVID [21]. There are two incidence peaks around 2–5 and 16–20 years of age [22]. CVID is one of the most frequent human immunodeficiencies with incidences ranging from 1:10,000 in Sweden to 1:30,000 individuals [19,20]. The infections seen in CVID are similar to other antibody deficiencies, with some unique exceptions. The majority of infections are caused by S. Pneumoniae, Moraxella catarrhalis, and H. influenzae. Giardia lamblia can cause clinical disease in patients with CVID. In addition to the infectious complications, patients with CVID have a propensity for the development of autoimmunity. This includes ITP, autoimmune hemolytic anemia, rheumatoid arthritis, SLE, autoimmune thyroiditis, vitiligo, and primary biliary cirrhosis [23]. An inflammatory bowel disease has also been associated with CVID, and can cause splenomegaly, chronic diarrhea and malnutrition [24]. A sarcoid-like granulomatous disease involving lungs, liver and spleen can be confused with lymphoma [25]. Malignancies in general are found at increased rates in CVID patients. There was a 23-fold increased risk for malignant lymphoma and a 50-fold increase in gastric cancer among 377 patients with hypogammaglobulinemia, primarily CVID [26]. A 100-fold increased risk for lymphoma was noted in 98 CVID patients who were followed for up to 13 years [27]. Because CVID is a heterogenous disease with variable phenotypes, a single causative defect is not found. Familial inheritance occurs in up to 25% of cases, but most are sporadic [28]. The disease may have different presentations within the same family. It may also appear to skip generations, suggesting variable penetrance. IgA deficiency alone may be found in one family member, while other affected individuals have a hypogammaglobulinemia of 2 isotypes. Current efforts to identify mutations responsible for the development of CVID, focus on T and B cell costimulatory molecule and markers of B cell differentiation. For example, a deficiency of switched memory B cells in patients with an autosomal recessive form of

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

745

CVID is due to mutations in the inducible costimulator gene [29]. Susceptibility loci for CVID have been identified on chromosome 5p [30] and in the major histocompatibility complex region on chromosome 6p [31].

Transient Hypogammaglobulinemia of Infancy The clinical phenotype of transient hypogammaglobulinemia of infancy (THI) has not been clearly defined, and different criteria are offered by different authors [32–34]. IgG levels are low compared to published norms for age, but are higher than those seen in agammaglobulinemia, and B cell numbers are normal. Immunoglobulin levels normalize by 2–3 years of age, which makes this a diagnosis that can only be made retrospectively. The age of patients being considered for this diagnosis should be between 6 months and 3 years of age. If only IgG is below 2SD for age, specific antibodies are normal and the infections are mild, it is possible to reassure the parents that a transient hypogammaglobulinemia of infancy is the most likely diagnosis and that follow-ups at 6 month intervals until the IgG normalizes is all that must be done. Infants presenting with diminished immunoglobulins who are otherwise immunologically normal might better be described by a broad, inclusive term such as hypoimmunoglobulinemia of early childhood [35]. Protective antibodies against tetanus and diphtheria toxins and H. influenza capsular polysaccharide also suggest that the hypogammaglobulinemia will be transient. Since some patients have eventually developed persistent antibody deficiencies [35,36], follow up is necessary. In all patients with hypogammaglobulinemia detected in the first 2–3 years of life, a careful family history and regular follow-up is recommended until the diagnosis of transient hypogammaglobulinemia can be documented retrospectively. The need for IgG replacement therapy is generally not necessary for these patients, although very frequent infections may warrant this treatment. In this case, careful monitoring of IgG trough levels while keeping the IgG dose and infusion intervals constant allows clinicians to determine when there has been a significant increase in the patient’s own IgG production to stop IgG replacement treatment.

Selective IgA Deficiency Selective IgA deficient patients have a serum IgA of less than 7 mg dl–1 (0.07 g L–1), but normal serum IgG and IgM. This deficiency can only be diagnosed reliably after 4 years of age [2] because IgA deficiency cannot be differentiated from absent or low IgA concentrations seen in normal individuals less than 4 years old. As for hypogammaglobulinemia in this age group, IgA concentrations should be followed at 6–12 month intervals until an IgA deficiency is definitively ruled out.

746

K. Paris et al.

Within selective IgA deficiency, it is possible to differentiate between patients in whom no IgA is detected even by very sensitive methods and those who have low but detectable IgA concentrations. The former group is at a higher risk for developing anti-IgA antibodies upon exposure to any blood product containing IgA, since no tolerance to this protein has been developed. Patients older than 4 years, who have a serum IgA below 2 SD of normal concentrations but above 7 mg ml–1, fall into an ill-defined category requiring further evaluation and follow-up only if they are symptomatic. As a group, many individuals with IgA deficiency are asymptomatic. Some patients with IgA deficiency have an increased incidence of upper respiratory tract infections, allergies, celiac-like enteropathy and autoimmune disease including SLE, rheumatoid arthritis, pernicious anemia and others [37]. The clinical manifestations associated with IgA deficiency in a given patient tend to remain constant with little tendency to develop other problems, e.g., patients who present with an autoimmune condition do not tend to develop recurrent infections. Patients with IgA deficiency who have recurrent infections should be evaluated for other associated antibody abnormalities, like IgG2 subclass or specific antibody deficiencies, or chronic allergic manifestations which may also predispose them to recurrent infections. Considering all its clinical forms including asymptomatic patients, selective IgA deficiency was the most common PID phenotype identified in many areas of the world [37]. The frequency of IgA deficiency in normal individuals (blood bank donors) varies from 1:396 to 1:2170 [4] and is somewhat higher in patients with recurrent infections, malignant, or autoimmune diseases [38].

IgG Subclass Deficiencies IgG subclass deficiencies can be found as isolated abnormalities or in combination with other immune deficiency syndromes like IgA deficiency, ataxia telangiectasia, the Wiskott Aldrich syndrome and multiple other immunodeficiencies [39]. Since IgG2, IgG3, and IgG4 do not contribute a large percentage to total IgG, they may be deficient without a decrease in total IgG serum concentrations. The severity of clinical manifestations, e.g., recurrent infections, is not related to the degree of IgG subclass deficiency. Asymptomatic patients with a complete IgG subclass deficiency due to g heavy chain deletions have been described [40]. Because of the difficulties in obtaining reliable IgG subclass determinations [8], the diagnosis of an IgG subclass deficiency should always be confirmed by repeated testing at least 1 month apart. The ability to produce and maintain adequate concentrations of specific antibodies to protein and polysaccharide antigens is more important than IgG subclass concentrations. IgG subclass deficiencies should be followed at regular intervals since they may be transient [41,42].

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

747

IgG1 Subclass Deficiency IgG1 constitutes 60–70% of total IgG, therefore IgG1 deficiencies nearly always cause a hypogammaglobulinemia.

IgG2 Subclass Deficiency IgG2 deficiencies are a heterogeneous group of abnormalities which includes various degrees of severity and persistence. Deficient IgG2 may occur as an isolated abnormality or in combination with IgG4 and/or IgA deficiencies. IgG2 deficiency is one of the most frequently identified abnormalities in patients with recurrent infections [43]. Deficiencies in IgG2 may lead to recurrent sinopulmonary infections, otitis media, and disseminated pneumococcal disease [44,45]. The high prevalence of recurrent infections in patients with IgG2 deficiency is likely due to the special relationship between IgG2 and polysaccharide antibodies. Most of the response to pneumococcal polysaccharides can be found in the IgG2 subclass [46,47]. Not surprisingly, patients with IgG2 subclass deficiency have several abnormalities in the production of antipolysaccharide antibodies, including responses to a restricted number of polysaccharides within the pneumococcal vaccine [42], poor immunological memory [42], and lack of development of specific antibodies of the IgG2 isotype [48].

IgG3 Subclass Deficiency IgG3 deficiency also has been described in patients with recurrent sinopulmonary infections [45]. Persistent IgG 3 deficiency is infrequently identified in patients with recurrent infections [43].

IgG4 Subclass Deficiency Many normal infants and children have very low or absent concentrations of IgG4, so this deficiency cannot be reliably diagnosed in children <10 years old [49]. Clinical relevance of an IgG4 deficiency is unlikely due to its small contribution to total IgG.

Specific Antibody Deficiency with Normal Immunoglobulins We now recognize deficiencies in response to pure polysaccharides and also, increasingly, to conjugated polysaccharide antigens. These deficiencies are typically diagnosed based on the response to pneumococcal polysaccharides. Ideally,

748

K. Paris et al.

one should be able to measure the response to immunization by obtaining pre- and post-immunization antibody concentrations. This is rarely possible for the response to pneumococcal serotypes present in the heptavalent conjugated pneumococcal vaccine, (PCV-7) since most children have received one or more doses of this vaccine before evaluation. This problem is obviated by using an interpretation of antipneumococcal antibody concentration results based both on antibody increases over pre-immunization concentrations (immune response) and on final concentrations of antibodies after immunization, regardless of increase from pre-immunization concentrations (antibody concentration). Adequate responses to individual pneumococcal polysaccharides can be arbitrarily defined as a post-immunization antibody concentration ³1.3 µg ml–1 or at least fourfold over baseline [50]. The syndrome of specific antibody deficiency is then defined using the combined response to all serotypes tested [10]. Some unimmunized patients in all age groups fail to demonstrate protective antibody titers to any pneumococcal serotype tested. This is unusual in individuals above two years of age who typically develop these antibodies in response to clinical or subclinical infections. Most adults have protective antibodies to all or at least 80% of serotypes tested, even before immunization with PPV. The overwhelming majority of these patients have a vigorous response to immunization. Therefore, low preimmunization antibody titers may not predict an underlying immunodeficiency. Immunocompetence cannot be differentiated from immunodeficiency without immunization and retesting after immunization.

Selective Anti-Pure (Non-Conjugated) Polysaccharide Antibody Deficiency Specific antibody deficiency with normal immunoglobulins is a primary immunodeficiency of unknown etiology [51–54]. It is frequently found in patients evaluated for recurrent infections, but the prevalence is unknown [43, 55]. Selective anti-polysaccharide antibody deficiencies are also frequent in patients with IgG subclass deficiencies [42], combined immunodeficiencies, congenital asplenia and in acquired conditions like HIV infection and splenic deficiency. Specific antibody deficiencies can also be seen in some patients with Down syndrome [43], the Netherton syndrome [56] and other congenital abnormalities that are constitutively associated with immunoglobulin or antibody deficiencies. The diagnosis of specific antibody deficiency with normal immunoglobulins (SADNI) should be considered in patients >2 years of age with recurrent upper and/ or lower respiratory tract infections and normal, IgG, IgA, and IgM concentrations. Since most children have received the pneumococcal conjugate vaccine, diagnosis requires the demonstration of an abnormal IgG antibody response to pneumococcal serotypes present exclusively in the polysaccharide vaccine [3, 8].

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

749

IgG replacement is an option for patients with proven recurrent infections and documented specific antibody deficiency. Prophylactic antibiotics are also used, keeping in mind the risk of developing antibiotic resistance. When the severity of infections warrants the use of IgG replacement treatment, it is wise to tell patients that the treatment will be stopped after a period of time and that the immune response will have to be reevaluated 4–6 months after discontinuation of IgG replacement. In children, improvement in responses to the polysaccharide vaccine may occur after treatment with intravenous immunoglobulins for 6–24 months [57]. This may be due to the maturation of the immune response with increasing age. Any one of these forms of specific antibody deficiency may be transient or permanent. Transient forms are common in children 2–5 years of age. The natural history of these syndromes is usually benign if they are properly managed, although failure to treat infections can lead to complications such as chronic sinusitis or mastoiditis. Further insights into the pathogenesis of this syndrome in different patients should eventually result in a more reliable assessment of the risk for persistent immune abnormalities and recurrent infections in some of these patients.

Treatment of Antibody Deficiencies The comprehensive management of patients with antibody deficiencies is complex. It requires an understanding of the risks and complications that are associated with each of the individual diseases. Infections are treated with appropriate antibiotics, ideally based on sensitivity profiles of causative bacteria. The other mainstay of treatment is either intravenous or subcutaneous gamma globulin. When given IV, the usual interval between infusions is every 3–4 weeks. For the subcutaneous route, more frequent infusions such as once or twice weekly, results in more uniform plasma IgG levels. Specialists are also required to be familiar with monitoring IgG dosing and infusion rates, as well as preventing and treating infections when they occur. Infections occur despite the best treatment plans due to the wide variety of causative agents and variable resistance patterns of the bacteria. The indication for IgG is absolute for patients with agammaglobulinemia, CVID and the hyper-IgM syndrome. When bronchiectasis is present, even in more mild antibody deficiencies, it is also required. Selective IgA deficiency is not an IVIG replacement therapy although in some cases, poor IgG specific antibody production, with or without IgG2 subclass deficiency may coexist and IVIG may be used. Intravenous IVIG can pose a risk of anaphylaxis for IgA deficient patients who have anti-IgA antibodies [58]. Live vaccines are not recommended in infants with known hypogammaglobulinemia. Most immunizations are unnecessary during IgG replacement treatment. The usual starting dose for IgG replacement is 400–600 mg IgG/kg every 3 or 4 weeks. The trough level of IgG should be at least 500 mg dL–1 [59]. Patients with known bronchiectasis or other pulmonary complications require trough levels >800 mg dL–1 to improve pulmonary outcome [60].

750

K. Paris et al.

Clinical Staging of Complications After diagnosis and initiation of treatment, it is necessary to consider complications of the patient’s underlying disease. These complications are often secondary to the frequent infections suffered by these patients, and may be present even at the time of diagnosis. Treatment choices may be dependent on their presence or absence, such as IgG dosing in patients with bronchiectasis. Sinus CT scans should be done in patients with a history of chronic sinusitis, and cultures of sinus contents considered, to direct therapy. High resolution chest CT scans should be performed to evaluate for bronchiectasis, even in patients without a significant history of lower respiratory infections. Subclinical or chronic low grade infections may also cause scarring. GI complaints, especially in patients with CVID should prompt evaluation by a specialist via endoscopy when an etiology is not readily found. If patients with CVID or other antibody deficiencies have clinical signs of an autoimmune disorder, evaluation of autoantibodies should be performed.

Summary Antibody deficiencies are the most common form of primary immunodeficiency found worldwide. Recognition of the t signs and symptoms of these disorders is important in order to diagnose and treat patients before complications develop. Because the impact of immune deficiency on individual patients is great, physicians should have a low threshold for evaluating these disorders despite knowing that in the majority of cases the results will be normal.

References 1. Notarangelo L, Casanova J-L, Fischer A, et al. (2004) Primary immunodeficiency diseases: An update. J Allergy Clin Immunol 114: 677–687 2. Conley M E, Nortarangelo L D, Etzioni A (1999) Diagnostic criteria for primary immunodeficiencies. Clin Immunol 93: 190–197 3. Sorensen R U, Moore C (2000) Antibody deficiency syndromes. Peds Clin NA 47: 1225–1252 4. Hanson L A, Bjorkander J, Oxelius V, Selective IgA deficiency. 1983: New York, pp. 62–84 5. Ochs H D, Wedgwood R J (1987) IgG subclass deficiencies. Ann Rev Med 38: 325–340 6. Cooper M D (1987) Current concepts. B lymphocytes. Normal development and function. N Engl J Med 317: 1452–1456 7. Conley M, Rohrer J, Minegishi Y (2000) X-linked agammaglobulinemia. Clin Rev Allergy Immunol 19: 183–204 8. Wasserman R L, Sorensen R U (1999) Evaluating children with respiratory tract infections: the role of immunization with bacterial polysaccharide vaccine. Pediatr Infect Dis J 18: 157–163 9. Lederman H M, Winkelstein J A (1985) X-linked agammaglobulinemia: an analysis of 96 patients. Medicine 64: 145–156

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

751

10. Paris K, Sorensen R (2007) Assessment and clinical interpretation of polysaccharide antibody response. Ann Allergy Asthma Immunol 99: 462–464 11. Landesman S H, Schiffman G (1981) Assessment of the antibody response to pneumococcal vacine in high risk population. Rev Infect Dis 3: S184–S197 12. Lawrence E M, Edwards K M, Schiffmann G, Thompson J M, Vaughn W K, Wright P F (1983) Pneumococcal vaccine in normal children. Primary and secondary vaccination. Am J Dis Child 137: 846–850 13. Ochs H, Buckley R H, Kobayashi R H, et al. (1992) Antibody responses to Bacteriophage oX174 in patients with adenosine deaminase deficiency. Blood 80: 1163–1171 14. Conley M, Mathias D, Treadaway J, Minegishi Y, Rohrer J M Y, Rohrer J (1998) Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet 62: 1034–1043 15. Holinski-Feder E, Weiss M, Brandau O, et al. (1998) Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics 101: 276–284 16. Wood P, Smith E, Hazelwood M, Joyce H, Granoff D, Kumararatne D (2000) Atypical btk deficiency presenting with selective polysaccharide antibody deficiency in the presence of normal serum immunoglobulin [Abstract]. J Allergy Clin Immunol 105: S219 17. Kainulainen L, Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, Ruuskanen O (1999) Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol 104: 1031–1036 18. Polmar S H, Sorensen R U, Immunoglobulin replacement therapy in primary immunodeficiency diseases, in Clinical Immunology: Principles and Practice, R. Rich, Ed. 1995, Mosby: St. Louis, pp. 1865–1875 19. Cunningham-Rundles C, Bodian C (1999) Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 92: 34–48 20. Spickett G (2001) Current perspectives on common variable immunodeficiency (CVID). Clin Exp Allergy 31(4): 536–542 21. Espanol T, Catala M, Hernandez M, Caragol I, Bertran J M (1996) Development of a common variable immunodeficiency in IgA-deficient patients. Clin Immunol Immunopathol 80: 333–335 22. Hermaszewski, R A, Webster A D (1993) Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 86: 31–42 23. Cunningham-Rundles C (1989) Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol 9: 22–33 24. Luzi G, Zullo A, Iebba F, et al. (2003) Duodenal pathology and clinical-immunological implications in common variable immunodeficiency patients. Am J Gastroenterol 98(1): 118–121 25. Fasano M B, Sullivan K E, Sarpong S B, et al. (1996) Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature. Medicine 75: 251–261 26. Kinlen L J, Webster A D, Bird A G, et al. (1985) Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet 1: 263–266 27. Cunningham-Rundles C, Siegal F P, Cunningham-Rundles S, Lieberman P (1987) Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol 7: 294–299 28. Hammarstrom L, Smith C I E, Genetic approach to common variable immunodeficiency and IgA deficiency, in Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, H.D. Ochs, C.I.E. Smith, J.M. Puck, Eds. 1999, Oxford University Press: New York, pp. 205–262 29. Grimbacher B, Hutloff A, Schlesier M, et al. (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4(3): 261–268 30. Braig D U, Schaffer A A, Glocker E, et al. (2003) Linkage of autosomal dominant common variable immunodeficiency to chromosome 5p and evidence for locus heterogeneity. Hum Genet 112(4): 369–378 31. Kralovicova J, Hammarstrom L, Plebani A, Webster AD, Vorechovsky I (2003) Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate HLA-DQ/DR as a

752

32. 33. 34. 35. 36. 37. 38. 39. 40.

41.

42. 43. 44. 45.

46.

47. 48.

49. 50.

51.

52. 53.

K. Paris et al. major susceptibility locus in selective IgA deficiency and common variable immunodeficiency. J Immunol 170(5): 2765–2775 Dalal I, Reid B, Nisbet-Brown E, Roifman C (1998) The outcome of patients with hypogamrnaglobulinemia in infancy and early childhood. J Pediatr 133: 144–146 Siegel R, Issekutz T, Schwaber J, Rosen F, Geha R (1981) Deficiency of T helper cells in transient hypogamrnaglobulinemia of infancy. N Engl J Med 305: 1307–1313 Kilic S, Tezcan I, Sonal, Metin A, Ersoy F (2000) Transient hypogammaglobulinemia of infancy: clinical and immunologic features of 40 new cases. Pediatrics International 42: 647–650 McGeady S J (1987) Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. J Pediatr 110: 47–50 Kornfeld S J, Kratz J, Haire R N, Litman G W, Good R A (1995) X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol 95: 915–917 Schoaffer F, Monteiro R, Volanakis J, Cooper M (1991) IgA deficiency. Immunodeficiency Rev 3: 15–44 Fasth A (1982) Primary immunodeficiency disorders in Sweden: Cases among children 1974–1979. J Clin Immunol 2: 86–92 Aucouturier P, Lacombe C, Bremard C, et al. (1989) Clin Immunol Immunopathol 51: 22–37 Lefranc M P, Hammarstrom L, Smith C I, Lefranc G (1991) Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis. Immunol Rev 2: 265–281 Ohga S, Okada K, Asahi T, Ueda K, Sakiyama Y, Matsumoto S (1995) Recurrent pneumococcal meningitis in a patient with transient IgG subclass deficiency. Acta Paediatr Jpn 37: 196–200 Sorensen R U, Hidalgo H, Moore C, Leiva L E (1996) Antipneumococcal antibody titers and IgG subclasses in children with recurrent respiratory infections. Pediatr Pulmonol 22: 167–173 Javier F C, Moore C M, Sorensen R U (2000) Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann Allergy Asthma Immunol 84: 25–30 Stanley P J, Corbo G, Cole P J (1984) Serum IgG subclasses in chronic and recurrent respiratory infections. Clin Exp Immunol 58: 703–708 Umetsu D T, Ambrosino D M, Quinti I, Siber G R, Geha R S (1985) Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency. N Engl J Med 313: 1247–1251 Siber G R, Schur P H, Aisenberg A C, Weitzman S A, Schiffman G (1980) Correlation between serum IgG2 concentrations and the antibody response to bacterial polysaccharide antigens. N Engl J Med 303: 178–182 Lim P L, Lau Y L (1994) Occurrence of IgG subclass antibodies to ovalbumin, avidin, and pneumococcal polysaccharide in children. Int Arch All Immunol 104: 137–143 Sanders L A, Rijkers G T, Tenbergen-Meekes A-M, Voorhorst-Ogink M M, Zegers B J (1995) Immunoglobulin isotype-specific antibody responses to pneumococcal polysaccharide vaccine in patients with recurrent bacterial respiratory tract infections. Pediatr Res 37: 812–819 Bird D, Duffy S, Isaacs D, Webster A D (1985) Reference ranges for IgG subclasses in preschool children. Arch Dis Child 60: 204–207 Sorensen R U, Leiva L E, Giangrosso P A, et al. (1998) Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine. Pediatr Infect Dis J 17: 685–691 Saxon A, Kobayashi R H, Stevens R H, Singer A D, Stiehm E R, Siegel S C (1980) In vitro analysis of humoral immunity in antibody deficiency with normal immunoglobulins. Clin Immunol Immunopathol 17: 235–244 French M A H, Harrison G (1984) Systemic antibody deficiency in patients without serum immunoglobulin deficiency or with selectivie IgA deficiency. Clin Exp Immunol 56: 18–22 Ambrosino D M, Siber G R, Chilmonczyk J B, Jernberg J B, Finberg R W (1987) An immunodeficiency characterized by impaired antibody responses to polysaccharide. N Engl J Med 316: 790–793

Antibody Deficiency Syndromes (Including Diagnosis and Treatment)

753

54. Sorensen R U, Leiva L E, Javier F C, et al. (1998) Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations. J Allergy Clin Immunol 102: 215–221 55. Hidalgo H, Moore C, Leiva L E, Sorensen R U (1996) Preimmunization and postimmunization pneumococcal antibody titers in children with recurrent infections. Ann Allergy 76: 341–346 56. Stryk S, Siegfried E, Knutsen A (1999) Selective antibody deficiency to bacterial polysaccharide antigens in patients with Netherton syndrome. Pediatr Dermatol 16(1): 19–22 57. Ortigas A P, Leiva L E, Moore C, Bradford N, Sorensen R U (1999) Natural history of specific antibody deficiency after IgG replacement therapy. Ann Allergy Asthma Immunol 82: 71 58. Burks A, Sampson HA, Buckley RH (1986) Anaphylactic reactions after gamma globulin administration in patients with hypogamma-globulinemia: detection of IgE antibodies to IgA. N Engl J Med 314(9): 560–564 59. Nelson R P, Ballow M (2003) Immunomodulation and immunotherapy: drugs, cytokines, cytokine receptors, and antibodies. J Allergy Clin Immunol 111: 720–732 60. Quartier P, Debre M, De Blic J, et al. (1999) Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 134: 589–597

Index

A Adjuvant, 205 Adverse effects, 38 Adverse reactions to foods, 635 Aerosol therapy, 245 Agonists, 38 Airway deposition, 245 Airway hyperresponsiveness, 171 Airway inflammation, 171, 187, 536 Airway remodelling, 69, 536, 716 Airway smooth muscle, 69 Allergen bronchoprovocation, 72 Allergenic peptides, 206 Allergens, 3, 417–428 avoidance, 419–420, 447 immunotherapy, 195, 427 Allergen specific immunotherapy, 468 Allergic disease, 379, 417–428 Allergic fungal sinusitis, 695 Allergic inflammation, 105 Allergic rhinitis, 41, 51, 63 management of, 30 prevalence, 397 treatment, 19, 42 Allergy, 347, 365, 397, 713 definition, 399–400 epidemic, 418 prediction, 419–420 prevention, 417 programme, 457–459 Almond, 681 Alternaria, 695 Amphotericin B topical, 695 Anaphylaxis, 325 Antibiotics, 407–408 Antibodies, 737 Anti-cytokine therapy, 468 Antifungals, 695

Antihistamines, 19, 37, 311 first generation, 20 second generation, 20–21 Anti-IgE, 51, 467 monoclonal antibodies, 687 therapy, 335 Anti-IL-4, 471 Anti-IL-5, 470 Anti-IL-9, 472 Anti-IL-13, 471, 472 Anti-inflammatory effect, 187 Antileukotrienes, 51, 63 Antimicrobial treatment, 621 Antioxidants, 423 Anti-prostanoids, 466 Anti-THF-α, 470 Apoptosis, 187 Arachidonic acid, 63 Aspergillus, 695 Aspirin-exacerbated respiratory disease (AERD), 73 Aspirin intolerance, 70 Asthma, 3, 45, 63, 91, 105, 145, 171, 187, 217, 347, 365, 379, 465, 511, 531, 543, 611, 713, 727 control, 565, 593 control test, 565 exacerbations, 74 phenotypes, 511 prevalence, 397 programme, 457 symptoms, 74 syndromes, 532 Asthma quality of life questionnaire (AQLQ), 565 Asthmatic children, 577 Asthmatic infants, 577 Atopic asthma, 534 Atopic dermatitis, 203, 259, 291, 621

755

756 Atopic dermatitis prevalence, 397 Atopic dermatitis/psoriasis, 105 Atopy, 3, 379 Avoidance, 3 Azelastine, 23

B Bacillus Calmette-Guérin (BCG), 426, 713 B cells, 737 BEAS-2B, 716 β2 Adrenoceptor, 91 β2 Agonists, 171 Beclomethasone, 76 Bell-shaped curve, 451 Beta agonists, 245 Birth, 365 Birth cohort, 397 Blocking antibodies, 197 Brazil nut, 682 Breastfeeding, 401–402 Bronchial hyperresponsiveness, 171 Bronchoalveolar lavage (BAL), 70 Bronchoconstriction, 67 Bronchodilation, 91

C Calcineurin antagonists, 259 Calcineurin inhibitors, 291, 621 Cancer, 714 Cardiotoxic effects, 40 Cashew, 681 Cats, 406 CC chemokines, 721 CD14, 677 CD40, 720 CD86, 720 CD4+ T-cell, 719 CD8+ T-cell, 719 Cetirizine, 21 Chemoattractant receptor homologousmolecule 2 (CRTH2) receptor antagonists, 467 Children, 46, 365, 531, 543, 611 Chitosan, 433 Chlorofluorocarbons, 245 Chromosome 5q31, 677 Chromosome 12q, 678 Chronic inflammation, 105 Classification, 145, 217 Co-existing lung diseases, 499 Cohort studies, 398 Common variable immune deficiency, 737

Index Cord blood, 417–428 Corticosteroids, 51 Cough, 535 Cromolyn, 593 Cross-sectional studies, 398 Cyclic AMP, 91 Cyclosporine A, 291 CysLT1 receptor, 66 CysLT2 receptor, 66 Cysteinyl-leukotrienes, 66 Cytokines, 417–428 Cytosine-phosphoguanosine (CpG), 425

D Day care, 406 Death, 499 Decongestants, 51 Definition, 145, 217 Definition of GC insensitive asthma, 134 Dendritic cells, 453, 718 Dermatitis, 105 Desensitisation, 217 Desloratadine, 22 Diagnosis, 365, 531 Diet and nutrition, 421–422 Digital airway inflammation, 139 Disease prevention, 347 DNA-adjuvanted, 205 Dogs, 406 Drinking water, 449 Drug delivery, 433 Dry powder inhalers, 245

E EAACI, 400 Eczema, 259 Edema, 68 Education, 621 Efficacy, 195 Elderly, 46, 499 Emergency care, 543 Emollients, 259 Endothelial cells, 68 Endotoxin, 426, 448, 499, 676, 677 Environment, 3, 448 Environmental factors, 404, 536 Environmental tobacco smoke, 404 Eosinophilic mucin rhinosinusitis, 695 Eosinophils, 65, 171, 187 Eosinophils and mast cells, 171 Epidemiology, 397, 499 Epigenetics, 137, 417–428

Index Epinephrine, 311 Exacerbation, 543 Exercise-induced bronchoconstriction, 72 Exercise-induced bronchospasm, 171 Exhaled breath condensate (EBC), 70 Exhaled nitric oxide, 565

F Family size, 406 Farming, 448 Farm milk, 448 Fatty acids, 417 Fexofenadine, 23 Fluticasone, 76 Food Allergen Labeling and Consumer Protection Act (FALCPA), 685 Food allergens, 635 Food allergy, 335 herbal formula, 687, 688 hypersensitivity, 635 Food intolerance, 635 Fungus, 695 Fungus ball, 695

G Gammaglobulin, 737 Gene-environmental interactions, 417 Genetic polymorphisms, 427 Genetics, 3 Genetics of asthma, 511 Glucocorticoid (GC), 259 insensitivity, 136 receptor α, 135 receptor β, 135 Glucocorticosteroids, 291, 621 G-protein, 38 Guidelines, 543

H Hazelnut, 680, 681 Hazelnut immunotherapy, 686 Heparins, 474 Hevea brasiliensis, 653 Histamine, 37 Histamine inverse receptor agonists, 38 Histamine receptors, 38 Histaminergic neuronal system, 37 Histology, 145, 217 Histone deacetylase (HDAC), 187 Host defense, 718 House dust mite, 404

757 H1-receptor antagonists, 51 H1-receptor inverse agonist generations, 41 Human leukocyte antigens (HLA), 678 Hydrofluoralkene, 245 Hydrolyzed formula, 402 Hygiene hypothesis, 397, 676, 714 Hypoallergenic infant formula, 402 Hypogammaglobulinemia, 737

I Ideal antihistamine, 47 IFN-γ, 720 Immune deficiency, 737 Immune development, 418 Immune system development, 347 Immunodeficiency, 737 Immunoglobulin E (IgE), 365, 684, 695, 715, 737 Immunomodulation, 417, 713 Immunomodulatory factors, 417 Immunostimulatory sequence-conjugated protein immunotherapy, 335 Immunosuppressives, 259 Immunotherapy, 217, 325, 425, 695 Impulse oscillometry, 565 Inducible nitric oxide synthase (iNOS), 717 Infantile diet, 402–403 Infants, 417 Infections, 407 Inflammation, 42 Influenza, 611 Inhaled allergens, 404–405 Inhaled beta-adrenergic agents, 311 Inhaled corticosteroids, 75, 171, 245, 577 Innate immune inflammation, 499 Interleukin IL-2, 716 IL-5, 716 IL-6, 717 IL-10, 472, 473, 721 IL-12, 721 IL-23, 721 Intervention, 397 Interventional birth cohort studies, 399 Intraconazole, 695 Intranasal antihistamines, 23 Intranasal corticosteroids, 24, 25 adverse effects of, 26, 27 Intravenous fluids, 311 Intravenous vasopressors, 311 Intrinsic asthma, 499 Invasive fungal sinusitis, 695 Irreversible obstruction, 499

758

Index

J Jet nebulizers, 245

Muramic acid, 450 Mycobacteria, 426

K Karelia Allergy Study, 449 Ketotifen, 593

N Naïve T-cell, 718 Nanotechnology, 433 Natural course of allergic diseases, 400 Natural history, 511 Nedocromil, 593 Netherton syndrome, 679 Neutrophilic asthma, 138 Nitric oxide (NO), 69, 311 NKT, 720 Non-IgE-mediated food allergy, 635 Nonsteroidal anti-inflammatory, 593 Nonsteroidal anti-inflammatory drugs (NSAID), 73 NRAMP1, 720 Nutrition, 401

L Lactating women, 47 Lactobacillus, 403 Latex allergen avoidance, 653 Latex allergy, 653 Leukocytes, 65 Leukotriene B4, 67 Leukotriene modifiers, 28, 593 Leukotriene receptor antagonists, 171, 466 Leukotrienes, 63, 465 Leukotrienes and histamine, 171 Leukotriene synthesis inhibitors, 466 Levocetirizine, 22 Linkage analysis, 677 Lipopolysaccharide, 717 5-Lipoxygenase, 63 Long-acting beta-2 agonists (LABAs), 75, 91 Long lasting effect, 198 Loratadine, 22 Low molecular weight heparins (LMWH), 475 Lung function, 365

M Major histocompatibility complex (MHC) class 1, 718 Mast cells, 65 Mast cell stabilizers anticholinergics, 29 chromones, 29 decongestants, 29 oral and intranasal, 29 Maternal diet, 401 Mechanisms, 195 subcutaneous immunotherapy (SCIT), 197 sublingual immunotherapy (SLIT), 201 Methylene blue, 311 Microbial exposures in the environment, 407 Mitogen activated protein (MAP) kinases, 136 Modern second generation H1 inverse agonists, 41 Montelukast (Singulair™), 71 Multicentre Allergy Study (MAS), 400 Multifaceted interventional studies, 408–409

O Observational birth cohort studies, 398–399 3-OH-fatty acids, 450 Olopatadine, 24 Omalizumab, 593, 687 Oral food challenge, 335 Oral immunotherapy, 335, 686 Oral tolerance, 217, 335

P Paracetamol, 408 Parasites, 451 PDE4, 105 PDE4 inhibitors-adverse events, 105 Peak expiratory flow rate, 565 Peanut, 680 Peanut allergy cross-reactivity, 682 incidence, 675 Peanut and tree nut allergens, 679 Peanut and tree nut allergy diagnosis, 683 prognosis, 684, 685 Peanut immunotherapy, 686 Peptide immunotherapy, 335, 686 Peptidoglycans, 452 Perception of asthma, 565 Pets, 405–406 Pharmacotherapy, 171 Phosphodiesterase, 105 Phosphodiesterase inhibitors, 467

Index Phosphodiesterase 4 inhibitors, 105 Phosphoinositide 3-kinase (PI3K) inhibitors, 475 Phototherapy, 259 Polysaccharide antigens, 737 Polymorphisms, 91, 453 Polyunsaturated fatty acid, 401 Pranlukast (Onon™), 71 Prebiotics, 424 Prediction, 365 Pregnancy, 417–428 Pregnant women, 46 Prematurity, 533 Pressurized metered dose inhalers, 245 Prevention, 3, 379, 433, 611 Prevention of asthma, 198, 202 Prevention products, 459 Primary prevention, 417–428, 456 Probiotics, 403, 424, 474 Prognosis, 365 Proinflammatory mediators, 43 Protease-activated receptors, 499 Psychological tolerance, 458 PUFA, 421–422 P2Y purinergic receptors, 67

R Radio allergosorbent test (RAST), 653 Recombinant allergens, 206, 207, 433 Recombinant IL-12, 473 Recombinant protein immunotherapy, 686 Recombinant proteins, 684 Regulatory T cells, 453 Respiratory infection, 347 Respiratory syncytial virus (RSV), 407, 714 Review, 565 Rhinitis, 217 Risk-benefit, 593 Risk factors, 145, 217, 365, 379 Roflumilast, 105 RSV bronchiolits, 533

S Safety, 201 Saprophytes, 448 Secondary prevention, 409, 456 Severe, 145, 217 Severe asthma, 543 Short acting β2 adrenoceptor selective agents (SABAs), 91 Signal transducer and activator of transcription-6 (STAT-6), 678

759 Skin testing, 653, 683 Sodium cromoglycate, 75, 727 Specific immunotherapy, 454 SPINK5, 679 Spirometry, 565 Sputum analysis, 565 Sputum eosinophilia, 565 Step-up schedule immunotherapy, 469 Steroids, 695 Study design, 397 Subcutaneous immunotherapy, 335 Sublingual, 217 Sublingual immunotherapy, 199, 200, 335, 686 Systemic therapy, 465

T T cells, 325 and eosinophils, 43 subsets, 454 γδ-T Cells, 719 Teichoic acids, 452 Tertiary prevention, 409 Thalidomide derivative-C-10004, 105 T helper-1 (TH1) cells, 470, 716 T helper-2 (TH2) cells, 470, 676, 716 Theophylline, 75, 105, 187, 593, 727 Therapeutics, 499 Therapy, 433 Therapy GC insensitive asthma, 140 Therapy infants, 538 TNX-901, 687 Tolerance, 447, 450 Tolerance restoration, 455 Toll-like receptors, 425, 452, 721 Toll like receptors 9 (TLR-9) antagonists, 475 Topical treatment, 621 Traditional Chinese Medicine, 335 Traffic related pollution, 404 Transforming growth factor (TGF-β), 719 Treatment, 145, 217, 259, 291, 531 Tree nut allergy cross-reactivity, 682 incidence, 675 Treg Cells, 717 Treg NKT, 719 Tregs, 137 Tuberculosis, 714 Tumor necrosis-α (TNF-α), 716 Tumor necrosis-β (TNF-β), 717 Type I resistance, 135 Type II resistance, 135 Types of GC insensitivity, 133

760 V Vaccinations, 407–408 Vaccines, 611 Venom, 325 Viral respiratory infections, 511 Viral wheeze, 534 Virus, 365 Vitamin C, 423 Vitamin D, 423 Vitamin E, 423

Index infants, 532 interpretation, 532 mechanism, 533 prognosis, 537 risk factors, 537 Wheezing, 531 World Allergy Organization (WAO), 455 World Health Organization (WHO), 455

X Xanthines, 105 W Walnut, 681 Well-controlled asthma, 565 Wheeze bronchitis, 535

Z Zafirlukast (Accolate™), 71 Zileuton (Zyflo™), 71